WO2011021397A1 - Colchicine derivatives - Google Patents

Colchicine derivatives Download PDF

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Publication number
WO2011021397A1
WO2011021397A1 PCT/JP2010/005136 JP2010005136W WO2011021397A1 WO 2011021397 A1 WO2011021397 A1 WO 2011021397A1 JP 2010005136 W JP2010005136 W JP 2010005136W WO 2011021397 A1 WO2011021397 A1 WO 2011021397A1
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WIPO (PCT)
Prior art keywords
deacetylcolchicine
chloro
group
bromo
thiocarbamoyl
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PCT/JP2010/005136
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French (fr)
Japanese (ja)
Inventor
廣光 高山
直子 八十歩
満里子 北島
隆 八重樫
健 松崎
正人 長岡
秀介 橋本
裕之 西山
卓弥 杉本
雅弘 小野
Original Assignee
国立大学法人千葉大学
株式会社ヤクルト本社
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Application filed by 国立大学法人千葉大学, 株式会社ヤクルト本社 filed Critical 国立大学法人千葉大学
Priority to JP2011527589A priority Critical patent/JP5829520B2/en
Publication of WO2011021397A1 publication Critical patent/WO2011021397A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/41—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring

Definitions

  • the present invention relates to a colchicine derivative useful as a medicament such as an anticancer agent and a medicament containing the same.
  • Colchicine is a kind of isoquinoline alkaloid having a tropolone ring, and is abundant in seeds and bulbs of Lily family saffron and has long been used as a therapeutic agent for gout. Colchicine was found to inhibit cell division by binding to tubulin, which not only maintains the structure of the cell as a cytoskeleton, but also acts as a transport pathway in signal transduction. In addition, it has a function of forming a spindle in cell division. Therefore, colchicine has attracted attention as being useful as an anticancer agent, like vinblastine and taxol. However, since colchicine also suppresses the division of normal cells, it has not been put into practical use.
  • Non-Patent Document 9 Non-Patent Document 9
  • the subject of this invention is providing the 4-position modification compound of colchicine, and a pharmaceutical using the same.
  • the present inventor has introduced a substituent such as a halogen atom at the 4-position of the A ring of colchicine and converted the side chain of the B ring, and has excellent anticancer activity and low toxicity. And the present compound was found to be useful as a pharmaceutical agent such as an anticancer agent.
  • R 1 represents a halogen atom, a hydroxy group, a nitro group, an amino group or a mono-, di- or tri-fluoromethyl group
  • R 2 , R 3 and R 4 each represent a methoxy group or a hydroxy group, or R 2 and R 3 or R 3 and R 4 together represent a methylenedioxy group or an ethylenedioxy group
  • R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group, an alkenyl group having 2 to 6 carbon atoms, —COR 7 , —COOR 8 , —SO 2 R 9 , -CONR 10 R 11 or -CSNR 12 R 13 , or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 5 and R 6 are bonded;
  • R 7 represents a hydrogen atom, an aryl group having 6 to 14 carbon atoms,
  • R 8 represents an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms or a cyclic amino group.
  • the alkyl group includes an amino group, an alkyl group One to three selected from an amino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a heteroaryl group may be substituted, and the cyclic amino group includes an alkyl group and an alkoxycarbonyl group.
  • R 9 represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, an aryl group or a heteroaryl group having 6 to 14 carbon atoms, and the alkyl group has 1 to 3 halogen atoms.
  • R 10 and R 11 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms, or 1 to 7 represents an acyl group, or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 10 and R 11 are bonded.
  • the alkyl group is selected from an aryl group and a heteroaryl group.
  • 1 to 3 may be substituted, and the acyl group having 1 to 7 carbon atoms may be substituted with 1 to 3 halogen atoms.
  • the cyclic amino group may be further substituted with an oxygen atom, a nitrogen atom, or a sulfur atom.
  • Atoms may be included;
  • R 12 and R 13 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, or a cyclic alkyl group having 3 to 7 carbon atoms; Together with the nitrogen atom to which 12 and R 13 are bonded, represents a 3- to 7-membered cyclic amino group, which includes an aryl group, heteroaryl group, cyclic amino group, amino group, alkylamino group, dialkyl One to three selected from an amino group, a hydroxy group, and an alkyloxy group may be substituted, and the cyclic alkyl group may be substituted with one to three hydroxy groups, and the aryl group includes 1 to 5 selected from dialkylamino group, alkyloxy group, alkyl group, cyano group, halogen atom, hydroxyalkyl group, hydroxyalkyloxy group, sulfam
  • An atom, a nitrogen atom or a sulfur atom may be contained, and 1 to 3 selected from an alkyl group, a hydroxy group, a halogen atom, an amino group, an acyl group and a dialkylamino group may be substituted;
  • R 1 is a chlorine atom, bromine atom or iodine atom
  • R 2 , R 3 and R 4 are methoxy groups
  • R 5 is a hydrogen atom
  • R 6 is an acetyl group.
  • R 1 is a hydroxy group
  • R 2 , R 3 and R 4 are methoxy groups.
  • this invention provides the pharmaceutical containing the colchicine derivative represented by General formula (1), its salt, or those solvates. Moreover, this invention provides the pharmaceutical composition containing the colchicine derivative represented by General formula (1), its salt, or those solvates, and a pharmaceutically acceptable carrier. Moreover, this invention provides the anticancer agent containing the colchicine derivative represented by General formula (1), its salt, or those solvates. Moreover, this invention provides the colchicine derivative for treatment represented by General formula (1), its salt, or those solvates. In addition, the present invention provides a method for treating cancer, comprising administering an effective amount of a colchicine derivative represented by the general formula (1), a salt thereof, or a solvate thereof.
  • the colchicine derivative of the present invention, a salt thereof, or a solvate thereof is useful as an anticancer agent because it has excellent anticancer activity in vitro and in vivo and has low toxicity.
  • the colchicine derivative of the present invention has a halogen atom, hydroxy group, nitro group, amino group or mono-, di- or tri-fluoro at the 4-position (R 1 ) of the A ring as represented by the general formula (1). It is characterized by having a specific substituent called a methyl group.
  • R 1 is a halogen atom
  • the compounds of the present invention in which R 1 is a halogen atom have strong anticancer activity and low toxicity.
  • R 1 represents a halogen atom, a hydroxy group, a nitro group, an amino group, or a mono-, di- or tri-fluoromethyl group, and among these, a halogen atom is particularly preferable.
  • a halogen atom a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom is mentioned.
  • R 2 , R 3 and R 4 each represent a methoxy group or a hydroxy group, or R 2 and R 3 or R 3 and R 4 together form a methylenedioxy group or ethylene Indicates a dioxy group.
  • R 1 is a hydroxy group
  • R 2 , R 3 and R 4 are all methoxy groups.
  • R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group, an alkenyl group having 2 to 6 carbon atoms, —COR 7 , —COOR 8 , —SO 2 R 9 , It represents —CONR 10 R 11 or —CSNR 12 R 13 , or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 5 and R 6 are bonded.
  • examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, Sec-butyl group, tert-butyl group, and n-pentyl group.
  • a linear or branched alkyl group such as an n-hexyl group, but an alkyl group having 1 to 4 carbon atoms is more preferable, and a methyl group, an ethyl group, an n-propyl group, and an isobutyl group are particularly preferable.
  • Examples of the arylalkyl group include a benzyl group and a phenethyl group, and a benzyl group is preferable.
  • Examples of the alkenyl group having 2 to 6 carbon atoms include vinyl group, allyl group, 2-butenyl group, isobutenyl group, etc., but a straight chain or branched chain alkenyl group having 3 to 5 carbon atoms is more preferable, especially an allyl group. An isobutenyl group is preferred.
  • the R 7 in -COR 7 represents a hydrogen atom, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, cyclic amino group, a cyclic alkyl group or an alkyl group having 1 to 6 carbon atoms having 3 to 7 carbon atoms,
  • the alkyl group includes cyclic alkyl groups, halogen atoms, amino groups, alkylamino groups, arylalkylamino groups, dialkylamino groups, cyclic amino groups, alkoxycarbonylamino groups, arylamino groups, heteroarylamino groups, carboxyl groups, alkoxy groups.
  • examples of the alkyl group having 1 to 6 carbon atoms include the same groups as the above R 5 and R 6, and an alkyl group having 1 to 4 carbon atoms is preferable, and in particular, a methyl group, an ethyl group, and an n-propyl group.
  • An isopropyl group and an isobutyl group are preferable.
  • Examples of the aryl group having 6 to 14 carbon atoms include a phenyl group, a naphthyl group, a tolyl group, and a xylyl group, and a phenyl group is particularly preferable.
  • Heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, imidazolyl, benzothiazolyl, benzoxazolyl , Indolyl group, pyrazinyl group, indazolyl group, benzothiadiazolyl group, benzoimidazolyl group, benzothiazolyl group, thiadiazolyl group, isoxazolyl group, triazolyl group, etc., but furyl group, thienyl group, pyrrolyl group, pyridinyl group, benzothiazolyl group , A benzoxazolyl group and an indolyl group are particularly preferred.
  • cyclic amino groups include pyrrolidino group, piperidino group, N-methylpiperidino group, N- (t-butoxycarbonyl) piperidino group, N-acetylpiperidino, N-benzoylpiperidino, N- (benzyloxycarbonyl) piperidino Examples thereof include an N-methylpiperidino group, an N- (t-butoxycarbonyl) piperidino group, an N-benzoylpiperidino group and an N- (benzyloxycarbonyl) piperidino group.
  • Examples of the cyclic alkyl group having 3 to 7 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc., and a cyclic alkyl group having 3 to 6 carbon atoms is preferable, and a cyclopropyl, cyclopentyl group, cyclohexane A hexyl group is particularly preferred.
  • examples of the cyclic alkyl group include a cyclic alkyl group having 3 to 7 carbon atoms, such as a cyclopropyl group and a cyclohexyl group.
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the alkylamino group include a C 1-6 alkylamino group such as a methylamino group and an ethylamino group.
  • Examples of the arylalkylamino group include a benzylamino group.
  • Examples of the dialkylamino group include a di (C 1-6 alkyl) amino group such as a dimethylamino group and a diethylamino group.
  • Examples of the cyclic amino group include a C 3-7 cyclic amino group such as an aziridino group, a pyrrolidino group, and a piperidino group.
  • Examples of the alkoxycarbonylamino group include a t-butoxycarbonylamino group.
  • Examples of the arylamino group include an anilino group.
  • Examples of the heteroarylamino group include a furylamino group, a thienylamino group, and a pyridinylamino group.
  • alkoxycarbonyl group examples include a C 1-67 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butyloxycarbonyl group, and a benzyloxycarbonyl group.
  • acyloxy group examples include C 1-6 acyloxy groups such as acetyloxy group and propionyloxy group.
  • dialkylaminoacyloxy group include di (C 1-6 alkyl) aminoacyloxy groups such as dimethylaminoacetyloxy group, diethylaminoacetyloxy group, dimethylaminopropionyloxy group, diethylaminobutyroyloxy group and the like.
  • Examples of the alkyloxy group include C 1-6 alkyloxy groups such as a methoxy group and an ethoxy group.
  • Examples of the aryl group include a phenyl group and a tolyl group.
  • Examples of the aryloxy group include a phenyloxy group and a tolyloxy group.
  • Examples of the arylalkyloxy group include a benzyloxy group and a triphenylmethyloxy group.
  • Examples of the heteroaryl group include a pyridyl group, a furyl group, and an oxazolyl group.
  • Examples of the heteroaryloxy group include a pyridyloxy group, a furyloxy group, and oxazolyloxy.
  • Examples of the acylthio group include a C 1-6 acylthio group such as an acetylthio group and a propionylthio group.
  • Examples of the dialkylaminoacylthio group include a di (C 1-6 alkyl) aminoacylthio group such as a dimethylaminoacetylthio group, a dimethylaminopropionylthio group, a diethylaminoacetylthio group, and a diethylaminobutyrylthio group.
  • Examples of the alkylthio group include a C 1-6 alkylthio group such as a methylthio group and an ethylthio group.
  • alkylsulfonyl group examples include C 1-6 alkylsulfonyl groups such as a methylsulfonyl group and an ethylsulfonyl group.
  • arylthio group examples include a phenylthio group and a tolylthio group.
  • heteroarylthio group examples include a pyridylthio group, a furylthio group, and oxazolylthio.
  • carbamoyloxy group examples include 4-piperidinopiperidine-1-carbonyloxy group and 1-methylpiperidine-4-carbonyloxy group.
  • Examples of the cyclic aminocarbamoyloxy group include 1- (benzyloxycarbonyl) piperidine-4-carbonyloxy group.
  • examples of the halogen atom include the same groups as described above.
  • examples of the alkoxy group include the same groups as described above.
  • examples of the alkylamino group include the same groups as described above.
  • Examples of the dialkylamino group include the same groups as described above.
  • examples of the alkyl group include the same groups as described above.
  • Examples of the aryl group include the same groups as described above.
  • Examples of the hydroxyalkyloxy group include 2-hydroxyethoxy group, 3-hydroxypropoxy group, 2-hydroxypropoxy group and the like.
  • examples of the alkyl group include the same groups as described above.
  • examples of the alkoxycarbonyl group include the same groups as described above.
  • Examples of the acyl group include an acetyl group, a propionyl group, and a benzoyl group.
  • R 8 in the -COOR 8 represents an alkyl group, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group or a cyclic amino group having 3 to 7 carbon atoms having 1 to 6 carbon atoms, said alkyl group May be substituted with 1 to 3 groups selected from an amino group, an alkylamino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a heteroaryl group.
  • alkyl group having 1 to 6 carbon atoms include the same groups as described above, and an alkyl group having 1 to 4 carbon atoms is preferable, and in particular, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a t-butyl group. Is preferred.
  • aryl group having 6 to 14 carbon atoms include the same groups as those described above for R 7, and a phenyl group is particularly preferable.
  • heteroaryl group examples include the same groups as those described above for R 7, and a pyridyl group and an indolyl group are particularly preferable.
  • cyclic alkyl group having 3 to 7 carbon atoms examples include the same groups as those described above for R 7, and a cyclopentyl group and a cyclohexyl group are particularly preferable.
  • cyclic amino group examples include the same groups as those described above for R 7, and an N-methylpiperidino group, an N- (t-butoxycarbonyl) piperidino group, and an N- (benzyloxycarbonyl) piperidino group are particularly preferable.
  • Examples of the substituent on the alkyl group represented by R 8 include an amino group, an alkylamino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group, or a heteroaryl group. Is particularly preferably a methylamino group or an ethylamino group.
  • As the dialkylamino group a dimethylamino group and a diethylamino group are particularly preferable.
  • As the cyclic amino group a pyrrolidino group and a piperidino group are particularly preferable.
  • alkoxycarbonyl group a methoxycarbonyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group are particularly preferable.
  • aryl group a phenyl group and a tolyl group are particularly preferable.
  • heteroaryl group a pyridyl group is particularly preferable.
  • R 9 in -SO 2 R 9 represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, an aryl group or a heteroaryl group having 6 to 14 carbon atoms.
  • the alkyl group may be substituted with 1 to 3 halogen atoms
  • the aryl group may be substituted with 1 to 3 alkyl groups having 1 to 6 carbon atoms.
  • Examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and an alkyl group having 1 to 4 carbon atoms, particularly a methyl group, an ethyl group, an isopropyl group, and an isobutyl group are preferable.
  • Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as described above, and a cyclopropyl group and a cyclohexyl group are preferable.
  • Examples of the aryl group having 6 to 14 carbon atoms include the same groups as described above, and a phenyl group and a tolyl group are particularly preferable.
  • Examples of the heteroaryl group include the same groups as described above, and a thienyl group is preferable.
  • Examples of the substituent on the alkyl group represented by R 9 include a halogen atom, and examples of the halogen atom include the same groups as those described above for R 7 .
  • Examples of the substituent on the aryl group represented by R 9 include an alkyl group having 1 to 6 carbon atoms, and examples of the alkyl group having 1 to 6 carbon atoms include the same groups as those described above for R 7 .
  • R 10 and R 11 in the above -CONR 10 R 11 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, having a carbon number of 3 to 7 A cyclic alkyl group or an acyl group having 1 to 7 carbon atoms, or a 3- to 7-membered cyclic amino group together with a nitrogen atom to which R 10 and R 11 are bonded.
  • 1 to 3 selected from the group and 1 to 3 heteroaryl groups may be substituted, and the acyl group having 1 to 7 carbon atoms may be substituted with 1 to 3 halogen atoms.
  • the cyclic amino group may further contain an oxygen atom, a nitrogen atom or a sulfur atom.
  • examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and a methyl group, an ethyl group, and a hexyl group are particularly preferable.
  • examples of the aryl group having 6 to 14 carbon atoms include the same groups as those described above for R 7, and a phenyl group is particularly preferable.
  • Examples of the heteroaryl group include the same groups as those described above for R 7, and a pyridyl group and an indolyl group are particularly preferable.
  • Examples of the substituent on the alkyl group represented by R 10 and R 11 include an aryl group or a heteroaryl group.
  • Examples of the aryl group include the same groups as those described above for R 7, and a phenyl group is particularly preferable.
  • Examples of the heteroaryl group include the same groups as those described above for R 7, and a furyl group and a thienyl group are particularly preferable.
  • Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as those described above for R 7, and a cyclohexyl group is particularly preferable.
  • Examples of the acyl group having 1 to 7 carbon atoms include an acetyl group.
  • Examples of the halogen atom substituted on the acyl group include the same groups as those described above for R 7 .
  • Examples of the 3- to 7-membered cyclic amino group formed by R 10 and R 11 together with the nitrogen atom include an aziridino group, a pyrrolidino group, and a piperidino group, and a piperidino group is particularly preferable.
  • the cyclic amino group of 3 to 7 membered ring formed by R 10 and R 11 together with a nitrogen atom and further containing an oxygen atom, a nitrogen atom or a sulfur atom includes a morpholino group, a piperazino group, an N— Examples include a methylpiperazino group, a thiomorpholino group, a thiomorpholino-1,1-dioxide group, and the like, and a morpholino group and a thiomorpholino group are particularly preferable.
  • R 12 and R 13 in the above -CSNR 12 R 13 are the same or different, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, the number heteroaryl group or C 3-7 having 6 to 14 carbon atoms Or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 12 and R 13 are bonded, and the alkyl group includes an aryl group, a heteroaryl group, a cyclic amino group 1 to 3 selected from an amino group, an alkylamino group, a dialkylamino group, a hydroxy group and an alkyloxy group may be substituted, and the cyclic alkyl group is substituted with 1 to 3 hydroxy groups.
  • the aryl group may be a dialkylamino group, an alkyloxy group, an alkyl group, a cyano group, a halogen atom, a hydroxyalkyl group, a hydroxyalkyloxy group, a sulfamoyl group.
  • hydroxy groups may be substituted, and the heteroaryl group may be substituted with 1 to 3 selected from alkyl groups, cyano groups, aryl groups and hydroxyalkyl groups,
  • the cyclic amino group may further contain an oxygen atom, a nitrogen atom or a sulfur atom, and further 1 to 3 selected from an alkyl group, a hydroxy group, a halogen atom, an amino group and a dialkylamino group are substituted. May be.
  • examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and an alkyl group having 1 to 4 carbon atoms, particularly a methyl group, an ethyl group, and an isobutyl group are preferable.
  • Examples of the aryl group having 6 to 14 carbon atoms include the same groups as those described above for R 7, and a phenyl group is particularly preferable.
  • Examples of the heteroaryl group include the same groups as R 7 described above, and a pyridyl group, an indolyl group, a pyridazinyl group, a pyrazinyl group, a benzothiadiazolyl group, a thiazolyl group, an isoxazolyl group, a pyrazolyl group, and a triazolyl group are particularly preferable.
  • Examples of the substituent on the alkyl group represented by R 12 and R 13 include an aryl group, a heteroaryl group, a cyclic amino group, an amino group, a dialkylamino group, a hydroxy group, and an alkyloxy group.
  • the same group as 7 is mentioned, A phenyl group is especially preferable.
  • Examples of the heteroaryl group include the same groups as those described above for R 7, and a furyl group and a thienyl group are particularly preferable.
  • Examples of the cyclic amino group include the same groups as those described above for R 7, and a morpholino group is preferable.
  • Examples of the alkylamino group include the same groups as those described above for R 7 .
  • Examples of the dialkylamino group include the same groups as those described above for R 7 .
  • Examples of the alkyloxy group include the same groups as those described above for R 7, and a methoxy group is particularly preferable.
  • Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as those described above for R 7, and a cyclohexyl group is particularly preferable.
  • Examples of the 3- to 7-membered cyclic amino group formed by R 12 and R 13 together with the nitrogen atom include an aziridino group, a pyrrolidino group, a piperidino group, an azepano group, and the like.
  • An aziridino group, a pyrrolidino group, a piperidino group The group is particularly preferred.
  • Examples of the cyclic amino group which is a 3- to 7-membered cyclic amino group formed by R 12 and R 13 together with a nitrogen atom and further contains an oxygen atom, a nitrogen atom or a sulfur atom include a morpholino group, a piperazino group, an N— Examples include a methylpiperazino group, a thiomorpholino group, a thiomorpholino-1,1-dioxide group, and the like, and a morpholino group and a thiomorpholino group are particularly preferable.
  • Examples of the alkyl group substituted on the cyclic amino group include the same groups as those described above for R 7, and a methyl group is particularly preferable.
  • Examples of the halogen atom substituted on the cyclic amino group include the same groups as those described above for R 7, and fluorine is particularly preferable.
  • Examples of the acyl group substituted on the cyclic amino group include the same groups as those described above for R 7 .
  • Examples of the dialkylamino group substituted on the cyclic amino group include the same groups as those described above for R 7 .
  • Examples of the alkyl group substituted on the heteroaryl group include a methyl group and an ethyl group.
  • Examples of the aryl group include a phenyl group.
  • Examples of the hydroxyalkyl group include a 2-hydroxyethyl group, a 3-hydroxypropyl group, Examples include 2-hydroxypropyl group.
  • Examples of the 3- to 7-membered cyclic amino group formed by R 5 and R 6 together with the nitrogen atom include an aziridino group, a pyrrolidino group, and a piperidino group.
  • R 5 and R 6 are hydrogen atom and alkyl group having 1 to 6 carbon atoms, an arylalkyl group, if an alkenyl group having 2 to 6 carbon atoms, may be the same or different, the R 5 or R 6
  • the other is preferably a hydrogen atom.
  • R 5 and R 6 A preferred combination of R 5 and R 6 will be described.
  • the following combinations (1) to (3) are particularly preferable.
  • R 6 is more preferably —COR 7 , —COOR 8 , —SO 2 R 9 or —CSNR 12 R 13 .
  • R 7 is a hydrogen atom; an alkyl group having 2 to 6 carbon atoms; a cyclic alkyl group having 3 to 7 carbon atoms; a C 3-7 cyclic alkyl group, a halogen atom, an amino group, C 1 -6 alkylamino group, C 6-14 arylalkylamino group, di (C 1-6 alkyl) amino group, cyclic amino group, C 1-6 alkoxycarbonylamino group, C 6-14 arylamino group, heteroarylamino Group, carboxyl group, C 1-6 alkoxycarbonyl group, hydroxy group, acyloxy group, di (C 1-6 alkyl) aminoacyloxy group, C 1-6 alkyloxy group, C 6-14 aryl group, C 6-14 Aryloxy group
  • R 8 is preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms, or a cyclic amino group
  • the alkyl group includes an amino group, a C 1-6 alkylamino group, a di (C 1-6 alkyl) amino group, a cyclic amino group, a carboxyl group, a C 1-6 alkoxycarbonyl group, a C 6-14 aryl group, and a hetero group.
  • the cyclic amino group may be substituted with a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group
  • the cyclic alkyl group May be substituted with a carboxyl group or an alkoxycarbonyl group.
  • R 9 is preferably a C 6-14 aryl group or a heteroaryl group.
  • R 6 is —CSNR 12 R 13 , R 12 and R 13 are the same or different and are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 5 to 6 carbon atoms, an aryl group, or a heteroaryl group.
  • a 4- to 6-membered cyclic amino group formed by R 12 and R 13 together with a nitrogen atom is preferable, and the alkyl group may be substituted with an alkyloxy group or a hydroxy group, and the aryl group 1 to 3 selected from a dialkylamino group, an alkyloxy group, an alkyl group, a cyano group, a halogen atom, a hydroxyalkyl group and a hydroxyalkyloxy group may be substituted, and the heteroaryl group has an alkyl group , A cyano group, an aryl group, and a hydroxyalkyl group may be substituted, and the cyclic amino group may contain an oxygen atom or a sulfur atom.
  • alkyl group one to three selected from halogen atoms may be substituted.
  • R 5 is a hydrogen atom and R 6 is an acetyl group
  • R 1 is not a chlorine atom, a bromine atom or an iodine atom.
  • colchicine derivative chosen from the following, its salt, or those solvates are preferable.
  • N- (benzyloxycarbonyl) -4-bromodeacetylcolchicine 4-bromo-N-[(methylthio) acetyl] deacetylcolchicine, 4-bromo-N-[(N ′, N′-dimethylamino) acetyl] deacetylcolchicine, 4-bromo-N-propyl deacetylcolchicine, 4-bromo-N- (hexylcarbamoyl) deacetylcolchicine, 4-bromo-N- (phenylcarbamoyl) deacetylcolchicine, 4-bromo-N- (hydroxyacetyl) deacetylcolchicine, 4-bromo-N- (isobutanesulfonyl) deacetylcolchicine, 4-bromo-N-tosyldeacetylcolchicine, 4-bromo-N- (2-thiophenesulfonyl)
  • the salt of the colchicine derivative of the present invention includes organic acid salts and inorganic acid salts.
  • the acid that forms the organic acid salt include acetic acid, propionic acid, lactic acid, malic acid, citric acid, tartaric acid, fumaric acid, maleic acid, and mesylic acid.
  • the inorganic acid forming the inorganic acid salt include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • the colchicine derivative of the present invention, a salt thereof or a solvate thereof is an optically active substance since the 7-position is an asymmetric carbon atom. Further, when there is an asymmetric carbon atom other than this position, an optical isomer based on the carbon atom may exist.
  • the present invention includes all these optical isomers.
  • the compound of the present invention includes a solvate such as a hydrate.
  • solvates of the colchicine derivative of the present invention include hydrates and ethanol solvates.
  • the colchicine derivative (1) of the present invention can be produced by introducing a halogen atom, a hydroxy group, a nitro group, an amino group, or a mono-, di- or trifluoromethyl group at the 4-position of the colchicine compound.
  • a halogen atom is performed by reacting a colchicine compound with a halogenating reagent such as N-fluorobenzenesulfonimide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like.
  • the halogenation reaction may be performed at 0 to 150 ° C. for 1 to 50 hours using a solvent such as acetic acid, acetonitrile or N, N-dimethylformamide.
  • the introduction of the nitro group is carried out by reacting the colchicine compound with a nitrating reagent such as diammonium cerium nitrate-trifluoroacetic anhydride, nitric acid, mixed acid, acetyl nitrate, or nitronium salt.
  • a nitrating reagent such as diammonium cerium nitrate-trifluoroacetic anhydride, nitric acid, mixed acid, acetyl nitrate, or nitronium salt.
  • This reaction may be carried out in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc., or a solvent such as acetic acid, nitromethane, nitroethane, etc. at ⁇ 78 to 150 ° C. for 1 to 50 hours.
  • the introduction of the hydroxy group can be carried out by introducing a formyl group at the 4-position of the colchicine compound and then oxidizing it.
  • a formyl group is introduced by reacting a colchicine compound with a Lewis acid such as tin chloride or aluminum chloride and dichloromethyl methyl ether.
  • the oxidation reaction of the formyl group can be performed by reacting, for example, magnesium monoperoxyphthalate.
  • the amino group may be introduced by reducing 4-nitrocolchicine by catalytic reduction or the like, or introducing a carboxyl group at the 4-position of colchicine and then converting the carboxyl group to an amino group.
  • the carboxyl group introduction reaction can be performed by oxidizing a 4-formylcolchicine compound. For example, sodium chlorite, Jones reagent, permanganate, silver oxide and the like may be reacted.
  • the carboxylic acid may be reacted directly with triethylamine and diphenyl phosphate azide, or the carboxylic acid may be acid chloride or acid hydrazide and reacted with sodium azide or nitrous acid derivative, etc. .
  • a mono-, di- or tri-fluoromethyl group is introduced by introducing a formyl group at the 4-position of the colchicine compound and then reducing the 4-position to a hydroxymethyl group, It can be performed by fluorination.
  • a difluoromethyl group it can be carried out by converting the formyl group at the 4-position to dithioacetal and then fluorinating.
  • the fluorinating reagent for example, hydrogen fluoride-pyridine complex, (diethylamino) sulfur trifluoride, etc. may be used.
  • the colchicine derivative of the present invention, a salt thereof, or a solvate thereof exhibits excellent cancer cell growth inhibitory activity in vitro and in vivo, as shown in Examples below. It is also less toxic. Therefore, the colchicine derivative of the present invention, a salt thereof or a solvate thereof is useful as an anticancer agent for mammals including humans.
  • the compound of the present invention can be administered as it is, but other pharmaceutically acceptable carriers such as a dispersion aid, Oral or injection such as powder, liquid, capsule, suspension, emulsion, syrup, elixir, granule, pill, tablet, troche, limonade, etc. Can be used in various dosage forms. These preparations can be produced by known methods.
  • the carrier examples include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose, and dextran; for example, gel-forming or water-soluble celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; Water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, ⁇ -cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, pectin and the like Water-absorbing and poorly water-soluble polysaccharides such as derivatives thereof; for example, water-absorbing and poorly water-soluble gums such as gum arabic, tragacanth gum, glycomannan and derivatives thereof; Cross-linked vinyl polymers such as cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; and
  • a solubilization treatment can be performed.
  • a solubilization treatment a method that can be generally applied to a medicine, for example, a method of adding a surfactant such as polyoxyethylene alcohol ethers, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, Examples thereof include a method using a water-soluble polymer such as polyethylene glycol. Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, and the like can be used.
  • cancer types to be targeted by the anticancer agent of the present invention include head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer,
  • Examples include endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor and the like.
  • the dosage of the medicament of the present invention may be appropriately adjusted according to the administration method, patient's symptoms, etc., but it is preferable to administer 1 mg to 10 g, further 100 mg to 10 g, particularly 500 mg to 10 g per day for an adult.
  • Example 1 Synthesis of 4-nitrocolchicine 14.3 mg (0.026 mmol, 1.05 eq) of diammonium cerium (IV) nitrate (CAN) was dissolved in 0.5 mL of dichloromethane, and 10 mg (0.025 mmol) of colchicine, 12.2 ⁇ L of trifluoroacetic anhydride (0.0875 mmol, 3.5 eq) was added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 4 times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried in vacuo.
  • Example 2 Synthesis of 4-hydroxycolchicine Dissolve 15.7 mg (0.037 mmol) of 4-formylcolchicine in 0.37 mL of methanol, add 22.3 mg (0.036 mmol, 3 eq) of 80% magnesium monoperoxyphthalate (MMPP), and then at room temperature for 4 hours. Stir. The reaction solution was quenched by adding saturated aqueous sodium hydrogen carbonate solution, acidified with 1N hydrochloric acid, and extracted four times with chloroform. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum.
  • MMPP magnesium monoperoxyphthalate
  • reaction solution was quenched by adding a saturated aqueous ammonium chloride solution, and extracted four times with 10% methanol / chloroform.
  • the organic layer was washed with saturated brine, dried over MgSO 4 , filtered, evaporated under reduced pressure, and dried in vacuo.
  • the obtained residue was purified by silica gel column chromatography (10% [10% acetic acid-containing methanol] / chloroform) to obtain 174.6 mg (yield 99%) of the title compound.
  • Example 3 Synthesis of 4-fluorocolchicine 30 mg (0.075 mmol) of colchicine was dissolved in 0.75 mL of formic acid, 47.3 mg (0.15 mmol, 2 eq) of N-fluorobenzenesulfonimide (NFSi) was added, and the atmosphere was 70 ° C. under an argon atmosphere. Stir for 12 hours. Then, 47.3 mg (0.15 mmol, 2 eq) of NFSi was added and stirred for 6.5 hours. Furthermore, 47.3 mg (0.15 mmol, 2 eq) of NFSi and 0.5 mL of formic acid were added, and the mixture was stirred for 6.5 hours.
  • NFSi N-fluorobenzenesulfonimide
  • Example 4 Synthesis of 4-aminocolchicine 5.0 mg (0.011 mmol) of colchicine-4-carboxylic acid was dissolved in 0.3 mL of tetrahydrofuran, and 2.3 ⁇ L (0.0165 mmol, 1.5 eq) of triethylamine, 2.8 ⁇ L of diphenylphosphoric acid azide (DPPA) under ice-cooling ( 0.013 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 4 hours. Further, 0.15 mL of water was added, and the mixture was boiled and refluxed for 1 hour. A saturated aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted 4 times with chloroform.
  • DPPA diphenylphosphoric acid azide
  • the product was purified by silica gel column chromatography (5% methanol / chloroform) to obtain 110.5 mg (quantitative yield) of 1,2- (methylenedioxy) -1,2-didemethoxycolchicine. Dissolve 60 mg (0.156 mmol) of this in 1.5 mL of dichloromethane, and add dropwise dropwise tin (IV) 55 ⁇ L (0.468 mmol, 3 eq) and 0.17 mL (1.872 mmol, 12 eq) of dichloromethyl methyl ether under ice-cooling. The mixture was stirred at 0 ° C. under an argon atmosphere for 30 minutes, then warmed to room temperature and further stirred for 6.5 hours.
  • reaction solution was quenched by adding a saturated aqueous sodium hydrogen carbonate solution, acidified with 1N hydrochloric acid, extracted four times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum.
  • the obtained residue was purified by silica gel column chromatography (4% methanol / chloroform) to obtain 8 mg (yield 21%) of the title compound.
  • the resulting aqueous layer was extracted 3 times with chloroform, and the organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and reduced pressure Distilled off and vacuum dried.
  • the obtained residue was purified by silica gel column chromatography (1% methanol / ethyl acetate) to obtain 132.8 mg (quantitative yield) of the desired product, N- (t-butoxycarbonyl) colchicine.
  • the reaction mixture was basified with 5M sodium hydroxide, extracted with chloroform three times, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum.
  • the obtained residue was purified by silica gel column chromatography (10% methanol / chloroform) to give the title compound (377 mg, yield 88%).
  • Example 5 Synthesis of 4-chloro-N- (t-butoxycarbonyl) colchicine 10 mg (0.023 mmol) of 4-chlorocolchicine was dissolved in 0.5 mL of acetonitrile, 2.8 mg (0.023 mmol, 1 eq) of dimethylaminopyridine was added, and triethylamine 9.6 ⁇ L (0.069 mmol, 3 eq) and di-t-butyl dicarbonate 26.4 ⁇ L (0.115 mmol, 5 eq) were sequentially added dropwise, and the mixture was boiled and refluxed at 100 ° C. for 10.5 hours. The reaction solution was diluted with chloroform and washed 3 times with saturated aqueous citric acid solution.
  • Example 6 4-Chloro-N- (t-butoxycarbonyl) deacetylcolchicine 130 mg (0.24 mmol) of 4-chloro-N- (t-butoxycarbonyl) colchicine was dissolved in 2.4 mL of methanol and 0.48 mL (0.48 mL) of 1M sodium methoxide was dissolved. mmol, 2 eq) was added dropwise and stirred at room temperature for 6 hours. The reaction solution was quenched by adding saturated brine, extracted four times with chloroform, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum.
  • Example 7 Synthesis of 4-chlorodeacetylcolchicine 95 mg (0.19 mmol) of 4-chloro-N- (t-butoxycarbonyl) deacetylcolchicine is dissolved in 0.27 mL (3.61 mmol, 19 eq) of trifluoroacetic acid, and 20 minutes at room temperature. Stir. The reaction mixture was basified with 5N sodium hydroxide, extracted 3 times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (5% ⁇ 10% methanol / chloroform) to obtain 65 mg (yield 87%) of the title compound.
  • Example 8 Synthesis of 4-chlorodeacetylcolchicine hydrochloride To 2 mL of methanol, 20 ⁇ L (0.28 mmol, 2 eq) of acetyl chloride was added dropwise and stirred under ice-cooling. To this solution, 55 mg (0.14 mmol) of 4-chlorodeacetylcolchicine dissolved in 1.5 mL of methanol was added dropwise under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was evaporated under reduced pressure and dried in vacuo to give 61.5 mg of the title compound.
  • Example 9 Synthesis of 4-fluoro-N- (t-butoxycarbonyl) colchicine 12 mg (0.029 mmol) of 4-fluorocolchicine was dissolved in 0.5 mL of acetonitrile, 3.5 mg (0.029 mmol, 1 eq) of dimethylaminopyridine was added, and triethylamine 12 ⁇ L (0.087 mmol, 3 eq) and di-t-butyl dicarbonate 33.3 ⁇ L (0.145 mmol, 5 eq) were added dropwise in that order, and the mixture was boiled and refluxed at 100 ° C. for 7.5 hours. The reaction solution was diluted with chloroform and washed 3 times with saturated aqueous citric acid solution.
  • Example 11 Synthesis of 4-fluoro deacetyl colchicine 65 mg (0.14 mmol) of 4-fluoro-N- (t-butoxycarbonyl) deacetyl colchicine was dissolved in 0.2 mL (2.66 mmol, 19 eq) of trifluoroacetic acid, and 40 minutes at room temperature. Stir. The reaction mixture was basified with 5N sodium hydroxide, extracted 3 times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% methanol / chloroform) to obtain 55 mg (quantitative yield) of the title compound.
  • Example 12 Synthesis of 4-fluorodeacetylcolchicine hydrochloride 21.3 ⁇ L (0.3 mmol, 2 eq) of acetyl chloride was added dropwise to 1.5 mL of methanol under ice-cooling and stirred. To the solution was added dropwise 55 mg (0.15 mmol) of 4-fluorodeacetylcolchicine dissolved in 1.5 mL of methanol under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was evaporated under reduced pressure and dried under vacuum to obtain 44.5 mg of the title compound.
  • Example 13 Synthesis of 4-chloro-N-propionyl deacetyl colchicine 10 mg (0.026 mmol) of 4-chloro deacetyl colchicine was dissolved in 0.5 mL of dichloromethane, and 2.3 ⁇ L (0.029 mmol, 1.1 eq) of pyridine and 2.3 ⁇ L of propionyl chloride under ice cooling. (0.026 mmol, 1 eq) was added dropwise in order, and the mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by adding water and made basic with saturated aqueous sodium bicarbonate.
  • Example 14 Synthesis of 4-chloro-N-formyldeacetylcolchicine Dissolve 11.8 mg (0.030 mmol) of 4-chlorodeacetylcolchicine in 0.4 mL of N, N-dimethylformamide, add 0.2 mL of ethyl formate, and stir at 80 ° C for 3 hours. did. Thereafter, the temperature was raised to 120 ° C. and stirred for 22 hours. The reaction solution was distilled off under reduced pressure and dried under vacuum. The obtained residue was purified by silica gel column chromatography (5% methanol / chloroform and 7% methanol / ethyl acetate) to give the title compound (12.5 mg, yield 99%).
  • reaction solution was quenched by adding saturated aqueous sodium hydrogen carbonate solution, extracted four times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum.
  • the obtained residue was purified by silica gel column chromatography (1% ⁇ 5% ⁇ 10% methanol / chloroform) to obtain 31.3 mg of the title compound (quantitative yield).
  • Example 17 Synthesis of 4-chloro-N, N-diethyl deacetyl colchicine 4-chlorodeacetyl colchicine (50 mg, 0.128 mmol) in methanol-acetic acid mixture (100: 1, 1.9 mL) under ice-cooling and argon gas atmosphere Acetaldehyde (25 ⁇ L, 0.128 ⁇ 3.5 mmol) and sodium cyanoborohydride (18 mg, 0.128 ⁇ 2.2 mmol) were added. The mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium hydrogen carbonate and ethyl acetate were added.
  • Example 24 Synthesis of 4-chloro-N-methyldeacetylcolchicine N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine (47 mg, 0.093 mmol) in dichloromethane (750 ⁇ L) in ice-cooled, Trifluoroacetic acid (300 ⁇ L) was added under an argon gas atmosphere. The solution was stirred under ice-cooling for 5 minutes and then at room temperature for 2 hours. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and chloroform and brine were added. The organic layer was taken and the aqueous layer was extracted again with chloroform.
  • Example 26 Separate synthesis method of 4-chloro-N-ethyldeacetylcolchicine To a solution of 4-chlorodeacetylcolchicine (0.150 g, 0.383 mmol) in dichloromethane-acetic acid (50: 1, 7.7 mL) at room temperature under argon gas atmosphere Then, acetaldehyde (20.4 ⁇ L, 0.383 ⁇ 0.95 mmol) was added and stirred for 10 minutes. To this solution was added sodium triacetoxyborohydride (0.179 mg, 0.383 ⁇ 2.2 mmol), and the mixture was stirred overnight at room temperature, and then ethyl acetate and saturated aqueous sodium hydrogen carbonate were added.
  • Example 27 Synthesis method of 4-chloro-N-ethyldeacetylcolchicine hydrochloride Methanol (2 mL) was ice-cooled and acetyl chloride (24.6 ⁇ L, 0.231 ⁇ 1.5 mmol) was added under an argon gas atmosphere. Stir for hours. To this solution was added a solution of 4-chloro-N-ethyldeacetylcolchicine (97 mg) in methanol (2 mL), and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in a small amount of chloroform and solidified by adding hexane.
  • Example 31 Synthesis of N-benzyl-4-chlorodeacetylcolchicine hydrochloride To a solution of N-benzyl-4-chlorodeacetylcolchicine (0.132 g, 0.274 mmol) in methanol (1 mL) under ice-cooling and argon gas atmosphere, 10 % HCl-methanol (166 ⁇ L, 0.274 ⁇ 1.5 mmol) was added. This solution was concentrated to dryness under reduced pressure to obtain the title compound (milky white solid, 142 mg, 0.274 mmol, quantitative).
  • Example 32 Synthesis of 4-chloro-N-propyldeacetylcolchicine N-allyl-4-chlorodeacetylcolchicine (36 mg, 0.0833 mmol) in an ethyl acetate (860 ⁇ L) solution under ice-cooling and argon gas atmosphere % Palladium on carbon (8 mg) and zinc bromide (11 mg) were added. The inside of the reaction vessel was deaerated and then replaced with hydrogen gas. The suspension was stirred overnight at room temperature under a hydrogen gas atmosphere. Unnecessary substances were removed with a microfilter (0.45 ⁇ m), and the filtrate was concentrated to dryness under reduced pressure.
  • Example 33 Synthesis of N-isobutyl-4-chlorodeacetylcolchicine
  • the title compound (milky white solid, 4) was synthesized from 4-chloro-N- (2-methylallyl) deacetylcolchicine. mg, 0.0090 mmol, 17%).
  • Example 36 Synthesis of 4-chloro-N- (1-methylpiperazin-4-yloxycarbonyl) deacetylcolchicine
  • the mixture was stirred overnight at room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added.
  • the organic layer was taken and the aqueous layer was further extracted with chloroform.
  • reaction solution was allowed to cool to room temperature, and then ethyl acetate and 10% citric acid were added to obtain an organic layer.
  • the organic layer was further washed with 10% citric acid and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure.
  • the residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 48 mg, 0.087 mmol, 68%).
  • Example 42 Synthesis of 4-chloro-N- (1-methylpiperazine-4-carbonyl) deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 3.8 mL
  • triethylamine 54 ⁇ L, 0.128 ⁇ 3.0 mmol
  • 1-methylpiperazine-4-carbonyl chloride hydrochloride (0.127 g, 0.128 ⁇ 5.0 mmol) were added.
  • This solution was refluxed for 6 hours under an argon gas atmosphere.
  • the reaction solution was allowed to cool to room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added to obtain an organic layer.
  • Example 45 Synthesis of 4-chloro-N- (cyclopropanecarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and cyclopropanecarbonyl chloride (12 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 46 Synthesis of 4-chloro-N-isovaleryl deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and isovaleryl chloride (16 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 47 Synthesis of 4-chloro-N-heptanoyl deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and heptanoyl chloride (20 microliters, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 48 Synthesis of 4-chloro-N- (cyclohexanecarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and cyclohexanecarbonyl chloride (17 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 50 Synthesis of 4-chloro-N- (phenylacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (21 ⁇ l, 0.128 ⁇ 1.5 mmol) and phenylacetyl chloride (25 ⁇ l, 0.128 ⁇ 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 40 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 51 Synthesis of 4-chloro-N- (pyridin-3-ylcarbonyl) deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 2 mL
  • Triethylamine 47 microliters, 0.128 * 2.7 mmol
  • nicotinic acid chloride hydrochloride 27 mg, 0.128 * 1.2 mmol
  • Example 52 Synthesis of 4-chloro-N- (pyridin-4-ylcarbonyl) deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 2 mL
  • Triethylamine 47 ⁇ l, 0.128 ⁇ 2.7 mmol
  • isonicotinic acid chloride hydrochloride 27 mg, 0.128 ⁇ 1.2 mmol
  • Example 54 Synthesis of 4-chloro-N- (trifluoroacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (6 mL) and cooled to 0 ° C. Trifluoroacetic anhydride (38 ⁇ l) was added thereto and stirred at 0 ° C. for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Example 55 Synthesis of 4-chloro-N- (methoxyacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 ⁇ l, 0.128 ⁇ 1.5 mmol) and methoxyacetyl chloride (14 ⁇ l, 0.128 ⁇ 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 58 Synthesis of 4-chloro-N-[(4-pyridylthio) acetyl] deacetylcolchicine Under argon atmosphere, (4-pyridylthio) acetic acid (26 mg, 0.128 ⁇ 1.2 mmol) was added to N, N-dimethylformamide (1 mL). Dissolved and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 59 Synthesis of N- (4-bromobutyryl) -4-chlorodeacetylcolchicine Dissolve 4-bromobutyric acid (43 mg, 0.128 ⁇ 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere at 0 ° C Cooled to. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 60 Synthesis of 4-chloro-N- (4-fluorobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorocolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 4-fluorobenzoyl chloride (15 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 61 Synthesis of 4-chloro-N- (3,5-difluorobenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere and cool to 0 ° C. did. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 3,5-difluorobenzoyl chloride (16 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 62 Synthesis of 4-chloro-N- (3,4,5-trifluorobenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere. Cooled to ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 3,4,5-trifluorobenzoyl chloride (17 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 64 Synthesis of 4-chloro-N- (3,4,5-trimethoxybenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere. The mixture was cooled to ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 3,4,5-trimethoxybenzoyl chloride (30 mg, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 65 Synthesis of 4-chloro-N- (2-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 2-methoxybenzoyl chloride (17 microliters, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 66 Synthesis of 4-chloro-N- (3-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 3-methoxybenzoyl chloride (17 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 30 minutes. After 0 minutes, water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 68 Synthesis of 4-chloro-N- [3- (dimethylamino) benzoyl] deacetylcolchicine Under argon atmosphere, 3- (dimethylamino) benzoic acid (25 mg, 0.128 ⁇ 1.2 mmol) was converted to N, N-dimethylformamide (1 (mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 69 Synthesis of 4-chloro-N- [4- (dimethylamino) benzoyl] deacetylcolchicine Under argon atmosphere, 4-dimethylaminobenzoic acid (25 mg, 0.128 ⁇ 1.2 mmol) was added to N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 70 Synthesis of 4-chloro-N- (2-fluorobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 2-fluorobenzoyl chloride (15 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 72 Synthesis of 4-chloro-N- (2,4-difluorobenzoyl) deacetylcolchicine Under argon atmosphere, 2,4-difluorobenzoic acid (24 mg, 0.128 ⁇ 1.2 mmol) was added to N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 73 Synthesis of 4-chloro-N- (pyridin-3-yloxyacetyl) deacetylcolchicine Under argon atmosphere, pyridin-3-yloxyacetic acid (24 mg, 0.128 ⁇ 1.2 mmol) was mixed with N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Triethylamine (21 ⁇ l, 0.128 ⁇ 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol), 1-hydroxybenzotriazole monohydrate ( 21 mg, 0.128 ⁇ 1.2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes.
  • 4-chloro deacetyl colchicine 50 mg, 0.128 mol was added there, and it returned to room temperature, and stirred for 4 hours.
  • Triethylamine (21 ⁇ l, 0.128 ⁇ 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol), 1-hydroxybenzotriazole monohydrate ( 21 mg, 0.128 ⁇ 1.2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes.
  • 4-chloro deacetyl colchicine 50 mg, 0.128 mol was added there, and it returned to room temperature, and stirred for 4 hours.
  • Example 76 Synthesis of 4-chloro-N- (methoxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and methyl chloroformate (10 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 78 Synthesis of 4-chloro-N- (isopropyloxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and isopropyl chloroformate (15 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 79 Synthesis of 4-chloro-N- (isobutyloxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and isobutyl chloroformate (17 microliters, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 80 Synthesis of 4-chloro-N- (phenoxycarbonyl) deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 2 mL
  • Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol
  • phenyl chloroformate (16 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 2 hours.
  • Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 82 Synthesis of 4-chloro-N- (methanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 ⁇ l, 0.128 ⁇ 1.5 mmol) and methanesulfonyl chloride (12 ⁇ l, 0.128 ⁇ 1.2 mmol) were added thereto and stirred at 0 ° C. for 1 hour. The reaction solution was quenched by adding water and extracted with chloroform.
  • Example 83 Synthesis of 4-chloro-N- (ethanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (198 mg, 0.505 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0 ° C. Triethylamine (142 ⁇ l, 0.487 ⁇ 2 mmol) and ethanesulfonyl chloride (72 ⁇ l, 0.487 ⁇ 1.5 mmol) were added thereto, and the mixture was stirred overnight while raising the temperature to room temperature. The reaction solution was quenched by adding water and extracted with chloroform.
  • Example 84 Synthesis of 4-chloro-N- (isopropanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 ⁇ l, 0.128 ⁇ 1.5 mmol) and isopropanesulfonyl chloride (17 ⁇ l, 0.128 ⁇ 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 2 hours.
  • Example 85 Synthesis of 4-chloro-N- (cyclopropanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 ⁇ l, 0.128 ⁇ 1.5 mmol) and cyclopropanesulfonyl chloride (12 ⁇ l, 0.128 ⁇ 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 1 hour.
  • Example 86 Synthesis of 4-chloro-N- (isobutanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 ⁇ l, 0.128 ⁇ 1.5 mmol) and isobutanesulfonyl chloride (12 ⁇ l, 0.128 ⁇ 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 1 hour.
  • reaction solution was quenched by adding water, extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 30 mg, 0.056 mmol, 44%).
  • Example 88 Synthesis of 4-chloro-N- (p-toluenesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 ⁇ l, 0.128 ⁇ 1.5 mmol) and p-toluenesulfonyl chloride (29 mg, 0.128 ⁇ 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 2 hours. The reaction solution was quenched by adding water and extracted with chloroform.
  • Example 91 Synthesis of 4-chloro-N- (ethylcarbamoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in methanol-water (2: 1, 1.5 mL) under an argon atmosphere at 0 ° C. Cooled to. Ethyl isocyanate (20 ⁇ l, 0.128 ⁇ 2 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 75 minutes. The reaction solution was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Example 92 Synthesis of 4-chloro-N- (isopropylcarbamoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in methanol-water (2: 1, 1.5 mL) under an argon atmosphere at 0 ° C. Cooled to. The isopropyl isocyanate (25 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Example 94 Synthesis of 4-chloro-N- (phenylcarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (200 mg, 0.510 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0 ° C. The phenyl isocyanate (110 microliters, 0.510 * 2 mmol) was added there, and it stirred at 0 degreeC for 2 hours.
  • reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (brown solid, 168 mg, 0.329 mmol, 65%). .
  • Example 96 Synthesis of 4-chloro-N- (dimethylcarbamoyl) deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 2 mL
  • Triethylamine 26 ⁇ l, 0.128 ⁇ 1.5 mmol
  • dimethylcarbamoyl chloride 14 ⁇ l, 0.128 ⁇ 1.2 mmol
  • reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (red-brown solid, 19 mg, 0.033 mmol, 13%).
  • silica gel chromatography Biotage Isolera One, SNAP 10 g, methanol / chloroform
  • Example 102 Synthesis of 4-chloro-N- (dimethylaminoacetyl) deacetylcolchicine Under argon atmosphere, N, N-dimethylglycine (41 mg, 0.332 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (2 mL). Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (76 mg, 0.332 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (54 mg, 0.332 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 103 Synthesis of 4-chloro-N- (dimethylaminoacetyl) deacetylcolchicine hydrochloride Under ice-cooling, acetyl chloride (24 ml, 0.224 ⁇ 1.5 mmol) was added dropwise to methanol (2 mL), followed by stirring for 1 hour. A methanol solution (2 ml) of 4-chloro-N-dimethylaminoacetyl-deacetylcolchicine (107 mg, 0.224 mmol) was added dropwise thereto and stirred at 0 ° C. for 150 minutes. The reaction mixture was concentrated to dryness and dried in vacuo to give the title compound (tan solid, 106 mg, 0.206 mmol, 92%).
  • Example 104 Synthesis of 4-chloro-N- (diethylaminoacetyl) deacetylcolchicine Under argon atmosphere, N, N-diethylglycine (66.9 mg, 0.255 ⁇ 2 mmol) was dissolved in N, N-dimethylformamide (1.5 mL). Cooled to ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (98 mg, 0.255 ⁇ 2 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.255 ⁇ 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 109 Synthesis of 4-chloro-N- (3-carboxypropionyl) deacetylcolchicine 4-chlorodeacetylcolchicine (80 mg, 0.204 mmol) was dissolved in dimethyl sulfoxide (510 ⁇ l) under an argon atmosphere. N-methylmorpholine (88 microliters, 0.204 * 5 mmol) and succinic anhydride (24 mg, 0.204 * 1.1 mmol) were added there, and it stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous citric acid solution and saturated brine.
  • N-methylmorpholine 88 microliters, 0.204 * 5 mmol
  • succinic anhydride 24 mg, 0.204 * 1.1 mmol
  • Example 110 Synthesis of 4-chloro-N- [3- (methoxycarbonyl) propionyl] deacetylcolchicine Under an argon atmosphere, 4-chloro-N- (4-carboxypropionyl) -deacetylcolchicine (56 mg, 0.114 mmol) was dissolved in toluene (56 mg, 0.114 mmol). 2.3 mL). Methanol (570 ⁇ l, 5 ml / mmol) and trimethylsilyldiazomethane (949 ⁇ l, 0.096 ⁇ 5 mmol, 0.6 M hexane solution) were added thereto, and the mixture was stirred at room temperature for 1 hour.
  • Example 111 Synthesis of 4-chloro-N- (4-carboxybutyryl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (100 mg, 0.255 mmol) was dissolved in dimethyl sulfoxide (638 ⁇ l). Thereto were added N-methylmorpholine (110 ⁇ l, 0.225 ⁇ 5 mmol) and glutaric anhydride (32 mg, 0.255 ⁇ 1.1 mmol), and the mixture was stirred at room temperature for 40 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous citric acid solution and saturated brine.
  • N-methylmorpholine 110 ⁇ l, 0.225 ⁇ 5 mmol
  • glutaric anhydride 32 mg, 0.255 ⁇ 1.1 mmol
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 67 mg, 0.129 mmol, 75%).
  • Example 114 Synthesis of 4-chloro-N- (pyridin-3-yloxycarbonyl) deacetylcolchicine A solution of 3-hydroxypyridine (50 mg, 0.526 mmol) in dichloromethane (1.1 mL) under ice-cooling and pyridine ( 55 ⁇ L, 0.526 ⁇ 1.3 mmol) and triphosgene (156 mg, 0.526 mmol) were added, and the mixture was stirred under ice-cooling for 10 minutes and then at room temperature for 3 hours.
  • the reaction mixture was concentrated to dryness under reduced pressure, the residue obtained was dissolved in dichloromethane (2 mL), and pyridine (18.6 ⁇ L, 0.0766 ⁇ 3 mmol) and 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) were added. did.
  • the mixture was stirred overnight at room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added.
  • the organic layer was taken and the aqueous layer was further extracted with chloroform.
  • the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • Example 122 Synthesis of 4-chloro-N- (thiomorpholine-4-thiocarbonyl) deacetylcolchicine
  • the title compound (milky white solid, 27 mg, 0.0504 mmol, 66%).
  • Thiomorpholine was used in place of diethylamine.
  • Example 123 Synthesis of 4-chloro-N- (1,1-dioxothiomorpholine-4-thiocarbonyl) deacetylcolchicine
  • 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine the title (Milky white solid, 30 mg, 0.0522 mmol, 68%) was obtained.
  • Thiomorpholine 1,1-dioxide was used in place of diethylamine.
  • Example 129 Synthesis of 4-chloro-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine
  • 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 37 mg, 0.0766 mmol, quantitative) was obtained.
  • 3- (pyrrolidin-1-yl) benzoic acid 2-hydroxy-2-methylpropionic acid was used.
  • Example 130 Synthesis of 4-chloro-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine Similar method to the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine Gave the title compound (milky white solid, 39 mg, 0.0766 mmol, quantitative). Instead of 3- (pyrrolidin-1-yl) benzoic acid, 3-hydroxy-2,2-dimethylpropionic acid was used.
  • Example 132 Synthesis of 4-chloro-N- (1-acetylpiperidine-4-carbonyl) deacetylcolchicine
  • 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 27 mg, 0.0492 mmol, 64%) was obtained.
  • 3- (pyrrolidin-1-yl) benzoic acid 1-acetylpiperidine-4-carboxylic acid was used.
  • Example 133 Synthesis of 4-chloro-N- (1-benzoylpiperidine-4-carbonyl) deacetylcolchicine
  • 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 42 mg, 0.0684 mmol, 89%) was obtained.
  • 3- (pyrrolidin-1-yl) benzoic acid 1-benzoylpiperidine-4-carboxylic acid was used.
  • Example 135 4-Chloro-N- (piperidine-4-carbonyl) deacetylcolchicine Synthesis of trifluoroacetate 4-chloro-N- [1- (tert-butyloxycarbonyl) piperidine-4-carbonyl] deacetylcolchicine (30 mg , 0.0797 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (400 ⁇ L) under ice cooling, and the mixture was stirred under ice cooling for 5 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated to dryness, and ether and hexane were added to the residue and sonicated.
  • Example 136 Synthesis of 4-chloro-N- [3- (dimethylaminomethyl) benzoyl] deacetylcolchicine
  • 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 35 mg, 0.0638 mmol, 83%) was obtained.
  • 3- (pyrrolidin-1-yl) benzoic acid 3- (dimethylaminomethyl) benzoic acid hydrochloride was used.
  • the aqueous layer was extracted again with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was sonicated with ethyl acetate (10 mL), hexane (10 mL) was added, and the mixture was allowed to stand overnight at room temperature. The precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to obtain the title compound (white solid, 1.15 g, 3.47 mmol, 92%).
  • Example 137 Synthesis of 4-chloro-N- [3- (triphenylmethyloxy) propionyl] deacetylcolchicine
  • 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 118 mg, 0.168 mmol, 94%) was obtained.
  • 3- (pyrrolidin-1-yl) benzoic acid 3- (triphenylmethyloxy) propionic acid was used.
  • Example 138 Synthesis of 4-chloro-N- (3-hydroxypropionyl) deacetylcolchicine 4-chloro-N- [3- (triphenylmethyloxy) propionyl] deacetylcolchicine (95 mg, 0.135 mmol) in methanol (0.5 mL) To the solution, p-toluenesulfonic acid monohydrate (5 mg, 0.135 ⁇ 0.2 mmol) was added at room temperature and stirred for 5 hours. The reaction solution was concentrated to dryness and purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 54 mg, 0.116 mmol, 86%). .
  • Example 139 Synthesis of 4-chloro-N- (methanesulfonylacetyl) deacetylcolchicine Methanesulfonylacetic acid (21 mg, 0.128 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL) under an argon atmosphere, and the solution was brought to 0 ° C. Cooled down. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 140 Synthesis of 4-chloro-N- [3- (dimethylamino) propionyl] deacetylcolchicine Under argon atmosphere, 3-dimethylaminopropionate hydrochloride (39 mg, 0.128 ⁇ 2 mmol) was converted to N, N-dimethylformamide (1 (mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 ⁇ 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 ⁇ 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 141 Synthesis of 4-chloro-N- [3- (diethylamino) propionyl] deacetylcolchicine Under argon atmosphere, 3-diethylaminopropionate hydrochloride (47 mg, 0.128 ⁇ 2 mmol) was added to N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 ⁇ 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 ⁇ 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 142 Synthesis of 4-chloro-N- (3-piperidinopropionyl) deacetylcolchicine Dissolve 1-piperidinepropionic acid (40 mg, 0.128 ⁇ 2 mmol) in N, N-dimethylformamide (1 mL) under argon atmosphere And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 ⁇ 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 ⁇ 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 145 Synthesis of 4-chloro-N- (1-methylpiperidin-4-ylcarbonyl) deacetylcolchicine Under argon atmosphere, 1-methylpiperidine-4-carboxylic acid hydrochloride (46 mg, 0.128 ⁇ 2 mmol) was converted to N, N Dissolved in 1-dimethylformamide (1 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 ⁇ 2 mmol), 1-hydroxybenzo Triazole monohydrate (35 mg, 0.128 ⁇ 2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 min.
  • the chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 16 mg, 0.035 mmol, 65%).
  • the chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 21 mg, quantitative).
  • Example 149 Synthesis of 4-chloro-N- [4- (dimethylamino) butyryl] deacetylcolchicine Under argon atmosphere, 4-dimethylaminobutyric acid hydrochloride (43 mg, 0.128 ⁇ 2 mmol) was added to N, N-dimethylformamide (1 mL ) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 ⁇ 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 ⁇ 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 150 Synthesis of 4-chloro-N- [2- (dimethylamino) benzoyl] deacetylcolchicine Under argon atmosphere, 2- (dimethylamino) benzoic acid (25 mg, 0.128 ⁇ 1.2 mmol) was converted to N, N-dimethylformamide (1 (mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 151 Synthesis of 4-chloro-N- (isobutylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. Thereto was added isobutyl isothiocyanate (31 ⁇ l, 0.128 ⁇ 2 mmol), and the mixture was stirred for 4 hours while warming to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 26 mg, 0.051 mmol, 40%).
  • Example 152 Synthesis of N- (benzylthiocarbamoyl) -4-chlorodeacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. Thereto was added benzyl isothiocyanate (34 ⁇ l, 0.128 ⁇ 2 mmol), and the mixture was stirred for 4 hours while warming to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Example 153 Synthesis of 4-chloro-N- (cyclohexylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. The cyclohexyl isothiocyanate (35 microliters, 0.128 * 2 mmol) was added there, and it returned to room temperature, and stirred for 6 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 26 mg, 0.049 mmol, 38%).
  • Example 154 Synthesis of 4-chloro-N-[(2-piperidinoethyl) thiocarbamoyl] deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 1 mL
  • 2-piperidinoethyl isothiocyanate 42 ⁇ l, 0.128 ⁇ 2 mmol
  • a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 33 mg, 0.059 mmol, 46%).
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 35 mg, 0.062 mmol, 49%).
  • Example 156 Synthesis of 4-chloro-N- (3-pyridylthiocarbamoyl) deacetylcolchicine
  • 4-chlorodeacetylcolchicine 50 mg, 0.128 mmol
  • dichloromethane 1 mL
  • 3-pyridyl isothiocyanate 29 ⁇ l, 0.128 ⁇ 2 mmol
  • a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Example 158 Synthesis of 4-chloro-N- (4-nitrobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 4-nitrobenzoyl chloride (24 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 159 Synthesis of 4-chloro-N- (2-naphthoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 2-naphthoyl chloride (24 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 160 Synthesis of 4-chloro-N- (2-nitrobenzoyl) deacetylcolchicine Dissolve 2-nitrobenzoic acid (26 mg, 0.128 ⁇ 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere. Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 161 Synthesis of 4-chloro-N- (4-methylbenzoyl) deacetylcolchicine Under argon atmosphere, p-toluic acid (21 mg, 0.128 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL). Cooled to ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 162 Synthesis of 4-chloro-N- (4-phenylbenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 4-phenyl benzoyl chloride (28 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 163 Synthesis of 4-chloro-N- (3,5-dinitrobenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere and cool to 0 ° C. did. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 3,5-dinitrobenzoyl chloride (30 mg, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 165 Synthesis of 4-chloro-N- (3-nitrobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 3-nitrobenzoyl chloride (27 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 168 Synthesis of 4-chloro-N- (2,4,6-trimethylbenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere at 0 ° C. Cooled to. Triethylamine (19 ⁇ l, 0.128 ⁇ 1.1 mmol) and 2,4,6-trimethylbenzoyl chloride (21 ⁇ l, 0.128 ⁇ 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 90 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • Example 170 Synthesis of 4-chloro-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine Under argon atmosphere, ⁇ -hydroxyisovaleric acid (16 ⁇ l, 0.128 ⁇ 1.2 mmol) was added to N, N-dimethylformamide (1 mL). And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 171 Synthesis of 4-chloro-N- [4- (benzyloxy) butyryl] deacetylcolchicine Under argon atmosphere, 4-benzyloxybutyric acid (27 ⁇ l, 0.128 ⁇ 1.2 mmol) was added to N, N-dimethylformamide (1 mL). Dissolved and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 172 Synthesis of 4-chloro-N- (2-cyanobenzoyl) deacetylcolchicine Dissolve 2-cyanobenzoic acid (23 mg, 0.128 ⁇ 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere. Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 175 Synthesis of 4-chloro-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine 1-hydroxy-1-cyclopropanecarboxylic acid (16 mg, 0.128 ⁇ 1.2 mmol) was converted to N, N-dimethylformamide ( 1 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • Example 176 Synthesis of 4-chloro-N- (3-phenylbenzoyl) deacetylcolchicine Under argon atmosphere, 3-biphenylcarboxylic acid (30 mg, 0.128 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL). Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 ⁇ 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 14 mg, 0.029 mmol, 41%).
  • Example 178 Synthesis of 4-bromo-N- (t-butyloxycarbonyl) colchicine 4-Bromocolchicine (363 mg, 0.76 mmol) was dissolved in acetonitrile (18 mL). Dimethylaminopyridine (93 mg, 0.76 ⁇ 1 mmol), triethylamine (0.318 mL, 0.76 ⁇ 3 mmol), dicarbonate-di-t-butyl (0.873 mL, 0.76 ⁇ 5 mmol) were added thereto, and the mixture was heated under reflux for 7 hours. did. After the reaction, an aqueous citric acid solution was added. Extracted with chloroform. Washed with saturated brine. Dried over anhydrous magnesium sulfate.
  • Example 180 Synthesis of 4-bromodeacetylcolchicine
  • 4-trifluoro-N- (t-butyloxycarbonyl) deacetylcolchicine (251 mg, 0.47 mmol) to trifluoroacetic acid (0.663 mL, 0.47 ⁇ 19 mmol)
  • trifluoroacetic acid 0.63 mL, 0.47 ⁇ 19 mmol
  • Example 181 Synthesis of 4-bromo-N-propionyl deacetyl colchicine 4-Bromo deacetyl colchicine (37 mg, 0.084 mmol) was dissolved in dichloromethane (1.0 mL). Propionyl chloride (0.009 mL, 0.084 ⁇ 1.2 mmol) and triethylamine (0.018 mL, 0.084 ⁇ 1.5 mmol) were added thereto and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (white solid, 40 mg, 96.7%).
  • Example 191 Synthesis of 4-bromo-N-[(methylthio) acetyl] deacetylcolchicine 4-Bromodeacetylcolchicine (126 mg, 0.29 mmol) was dissolved in N, N-dimethylformamide (2.5 mL) and cooled on ice. Methylthioacetic acid (0.030 mL, 0.29 ⁇ 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (67 mg, 0.29 ⁇ 1.2 mmol), 1-hydroxybenzotriazole monohydrate (47 mg, 0.29 ⁇ 1.2 mmol) was added and stirred at room temperature for 2 hours.
  • N, N-dimethylaminoacetic acid 35 mg, 0.28 ⁇ 1.2 mmol
  • 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride 65 mg, 0.28 ⁇ 1.2 mmol
  • 1-hydroxybenzo Triazole monohydrate 46 mg, 0.28 ⁇ 1.2 mmol
  • the product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off.
  • Example 196 Synthesis of 4-bromo-N- (hydroxyacetyl) deacetylcolchicine N- (acetoxyacetyl) -4-bromodeacetylcolchicine (58 mg, 0.11 mmol) was dissolved in methanol (1.2 mL) and dichloromethane (1.2 mL) . Sodium methoxide (12 mg, 0.11 ⁇ 2 mmol) was added thereto and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 31 mg, 57.0%).
  • Example 200 Synthesis of 4-bromo-N- (2,4-difluorobenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (62 mg, 0.14 mmol) was dissolved in N, N-dimethylformamide (1.3 mL) and ice-cooled. . 2,4-difluorobenzoic acid (27 mg, 0.14 ⁇ 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol), 1-hydroxybenzo Triazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) was added and stirred overnight at room temperature.
  • Example 205 Synthesis of 4-bromo-N- (phenylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (68 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). The phenyl isothiocyanate (0.038 mL, 0.16 * 2 mmol) was added there, and it stirred at room temperature for 5 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 97 mg, quant.).
  • Example 206 Synthesis of 4-bromo-N- (N ′, N′-diethylcarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (113 mg, 0.26 mmol) was dissolved in 1,2-dichloroethane (2.2 mL). Diethylcarbamoyl chloride (0.049 mL, 0.26 ⁇ 1.5 mmol) and triethylamine (0.072 mL, 0.26 ⁇ 2 mmol) were added thereto, and the mixture was heated to reflux for 3 hours. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off.
  • Example 208 Synthesis of 4-bromo-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine Hydroxypivalic acid (20 mg, 0.14 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (0.4 mL) . Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight.
  • Example 209 Synthesis of 4-bromo-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine 2-Hydroxyisobutyric acid (18 mg, 0.14 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (0.4 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight.
  • Example 210 Synthesis of 4-bromo-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine 2-ethyl-2-hydroxybutyric acid (23 mg, 0.14 ⁇ 1.2 mmol) in N, N-dimethylformamide (0.4 mL) Dissolved in. Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) at room temperature. Stir for 30 minutes.
  • Example 211 Synthesis of 4-bromo-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine 1-hydroxy-1-cyclopropanecarboxylic acid (17 mg, 0.14 ⁇ 1.2 mmol) was added to N, N-dimethylformamide (0.4 mL). Dissolved. Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) at room temperature. Stir for 1 hour.
  • Example 212 Synthesis of 4-bromo-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine (0.4 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) at room temperature. Stir for 1 hour. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off.
  • the product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 74 mg, 95.6%).
  • Example 213 Synthesis of 4-bromo-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine ⁇ -hydroxyisovaleric acid (41 mg, 0.29 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (0.8 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (67 mg, 0.29 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (47 mg, 0.29 ⁇ 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (127 mg, 0.29 mmol) was added there, and it stirred at room temperature overnight.
  • Example 214 Synthesis of 4-bromo-N- [4- (benzyloxy) butyryl] deacetylcolchicine 4-Benzyloxybutyric acid (0.060 mL, 0.28 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (1.2 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (65 mg, 0.28 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (46 mg, 0.28 ⁇ 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (124 mg, 0.28 mmol) was added there, and it stirred at room temperature overnight.
  • Example 218 Synthesis of 4-bromo-N- (4-methylbenzoyl) deacetylcolchicine p-Toluic acid (23 mg, 0.14 ⁇ 1.2 mmol) was dissolved in N, N-dimethylformamide (0.4 mL). 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 ⁇ 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 ⁇ 1.2 mmol) were added thereto. Stir at room temperature for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight.
  • Example 220 Synthesis of 4-bromo-N- (isobutylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (62 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). The isobutyl isothiocyanate (32 mg, 0.14 * 2 mmol) was added there, and it stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (BiotageIsolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 33 mg, 42.7%).
  • Example 231 Synthesis of 4-bromo-N- (morpholin-4-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (60 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL) and cooled on ice. Thiophosgene (0.011 mL, 0.14 ⁇ 1.05 mmol) and triethylamine (0.047 mL, 0.14 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred for 2 hours under ice cooling. Morpholine (0.024 mL, 0.14 ⁇ 2 mmol) was added thereto and stirred at room temperature overnight.
  • Example 234 Synthesis of 4-chloro-2,3- (methylenedioxy) -2,3-didemethoxycolchicine 4-chloro-2,3-didemethylcolchicine (51 mg, 0.126 mmol) was dissolved in acetonitrile (1.5 mL) . Potassium carbonate (35 mg, 0.126 ⁇ 2 mmol) and bromochloromethane (0.016 mL, 0.126 ⁇ 2 mmol) were added thereto, and the mixture was heated to reflux for 7 hours.
  • Example 238 Synthesis of 4-chloro-1,2- (methylenedioxy) -1,2-didemethoxycolchicine 1,2- (methylenedioxy) -1,2-didemethoxycolchicine (23 mg, 0.0599 mmol) in acetonitrile ( 0.5 mL). N-chlorosuccinimide (10 mg, 0.749 mmol) was added thereto, and the mixture was stirred at room temperature for 2 days. The title compound (yellow solid, 11 mg, 43.9%) was obtained using a preparative LC system with an MS trigger manufactured by Waters.
  • Example 239 Synthesis of 4-chloro-N- (ethylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in methanol-water (2: 1, 1.5 mL). Cooled to ° C. The ethyl isothiocyanate (22 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Example 240 Synthesis of 4-chloro-N- (phenylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in methanol-water (2: 1, 1.5 mL). Cooled to ° C. The phenyl isothiocyanate (30 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • Example 241 Synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine 4-chloro-N- (hydroxyacetyl) deacetylcolchicine (0.107 g, 0.238 mmol) in dichloromethane (for organic synthesis) , 5 mL) solution under ice-cooling and argon gas atmosphere, 4-dimethylaminopyridine (12 mg, 0.238 ⁇ 0.4 mmol), triethylamine (82.9 ⁇ L, 0.238 ⁇ 2.5 mmol) and 4-piperidinopiperidine- 1-Carbonyl chloride (0.121 g, 0.238 ⁇ 2.2 mmol) was added.
  • Example 243 Synthesis of 4-chloro-N- (1-methylpiperazine-4-carboxyacetyl) deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine Gave the title compound (milky solid, 25 mg, 0.043 mmol, 61%). Instead of 4-piperidinopiperidine-1-carbonyl chloride, 1-methylpiperazine-4-carbonyl chloride hydrochloride (8.8 eq.) And triethylamine (19 eq.) Were used.
  • Example 245 Synthesis of 4-chloro-N- [3- (dimethylamino) propionyloxyacetyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine Gave the title compound (milky white solid, 33 mg). N, N-dimethylhomoglycine was used instead of 4-piperidinopiperidine-1-carbonyl chloride. ESI-MS m / z: 549 [M + H] + .
  • the reaction was diluted with chloroform and brine and the organic layer was taken.
  • the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • the residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 72 mg, 0.104 mmol, 94%).
  • the obtained residue was purified by silica gel flash column chromatography (5% methanol / ethyl acetate ⁇ 10% methanol / ethyl acetate), and the desired 4-chloro-N- (thioacetoxyacetyl) deacetylcolchicine (55.8 mg , 98%).
  • Example 249 Synthesis of 4-chloro-N- [1- (ethoxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine 1- (ethoxycarbonyl) piperidine-4-carboxylic acid (17 mg, 0.0766 ⁇ 1.1 mmol) in dichloromethane (2 1) -ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (16 mg, 0.0766 ⁇ 1.1 mmol) and 1-hydroxybenzotriazole monohydrate under ice-cooling and argon gas atmosphere (13 mg, 0.0766 ⁇ 1.1 mmol) was added and stirred for 30 minutes.
  • Example 251 Synthesis of 4- (difluoromethyl) colchicine
  • N-iodosuccinimide 87 mg, 0.0966 ⁇ 4 mmol
  • dichloromethane 5 mL
  • hydrogen fluoride / pyridine (HF: 65%, 119 mg, 0.0966 ⁇ 40 mmol) in dichloromethane (1 mL) was added.
  • a solution of 4-([1,3] dithian-2-yl) colchicine 50 mg, 0.0966 mmol) in dichloromethane (1 mL) was added, and the temperature was gradually returned to room temperature. Stir overnight.
  • Example 252 Synthesis of 4-chloro-N- (N ', N'-dimethylthiocarbamoyl) deacetylcolchicine
  • 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (pale yellow solid, 37 mg, 0.0766 mmol, quantitative) was obtained. Instead of diethylamine, dimethylamine hydrochloride and triethylamine were used.
  • Example 254 Synthesis of 4-chloro-N- [N'-ethyl-N'-propylthiocarbamoyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (milky white solid, 40 mg, 0.0766 mmol, quantitative). N-ethyl-n-propylamine was used in place of diethylamine.
  • Example 255 Synthesis of 4-chloro-N-[(4-hydroxypiperidin-1-yl) thiocarbonyl] deacetylcolchicine Similar to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine By the method, the title compound (milky white solid, 41 mg, 0.0766 mmol, quantitative) was obtained. Instead of diethylamine, 4-hydroxypiperidine was used.
  • Example 256 Synthesis of 4-chloro-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine Similar to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine By the method, the title compound (pale yellow solid, 41 mg, 0.0766 mmol, quantitative) was obtained. 4-methylpiperidine was used instead of diethylamine.
  • Example 257 Synthesis of 4-chloro-N- ⁇ N '-[2- (dimethylamino) ethyl] -N'-methylthiocarbamoyl ⁇ deacetylcolchicine 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetyl
  • the title compound (milky white solid, 38 mg, 0.0710 mmol, 93%) was obtained by a method similar to the synthesis of colchicine. Instead of diethylamine, N, N, N′-trimethylethylenediamine was used.
  • Example 258 Synthesis of 4-chloro-N- ⁇ [4- (dimethylamino) piperidin-1-yl] thiocarbamoyl ⁇ deacetylcolchicine Synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine In the same manner, the title compound (milky white solid, 28 mg, 0.0499 mmol, 65%) was obtained. 4- (Dimethylamino) piperidine was used in place of diethylamine.
  • Example 259 Synthesis of 4-chloro-N- (N'-ethyl-N'-methylthiocarbamoyl) deacetylcolchicine The same method as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine To give the title compound (pale yellow solid, 37 mg, 0.0746 mmol, 97%). Instead of diethylamine, N-ethylmethylamine was used.
  • Example 260 Synthesis of 4-chloro-N- [1-acetylpiperazin-4-yl) thiocarbonyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (milky solid, 32 mg, 0.0570 mmol, 74%). 1-acetylpiperazine was used in place of diethylamine.
  • Example 266 Synthesis of N-[(azetidin-1-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine
  • the title compound (milky white solid, 7 mg, 0.0138 mmol, 18%) was obtained.
  • diethylamine azetidine was used. Purification was performed by high performance liquid chromatography.
  • Example 268 Synthesis of 4-chloro-N-[(cis-2,6-dimethylmorpholin-4-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (pale yellow solid, 42 mg, 0.0766 mmol, quantitative) was obtained in the same manner as in the synthesis. Cis-2,6-dimethylmorpholine was used in place of diethylamine.
  • Example 272 Synthesis of 4-chloro-N- [4- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (milky white solid, 37 mg, 0.0644 mmol, 84%). Instead of diethylamine, 2- (4-aminophenyl) ethanol was used.
  • Example 274 Synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine
  • 4-cyanoaniline 14 mg, 0.0766 ⁇ 1.5 mmol
  • dichloromethane 1.5 mL
  • thiophosgene 8.75 ⁇ L, 0.0766 ⁇ 1.5 mmol
  • triethylamine 32.0 ⁇ L, 0.0766 ⁇ 3 mmol
  • Example 276 Synthesis of 4-chloro-N-[(2-methoxyphenyl) thiocarbamoyl] deacetylcolchicine
  • the title (Milky white solid, 14 mg, 0.0253 mmol, 33%) was obtained.
  • 4-cyanoaniline o-anisidine was used.
  • Example 278 Synthesis of 4-chloro-N-[(3-cyanophenyl) thiocarbamoyl] deacetylcolchicine
  • the title (Light brown solid, 42 mg, 0.0766 mmol, quantitative) was obtained.
  • 4-cyanoaniline 3-cyanoaniline was used.
  • Example 280 Synthesis of 4-chloro-N-[(2-chlorophenyl) thiocarbamoyl] deacetylcolchicine
  • the title The compound (milky white solid, 36 mg, 0.0536 mmol, 70%) was obtained.
  • 4-cyanoaniline 2-chloroaniline was used.
  • Example 281 Synthesis of 4-chloro-N-[(3-chlorophenyl) thiocarbamoyl] deacetylcolchicine
  • the title The compound (milky white solid, 40 mg, 0.0712 mmol, 93%) was obtained.
  • 4-cyanoaniline 3-chloroaniline was used.
  • Example 283 Synthesis of 4-chloro-N-[(2-cyanophenyl) thiocarbamoyl] deacetylcolchicine
  • 2-cyanoaniline 14 mg, 0.0766 ⁇ 1.5 mmol
  • dichloromethane-water 1: 1, 3 mL
  • thiophosgene 8.75 ⁇ L, 0.0766 ⁇ 1.5 mmol
  • To the reaction solution was added 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) in dichloromethane (0.5 mL) and sodium carbonate (12 mg, 0.0766 ⁇ 1.5 mmol) in water (0.5 mL). For 40 minutes.
  • Example 284 Synthesis of 4-chloro-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine
  • Imidazole-1-thiocarboxylic acid thiazol-2-ylamide (18 mg, 0.0766 ⁇ 1.1 mmol) was added and boiled under reflux for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and 10% aqueous sodium hydrogensulfate solution were added, and the organic layer was taken.
  • Example 286 Synthesis of 4-chloro-N- (methylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (63 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours.
  • Methylamine hydrochloride 22 mg, 0.16 ⁇ 2 mmol
  • triethylamine 0.045 mL, 0.16 ⁇ 2 mmol
  • the solvent was distilled off.
  • the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 58 mg, 77.9%).
  • Example 294 Synthesis of 4-chloro-N- [2- (dimethylamino) ethylthiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Dimethylaminoethylamine (0.035 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature.
  • Example 300 Synthesis of 4-chloro-N-[(1-methylpiperidin-4-yl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. 4-amino-1-methylpiperidine (37 mg, 0.16 ⁇ 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off.
  • Example 301 Synthesis of 4-chloro-N- (cycloheptylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Cycloheptylamine (0.041 mL, 0.16 ⁇ 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off.
  • Example 302 Synthesis of 4-chloro-N-[(2-methoxyethyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Methoxyethylamine (0.028 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature.
  • Example 303 Synthesis of 4-chloro-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2,2,2-trifluoroethylamine (0.025 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature.
  • Example 304 Synthesis of 4-chloro-N-[(indan-2-yl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2-Aminoindane (0.042 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off.
  • Example 306 Synthesis of 4-chloro-N-[(3,5-dimethylisoxazol-4-yl) thiocarbamoyl] deacetylcolchicine 4-amino-3,5-dimethyloxazole (27 mg, 0.16 ⁇ 1.5 mmol) was added to dichloromethane ( 1 mL). Thiophosgene (0.018 mL, 0.16 ⁇ 1.5 mmol) and triethylamine (0.067 mL, 0.16 ⁇ 3 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. 4-chloro deacetyl colchicine (62 mg, 0.16 mmol) was added there, and it stirred at room temperature overnight.
  • Example 307 Synthesis of 4-chloro-N-[(4-hydroxyphenyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. P-hydroxy aniline (35 mg, 0.16 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off.
  • Example 308 Synthesis of 4-chloro-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine Dissolve 3-amino-5-methylpyrazole (23 mg, 0.16 ⁇ 1.5 mmol) in dichloromethane (1 mL) did. Thiophosgene (0.018 mL, 0.16 ⁇ 1.5 mmol) and triethylamine (0.067 mL, 0.16 ⁇ 3 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 4-chloro deacetyl colchicine (62 mg, 0.16 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off.
  • Example 311 Synthesis of 4-bromo-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2,2,2-trifluoroethylamine (0.025 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature.
  • Example 315 Synthesis of 4-bromo-N- ⁇ [2- (4-morpholino) ethyl] thiocarbamoyl ⁇ deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2- (4-morpholino) ethylamine (0.042 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature.
  • Example 316 Synthesis of 4-bromo-N- (N ′, N′-dimethylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour.
  • Example 317 Synthesis of 4-bromo-N- (N′-ethyl-N′-methylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 ⁇ 1.05 mmol) and triethylamine (0.054 mL, 0.16 ⁇ 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Ethylmethylamine (0.027 mL, 0.16 ⁇ 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off.
  • Example 320 Synthesis of 4-chloro-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine 3-isothiocyanate-5methylisoxazole (32 mg, 0.19 ⁇ 1.2 mmol) was dissolved in dichloromethane. 4-chloro deacetyl colchicine (75 mg, 0.19 mmol) and triethylamine (0.04 mL, 0.19 ⁇ 1.5 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off.
  • Example 321 Synthesis of 4-chloro-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chlorodeacetylcolchicine (61 mg, 0.156 mmol) in DMF (2 mL ). Thereto was added imidazole-1-carbothioic acid (5-methyl-1,2,4-triazol-3-yl) -amide (36 mg, 0.156 ⁇ 1.1 mmol), and the mixture was stirred at 60 ° C. for 2 hours. After the reaction, the solvent was distilled off. Ethyl acetate was added and washed with saturated aqueous sodium hydrogen carbonate and saturated brine.
  • Example 323 Synthesis of 4-chloro-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7- (isothiocyanate deacetylamido) colchicine (72 mg, 0.166 mmol) Dissolved in DMF (1 mL). 3-amino-1,2,4-triazole (17 mg, 0.166 ⁇ 1.2 mmol) was added thereto, and the mixture was stirred at 80 ° C. for 1 hour. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off.
  • Example 325 Synthesis of 4-chloro-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7- (isothiocyanate deacetylamido) colchicine (77 mg, 0.178 mmol) was converted to DMF (1 mL). 3-amino-4-cyanopyrazole (23 mg, 0.178 ⁇ 1.2 mmol) was added thereto, and the mixture was stirred at 80 ° C. for 4 hours. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 100 g, methanol / chloroform) to obtain the title compound (yellow solid, 4.10 g, 7.80 mmol, 70%).
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 100 g, methanol / chloroform) to obtain the title compound (brown solid, 3.42 g, 5.47 mmol, 70%).
  • Example 329 Synthesis of 4-iododeacetylcolchicine N- (t-butyloxycarbonyl) -4-iododeacetylcolchicine (515 mg, 0.883 mmol) was dissolved in trifluoroacetic acid (1.3 mL) under an argon atmosphere, and 3 Stir for hours. The reaction mixture was cooled to 0 ° C., basified with 1N aqueous sodium hydroxide solution, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 355 mg, 0.735 mmol, 83%).
  • Example 330 Synthesis of 4-iodo-N-propionyl deacetyl colchicine Under an argon atmosphere, 4-iodo deacetyl colchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 ⁇ l, 0.103 ⁇ 1.1 mmol) and propionyl chloride (9 ⁇ l, 0.103 ⁇ 1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 41 mg, 0.076 mmol, 74%).
  • Example 331 Synthesis of N-cyclopropylcarbonyl-4-iododeacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 ⁇ l, 0.103 ⁇ 1.1 mmol) and cyclopropanecarbonyl chloride (9 ⁇ l, 0.103 ⁇ 1.1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour.
  • Example 332 Synthesis of 4-iodo-N- (trifluoroacetyl) deacetylcolchicine
  • 4-iododeacetylcolchicine 50 mg, 0.103 mmol
  • dichloromethane 2 mL
  • Trifluoroacetic anhydride 29 microliters, 0.103 * 2 mmol
  • Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
  • the obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 52 mg, 0.090 mmol, 87%).
  • Example 335 Synthesis of 4-iodo-N- (4-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 ⁇ l, 0.103 ⁇ 1.1 mmol) and 4-methoxybenzoyl chloride (18 mg, 0.103 ⁇ 1 mmol) were added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 3 hours. Water was added to the reaction solution to quench, 0.1 N hydrochloric acid was added, and the mixture was extracted with chloroform.
  • the chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated.
  • the obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 46 mg, 0.075 mmol, 72%).

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Abstract

Provided are 4-modified colchicine compounds and medicines using the same. Specifically provided are colchicine derivatives represented by general formula (1), salts thereof, and solvates of the same. In general formula (1), R1 is a halogen atom, a hydroxyl group, a nitro group, an amino group, or a mono-, di- or tri-fluoromethyl group; R2, R3 and R4 are each a methoxy group or a hydroxyl group, or alternatively R2 and R3, or R3 and R4 together represent a methylenedioxy group; R5 and R6 may be the same or different and are each a hydrogen atom, a C1-6 alkyl group, an arylalkyl group, a C2-6 alkenyl group, -COR7, -COOR8, -SO2R9, -CONR10R11, or -CSNR12R13, or alternatively R5 and R6 together with the nitrogen atom to which R5 and R6 are bonded may form a three- to seven-membered cyclic amino group; R7 is a C1-6 alkyl group or the like; R8 is a C1-6 alkyl group or the like; R9 is a C1-6 alkyl group or the like; R10 and R11 may be the same or different and are each a hydrogen atom, a C1-6 alkyl group, or the like; and R12 and R13 may be the same or different and are each a hydrogen atom, an alkyl group, or the like.

Description

コルヒチン誘導体Colchicine derivatives
　本発明は、抗癌剤等の医薬として有用なコルヒチン誘導体及びこれを含有する医薬に関する。 The present invention relates to a colchicine derivative useful as a medicament such as an anticancer agent and a medicament containing the same.
　コルヒチンは、トロポロン環を有するイソキノリンアルカロイドの一種であり、ユリ科イヌサフランの種子や球根に多く含まれており、古くから痛風の治療薬として用いられてきた。コルヒチンは、チューブリンに結合することにより細胞分裂を抑制する作用を有することが見出され、当該チューブリンは細胞骨格として細胞の構造を維持するだけでなく、シグナル伝達における輸送路としても作用し、細胞分裂において紡錘体を形成する機能を有する。従って、コルヒチンは、ビンブラスチンやタキソールと同様に抗癌剤として有用であるとして注目された。しかし、コルヒチンは正常細胞の分裂も抑制してしまうため、実用化には至っていない。 Colchicine is a kind of isoquinoline alkaloid having a tropolone ring, and is abundant in seeds and bulbs of Lily family saffron and has long been used as a therapeutic agent for gout. Colchicine was found to inhibit cell division by binding to tubulin, which not only maintains the structure of the cell as a cytoskeleton, but also acts as a transport pathway in signal transduction. In addition, it has a function of forming a spindle in cell division. Therefore, colchicine has attracted attention as being useful as an anticancer agent, like vinblastine and taxol. However, since colchicine also suppresses the division of normal cells, it has not been put into practical use.
　コルヒチンをリード化合物として種々の誘導体が合成され、その生物活性に関する報告がなされている。その中で、コルヒチンは、Ａ環とＣ環を介してチューブリンと相互作用することが明らかとなり、Ａ環やＣ環の置換基の修飾やＣ環をベンゼン環に変えた化合物などが合成されている（非特許文献１～８）。 Various derivatives have been synthesized using colchicine as a lead compound, and reports on their biological activity have been made. Among them, colchicine has been shown to interact with tubulin via the A and C rings, and compounds such as modification of substituents on the A and C rings and changes of the C ring to benzene rings have been synthesized. (Non-Patent Documents 1 to 8).
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　近年では、Ｂ環部分がチューブリンへの不可逆的な結合に関与しているのではないかと考えられるようになり、Ｂ環側鎖を変換したコルヒチン誘導体も注目を集めている（非特許文献９、１０）。 In recent years, it has been considered that the B ring portion may be involved in irreversible binding to tubulin, and colchicine derivatives obtained by converting the B ring side chain are also attracting attention (Non-Patent Document 9). 10).
　しかしながら、従来のコルヒチンのＡ環部分の修飾は、そのほとんどが、１～３位のメトキシ基の変換であり、４位への修飾はほとんど行われていなかった。
　従って、本発明の課題は、コルヒチンの４位修飾化合物及びこれを用いた医薬を提供することにある。 However, most of the conventional modifications of the A-ring portion of colchicine are conversion of the methoxy group at the 1 to 3 position, and the modification to the 4 position has hardly been performed.
Therefore, the subject of this invention is providing the 4-position modification compound of colchicine, and a pharmaceutical using the same.
　そこで、本発明者は、コルヒチンのＡ環の４位にハロゲン原子等の置換基を導入し、かつＢ環の側鎖を変換したところ、優れた抗癌活性を有し、かつ毒性が低い化合物が得られ、当該化合物は抗癌剤等の医薬として有用であることを見出し、本発明を完成した。 Accordingly, the present inventor has introduced a substituent such as a halogen atom at the 4-position of the A ring of colchicine and converted the side chain of the B ring, and has excellent anticancer activity and low toxicity. And the present compound was found to be useful as a pharmaceutical agent such as an anticancer agent.
　すなわち、本発明は、次の一般式（１） That is, the present invention provides the following general formula (1)
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
（式中、Ｒ1はハロゲン原子、ヒドロキシ基、ニトロ基、アミノ基又はモノ－、ジ－若しくはトリ－フルオロメチル基を示し；
Ｒ2、Ｒ3及びＲ4はそれぞれメトキシ基、又はヒドロキシ基を示すか、Ｒ2とＲ3又はＲ3とＲ4が一緒になってメチレンジオキシ基、又はエチレンジオキシ基を示し；
Ｒ5及びＲ6は同一又は異なって、水素原子、炭素数１～６のアルキル基、アリールアルキル基、炭素数２～６のアルケニル基、－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9、－ＣＯＮＲ10Ｒ11又は－ＣＳＮＲ12Ｒ13を示すか、Ｒ5とＲ6が結合する窒素原子と一緒になって３～７員の環状アミノ基を示し；
Ｒ7は水素原子、炭素数６～１４のアリール基、ヘテロアリール基、環状アミノ基、炭素数３～７の環状アルキル基又は炭素数１～６のアルキル基を示し、当該アルキル基には環状アルキル基、ハロゲン原子、アミノ基、アルキルアミノ基、アリールアルキルアミノ基、ジアルキルアミノ基、環状アミノ基、アルコキシカルボニルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、カルボキシル基、アルコキシカルボニル基、ヒドロキシ基、アシルオキシ基、ジアルキルアミノアシルオキシ基、アルキルオキシ基、アリール基、アリールオキシ基、アリールアルキルオキシ基、ヘテロアリール基、ヘテロアリールオキシ基、チオール基、アシルチオ基、ジアルキルアミノアシルチオ基、アルキルチオ基、アルキルスルホニル基、アリールチオ基、ヘテロアリールチオ基、カルバモイルオキシ基及び環状アミノカルボニルオキシ基から選ばれる１～３個が置換していてもよく、当該アリール基にはハロゲン原子、アルコキシ基、ニトロ基、シアノ基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、アルキル基、アリール基、アルキルアミノアルキル基及びヒドロキシアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはアルキル基、アルコキシカルボニル基及びアシル基から選ばれる１～２個が置換していてもよい；
Ｒ8は炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は環状アミノ基を示し、当該アルキル基にはアミノ基、アルキルアミノ基、ジアルキルアミノ基、環状アミノ基、カルボキシル基、アルコキシカルボニル基、アリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはアルキル基及びアルコキシカルボニル基から選ばれる１～２個が置換していてもよく、当該環状アルキル基にはカルボキシル基及びアルコキシカルボニル基から選ばれる１～３個が置換していてもよい；
Ｒ9は炭素数１～６のアルキル基、炭素数３～７の環状アルキル基、炭素数６～１４のアリール基又はヘテロアリール基を示し、当該アルキル基には１～３個のハロゲン原子が置換していてもよく、当該アリール基には１～３個のアルキル基が置換していてもよい；
Ｒ10とＲ11は同一又は異なって、水素原子、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は炭素数１～７のアシル基を示すか、Ｒ10とＲ11が結合する窒素原子と一緒になって３～７員環の環状アミノ基を示し、当該アルキル基にはアリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、炭素数１～７のアシル基には１～３個のハロゲン原子が置換していてもよく、当該環状アミノ基にはさらに酸素原子、窒素原子又は硫黄原子が含まれていてもよい；
Ｒ12とＲ13は同一又は異なって、水素原子、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基又は炭素数３～７の環状アルキル基を示すか、Ｒ12とＲ13が結合する窒素原子と一緒になって３～７員環の環状アミノ基を示し、当該アルキル基にはアリール基、ヘテロアリール基、環状アミノ基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、ヒドロキシ基及びアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該環状アルキル基には１～３個のヒドロキシ基が置換していても良く、当該アリール基にはジアルキルアミノ基、アルキルオキシ基、アルキル基、シアノ基、ハロゲン原子、ヒドロキシアルキル基、ヒドロキシアルキルオキシ基、スルファモイル基及びヒドロキシ基から選ばれる１～３個が置換していてもよく、当該ヘテロアリール基にはアルキル基、シアノ基、アリール基及びヒドロキシアルキル基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはさらに酸素原子、窒素原子又は硫黄原子が含まれていてもよく、さらにアルキル基、ヒドロキシ基、ハロゲン原子、アミノ基、アシル基及びジアルキルアミノ基から選ばれる１～３個が置換していてもよい；
　ただし、Ｒ1が塩素原子、臭素原子又はヨウ素原子であり、Ｒ2、Ｒ3及びＲ4がメトキシ基であり、Ｒ5が水素原子であり、かつＲ6がアセチル基である場合を除く。Ｒ1がヒドロキシ基のとき、Ｒ2、Ｒ3及びＲ4はメトキシ基である。）
で表されるコルヒチン誘導体、その塩又はそれらの溶媒和物を提供するものである。 Wherein R 1 represents a halogen atom, a hydroxy group, a nitro group, an amino group or a mono-, di- or tri-fluoromethyl group;
R 2 , R 3 and R 4 each represent a methoxy group or a hydroxy group, or R 2 and R 3 or R 3 and R 4 together represent a methylenedioxy group or an ethylenedioxy group;
R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group, an alkenyl group having 2 to 6 carbon atoms, —COR 7 , —COOR 8 , —SO 2 R 9 , -CONR 10 R 11 or -CSNR 12 R 13 , or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 5 and R 6 are bonded;
R 7 represents a hydrogen atom, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic amino group, a cyclic alkyl group having 3 to 7 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Alkyl group, halogen atom, amino group, alkylamino group, arylalkylamino group, dialkylamino group, cyclic amino group, alkoxycarbonylamino group, arylamino group, heteroarylamino group, carboxyl group, alkoxycarbonyl group, hydroxy group, Acyloxy group, dialkylaminoacyloxy group, alkyloxy group, aryl group, aryloxy group, arylalkyloxy group, heteroaryl group, heteroaryloxy group, thiol group, acylthio group, dialkylaminoacylthio group, alkylthio group, alkylsulfonyl group , Ally One to three selected from a thio group, a heteroarylthio group, a carbamoyloxy group and a cyclic aminocarbonyloxy group may be substituted, and the aryl group includes a halogen atom, an alkoxy group, a nitro group, a cyano group, an amino group. 1 to 3 groups selected from a group, an alkylamino group, a dialkylamino group, an alkyl group, an aryl group, an alkylaminoalkyl group and a hydroxyalkyloxy group may be substituted, and the cyclic amino group includes an alkyl group, an alkoxy group 1 to 2 selected from a carbonyl group and an acyl group may be substituted;
R 8 represents an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms or a cyclic amino group. The alkyl group includes an amino group, an alkyl group One to three selected from an amino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a heteroaryl group may be substituted, and the cyclic amino group includes an alkyl group and an alkoxycarbonyl group. 1 to 2 selected from a group may be substituted, and the cyclic alkyl group may be substituted with 1 to 3 selected from a carboxyl group and an alkoxycarbonyl group;
R 9 represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, an aryl group or a heteroaryl group having 6 to 14 carbon atoms, and the alkyl group has 1 to 3 halogen atoms. May be substituted, and the aryl group may be substituted with 1 to 3 alkyl groups;
R 10 and R 11 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms, or 1 to 7 represents an acyl group, or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 10 and R 11 are bonded. The alkyl group is selected from an aryl group and a heteroaryl group. 1 to 3 may be substituted, and the acyl group having 1 to 7 carbon atoms may be substituted with 1 to 3 halogen atoms. The cyclic amino group may be further substituted with an oxygen atom, a nitrogen atom, or a sulfur atom. Atoms may be included;
R 12 and R 13 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, or a cyclic alkyl group having 3 to 7 carbon atoms; Together with the nitrogen atom to which 12 and R 13 are bonded, represents a 3- to 7-membered cyclic amino group, which includes an aryl group, heteroaryl group, cyclic amino group, amino group, alkylamino group, dialkyl One to three selected from an amino group, a hydroxy group, and an alkyloxy group may be substituted, and the cyclic alkyl group may be substituted with one to three hydroxy groups, and the aryl group includes 1 to 5 selected from dialkylamino group, alkyloxy group, alkyl group, cyano group, halogen atom, hydroxyalkyl group, hydroxyalkyloxy group, sulfamoyl group and hydroxy group 1 to 3 selected from an alkyl group, a cyano group, an aryl group and a hydroxyalkyl group may be substituted on the heteroaryl group, and the cyclic amino group may be further substituted with oxygen. An atom, a nitrogen atom or a sulfur atom may be contained, and 1 to 3 selected from an alkyl group, a hydroxy group, a halogen atom, an amino group, an acyl group and a dialkylamino group may be substituted;
However, R 1 is a chlorine atom, bromine atom or iodine atom, R 2 , R 3 and R 4 are methoxy groups, R 5 is a hydrogen atom, and R 6 is an acetyl group. When R 1 is a hydroxy group, R 2 , R 3 and R 4 are methoxy groups. )
The colchicine derivative represented by these, its salt, or those solvates are provided.
　また、本発明は、一般式（１）で表されるコルヒチン誘導体、その塩又はそれらの溶媒和物を含有する医薬を提供するものである。
　また、本発明は、一般式（１）で表されるコルヒチン誘導体、その塩又はそれらの溶媒和物、及び薬学的に許容される担体を含有する医薬組成物を提供するものである。
　また、本発明は、一般式（１）で表されるコルヒチン誘導体、その塩又はそれらの溶媒和物を含有する抗癌剤を提供するものである。
　また、本発明は、一般式（１）で表される治療用のコルヒチン誘導体、その塩又はそれらの溶媒和物を提供するものである。
　また、本発明は、一般式（１）で表されるコルヒチン誘導体、その塩又はそれらの溶媒和物の有効量を投与することを特徴とする癌の治療方法を提供するものである。 Moreover, this invention provides the pharmaceutical containing the colchicine derivative represented by General formula (1), its salt, or those solvates.
Moreover, this invention provides the pharmaceutical composition containing the colchicine derivative represented by General formula (1), its salt, or those solvates, and a pharmaceutically acceptable carrier.
Moreover, this invention provides the anticancer agent containing the colchicine derivative represented by General formula (1), its salt, or those solvates.
Moreover, this invention provides the colchicine derivative for treatment represented by General formula (1), its salt, or those solvates.
In addition, the present invention provides a method for treating cancer, comprising administering an effective amount of a colchicine derivative represented by the general formula (1), a salt thereof, or a solvate thereof.
　本発明のコルヒチン誘導体、その塩又はそれらの溶媒和物は、ｉｎ　ｖｉｔｒｏ及びｉｎ　ｖｉｖｏで優れた抗癌活性を有し、かつ毒性が低いので抗癌剤として有用である。 The colchicine derivative of the present invention, a salt thereof, or a solvate thereof is useful as an anticancer agent because it has excellent anticancer activity in vitro and in vivo and has low toxicity.
　本発明のコルヒチン誘導体は、一般式（１）で表されるように、Ａ環の４位（Ｒ1）にハロゲン原子、ヒドロキシ基、ニトロ基、アミノ基又はモノ－、ジ－若しくはトリ－フルオロメチル基という特定の置換基を有する点に特徴がある。特にＲ1がハロゲン原子である本発明化合物の抗癌活性は強力であり、毒性も低い。 The colchicine derivative of the present invention has a halogen atom, hydroxy group, nitro group, amino group or mono-, di- or tri-fluoro at the 4-position (R 1 ) of the A ring as represented by the general formula (1). It is characterized by having a specific substituent called a methyl group. In particular, the compounds of the present invention in which R 1 is a halogen atom have strong anticancer activity and low toxicity.
　一般式（１）中、Ｒ1は、ハロゲン原子、ヒドロキシ基、ニトロ基、アミノ基又はモノ－、ジ－若しくはトリ－フルオロメチル基を示すが、このうちハロゲン原子が特に好ましい。ここで、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子又はヨウ素原子が挙げられる。 In the general formula (1), R 1 represents a halogen atom, a hydroxy group, a nitro group, an amino group, or a mono-, di- or tri-fluoromethyl group, and among these, a halogen atom is particularly preferable. Here, as a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom is mentioned.
　一般式（１）中、Ｒ2、Ｒ3及びＲ4はそれぞれメトキシ基、又はヒドロキシ基を示すか、Ｒ2とＲ3又はＲ3とＲ4が一緒になってメチレンジオキシ基、又はエチレンジオキシ基を示す。Ｒ1がヒドロキシ基の場合は、Ｒ2、Ｒ3及びＲ4はすべてメトキシ基である。 In general formula (1), R 2 , R 3 and R 4 each represent a methoxy group or a hydroxy group, or R 2 and R 3 or R 3 and R 4 together form a methylenedioxy group or ethylene Indicates a dioxy group. When R 1 is a hydroxy group, R 2 , R 3 and R 4 are all methoxy groups.
　Ｒ5及びＲ6は同一又は異なって、水素原子、炭素数１～６のアルキル基、アリールアルキル基、炭素数２～６のアルケニル基、－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9、－ＣＯＮＲ10Ｒ11又は－ＣＳＮＲ12Ｒ13を示すか、Ｒ5とＲ6が結合する窒素原子と一緒になって３～７員の環状アミノ基を示す。ここで、炭素数１～６のアルキル基としては、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、Ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基等の直鎖又は分岐鎖のアルキル基が挙げられるが、炭素数１～４のアルキル基がより好ましく、特にメチル基、エチル基、ｎ－プロピル基、イソブチル基が好ましい。アリールアルキル基としては、ベンジル基、フェネチル基等が挙げられるがベンジル基が好ましい。炭素数２～６のアルケニル基としてはビニル基、アリル基、２－ブテニル基、イソブテニル基等が挙げられるが、炭素数３～５の直鎖又は分岐鎖のアルケニル基がより好ましく、特にアリル基、イソブテニル基が好ましい。 R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group, an alkenyl group having 2 to 6 carbon atoms, —COR 7 , —COOR 8 , —SO 2 R 9 , It represents —CONR 10 R 11 or —CSNR 12 R 13 , or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 5 and R 6 are bonded. Here, examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, Sec-butyl group, tert-butyl group, and n-pentyl group. A linear or branched alkyl group such as an n-hexyl group, but an alkyl group having 1 to 4 carbon atoms is more preferable, and a methyl group, an ethyl group, an n-propyl group, and an isobutyl group are particularly preferable. Examples of the arylalkyl group include a benzyl group and a phenethyl group, and a benzyl group is preferable. Examples of the alkenyl group having 2 to 6 carbon atoms include vinyl group, allyl group, 2-butenyl group, isobutenyl group, etc., but a straight chain or branched chain alkenyl group having 3 to 5 carbon atoms is more preferable, especially an allyl group. An isobutenyl group is preferred.
　上記－ＣＯＲ7におけるＲ7は、水素原子、炭素数６～１４のアリール基、ヘテロアリール基、環状アミノ基、炭素数３～７の環状アルキル基又は炭素数１～６のアルキル基を示し、当該アルキル基には環状アルキル基、ハロゲン原子、アミノ基、アルキルアミノ基、アリールアルキルアミノ基、ジアルキルアミノ基、環状アミノ基、アルコキシカルボニルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、カルボキシル基、アルコキシカルボニル基、ヒドロキシ基、アシルオキシ基、ジアルキルアミノアシルオキシ基、アルキルオキシ基、アリール基、アリールオキシ基、アリールアルキルオキシ基、ヘテロアリール基、ヘテロアリールオキシ基、チオール基、アシルチオ基、ジアルキルアミノアシルチオ基、アルキルチオ基、アルキルスルホニル基、アリールチオ基、ヘテロアリールチオ基、カルバモイルオキシ基及び環状アミノカルボニルオキシ基から選ばれる１～３個が置換していてもよく、当該アリール基にはハロゲン原子、アルコキシ基、ニトロ基、シアノ基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、アルキル基、アリール基、アルキルアミノアルキル基及びヒドロキシアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはアルキル基、アルコキシカルボニル基及びアシル基から選ばれる１～２個が置換していてもよい。ここで、炭素数１～６のアルキル基としては、前記Ｒ5及びＲ6と同様の基が挙げられ、炭素数１～４のアルキル基が好ましく、特にメチル基、エチル基、ｎ－プロピル基、イソプロピル基、イソブチル基が好ましい。また、炭素数６～１４のアリール基としては、フェニル基、ナフチル基、トリル基、キシリル基等が挙げられるが、フェニル基が特に好ましい。ヘテロアリール基としては、フリル基、チエニル基、ピロリル基、チアゾリル基、チアジアゾリル基、ピラゾリル基、ピリジニル基、ピラジニル基、ピリミジニル基、ピリダジニル基、オキサゾリル基、イミダゾリル基、ベンゾチアゾリル基、ベンゾオキサゾリル基、インドリル基、ピラジニル基、インダゾリル基、ベンゾチアジアゾリル基、ベンゾイミダゾリル基、ベンゾチアゾリル基、チアジアゾリル基、イソオキサゾリル基、トリアゾリル基等が挙げられるが、フリル基、チエニル基、ピロリル基、ピリジニル基、ベンゾチアゾリル基、ベンゾオキサゾリル基、インドリル基が特に好ましい。環状アミノ基としては、ピロリジノ基、ピペリジノ基、Ｎ－メチルピペリジノ基、Ｎ－（ｔ－ブトキシカルボニル）ピペリジノ基、Ｎ－アセチルピペリジノ、Ｎ－ベンゾイルピペリジノ、Ｎ－（ベンジルオキシカルボニル）ピペリジノ基等が挙げられるが、Ｎ－メチルピペリジノ基、Ｎ－（ｔ－ブトキシカルボニル）ピペリジノ基、Ｎ－ベンゾイルピペリジノ、Ｎ－（ベンジルオキシカルボニル）ピペリジノ基が特に好ましい。炭素数３～７の環状アルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基等が挙げられ、炭素数３～６の環状アルキル基が好ましく、シクロプロピル、シクロペンチル基、シクロへキシル基が特に好ましい。 The R 7 in -COR 7 represents a hydrogen atom, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, cyclic amino group, a cyclic alkyl group or an alkyl group having 1 to 6 carbon atoms having 3 to 7 carbon atoms, The alkyl group includes cyclic alkyl groups, halogen atoms, amino groups, alkylamino groups, arylalkylamino groups, dialkylamino groups, cyclic amino groups, alkoxycarbonylamino groups, arylamino groups, heteroarylamino groups, carboxyl groups, alkoxy groups. Carbonyl group, hydroxy group, acyloxy group, dialkylaminoacyloxy group, alkyloxy group, aryl group, aryloxy group, arylalkyloxy group, heteroaryl group, heteroaryloxy group, thiol group, acylthio group, dialkylaminoacylthio group, Alkylthio group, alkyl 1 to 3 groups selected from a rusulfonyl group, an arylthio group, a heteroarylthio group, a carbamoyloxy group and a cyclic aminocarbonyloxy group may be substituted, and the aryl group includes a halogen atom, an alkoxy group, a nitro group, One to three selected from a cyano group, an amino group, an alkylamino group, a dialkylamino group, an alkyl group, an aryl group, an alkylaminoalkyl group and a hydroxyalkyloxy group may be substituted, and the cyclic amino group includes One or two selected from an alkyl group, an alkoxycarbonyl group and an acyl group may be substituted. Here, examples of the alkyl group having 1 to 6 carbon atoms include the same groups as the above R 5 and R 6, and an alkyl group having 1 to 4 carbon atoms is preferable, and in particular, a methyl group, an ethyl group, and an n-propyl group. An isopropyl group and an isobutyl group are preferable. Examples of the aryl group having 6 to 14 carbon atoms include a phenyl group, a naphthyl group, a tolyl group, and a xylyl group, and a phenyl group is particularly preferable. Heteroaryl groups include furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, imidazolyl, benzothiazolyl, benzoxazolyl , Indolyl group, pyrazinyl group, indazolyl group, benzothiadiazolyl group, benzoimidazolyl group, benzothiazolyl group, thiadiazolyl group, isoxazolyl group, triazolyl group, etc., but furyl group, thienyl group, pyrrolyl group, pyridinyl group, benzothiazolyl group , A benzoxazolyl group and an indolyl group are particularly preferred. Examples of cyclic amino groups include pyrrolidino group, piperidino group, N-methylpiperidino group, N- (t-butoxycarbonyl) piperidino group, N-acetylpiperidino, N-benzoylpiperidino, N- (benzyloxycarbonyl) piperidino Examples thereof include an N-methylpiperidino group, an N- (t-butoxycarbonyl) piperidino group, an N-benzoylpiperidino group and an N- (benzyloxycarbonyl) piperidino group. Examples of the cyclic alkyl group having 3 to 7 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc., and a cyclic alkyl group having 3 to 6 carbon atoms is preferable, and a cyclopropyl, cyclopentyl group, cyclohexane A hexyl group is particularly preferred.
　Ｒ7で示されるアルキル基上の置換基のうち、環状アルキル基としては、炭素数３～７の環状アルキル基、例えばシクロプロピル基、シクロへキシル基が挙げられる。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。アルキルアミノ基としては、Ｃ1-6アルキルアミノ基、例えばメチルアミノ基、エチルアミノ基が挙げられる。アリールアルキルアミノ基としては、例えばベンジルアミノ基が挙げられる。ジアルキルアミノ基としては、ジ（Ｃ1-6アルキル）アミノ基、例えばジメチルアミノ基、ジエチルアミノ基が挙げられる。環状アミノ基としては、Ｃ3-7環状アミノ基、例えばアジリジノ基、ピロリジノ基、ピペリジノ基等が挙げられる。アルコキシカルボニルアミノ基としては、ｔ－ブトキシカルボニルアミノ基等が挙げられる。アリールアミノ基としては、アニリノ基等が挙げられる。ヘテロアリールアミノ基としては、フリルアミノ基、チエニルアミノ基、ピリジニルアミノ基等が挙げられる。アルコキシカルボニル基としては、Ｃ1-67アルコキシカルボニル基、例えばメトキシカルボニル基、エトキシカルボニル基、tert-ブチルオキシカルボニル基、ベンジルオキシカルボニル基等が挙げられる。アシルオキシ基としては、Ｃ1-6アシルオキシ基、例えばアセチルオキシ基、プロピオニルオキシ基等が挙げられる。ジアルキルアミノアシルオキシ基としては、ジ（Ｃ1-6アルキル）アミノアシルオキシ基、例えばジメチルアミノアセチルオキシ基、ジエチルアミノアセチルオキシ基、ジメチルアミノプロピオニルオキシ基、ジエチルアミノブチロイルオキシ基等が挙げられる。アルキルオキシ基としては、Ｃ1-6アルキルオキシ基、例えばメトキシ基、エトキシ基等が挙げられる。アリール基としては、例えばフェニル基、トリル基等が挙げられる。アリールオキシ基としては、例えばフェニルオキシ基、トリルオキシ基等が挙げられる。アリールアルキルオキシ基としては、例えばベンジルオキシ基、トリフェニルメチルオキシ基等が挙げられる。ヘテロアリール基としては、ピリジル基、フリル基、オキサゾリル基等が挙げられる。ヘテロアリールオキシ基としては、例えばピリジルオキシ基、フリルオキシ基、オキサゾリルオキシ等が挙げられる。アシルチオ基としては、Ｃ1-6アシルチオ基、例えばアセチルチオ基、プロピオニルチオ基が挙げられる。ジアルキルアミノアシルチオ基としては、ジ（Ｃ1-6アルキル）アミノアシルチオ基、例えばジメチルアミノアセチルチオ基、ジメチルアミノプロピオニルチオ基、ジエチルアミノアセチルチオ基、ジエチルアミノブチリルチオ基等が挙げられる。アルキルチオ基としては、Ｃ1-6アルキルチオ基、例えばメチルチオ基、エチルチオ基等が挙げられる。アルキルスルホニル基としては、Ｃ1-6アルキルスルホニル基、例えばメチルスルホニル基、エチルスルホニル基等が挙げられる。アリールチオ基としては、例えばフェニルチオ基、トリルチオ基等が挙げられる。ヘテロアリールチオ基としては、例えばピリジルチオ基、フリルチオ基、オキサゾリルチオ等が挙げられる。カルバモイルオキシ基としては、例えば４－ピペリジノピペリジン－１－カルボニルオキシ基、１－メチルピペリジン－４－カルボニルオキシ基等が挙げられる。環状アミノカルバモイルオキシ基としては、例えば１－（ベンジルオキシカルボニル）ピペリジン－４－カルボニルオキシ基等が挙げられる。Ｒ7で示されるアリール基上の置換基のうち、ハロゲン原子としては前記と同様の基が挙げられる。アルコキシ基としては前記と同様の基が挙げられる。アルキルアミノ基としては前記と同様の基が挙げられる。ジアルキルアミノ基としては前記と同様の基が挙げられる。アルキル基としては前記と同様の基が挙げられる。アリール基としては前記と同様の基が挙げられる。アルキルアミノアルキル基としては、Ｃ1－6アルキルアミノＣ1－6アルキル基、例えばジメチルアミノメチル基、モルホリノ－４－メチル基等が挙げられる。ヒドロキシアルキルオキシ基としては、例えば２－ヒドロキシエトキシ基、３－ヒドロキシプロポキシ基、２－ヒドロキシプロポキシ基等が挙げられる。Ｒ7で示される環状アミノ基上の置換基のうち、アルキル基としては前記と同様の基が挙げられる。アルコキシカルボニル基としては前記と同様の基が挙げられる。アシル基としてはアセチル基、プロピオニル基、ベンゾイル基等が挙げられる。 Among the substituents on the alkyl group represented by R 7 , examples of the cyclic alkyl group include a cyclic alkyl group having 3 to 7 carbon atoms, such as a cyclopropyl group and a cyclohexyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkylamino group include a C 1-6 alkylamino group such as a methylamino group and an ethylamino group. Examples of the arylalkylamino group include a benzylamino group. Examples of the dialkylamino group include a di (C 1-6 alkyl) amino group such as a dimethylamino group and a diethylamino group. Examples of the cyclic amino group include a C 3-7 cyclic amino group such as an aziridino group, a pyrrolidino group, and a piperidino group. Examples of the alkoxycarbonylamino group include a t-butoxycarbonylamino group. Examples of the arylamino group include an anilino group. Examples of the heteroarylamino group include a furylamino group, a thienylamino group, and a pyridinylamino group. Examples of the alkoxycarbonyl group include a C 1-67 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butyloxycarbonyl group, and a benzyloxycarbonyl group. Examples of the acyloxy group include C 1-6 acyloxy groups such as acetyloxy group and propionyloxy group. Examples of the dialkylaminoacyloxy group include di (C 1-6 alkyl) aminoacyloxy groups such as dimethylaminoacetyloxy group, diethylaminoacetyloxy group, dimethylaminopropionyloxy group, diethylaminobutyroyloxy group and the like. Examples of the alkyloxy group include C 1-6 alkyloxy groups such as a methoxy group and an ethoxy group. Examples of the aryl group include a phenyl group and a tolyl group. Examples of the aryloxy group include a phenyloxy group and a tolyloxy group. Examples of the arylalkyloxy group include a benzyloxy group and a triphenylmethyloxy group. Examples of the heteroaryl group include a pyridyl group, a furyl group, and an oxazolyl group. Examples of the heteroaryloxy group include a pyridyloxy group, a furyloxy group, and oxazolyloxy. Examples of the acylthio group include a C 1-6 acylthio group such as an acetylthio group and a propionylthio group. Examples of the dialkylaminoacylthio group include a di (C 1-6 alkyl) aminoacylthio group such as a dimethylaminoacetylthio group, a dimethylaminopropionylthio group, a diethylaminoacetylthio group, and a diethylaminobutyrylthio group. Examples of the alkylthio group include a C 1-6 alkylthio group such as a methylthio group and an ethylthio group. Examples of the alkylsulfonyl group include C 1-6 alkylsulfonyl groups such as a methylsulfonyl group and an ethylsulfonyl group. Examples of the arylthio group include a phenylthio group and a tolylthio group. Examples of the heteroarylthio group include a pyridylthio group, a furylthio group, and oxazolylthio. Examples of the carbamoyloxy group include 4-piperidinopiperidine-1-carbonyloxy group and 1-methylpiperidine-4-carbonyloxy group. Examples of the cyclic aminocarbamoyloxy group include 1- (benzyloxycarbonyl) piperidine-4-carbonyloxy group. Of the substituents on the aryl group represented by R 7 , examples of the halogen atom include the same groups as described above. Examples of the alkoxy group include the same groups as described above. Examples of the alkylamino group include the same groups as described above. Examples of the dialkylamino group include the same groups as described above. Examples of the alkyl group include the same groups as described above. Examples of the aryl group include the same groups as described above. The alkylamino group, C 1 - 6 alkylamino C 1 - 6 alkyl group, for example, dimethylaminomethyl group, and morpholino-4-methyl group. Examples of the hydroxyalkyloxy group include 2-hydroxyethoxy group, 3-hydroxypropoxy group, 2-hydroxypropoxy group and the like. Of the substituents on the cyclic amino group represented by R 7 , examples of the alkyl group include the same groups as described above. Examples of the alkoxycarbonyl group include the same groups as described above. Examples of the acyl group include an acetyl group, a propionyl group, and a benzoyl group.
　上記－ＣＯＯＲ8におけるＲ8は、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は環状アミノ基を示し、当該アルキル基にはアミノ基、アルキルアミノ基、ジアルキルアミノ基、環状アミノ基、カルボキシル基、アルコキシカルボニル基、アリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはアルキル基及びアルコキシカルボニル基から選ばれる１～２個が置換していてもよく、当該環状アルキル基にはカルボキシル基及びアルコキシカルボニル基から選ばれる１～３個が置換していてもよい。ここで、炭素数１～６のアルキル基としては、前記と同じ基が挙げられ、炭素数１～４のアルキル基が好ましく、特にメチル基、エチル基、イソプロピル基、イソブチル基、ｔ－ブチル基が好ましい。炭素数６～１４のアリール基としては、前記Ｒ7と同様の基が挙げられ、フェニル基が特に好ましい。ヘテロアリール基としては、前記Ｒ7と同様の基が挙げられ、ピリジル基、インドリル基が特に好ましい。炭素数３～７の環状アルキル基としては前記Ｒ7と同様の基が挙げられ、シクロペンチル基、シクロへキシル基が特に好ましい。環状アミノ基としては、前記Ｒ7と同様の基が挙げられ、Ｎ－メチルピペリジノ基、Ｎ－（ｔ－ブトキシカルボニル）ピペリジノ基、Ｎ－（ベンジルオキシカルボニル）ピペリジノ基が特に好ましい。Ｒ8で示されるアルキル基上の置換基としては、アミノ基、アルキルアミノ基、ジアルキルアミノ基、環状アミノ基、カルボキシル基、アルコキシカルボニル基、アリール基又はヘテロアリール基が挙げられ、アルキルアミノ基としては、メチルアミノ基、エチルアミノ基が特に好ましい。ジアルキルアミノ基としては、ジメチルアミノ基、ジエチルアミノ基が特に好ましい。環状アミノ基としては、ピロリジノ基、ピペリジノ基が特に好ましい。アルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、ベンジルオキシカルボニル基が特に好ましい。アリール基としては、フェニル基、トリル基が特に好ましい。ヘテロアリール基としては、ピリジル基が特に好ましい。 R 8 in the -COOR 8 represents an alkyl group, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group or a cyclic amino group having 3 to 7 carbon atoms having 1 to 6 carbon atoms, said alkyl group May be substituted with 1 to 3 groups selected from an amino group, an alkylamino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a heteroaryl group. 1 to 2 selected from an alkyl group and an alkoxycarbonyl group may be substituted, and the cyclic alkyl group may be substituted with 1 to 3 selected from a carboxyl group and an alkoxycarbonyl group. Here, examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and an alkyl group having 1 to 4 carbon atoms is preferable, and in particular, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a t-butyl group. Is preferred. Examples of the aryl group having 6 to 14 carbon atoms include the same groups as those described above for R 7, and a phenyl group is particularly preferable. Examples of the heteroaryl group include the same groups as those described above for R 7, and a pyridyl group and an indolyl group are particularly preferable. Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as those described above for R 7, and a cyclopentyl group and a cyclohexyl group are particularly preferable. Examples of the cyclic amino group include the same groups as those described above for R 7, and an N-methylpiperidino group, an N- (t-butoxycarbonyl) piperidino group, and an N- (benzyloxycarbonyl) piperidino group are particularly preferable. Examples of the substituent on the alkyl group represented by R 8 include an amino group, an alkylamino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group, or a heteroaryl group. Is particularly preferably a methylamino group or an ethylamino group. As the dialkylamino group, a dimethylamino group and a diethylamino group are particularly preferable. As the cyclic amino group, a pyrrolidino group and a piperidino group are particularly preferable. As the alkoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group are particularly preferable. As the aryl group, a phenyl group and a tolyl group are particularly preferable. As the heteroaryl group, a pyridyl group is particularly preferable.
　上記－ＳＯ2Ｒ9におけるＲ9は、炭素数１～６のアルキル基、炭素数３～７の環状アルキル基、炭素数６～１４のアリール基又はヘテロアリール基を示す。当該アルキル基には１～３個のハロゲン原子が置換していてもよく、当該アリール基には１～３個の炭素数１～６のアルキル基が置換していてもよい。炭素数１～６のアルキル基としては、前記と同じ基が挙げられ、炭素数１～４のアルキル基、特にメチル基、エチル基、イソプロピル基、イソブチル基が好ましい。炭素数３～７の環状アルキル基としては、前記と同じ基が挙げられ、シクロプロピル基、シクロへキシル基が好ましい。炭素数６～１４のアリール基としては、前記と同じ基が挙げられ、特にフェニル基、トリル基が好ましい。ヘテロアリール基としては、前記と同じ基が挙げられ、チエニル基が好ましい。Ｒ9で示されるアルキル基上の置換基としては、ハロゲン原子が挙げられ、ハロゲン原子としては、前記Ｒ7と同様の基が挙げられる。Ｒ9で示されるアリール基上の置換基としては、炭素数１～６のアルキル基が挙げられ、炭素数１～６のアルキル基としては、前記Ｒ7と同様の基が挙げられる。 Said R 9 in -SO 2 R 9 represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, an aryl group or a heteroaryl group having 6 to 14 carbon atoms. The alkyl group may be substituted with 1 to 3 halogen atoms, and the aryl group may be substituted with 1 to 3 alkyl groups having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and an alkyl group having 1 to 4 carbon atoms, particularly a methyl group, an ethyl group, an isopropyl group, and an isobutyl group are preferable. Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as described above, and a cyclopropyl group and a cyclohexyl group are preferable. Examples of the aryl group having 6 to 14 carbon atoms include the same groups as described above, and a phenyl group and a tolyl group are particularly preferable. Examples of the heteroaryl group include the same groups as described above, and a thienyl group is preferable. Examples of the substituent on the alkyl group represented by R 9 include a halogen atom, and examples of the halogen atom include the same groups as those described above for R 7 . Examples of the substituent on the aryl group represented by R 9 include an alkyl group having 1 to 6 carbon atoms, and examples of the alkyl group having 1 to 6 carbon atoms include the same groups as those described above for R 7 .
　上記の－ＣＯＮＲ10Ｒ11におけるＲ10とＲ11は、同一又は異なって、水素原子、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は炭素数１～７のアシル基を示すか、Ｒ10とＲ11が結合する窒素原子と一緒になって３～７員環の環状アミノ基を示し、当該アルキル基にはアリール基及び１～３個のヘテロアリール基から選ばれる１～３個が置換していてもよく、炭素数１～７のアシル基には１～３個のハロゲン原子が置換していてもよく、当該環状アミノ基にはさらに酸素原子、窒素原子又は硫黄原子が含まれてもよい。ここで、炭素数１～６のアルキル基としては、前記と同じ基が挙げられ、特にメチル基、エチル基、ヘキシル基が好ましい。炭素数６～１４のアリール基としては、前記Ｒ7と同様の基が挙げられ、フェニル基が特に好ましい。ヘテロアリール基としては、前記Ｒ7と同様の基が挙げられ、ピリジル基、インドリル基が特に好ましい。Ｒ10及びＲ11で示されるアルキル基上の置換基としてはアリール基、又はヘテロアリール基が挙げられ、アリール基としては前記Ｒ7と同様の基が挙げられ、フェニル基が特に好ましい。ヘテロアリール基としては、前記Ｒ7と同様の基が挙げられ、フリル基、チエニル基が特に好ましい。炭素数３～７の環状アルキル基としては、前記Ｒ7と同じ基が挙げられ、シクロへキシル基が特に好ましい。炭素数１～７のアシル基としては、例えばアセチル基が挙げられる。当該アシル基上に置換するハロゲン原子としては、上記Ｒ7と同様の基が挙げられる。Ｒ10及びＲ11が、窒素原子と一緒になって形成する３～７員環の環状アミノ基としてはアジリジノ基、ピロリジノ基、ピペリジノ基が挙げられ、ピペリジノ基が特に好ましい。Ｒ10及びＲ11が窒素原子と一緒になって形成する３～７員環の環状アミノ基でさらに酸素原子、窒素原子又は硫黄原子を含む環状アミノ基としては、モルホリノ基、ピペラジノ基、Ｎ－メチルピペラジノ基、チオモルホリノ基、チオモルホリノ－１，１－ジオキシド基等が挙げられ、モルホリノ基、チオモルホリノ基が特に好ましい。 R 10 and R 11 in the above -CONR 10 R 11 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, having a carbon number of 3 to 7 A cyclic alkyl group or an acyl group having 1 to 7 carbon atoms, or a 3- to 7-membered cyclic amino group together with a nitrogen atom to which R 10 and R 11 are bonded. 1 to 3 selected from the group and 1 to 3 heteroaryl groups may be substituted, and the acyl group having 1 to 7 carbon atoms may be substituted with 1 to 3 halogen atoms. The cyclic amino group may further contain an oxygen atom, a nitrogen atom or a sulfur atom. Here, examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and a methyl group, an ethyl group, and a hexyl group are particularly preferable. Examples of the aryl group having 6 to 14 carbon atoms include the same groups as those described above for R 7, and a phenyl group is particularly preferable. Examples of the heteroaryl group include the same groups as those described above for R 7, and a pyridyl group and an indolyl group are particularly preferable. Examples of the substituent on the alkyl group represented by R 10 and R 11 include an aryl group or a heteroaryl group. Examples of the aryl group include the same groups as those described above for R 7, and a phenyl group is particularly preferable. Examples of the heteroaryl group include the same groups as those described above for R 7, and a furyl group and a thienyl group are particularly preferable. Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as those described above for R 7, and a cyclohexyl group is particularly preferable. Examples of the acyl group having 1 to 7 carbon atoms include an acetyl group. Examples of the halogen atom substituted on the acyl group include the same groups as those described above for R 7 . Examples of the 3- to 7-membered cyclic amino group formed by R 10 and R 11 together with the nitrogen atom include an aziridino group, a pyrrolidino group, and a piperidino group, and a piperidino group is particularly preferable. The cyclic amino group of 3 to 7 membered ring formed by R 10 and R 11 together with a nitrogen atom and further containing an oxygen atom, a nitrogen atom or a sulfur atom includes a morpholino group, a piperazino group, an N— Examples include a methylpiperazino group, a thiomorpholino group, a thiomorpholino-1,1-dioxide group, and the like, and a morpholino group and a thiomorpholino group are particularly preferable.
　上記の－ＣＳＮＲ12Ｒ13におけるＲ12とＲ13は、同一又は異なって、水素原子、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基又は炭素数３～７の環状アルキル基を示すか、Ｒ12とＲ13が結合する窒素原子と一緒になって３～７員環の環状アミノ基を示し、当該アルキル基にはアリール基、ヘテロアリール基、環状アミノ基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、ヒドロキシ基及びアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該環状アルキル基には１～３個のヒドロキシ基が置換していてもよく、当該アリール基にはジアルキルアミノ基、アルキルオキシ基、アルキル基、シアノ基、ハロゲン原子、ヒドロキシアルキル基、ヒドロキシアルキルオキシ基、スルファモイル基及びヒドロキシ基から選ばれる１～３個が置換してもよく、当該ヘテロアリール基にはアルキル基、シアノ基、アリール基及びヒドロキシアルキル基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはさらに酸素原子、窒素原子又は硫黄原子が含まれてもよく、さらにはアルキル基、ヒドロキシ基、ハロゲン原子、アミノ基及びジアルキルアミノ基から選ばれる１～３個が置換していてもよい。ここで、炭素数１～６のアルキル基としては、前記と同じ基が挙げられ、炭素数１～４のアルキル基、特にメチル基、エチル基、イソブチル基が好ましい。炭素数６～１４のアリール基としては、前記Ｒ7と同様の基が挙げられ、フェニル基が特に好ましい。ヘテロアリール基としては、前記Ｒ7と同様の基が挙げられ、ピリジル基、インドリル基、ピリダジニル基、ピラジニル基、ベンゾチアジアゾリル基、チアゾリル基、イソオキサゾリル基、ピラゾリル基、トリアゾリル基が特に好ましい。Ｒ12及びＲ13で示されるアルキル基上の置換基としてはアリール基、ヘテロアリール基、環状アミノ基、アミノ基、ジアルキルアミノ基、ヒドロキシ基及びアルキルオキシ基が挙げられ、アリール基としては前記Ｒ7と同様の基が挙げられ、フェニル基が特に好ましい。ヘテロアリール基としては、前記Ｒ7と同様の基が挙げられ、フリル基、チエニル基が特に好ましい。環状アミノ基としては、前記Ｒ7と同様の基が挙げられ、モルホリノ基が好ましい。アルキルアミノ基としては、前記R7と同様の基が挙げられる。ジアルキルアミノ基としては、前記R7と同様の基が挙げられる。アルキルオキシ基としては、前記R7と同様の基が挙げられ、特にメトキシ基が好ましい。炭素数３～７の環状アルキル基としては、前記Ｒ7と同じ基が挙げられ、シクロへキシル基が特に好ましい。Ｒ12及びＲ13が、窒素原子と一緒になって形成する３～７員環の環状アミノ基としてはアジリジノ基、ピロリジノ基、ピペリジノ基、アゼパノ基等が挙げられ、アジリジノ基、ピロリジノ基、ピペリジノ基が特に好ましい。Ｒ12及びＲ13が窒素原子と一緒になって形成する３～７員環の環状アミノ基でさらに酸素原子、窒素原子又は硫黄原子を含む環状アミノ基としては、モルホリノ基、ピペラジノ基、Ｎ－メチルピペラジノ基、チオモルホリノ基、チオモルホリノ－１，１－ジオキシド基等が挙げられ、モルホリノ基、チオモルホリノ基が特に好ましい。当該環状アミノ基上に置換するアルキル基としては、前記Ｒ7と同じ基が挙げられ、メチル基が特に好ましい。当該環状アミノ基上に置換するハロゲン原子としては、前記Ｒ7と同じ基が挙げられ、フッ素が特に好ましい。当該環状アミノ基上に置換するアシル基としては、前記Ｒ7と同じ基が挙げられる。当該環状アミノ基上に置換するジアルキルアミノ基としては、前記Ｒ7と同じ基が挙げられる。当該ヘテロアリール基上に置換するアルキル基としてはメチル基、エチル基等が挙げられ、アリール基としてはフェニル基等が挙げられ、ヒドロキシアルキル基としては２－ヒドロキシエチル基、３－ヒドロキシプロピル基、２－ヒドロキシプロピル基等が挙げられる。 R 12 and R 13 in the above -CSNR 12 R 13 are the same or different, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, the number heteroaryl group or C 3-7 having 6 to 14 carbon atoms Or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 12 and R 13 are bonded, and the alkyl group includes an aryl group, a heteroaryl group, a cyclic amino group 1 to 3 selected from an amino group, an alkylamino group, a dialkylamino group, a hydroxy group and an alkyloxy group may be substituted, and the cyclic alkyl group is substituted with 1 to 3 hydroxy groups. The aryl group may be a dialkylamino group, an alkyloxy group, an alkyl group, a cyano group, a halogen atom, a hydroxyalkyl group, a hydroxyalkyloxy group, a sulfamoyl group. And 1 to 3 selected from hydroxy groups may be substituted, and the heteroaryl group may be substituted with 1 to 3 selected from alkyl groups, cyano groups, aryl groups and hydroxyalkyl groups, The cyclic amino group may further contain an oxygen atom, a nitrogen atom or a sulfur atom, and further 1 to 3 selected from an alkyl group, a hydroxy group, a halogen atom, an amino group and a dialkylamino group are substituted. May be. Here, examples of the alkyl group having 1 to 6 carbon atoms include the same groups as described above, and an alkyl group having 1 to 4 carbon atoms, particularly a methyl group, an ethyl group, and an isobutyl group are preferable. Examples of the aryl group having 6 to 14 carbon atoms include the same groups as those described above for R 7, and a phenyl group is particularly preferable. Examples of the heteroaryl group include the same groups as R 7 described above, and a pyridyl group, an indolyl group, a pyridazinyl group, a pyrazinyl group, a benzothiadiazolyl group, a thiazolyl group, an isoxazolyl group, a pyrazolyl group, and a triazolyl group are particularly preferable. Examples of the substituent on the alkyl group represented by R 12 and R 13 include an aryl group, a heteroaryl group, a cyclic amino group, an amino group, a dialkylamino group, a hydroxy group, and an alkyloxy group. The same group as 7 is mentioned, A phenyl group is especially preferable. Examples of the heteroaryl group include the same groups as those described above for R 7, and a furyl group and a thienyl group are particularly preferable. Examples of the cyclic amino group include the same groups as those described above for R 7, and a morpholino group is preferable. Examples of the alkylamino group include the same groups as those described above for R 7 . Examples of the dialkylamino group include the same groups as those described above for R 7 . Examples of the alkyloxy group include the same groups as those described above for R 7, and a methoxy group is particularly preferable. Examples of the cyclic alkyl group having 3 to 7 carbon atoms include the same groups as those described above for R 7, and a cyclohexyl group is particularly preferable. Examples of the 3- to 7-membered cyclic amino group formed by R 12 and R 13 together with the nitrogen atom include an aziridino group, a pyrrolidino group, a piperidino group, an azepano group, and the like. An aziridino group, a pyrrolidino group, a piperidino group The group is particularly preferred. Examples of the cyclic amino group which is a 3- to 7-membered cyclic amino group formed by R 12 and R 13 together with a nitrogen atom and further contains an oxygen atom, a nitrogen atom or a sulfur atom include a morpholino group, a piperazino group, an N— Examples include a methylpiperazino group, a thiomorpholino group, a thiomorpholino-1,1-dioxide group, and the like, and a morpholino group and a thiomorpholino group are particularly preferable. Examples of the alkyl group substituted on the cyclic amino group include the same groups as those described above for R 7, and a methyl group is particularly preferable. Examples of the halogen atom substituted on the cyclic amino group include the same groups as those described above for R 7, and fluorine is particularly preferable. Examples of the acyl group substituted on the cyclic amino group include the same groups as those described above for R 7 . Examples of the dialkylamino group substituted on the cyclic amino group include the same groups as those described above for R 7 . Examples of the alkyl group substituted on the heteroaryl group include a methyl group and an ethyl group. Examples of the aryl group include a phenyl group. Examples of the hydroxyalkyl group include a 2-hydroxyethyl group, a 3-hydroxypropyl group, Examples include 2-hydroxypropyl group.
　Ｒ5及びＲ6が、窒素原子と一緒になって形成する３～７員の環状アミノ基としては、アジリジノ基、ピロリジノ基、ピペリジノ基等が挙げられる。 Examples of the 3- to 7-membered cyclic amino group formed by R 5 and R 6 together with the nitrogen atom include an aziridino group, a pyrrolidino group, and a piperidino group.
　Ｒ5及びＲ6は、水素原子及び炭素数１～６のアルキル基、アリールアルキル基、炭素数２～６のアルケニル基を示す場合は、同一でも異なっていてもよく、Ｒ5又はＲ6の一方が－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9、－ＣＯＮＲ10Ｒ11又は－ＣＳＮＲ12Ｒ13を示す場合には、他方は水素原子であるのが好ましい。 R 5 and R 6 are hydrogen atom and alkyl group having 1 to 6 carbon atoms, an arylalkyl group, if an alkenyl group having 2 to 6 carbon atoms, may be the same or different, the R 5 or R 6 When one shows —COR 7 , —COOR 8 , —SO 2 R 9 , —CONR 10 R 11 or —CSNR 12 R 13 , the other is preferably a hydrogen atom.
　Ｒ5及びＲ6の好ましい組み合せについて説明する。以下の（１）～（３）の組み合せが特に好ましい。
（１）Ｒ5及びＲ6が水素原子の場合。
（２）Ｒ5が水素原子であり、Ｒ6が－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9、－ＣＯＮＲ10Ｒ11又は－ＣＳＮＲ12Ｒ13である場合。
（３）Ｒ5が－ＣＯＲ7で、Ｒ6が－ＣＯＯＲ8の場合。 A preferred combination of R 5 and R 6 will be described. The following combinations (1) to (3) are particularly preferable.
(1) When R 5 and R 6 are hydrogen atoms.
(2) When R 5 is a hydrogen atom and R 6 is —COR 7 , —COOR 8 , —SO 2 R 9 , —CONR 10 R 11, or —CSNR 12 R 13 .
(3) When R 5 is —COR 7 and R 6 is —COOR 8 .
　上記（２）のうち、Ｒ6は－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9又は－ＣＳＮＲ12Ｒ13がさらに好ましい。
　Ｒ6が－ＣＯＲ7の場合、Ｒ7は水素原子；炭素数２～６のアルキル基；炭素数３～７の環状アルキル基；Ｃ3-7環状アルキル基、ハロゲン原子、アミノ基、Ｃ1-6アルキルアミノ基、Ｃ6-14アリールアルキルアミノ基、ジ（Ｃ1-6アルキル）アミノ基、環状アミノ基、Ｃ1-6アルコキシカルボニルアミノ基、Ｃ6-14アリールアミノ基、ヘテロアリールアミノ基、カルボキシル基、Ｃ1-6アルコキシカルボニル基、ヒドロキシ基、アシルオキシ基、ジ（Ｃ1-6アルキル）アミノアシルオキシ基、Ｃ1-6アルキルオキシ基、Ｃ6-14アリール基、Ｃ6-14アリールオキシ基、Ｃ6-14アリールアルキルオキシ基、ヘテロアリール基、ヘテロアリールオキシ基、チオール基、アシルチオ基、ジ（Ｃ1-6アルキル）アミノアシルチオ基、Ｃ1-6アルキルチオ基、Ｃ1-6アルキルスルホニル基、Ｃ6-14アリールチオ基及びヘテロアリールチオ基から選ばれる１～３個が置換した炭素数１～６のアルキル基；あるいはハロゲン原子、Ｃ1-6アルコキシ基、ニトロ基、シアノ基、アミノ基、Ｃ1-6アルキルアミノ基、ジ（Ｃ1-6アルキル）アミノ基、Ｃ1-6アルキル基、Ｃ6-14アリール基及びＣ1-6アルキルアミノアルキル基から選ばれる１～３個が置換していてもよいＣ6-14アリール基又はヘテロアリール基が好ましい。 Of the above (2), R 6 is more preferably —COR 7 , —COOR 8 , —SO 2 R 9 or —CSNR 12 R 13 .
When R 6 is —COR 7 , R 7 is a hydrogen atom; an alkyl group having 2 to 6 carbon atoms; a cyclic alkyl group having 3 to 7 carbon atoms; a C 3-7 cyclic alkyl group, a halogen atom, an amino group, C 1 -6 alkylamino group, C 6-14 arylalkylamino group, di (C 1-6 alkyl) amino group, cyclic amino group, C 1-6 alkoxycarbonylamino group, C 6-14 arylamino group, heteroarylamino Group, carboxyl group, C 1-6 alkoxycarbonyl group, hydroxy group, acyloxy group, di (C 1-6 alkyl) aminoacyloxy group, C 1-6 alkyloxy group, C 6-14 aryl group, C 6-14 Aryloxy group, C 6-14 arylalkyloxy group, heteroaryl group, heteroaryloxy group, thiol group, acylthio group, di (C 1-6 alkyl) aminoacylthio group, C 1-6 alkylthio group, C 1- 6 alkylene Sulfonyl group, C 6-14 alkyl group having 1 to 3 carbon number of 1 was substituted to 6 selected from the arylthio group and heteroarylthio group; or a halogen atom, C 1-6 alkoxy group, a nitro group, a cyano group, 1-3 selected from an amino group, a C 1-6 alkylamino group, a di (C 1-6 alkyl) amino group, a C 1-6 alkyl group, a C 6-14 aryl group and a C 1-6 alkylaminoalkyl group An optionally substituted C 6-14 aryl group or heteroaryl group is preferred.
　Ｒ6が－ＣＯＯＲ8の場合、Ｒ8は炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は環状アミノ基が好ましく、当該アルキル基にはアミノ基、Ｃ1-6アルキルアミノ基、ジ（Ｃ1-6アルキル）アミノ基、環状アミノ基、カルボキシル基、Ｃ1-6アルコキシカルボニル基、Ｃ6-14アリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはＣ1-6アルキル基又はＣ1-6アルコキシカルボニル基が置換していてもよく、当該環状アルキル基にはカルボキシル基、アルコキシカルボニル基が置換していてもよい。 When R 6 is —COOR 8 , R 8 is preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms, or a cyclic amino group, The alkyl group includes an amino group, a C 1-6 alkylamino group, a di (C 1-6 alkyl) amino group, a cyclic amino group, a carboxyl group, a C 1-6 alkoxycarbonyl group, a C 6-14 aryl group, and a hetero group. 1 to 3 selected from an aryl group may be substituted, the cyclic amino group may be substituted with a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group, and the cyclic alkyl group May be substituted with a carboxyl group or an alkoxycarbonyl group.
　Ｒ6が－ＳＯ2Ｒ9の場合、Ｒ9はＣ6-14アリール基又はヘテロアリール基が好ましい。Ｒ6が－ＣＳＮＲ12Ｒ13の場合、Ｒ12とＲ13は同一又は異なって、水素原子、炭素数１～４のアルキル基、炭素数５～６の環状アルキル基、アリール基、ヘテロアリール基又はＲ12とＲ13が窒素原子と一緒になって形成する４～６員環の環状アミノ基が好ましく、当該アルキル基にはアルキルオキシ基、ヒドロキシ基が置換していてもよく、当該アリール基にはジアルキルアミノ基、アルキルオキシ基、アルキル基、シアノ基、ハロゲン原子、ヒドロキシアルキル基及びヒドロキシアキルオキシ基から選ばれる１～３個が置換していてもよく、当該ヘテロアリール基にはアルキル基、シアノ基、アリール基、ヒドロキシアルキル基から選ばれる１～３個が置換していてもよく、当該環状アミノ基には酸素原子、硫黄原子が含まれていてもよく、さらにはアルキル基、ハロゲン原子から選ばれる１～３個が置換していてもよい。ただし、Ｒ5が水素原子であり、Ｒ6がアセチル基の場合、Ｒ1は塩素原子、臭素原子又はヨウ素原子ではない。 When R 6 is —SO 2 R 9 , R 9 is preferably a C 6-14 aryl group or a heteroaryl group. When R 6 is —CSNR 12 R 13 , R 12 and R 13 are the same or different and are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 5 to 6 carbon atoms, an aryl group, or a heteroaryl group. Alternatively, a 4- to 6-membered cyclic amino group formed by R 12 and R 13 together with a nitrogen atom is preferable, and the alkyl group may be substituted with an alkyloxy group or a hydroxy group, and the aryl group 1 to 3 selected from a dialkylamino group, an alkyloxy group, an alkyl group, a cyano group, a halogen atom, a hydroxyalkyl group and a hydroxyalkyloxy group may be substituted, and the heteroaryl group has an alkyl group , A cyano group, an aryl group, and a hydroxyalkyl group may be substituted, and the cyclic amino group may contain an oxygen atom or a sulfur atom. Furthermore alkyl group, one to three selected from halogen atoms may be substituted. However, when R 5 is a hydrogen atom and R 6 is an acetyl group, R 1 is not a chlorine atom, a bromine atom or an iodine atom.
　本発明において、下記から選ばれるコルヒチン誘導体、その塩又はそれらの溶媒和物が好ましい。
　４－ニトロコルヒチン、
　４－ヒドロキシコルヒチン、
　４－フルオロコルヒチン、
　４－アミノコルヒチン、
　４－クロロデアセチルコルヒチン、
　４－フルオロデアセチルコルヒチン、
　４－クロロ－Ｎ－プロピオニルデアセチルコルヒチン、
　４－クロロ－Ｎ－ホルミルデアセチルコルヒチン、
　４－クロロ－Ｎ－（クロロアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）コルヒチン、
　４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）デアセチルコルヒチン、 In this invention, the colchicine derivative chosen from the following, its salt, or those solvates are preferable.
4-nitrocolchicine,
4-hydroxycolchicine,
4-fluorocolchicine,
4-aminocolchicine,
4-chlorodeacetylcolchicine,
4-fluorodeacetylcolchicine,
4-chloro-N-propionyl deacetylcolchicine,
4-chloro-N-formyl deacetyl colchicine,
4-chloro-N- (chloroacetyl) deacetylcolchicine,
4-chloro-N- (t-butoxycarbonyl) colchicine,
4-chloro-N- (t-butoxycarbonyl) deacetylcolchicine,
　４－クロロ－Ｎ，Ｎ－ジメチルデアセチルコルヒチン、
　４－クロロ－Ｎ，Ｎ－ジエチルデアセチルコルヒチン、
　４－クロロ－７－（ピペラジン－１－イル）－７－デ（アセチルアミノ）コルヒチン、
　Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロ－Ｎ－メチルデアセチルコルヒチン、
　Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロ－Ｎ－エチルデアセチルコルヒチン、
　Ｎ－アリル－４－クロロ－Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）デアセチルコルヒチン、
　Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロ－Ｎ－（２－メチルアリル）デアセチルコルヒチン、
　Ｎ－ベンジル－Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－メチルデアセチルコルヒチン、
　４－クロロ－Ｎ－エチルデアセチルコルヒチン、
　Ｎ－アリル－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（２－メチルアリル）デアセチルコルヒチン、
　Ｎ－ベンジル－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－プロピルデアセチルコルヒチン、
　Ｎ－イソブチル－４－クロロデアセチルコルヒチン、
　Ｎ－（アセトキシアセチル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（ヒドロキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－メチルピペラジン－４－イルオキシカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－イルオキシカルボニル］デアセチルコルヒチン、 4-chloro-N, N-dimethyldeacetylcolchicine,
4-chloro-N, N-diethyldeacetylcolchicine,
4-chloro-7- (piperazin-1-yl) -7-de (acetylamino) colchicine,
N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine,
N- (tert-butyloxycarbonyl) -4-chloro-N-ethyldeacetylcolchicine,
N-allyl-4-chloro-N- (tert-butyloxycarbonyl) deacetylcolchicine,
N- (tert-butyloxycarbonyl) -4-chloro-N- (2-methylallyl) deacetylcolchicine,
N-benzyl-N- (tert-butyloxycarbonyl) -4-chlorodeacetylcolchicine,
4-chloro-N-methyldeacetylcolchicine,
4-chloro-N-ethyldeacetylcolchicine,
N-allyl-4-chlorodeacetylcolchicine,
4-chloro-N- (2-methylallyl) deacetylcolchicine,
N-benzyl-4-chlorodeacetylcolchicine,
4-chloro-N-propyl deacetylcolchicine,
N-isobutyl-4-chlorodeacetylcolchicine,
N- (acetoxyacetyl) -4-chlorodeacetylcolchicine,
4-chloro-N- (hydroxyacetyl) deacetylcolchicine,
4-chloro-N- (1-methylpiperazin-4-yloxycarbonyl) deacetylcolchicine,
4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl] deacetylcolchicine,
　４－クロロ－Ｎ－（ピペリジン－４－イルオキシカルボニル）デアセチルコルヒチン、
　Ｎ－［ｔｒａｎｓ－１－（ベンジルオキシカルボニル）シクロヘキサン－４－イルオキシカルボニル］－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（チオモルホリン－４－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１，１－ジオキソチオモルホリン－４－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－メチルピペラジン－４－カルボニル）デアセチルコルヒチン、
　Ｎ－ブチリル－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－イソブチリルデアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロプロパンカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－イソバレリルデアセチルコルヒチン、
　４－クロロ－Ｎ－ヘプタノイルデアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロヘキサンカルボニル）デアセチルコルヒチン、
　Ｎ－ベンゾイル－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（フェニルアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－３－イルカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－４－イルカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－２－イルカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（トリフルオロアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（メトキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（フェノキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［（メチルチオ）アセチル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－ピリジルチオ）アセチル］デアセチルコルヒチン、
　Ｎ－（４－ブロモブチリル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（４－フルオロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３，５－ジフルオロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３，４，５－トリフルオロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－メトキシベンゾイル）デアセチルコルヒチン、 4-chloro-N- (piperidin-4-yloxycarbonyl) deacetylcolchicine,
N- [trans-1- (benzyloxycarbonyl) cyclohexane-4-yloxycarbonyl] -4-chlorodeacetylcolchicine,
4-chloro-N- (thiomorpholine-4-carbonyl) deacetylcolchicine,
4-chloro-N- (1,1-dioxothiomorpholine-4-carbonyl) deacetylcolchicine,
4-chloro-N- (1-methylpiperazine-4-carbonyl) deacetylcolchicine,
N-butyryl-4-chlorodeacetylcolchicine,
4-chloro-N-isobutyryl deacetylcolchicine,
4-chloro-N- (cyclopropanecarbonyl) deacetylcolchicine,
4-chloro-N-isovaleryl deacetylcolchicine,
4-chloro-N-heptanoyl deacetylcolchicine,
4-chloro-N- (cyclohexanecarbonyl) deacetylcolchicine,
N-benzoyl-4-chlorodeacetylcolchicine,
4-chloro-N- (phenylacetyl) deacetylcolchicine,
4-chloro-N- (pyridin-3-ylcarbonyl) deacetylcolchicine,
4-chloro-N- (pyridin-4-ylcarbonyl) deacetylcolchicine,
4-chloro-N- (pyridin-2-ylcarbonyl) deacetylcolchicine,
4-chloro-N- (trifluoroacetyl) deacetylcolchicine,
4-chloro-N- (methoxyacetyl) deacetylcolchicine,
4-chloro-N- (phenoxyacetyl) deacetylcolchicine,
4-chloro-N-[(methylthio) acetyl] deacetylcolchicine,
4-chloro-N-[(4-pyridylthio) acetyl] deacetylcolchicine,
N- (4-bromobutyryl) -4-chlorodeacetylcolchicine,
4-chloro-N- (4-fluorobenzoyl) deacetylcolchicine,
4-chloro-N- (3,5-difluorobenzoyl) deacetylcolchicine,
4-chloro-N- (3,4,5-trifluorobenzoyl) deacetylcolchicine,
4-chloro-N- (4-methoxybenzoyl) deacetylcolchicine,
　４－クロロ－Ｎ－（３，４，５－トリメトキシベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－メトキシベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－メトキシベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［（フェニルチオ）アセチル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－フルオロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－フルオロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２，４－ジフルオロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－３－イルオキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－２－イルアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－３－イルアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（メトキシカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（エトキシカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（イソプロピルオキシカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（イソブチルオキシカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（フェノキシカルボニル）デアセチルコルヒチン、
　Ｎ－（ベンジルオキシカルボニル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（メタンスルホニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（エタンスルホニル）デアセチルコルヒチン、 4-chloro-N- (3,4,5-trimethoxybenzoyl) deacetylcolchicine,
4-chloro-N- (2-methoxybenzoyl) deacetylcolchicine,
4-chloro-N- (3-methoxybenzoyl) deacetylcolchicine,
4-chloro-N-[(phenylthio) acetyl] deacetylcolchicine,
4-chloro-N- [3- (dimethylamino) benzoyl] deacetylcolchicine,
4-chloro-N- [4- (dimethylamino) benzoyl] deacetylcolchicine,
4-chloro-N- (2-fluorobenzoyl) deacetylcolchicine,
4-chloro-N- (3-fluorobenzoyl) deacetylcolchicine,
4-chloro-N- (2,4-difluorobenzoyl) deacetylcolchicine,
4-chloro-N- (pyridin-3-yloxyacetyl) deacetylcolchicine,
4-chloro-N- (pyridin-2-ylacetyl) deacetylcolchicine,
4-chloro-N- (pyridin-3-ylacetyl) deacetylcolchicine,
4-chloro-N- (methoxycarbonyl) deacetylcolchicine,
4-chloro-N- (ethoxycarbonyl) deacetylcolchicine,
4-chloro-N- (isopropyloxycarbonyl) deacetylcolchicine,
4-chloro-N- (isobutyloxycarbonyl) deacetylcolchicine,
4-chloro-N- (phenoxycarbonyl) deacetylcolchicine,
N- (benzyloxycarbonyl) -4-chlorodeacetylcolchicine,
4-chloro-N- (methanesulfonyl) deacetylcolchicine,
4-chloro-N- (ethanesulfonyl) deacetylcolchicine,
　４－クロロ－Ｎ－（イソプロパンスルホニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロプロパンスルホニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（イソブタンスルホニル）デアセチルコルヒチン、
　Ｎ－（ベンゼンスルホニル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（ｐ－トルエンスルホニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－チオフェンスルホニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（トリフルオロメタンスルホニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（エチルカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（イソプロピルカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ヘキシルカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（フェニルカルバモイル）デアセチルコルヒチン、
　Ｎ－（ベンジルカルバモイル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（ジメチルカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ジエチルカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（モルフォリン－４－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピロリジン－１－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピペリジン－１－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（トリクロロアセチルカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ジメチルアミノアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ジエチルアミノアセチル）デアセチルコルヒチン、
　Ｎ－（ｔ－ブチルオキシカルボニルアミノアセチル）－４－クロロデアセチルコルヒチン、 4-chloro-N- (isopropanesulfonyl) deacetylcolchicine,
4-chloro-N- (cyclopropanesulfonyl) deacetylcolchicine,
4-chloro-N- (isobutanesulfonyl) deacetylcolchicine,
N- (benzenesulfonyl) -4-chlorodeacetylcolchicine,
4-chloro-N- (p-toluenesulfonyl) deacetylcolchicine,
4-chloro-N- (2-thiophenesulfonyl) deacetylcolchicine,
4-chloro-N- (trifluoromethanesulfonyl) deacetylcolchicine,
4-chloro-N- (ethylcarbamoyl) deacetylcolchicine,
4-chloro-N- (isopropylcarbamoyl) deacetylcolchicine,
4-chloro-N- (hexylcarbamoyl) deacetylcolchicine,
4-chloro-N- (phenylcarbamoyl) deacetylcolchicine,
N- (benzylcarbamoyl) -4-chlorodeacetylcolchicine,
4-chloro-N- (dimethylcarbamoyl) deacetylcolchicine,
4-chloro-N- (diethylcarbamoyl) deacetylcolchicine,
4-chloro-N- (morpholine-4-carbonyl) deacetylcolchicine,
4-chloro-N- (pyrrolidine-1-carbonyl) deacetylcolchicine,
4-chloro-N- (piperidine-1-carbonyl) deacetylcolchicine,
4-chloro-N- (trichloroacetylcarbamoyl) deacetylcolchicine,
4-chloro-N- (dimethylaminoacetyl) deacetylcolchicine,
4-chloro-N- (diethylaminoacetyl) deacetylcolchicine,
N- (t-butyloxycarbonylaminoacetyl) -4-chlorodeacetylcolchicine,
　４－クロロ－Ｎ－（アミノアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピロリジン－１－イルアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピペリジン－１－イルアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－カルボキシプロピオニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（メトキシカルボニル）プロピオニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－カルボキシブチリル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（メトキシカルボニル）ブチリル］デアセチルコルヒチン、
　Ｎ－（ｔｒａｎｓ－１－カルボキシシクロヘキサン－４－イルオキシカルボニル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（ピリジン－３－イルオキシカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－（ジメチルアミノ）プロピル－３－イルオキシカルボニル］デアセチルコルヒチン、 4-chloro-N- (aminoacetyl) deacetylcolchicine,
4-chloro-N- (pyrrolidin-1-ylacetyl) deacetylcolchicine,
4-chloro-N- (piperidin-1-ylacetyl) deacetylcolchicine,
4-chloro-N- (3-carboxypropionyl) deacetylcolchicine,
4-chloro-N- [3- (methoxycarbonyl) propionyl] deacetylcolchicine,
4-chloro-N- (4-carboxybutyryl) deacetylcolchicine,
4-chloro-N- [4- (methoxycarbonyl) butyryl] deacetylcolchicine,
N- (trans-1-carboxycyclohexane-4-yloxycarbonyl) -4-chlorodeacetylcolchicine,
4-chloro-N- (pyridin-3-yloxycarbonyl) deacetylcolchicine,
4-chloro-N- [1- (dimethylamino) propyl-3-yloxycarbonyl] deacetylcolchicine,
　４－クロロ－Ｎ－［３－（ピロリジン－１－イル）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（４－モルホリニルメチル）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（ジエチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピロリジン－１－チオカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ピペリジン－１－チオカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（モルホリン－４－チオカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（チオモルホリン－４－チオカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１，１－ジオキソチオモルホリン－４－チオカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－メチルピペラジン－４－チオカルボニル）デアセチルコルヒチン、
　（Ｓ）－４－クロロ－Ｎ－（２－アセトキシプロピオニル）デアセチルコルヒチン、
　（Ｓ）－４－クロロ－Ｎ－（２－ヒドロキシプロピオニル）デアセチルコルヒチン、
　（Ｒ）－４－クロロ－Ｎ－（２－アセトキシプロピオニル）デアセチルコルヒチン、
　（Ｒ）－４－クロロ－Ｎ－（２－ヒドロキシプロピオニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－ヒドロキシ－２－メチルプロピオニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－ヒドロキシ－２，２－ジメチルプロピオニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［２，２－ビス（ヒドロキシメチル）プロピオニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－アセチルピペリジン－４－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－ベンゾイルピペリジン－４－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－（ｔｅｒｔ－ブチルオキシカルボニル）ピペリジン－４－カルボニル］デアセチルコルヒチン、 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine,
4-chloro-N- [4- (4-morpholinylmethyl) benzoyl] deacetylcolchicine,
4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (pyrrolidine-1-thiocarbonyl) deacetylcolchicine,
4-chloro-N- (piperidine-1-thiocarbonyl) deacetylcolchicine,
4-chloro-N- (morpholine-4-thiocarbonyl) deacetylcolchicine,
4-chloro-N- (thiomorpholine-4-thiocarbonyl) deacetylcolchicine,
4-chloro-N- (1,1-dioxothiomorpholine-4-thiocarbonyl) deacetylcolchicine,
4-chloro-N- (1-methylpiperazine-4-thiocarbonyl) deacetylcolchicine,
(S) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine,
(S) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine,
(R) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine,
(R) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine,
4-chloro-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine,
4-chloro-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine,
4-chloro-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine,
4-chloro-N- (1-acetylpiperidine-4-carbonyl) deacetylcolchicine,
4-chloro-N- (1-benzoylpiperidine-4-carbonyl) deacetylcolchicine,
4-chloro-N- [1- (tert-butyloxycarbonyl) piperidine-4-carbonyl] deacetylcolchicine,
　４－クロロ－Ｎ－（ピペリジン－４－カルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（ジメチルアミノメチル）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（トリフェニルメチルオキシ）プロピオニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－ヒドロキシプロピオニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（メタンスルホニルアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（ジメチルアミノ）プロピオニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（ジエチルアミノ）プロピオニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－ピペリジノプロピオニル）デアセチルコルヒチン、
　Ｎ－［Ｎ’－（ｔ－ブチルオキシカルボニル）－Ｎ’－メチルアミノアセチル］－４－クロロデアセチルコルヒチン、
　Ｎ－［Ｎ’－ベンジル－Ｎ’－（ｔ－ブチルオキシカルボニル）アミノアセチル］－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（１－メチルピペリジン－４－イルカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－イルカルボニル］デアセチルコルヒチン、 4-chloro-N- (piperidine-4-carbonyl) deacetylcolchicine,
4-chloro-N- [3- (dimethylaminomethyl) benzoyl] deacetylcolchicine,
4-chloro-N- [3- (triphenylmethyloxy) propionyl] deacetylcolchicine,
4-chloro-N- (3-hydroxypropionyl) deacetylcolchicine,
4-chloro-N- (methanesulfonylacetyl) deacetylcolchicine,
4-chloro-N- [3- (dimethylamino) propionyl] deacetylcolchicine,
4-chloro-N- [3- (diethylamino) propionyl] deacetylcolchicine,
4-chloro-N- (3-piperidinopropionyl) deacetylcolchicine,
N- [N ′-(t-butyloxycarbonyl) -N′-methylaminoacetyl] -4-chlorodeacetylcolchicine,
N- [N′-benzyl-N ′-(t-butyloxycarbonyl) aminoacetyl] -4-chlorodeacetylcolchicine,
4-chloro-N- (1-methylpiperidin-4-ylcarbonyl) deacetylcolchicine,
4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine,
　４－クロロ－Ｎ－（Ｎ’－メチルアミノアセチル）デアセチルコルヒチン、
　Ｎ－（Ｎ’－ベンジルアミノアセチル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（ジメチルアミノ）ブチリル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［２－（ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（イソブチルチオカルバモイル）デアセチルコルヒチン、
　Ｎ－（ベンジルチオカルバモイル）－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロヘキシルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２－ピペリジノエチル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－｛［２－（４－モルフォリノ）エチル］チオカルバモイル｝デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－ピリジルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［ｐ－（ジメチルアミノ）フェニルチオカルバモイル］デアセチルコルヒチン、 4-chloro-N- (N′-methylaminoacetyl) deacetylcolchicine,
N- (N′-benzylaminoacetyl) -4-chlorodeacetylcolchicine,
4-chloro-N- [4- (dimethylamino) butyryl] deacetylcolchicine,
4-chloro-N- [2- (dimethylamino) benzoyl] deacetylcolchicine,
4-chloro-N- (isobutylthiocarbamoyl) deacetylcolchicine,
N- (benzylthiocarbamoyl) -4-chlorodeacetylcolchicine,
4-chloro-N- (cyclohexylthiocarbamoyl) deacetylcolchicine,
4-chloro-N-[(2-piperidinoethyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-{[2- (4-morpholino) ethyl] thiocarbamoyl} deacetylcolchicine,
4-chloro-N- (3-pyridylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- [p- (dimethylamino) phenylthiocarbamoyl] deacetylcolchicine,
　４－クロロ－Ｎ－（４－ニトロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－ナフトイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－ニトロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－メチルベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－フェニルベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３，５－ジニトロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３，５－ジメチルベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－ニトロベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３，５－ジメトキシベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２，４－ジメトキシベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２，４，６－トリメチルベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－シアノベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－ヒドロキシ－３－メチルブチリル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（ベンジルオキシ）ブチリル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－シアノベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－シアノベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－エチル－２－ヒドロキシブチリル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－ヒドロキシシクロプロパンカルボニル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－フェニルベンゾイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－ヒドロキシブチリル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ｔ－ブチルオキシカルボニル）コルヒチン、 4-chloro-N- (4-nitrobenzoyl) deacetylcolchicine,
4-chloro-N- (2-naphthoyl) deacetylcolchicine,
4-chloro-N- (2-nitrobenzoyl) deacetylcolchicine,
4-chloro-N- (4-methylbenzoyl) deacetylcolchicine,
4-chloro-N- (4-phenylbenzoyl) deacetylcolchicine,
4-chloro-N- (3,5-dinitrobenzoyl) deacetylcolchicine,
4-chloro-N- (3,5-dimethylbenzoyl) deacetylcolchicine,
4-chloro-N- (3-nitrobenzoyl) deacetylcolchicine,
4-chloro-N- (3,5-dimethoxybenzoyl) deacetylcolchicine,
4-chloro-N- (2,4-dimethoxybenzoyl) deacetylcolchicine,
4-chloro-N- (2,4,6-trimethylbenzoyl) deacetylcolchicine,
4-chloro-N- (4-cyanobenzoyl) deacetylcolchicine,
4-chloro-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine,
4-chloro-N- [4- (benzyloxy) butyryl] deacetylcolchicine,
4-chloro-N- (2-cyanobenzoyl) deacetylcolchicine,
4-chloro-N- (3-cyanobenzoyl) deacetylcolchicine,
4-chloro-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine,
4-chloro-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine,
4-chloro-N- (3-phenylbenzoyl) deacetylcolchicine,
4-chloro-N- (4-hydroxybutyryl) deacetylcolchicine,
4-bromo-N- (t-butyloxycarbonyl) colchicine,
　４－ブロモ－Ｎ－（ｔ－ブチルオキシカルボニル）デアセチルコルヒチン、
　４－ブロモデアセチルコルヒチン、
　４－ブロモ－Ｎ－プロピオニルデアセチルコルヒチン、
　４－ブロモ－Ｎ－（シクロヘキサンカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－ベンゾイルデアセチルコルヒチン、
　４－ブロモ－Ｎ－（フェニルアセチル）デアセチルコルヒチン、
　Ｎ－アリル－４－ブロモ－Ｎ－（ｔ－ブチルオキシカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（トリフルオロアセチル）デアセチルコルヒチン、
　Ｎ－（アセトキシアセチル）－４－ブロモデアセチルコルヒチン、
　４－ブロモ－Ｎ－（２－ピリジンカルボニル）デアセチルコルヒチン、
　Ｎ－アリル－４－ブロモデアセチルコルヒチン、 4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine,
4-bromodeacetyl colchicine,
4-bromo-N-propionyl deacetylcolchicine,
4-bromo-N- (cyclohexanecarbonyl) deacetylcolchicine,
4-bromo-N-benzoyl deacetyl colchicine,
4-bromo-N- (phenylacetyl) deacetylcolchicine,
N-allyl-4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine,
4-bromo-N- (trifluoroacetyl) deacetylcolchicine,
N- (acetoxyacetyl) -4-bromodeacetylcolchicine,
4-bromo-N- (2-pyridinecarbonyl) deacetylcolchicine,
N-allyl-4-bromodeacetylcolchicine,
　Ｎ－（ベンジルオキシカルボニル）－４－ブロモデアセチルコルヒチン、
　４－ブロモ－Ｎ－[（メチルチオ）アセチル]デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（Ｎ’，Ｎ’－ジメチルアミノ）アセチル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－プロピルデアセチルコルヒチン、
　４－ブロモ－Ｎ－（ヘキシルカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（フェニルカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ヒドロキシアセチル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（イソブタンスルホニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－トシルデアセチルコルヒチン、
　４－ブロモ－Ｎ－（２－チオフェンスルホニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（２，４－ジフルオロベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［３－（Ｎ’，Ｎ’－ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－（２－フルオロベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（３－メトキシベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（エチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（フェニルチオカルバモイル）デアセチルコルヒチン、 N- (benzyloxycarbonyl) -4-bromodeacetylcolchicine,
4-bromo-N-[(methylthio) acetyl] deacetylcolchicine,
4-bromo-N-[(N ′, N′-dimethylamino) acetyl] deacetylcolchicine,
4-bromo-N-propyl deacetylcolchicine,
4-bromo-N- (hexylcarbamoyl) deacetylcolchicine,
4-bromo-N- (phenylcarbamoyl) deacetylcolchicine,
4-bromo-N- (hydroxyacetyl) deacetylcolchicine,
4-bromo-N- (isobutanesulfonyl) deacetylcolchicine,
4-bromo-N-tosyldeacetylcolchicine,
4-bromo-N- (2-thiophenesulfonyl) deacetylcolchicine,
4-bromo-N- (2,4-difluorobenzoyl) deacetylcolchicine,
4-bromo-N- [3- (N ′, N′-dimethylamino) benzoyl] deacetylcolchicine,
4-bromo-N- (2-fluorobenzoyl) deacetylcolchicine,
4-bromo-N- (3-methoxybenzoyl) deacetylcolchicine,
4-bromo-N- (ethylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (phenylthiocarbamoyl) deacetylcolchicine,
　４－ブロモ－Ｎ－（Ｎ’，Ｎ’－ジエチルカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ピペリジン－１－イルカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（３－ヒドロキシ－２，２－ジメチルプロピオニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（２－ヒドロキシ－２－メチルプロピオニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（２－エチル－２－ヒドロキシブチリル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（１－ヒドロキシシクロプロパンカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［２，２－ビス（ヒドロキシメチル）プロピオニル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－（３－ヒドロキシ－３－メチルブチリル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［４－（ベンジルオキシ）ブチリル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－（３－ニトロベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（４－シアノベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（３，５－ジメチルベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（４－メチルベンゾイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－[３－（ピロリジン－１－イル）ベンゾイル]デアセチルコルヒチン、
　４－ブロモ－Ｎ－（イソブチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ベンジルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［４－（Ｎ’，Ｎ’－ジメチルアミノ）フェニルチオカルバモイル］デアセチルコルヒチン、 4-bromo-N- (N ′, N′-diethylcarbamoyl) deacetylcolchicine,
4-bromo-N- (piperidin-1-ylcarbonyl) deacetylcolchicine,
4-bromo-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine,
4-bromo-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine,
4-bromo-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine,
4-bromo-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine,
4-bromo-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine,
4-bromo-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine,
4-bromo-N- [4- (benzyloxy) butyryl] deacetylcolchicine,
4-bromo-N- (3-nitrobenzoyl) deacetylcolchicine,
4-bromo-N- (4-cyanobenzoyl) deacetylcolchicine,
4-bromo-N- (3,5-dimethylbenzoyl) deacetylcolchicine,
4-bromo-N- (4-methylbenzoyl) deacetylcolchicine,
4-bromo-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine,
4-bromo-N- (isobutylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (benzylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- [4- (N ′, N′-dimethylamino) phenylthiocarbamoyl] deacetylcolchicine,
　４－ブロモ－Ｎ－（ピリジン－３－イルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（Ｎ’，Ｎ’－ジエチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ピロリジン－１－イルチオカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ピペリジン－１－イルチオカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（４－ヒドロキシブチリル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（チオモルホリン－４－イルチオカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（１，１－ジオキソチオモルホリン－４－イルチオカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（４－メチルピペラジン－１－イルチオカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（モルホリン－４－イルチオカルボニル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（エタンスルホニル）デアセチルコルヒチン、
　４－クロロ－２，３－ジデメチルコルヒチン、
　４－クロロ－２，３－（メチレンジオキシ）－２，３－ジデメトキシコルヒチン、
　４－クロロ－２，３－（エチレンジオキシ）－２，３－ジデメトキシコルヒチン、
　４－クロロ－１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチン、
　４－クロロ－Ｎ－（エチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（フェニルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（４－ピペリジノピペリジン－１－カルボキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（１－メチルピペラジン－４－カルボキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ジメチルアミノアセトキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（ジメチルアミノ）プロピオニルオキシアセチル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－カルボキシアセチル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（チオアセトキシアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（メルカプトアセチル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－（エトキシカルボニル）ピペリジン－４－イルカルボニル］デアセチルコルヒチン、
　４－（フルオロメチル）コルヒチン、
　４－（ジフルオロメチル）コルヒチン、
　４－クロロ－Ｎ－（Ｎ’，Ｎ’－ジメチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（Ｎ’，Ｎ’－ジプロピルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［Ｎ’－エチル－Ｎ’－プロピルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－ヒドロキシピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－メチルピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－｛Ｎ’－［２－（ジメチルアミノ）エチル］－Ｎ’－メチルチオカルバモイル｝デアセチルコルヒチン、
　４－クロロ－Ｎ－｛［４－（ジメチルアミノ）ピペリジン－１－イル］チオカルバモイル｝デアセチルコルヒチン、
　４－クロロ－Ｎ－（Ｎ’－エチル－Ｎ’－メチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［１－アセチルピペラジン－４－イル）チオカルボニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［Ｎ’－（２－ヒドロキシエチル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［Ｎ’－（３－ヒドロキシプロピル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［Ｎ’，Ｎ’－ビス（２－ヒドロキシエチル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３－ヒドロキシプロピル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４，４－ジフルオロピペリジン－１－イル）チオカルバモイル］デアセチルコルヒチン、
　Ｎ－［（アゼチジン－１－イル）チオカルバモイル］－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－［（インダゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（２－トリルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（３－トリルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（ジメチルアミノ）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（２－ヒドロキシエチル）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（２－ヒドロキシエチル）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［２，１，３－ベンゾチアジアゾール－４－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３，４－ジメトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２－クロロフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３－クロロフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－クロロフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（チアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（チオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（メチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ｎ－プロピルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ｎ－ブチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ｔｅｒｔ－ブチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロペンチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（イソプロピルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（ｎ－ヘキシルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ｔｒａｎｓ－４－ヒドロキシシクロヘキシル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［２－（ジメチルアミノ）エチルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２－ヒドロキシエチル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ｐ－トルイル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロプロピルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－（アリルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１－メチルピペリジン－４－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－（シクロへプチルチオカルバモイル）デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２－メトキシエチル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（２，２，２－トリフルオロエチル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（インダン－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－スルファモイルフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３，５－ジメチルイソオキサゾール－４－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－ヒドロキシフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（５－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－（プロピルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（ブチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（２，２，２－トリフルオロエチル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－（シクロペンチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（シクロヘキシルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（４－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－｛［２－（４－モルホリノ）エチル］チオカルバモイル｝デアセチルコルヒチン、
　４－ブロモ－Ｎ－（Ｎ’，Ｎ’－ジメチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（Ｎ’－エチル－Ｎ’－メチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（４－メチルピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（４，４－ジフルオロ－ピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（５－メチルイソオキサゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（５－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（イソオキサゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（３，４－ジメチルイソオキサゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－シアノピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（５－フェニルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　Ｎ－（ｔ－ブチルオキシカルボニル）－４－ヨードコルヒチン、
　Ｎ－（ｔ－ブチルオキシカルボニル）－４－ヨードデアセチルコルヒチン、
　４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－プロピオニルデアセチルコルヒチン、
　Ｎ－シクロプロピルカルボニル－４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－（トリフルオロアセチル）デアセチルコルヒチン、
　Ｎ－エチルスルホニル－４－ヨードデアセチルコルヒチン、
　Ｎ－［３－（ジメチルアミノ）ベンゾイル］－４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－（４－メトキシベンゾイル）デアセチルコルヒチン、
　４－ヨード－Ｎ－（４－ニトロベンゾイル）デアセチルコルヒチン、
　Ｎ－（３，５－ジフルオロベンゾイル）－４－ヨードデアセチルコルヒチン、
　Ｎ－（３－シアノベンゾイル）－４－ヨードデアセチルコルヒチン、
　Ｎ－（アセトキシアセチル）－４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－（フェニルアセチル）デアセチルコルヒチン、
　４－ヨード－Ｎ－プロピルデアセチルコルヒチン、
　Ｎ－（ヒドロキシアセチル）－４－ヨードデアセチルコルヒチン、
　Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－イルカルボニル］－４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－（ピリジン－４－イルカルボニル）デアセチルコルヒチン、
　Ｎ－フェニルスルホニル－４－ヨードデアセチルコルヒチン、
　Ｎ－（シクロヘキシルチオカルバモイル）－４－ヨードデアセチルコルヒチン、
　Ｎ－［４－（ジメチルアミノ）フェニルチオカルバモイル］－４－ヨードデアセチルコルヒチン、
　Ｎ－（ベンジルカルバモイル）－４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－［（ピペリジン－１－イル）カルボニル］デアセチルコルヒチン、
　Ｎ－エチル－４－ヨードデアセチルコルヒチン、
　４－ヨード－Ｎ－［（ピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
　４－ヨード－Ｎ－［（チオモルホリン－４－イル）チオカルボニル］デアセチルコルヒチン、
　Ｎ－［（ベンゾイミダゾール－２－イル）チオカルバモイル］－４－クロロデアセチルコルヒチン、
　Ｎ－［（ベンゾチアゾール－２－イル）チオカルバモイル］－４－クロロデアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピリミジン－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピリダジン－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピリジン－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４－メチルチアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（４，５－ジメチルチアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピリジン－４－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（２－ヒドロキシエトキシ）ベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（２－ヒドロキシエトキシ）－４－メトキシベンゾイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピラジン－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１，３，４－チアジアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（ピリミジン－５－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［３－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［４－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１，２－ジメチルイミダゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）－２－メチルイミダゾール－５－イル］チオカルバモイル｝デアセチルコルヒチン、
　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）ピラゾール－５－イル］チオカルバモイル｝デアセチルコルヒチン、
　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）ピラゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（５－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（１－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（４－シアノピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（５－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（１－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（ピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（３，４－ジメチルイソオキサゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（５－メチルイソオキサゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（４－メチルチアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（チアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［３－（２－ヒドロキシエチル）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（ピリダジン－３－イル）チオカルバモイル］デアセチルコルヒチン、
　Ｎ－［（アゼチジン－１－イル）チオカルボニル］－４－ブロモデアセチルコルヒチン、
　４－ブロモ－Ｎ－（メチルチオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－（チオカルバモイル）デアセチルコルヒチン、
　４－ブロモ－Ｎ－｛［１－（２－ヒドロキシエチル）－１，２，４－トリアゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン、
　４－ブロモ－Ｎ－｛［１－（２－ヒドロキシエチル）ピラゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン、
　４－ブロモ－Ｎ－［４－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［３－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（４－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［（２－ヒドロキシエチル）チオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［Ｎ’－（２－ヒドロキシエチル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
　４－ブロモ－Ｎ－［Ｎ’－（３－ヒドロキシプロピル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－［（１－メチル－１，２，４－トリアゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）－１，２，４－トリアゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン。 4-bromo-N- (pyridin-3-ylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (N ′, N′-diethylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (pyrrolidin-1-ylthiocarbonyl) deacetylcolchicine,
4-bromo-N- (piperidin-1-ylthiocarbonyl) deacetylcolchicine,
4-bromo-N- (4-hydroxybutyryl) deacetylcolchicine,
4-bromo-N- (thiomorpholin-4-ylthiocarbonyl) deacetylcolchicine,
4-bromo-N- (1,1-dioxothiomorpholin-4-ylthiocarbonyl) deacetylcolchicine,
4-bromo-N- (4-methylpiperazin-1-ylthiocarbonyl) deacetylcolchicine,
4-bromo-N- (morpholin-4-ylthiocarbonyl) deacetylcolchicine,
4-bromo-N- (ethanesulfonyl) deacetylcolchicine,
4-chloro-2,3-didemethylcolchicine,
4-chloro-2,3- (methylenedioxy) -2,3-didemethoxycolchicine,
4-chloro-2,3- (ethylenedioxy) -2,3-didemethoxycolchicine,
4-chloro-1,2- (methylenedioxy) -1,2-didemethoxycolchicine,
4-chloro-N- (ethylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (phenylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine,
4-chloro-N- (1-methylpiperazine-4-carboxyacetyl) deacetylcolchicine,
4-chloro-N- (dimethylaminoacetoxyacetyl) deacetylcolchicine,
4-chloro-N- [3- (dimethylamino) propionyloxyacetyl] deacetylcolchicine,
4-chloro-N- [1- (benzyloxycarbonyl) piperidine-4-carboxyacetyl] deacetylcolchicine,
4-chloro-N- (thioacetoxyacetyl) deacetylcolchicine,
4-chloro-N- (mercaptoacetyl) deacetylcolchicine,
4-chloro-N- [1- (ethoxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine,
4- (fluoromethyl) colchicine,
4- (difluoromethyl) colchicine,
4-chloro-N- (N ′, N′-dimethylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (N ′, N′-dipropylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- [N′-ethyl-N′-propylthiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-hydroxypiperidin-1-yl) thiocarbonyl] deacetylcolchicine,
4-chloro-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine,
4-chloro-N- {N ′-[2- (dimethylamino) ethyl] -N′-methylthiocarbamoyl} deacetylcolchicine,
4-chloro-N-{[4- (dimethylamino) piperidin-1-yl] thiocarbamoyl} deacetylcolchicine,
4-chloro-N- (N′-ethyl-N′-methylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- [1-acetylpiperazin-4-yl) thiocarbonyl] deacetylcolchicine,
4-chloro-N- [N ′-(2-hydroxyethyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
4-chloro-N- [N ′-(3-hydroxypropyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
4-chloro-N- [N ′, N′-bis (2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3-hydroxypropyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4,4-difluoropiperidin-1-yl) thiocarbamoyl] deacetylcolchicine,
N-[(azetidin-1-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine,
4-chloro-N-[(indazol-5-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(cis-2,6-dimethylmorpholin-4-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- (2-tolylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (3-tolylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- [3- (dimethylamino) phenylthiocarbamoyl] deacetylcolchicine,
4-chloro-N- [4- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine,
4-chloro-N- [3- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- [2,1,3-benzothiadiazol-4-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(2-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3,4-dimethoxyphenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(2-chlorophenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3-chlorophenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-chlorophenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(2-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- (thiocarbamoyl) deacetylcolchicine,
4-chloro-N- (methylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (n-propylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (n-butylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (tert-butylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (cyclopentylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (isopropylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (n-hexylthiocarbamoyl) deacetylcolchicine,
4-chloro-N-[(trans-4-hydroxycyclohexyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- [2- (dimethylamino) ethylthiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(p-toluyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- (cyclopropylthiocarbamoyl) deacetylcolchicine,
4-chloro-N- (allylthiocarbamoyl) deacetylcolchicine,
4-chloro-N-[(1-methylpiperidin-4-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- (cycloheptylthiocarbamoyl) deacetylcolchicine,
4-chloro-N-[(2-methoxyethyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(indan-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-sulfamoylphenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3,5-dimethylisoxazol-4-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-hydroxyphenyl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N- (propylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (butylthiocarbamoyl) deacetylcolchicine,
4-bromo-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N- (cyclopentylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (cyclohexylthiocarbamoyl) deacetylcolchicine,
4-bromo-N-[(4-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-{[2- (4-morpholino) ethyl] thiocarbamoyl} deacetylcolchicine,
4-bromo-N- (N ′, N′-dimethylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (N′-ethyl-N′-methylthiocarbamoyl) deacetylcolchicine,
4-bromo-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine,
4-bromo-N-[(4,4-difluoro-piperidin-1-yl) thiocarbonyl] deacetylcolchicine,
4-chloro-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(isoxazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(3,4-dimethylisoxazol-5-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(5-phenylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
N- (t-butyloxycarbonyl) -4-iodocolchicine,
N- (t-butyloxycarbonyl) -4-iododeacetylcolchicine,
4-iodo deacetyl colchicine,
4-iodo-N-propionyl deacetyl colchicine,
N-cyclopropylcarbonyl-4-iododeacetylcolchicine,
4-iodo-N- (trifluoroacetyl) deacetylcolchicine,
N-ethylsulfonyl-4-iododeacetylcolchicine,
N- [3- (dimethylamino) benzoyl] -4-iododeacetylcolchicine,
4-iodo-N- (4-methoxybenzoyl) deacetylcolchicine,
4-iodo-N- (4-nitrobenzoyl) deacetylcolchicine,
N- (3,5-difluorobenzoyl) -4-iododeacetylcolchicine,
N- (3-cyanobenzoyl) -4-iododeacetylcolchicine,
N- (acetoxyacetyl) -4-iododeacetylcolchicine,
4-iodo-N- (phenylacetyl) deacetylcolchicine,
4-iodo-N-propyl deacetylcolchicine,
N- (hydroxyacetyl) -4-iododeacetylcolchicine,
N- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] -4-iododeacetylcolchicine,
4-iodo-N- (pyridin-4-ylcarbonyl) deacetylcolchicine,
N-phenylsulfonyl-4-iododeacetylcolchicine,
N- (cyclohexylthiocarbamoyl) -4-iododeacetylcolchicine,
N- [4- (dimethylamino) phenylthiocarbamoyl] -4-iododeacetylcolchicine,
N- (benzylcarbamoyl) -4-iododeacetylcolchicine,
4-iodo-N-[(piperidin-1-yl) carbonyl] deacetylcolchicine,
N-ethyl-4-iododeacetylcolchicine,
4-iodo-N-[(piperidin-1-yl) thiocarbonyl] deacetylcolchicine,
4-iodo-N-[(thiomorpholin-4-yl) thiocarbonyl] deacetylcolchicine,
N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine,
N-[(benzothiazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine,
4-chloro-N-[(pyrimidin-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(pyridazin-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(pyridin-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(pyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(1-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4-methylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(4,5-dimethylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(pyridin-4-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- [3- (2-hydroxyethoxy) benzoyl] deacetylcolchicine,
4-chloro-N- [3- (2-hydroxyethoxy) -4-methoxybenzoyl] deacetylcolchicine,
4-chloro-N-[(pyrazin-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(1,3,4-thiadiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(pyrimidin-5-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N- [3- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
4-chloro-N- [4- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(1,2-dimethylimidazol-5-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-{[1- (2-hydroxyethyl) -2-methylimidazol-5-yl] thiocarbamoyl} deacetylcolchicine,
4-chloro-N-{[1- (2-hydroxyethyl) pyrazol-5-yl] thiocarbamoyl} deacetylcolchicine,
4-chloro-N-{[1- (2-hydroxyethyl) pyrazol-3-yl] thiocarbamoyl} deacetylcolchicine,
4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(1-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(1-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(pyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(3,4-dimethylisoxazol-5-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(4-methylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N- [3- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(pyridazin-3-yl) thiocarbamoyl] deacetylcolchicine,
N-[(azetidin-1-yl) thiocarbonyl] -4-bromodeacetylcolchicine,
4-bromo-N- (methylthiocarbamoyl) deacetylcolchicine,
4-bromo-N- (thiocarbamoyl) deacetylcolchicine,
4-bromo-N-{[1- (2-hydroxyethyl) -1,2,4-triazol-3-yl] thiocarbamoyl} deacetylcolchicine,
4-bromo-N-{[1- (2-hydroxyethyl) pyrazol-3-yl] thiocarbamoyl} deacetylcolchicine,
4-bromo-N- [4- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
4-bromo-N- [3- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N-[(2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine,
4-bromo-N- [N ′-(2-hydroxyethyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
4-bromo-N- [N ′-(3-hydroxypropyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(1-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
4-chloro-N-[(1-methyl-1,2,4-triazol-5-yl) thiocarbamoyl] deacetylcolchicine,
4-Chloro-N-{[1- (2-hydroxyethyl) -1,2,4-triazol-3-yl] thiocarbamoyl} deacetylcolchicine.
　本発明のコルヒチン誘導体の塩としては、有機酸塩及び無機酸塩が挙げられる。有機酸塩を形成する酸としては、酢酸、プロピオン酸、乳酸、リンゴ酸、クエン酸、酒石酸、フマル酸、マレイン酸、メシル酸等が挙げられる。無機酸塩を形成する無機酸としては、塩酸、硝酸、硫酸、リン酸、臭化水素酸等が挙げられる。 The salt of the colchicine derivative of the present invention includes organic acid salts and inorganic acid salts. Examples of the acid that forms the organic acid salt include acetic acid, propionic acid, lactic acid, malic acid, citric acid, tartaric acid, fumaric acid, maleic acid, and mesylic acid. Examples of the inorganic acid forming the inorganic acid salt include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
　本発明のコルヒチン誘導体、その塩又はそれらの溶媒和物は、７位が不斉炭素原子であることから、光学活性体である。また、この位置以外に不斉炭素原子がある場合は、その炭素原子に基づく光学異性体が存在し得る。本発明は、これらの光学異性体を全て含むものである。さらに、本発明化合物は、水和物等の溶媒和物の形態である場合も含まれる。 The colchicine derivative of the present invention, a salt thereof or a solvate thereof is an optically active substance since the 7-position is an asymmetric carbon atom. Further, when there is an asymmetric carbon atom other than this position, an optical isomer based on the carbon atom may exist. The present invention includes all these optical isomers. Furthermore, the compound of the present invention includes a solvate such as a hydrate.
　本発明のコルヒチン誘導体の溶媒和物としては、水和物、エタノール溶媒和物等が挙げられる。 Examples of solvates of the colchicine derivative of the present invention include hydrates and ethanol solvates.
　本発明のコルヒチン誘導体（１）は、コルヒチン化合物の４位にハロゲン原子、ヒドロキシ基、ニトロ基、アミノ基又はモノ－、ジ－若しくはトリ－フルオロメチル基を導入することにより製造することができる。例えばハロゲン原子の導入は、コルヒチン化合物に、Ｎ－フルオロベンゼンスルホンイミド、Ｎ－クロロコハク酸イミド、Ｎ－ブロモコハク酸イミド、Ｎ－ヨードコハク酸イミド等のハロゲン化試薬を反応させることにより行われる。当該ハロゲン化反応は、酢酸、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒を用いて、０～１５０℃で１～５０時間行えばよい。 The colchicine derivative (1) of the present invention can be produced by introducing a halogen atom, a hydroxy group, a nitro group, an amino group, or a mono-, di- or trifluoromethyl group at the 4-position of the colchicine compound. For example, the introduction of a halogen atom is performed by reacting a colchicine compound with a halogenating reagent such as N-fluorobenzenesulfonimide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. The halogenation reaction may be performed at 0 to 150 ° C. for 1 to 50 hours using a solvent such as acetic acid, acetonitrile or N, N-dimethylformamide.
　ニトロ基の導入は、コルヒチン化合物に、硝酸二アンモニウムセリウム－トリフルオロ酢酸無水物、硝酸、混酸、硝酸アセチル、ニトロニウム塩等のニトロ化試薬を反応させることにより行われる。この反応は、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、酢酸、ニトロメタン、ニトロエタン等の溶媒中、－７８～１５０℃で１～５０時間行えばよい。 The introduction of the nitro group is carried out by reacting the colchicine compound with a nitrating reagent such as diammonium cerium nitrate-trifluoroacetic anhydride, nitric acid, mixed acid, acetyl nitrate, or nitronium salt. This reaction may be carried out in a halogenated hydrocarbon solvent such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc., or a solvent such as acetic acid, nitromethane, nitroethane, etc. at −78 to 150 ° C. for 1 to 50 hours.
　ヒドロキシ基の導入は、コルヒチン化合物の４位にホルミル基を導入し、次いで酸化することにより行うことができる。まず、ホルミル基の導入は、コルヒチン化合物に、塩化スズ、塩化アルミニウム等のルイス酸とジクロロメチルメチルエーテル等を反応させることにより行われる。次いで、当該ホルミル基の酸化反応は、例えば、モノペルオキシフタル酸　マグネシウム等を反応させることにより行うことができる。 The introduction of the hydroxy group can be carried out by introducing a formyl group at the 4-position of the colchicine compound and then oxidizing it. First, a formyl group is introduced by reacting a colchicine compound with a Lewis acid such as tin chloride or aluminum chloride and dichloromethyl methyl ether. Subsequently, the oxidation reaction of the formyl group can be performed by reacting, for example, magnesium monoperoxyphthalate.
　アミノ基の導入は、４－ニトロコルヒチンを接触還元等により還元するか、又はコルヒチンの４位にカルボキシル基を導入し、次いでこのカルボキシル基をアミノ基に変換すればよい。まず、カルボキシル基の導入反応は、４－ホルミルコルヒチン化合物を酸化することにより行うことができ、例えば亜塩素酸ナトリウム、Ｊｏｎｅｓ試薬、過マンガン酸塩、酸化銀等を反応させればよい。カルボキシル基のアミノ基への変換には、カルボン酸を直接トリエチルアミンとジフェニルリン酸アジドと反応させるか、カルボン酸を酸塩化物又は酸ヒドラジドとしアジ化ナトリウム又は亜硝酸誘導体等を反応させればよい。 The amino group may be introduced by reducing 4-nitrocolchicine by catalytic reduction or the like, or introducing a carboxyl group at the 4-position of colchicine and then converting the carboxyl group to an amino group. First, the carboxyl group introduction reaction can be performed by oxidizing a 4-formylcolchicine compound. For example, sodium chlorite, Jones reagent, permanganate, silver oxide and the like may be reacted. To convert the carboxyl group to an amino group, the carboxylic acid may be reacted directly with triethylamine and diphenyl phosphate azide, or the carboxylic acid may be acid chloride or acid hydrazide and reacted with sodium azide or nitrous acid derivative, etc. .
　モノ－、ジ－若しくはトリ－フルオロメチル基の導入は、モノフルオロメチル基の場合、コルヒチン化合物の４位にホルミル基を導入し、次いで還元により４位をヒドロキシメチル基とした後、ヒドロキシ部分をフッ素化することにより行うことができる。ジフルオロメチル基の場合、４位のホルミル基をジチオアセタールへと変換した後、フッ素化することにより行うことができる。フッ素化試薬としては、例えばフッ化水素－ピリジン錯体、（ジエチルアミノ）サルファートリフルオリド等を用いればよい。 In the case of a monofluoromethyl group, a mono-, di- or tri-fluoromethyl group is introduced by introducing a formyl group at the 4-position of the colchicine compound and then reducing the 4-position to a hydroxymethyl group, It can be performed by fluorination. In the case of a difluoromethyl group, it can be carried out by converting the formyl group at the 4-position to dithioacetal and then fluorinating. As the fluorinating reagent, for example, hydrogen fluoride-pyridine complex, (diethylamino) sulfur trifluoride, etc. may be used.
　本発明のコルヒチン誘導体、その塩又はそれらの溶媒和物は、後記実施例に示すように、ｉｎ　ｖｉｔｒｏ及びｉｎ　ｖｉｖｏにおいて優れた癌細胞増殖阻害活性を示す。また、毒性も低い。従って、本発明のコルヒチン誘導体、その塩又はそれらの溶媒和物は、ヒトを含む哺乳類の抗癌剤として有用である。 The colchicine derivative of the present invention, a salt thereof, or a solvate thereof exhibits excellent cancer cell growth inhibitory activity in vitro and in vivo, as shown in Examples below. It is also less toxic. Therefore, the colchicine derivative of the present invention, a salt thereof or a solvate thereof is useful as an anticancer agent for mammals including humans.
　本発明のコルヒチン誘導体、その塩又はそれらの溶媒和物を医薬として用いる場合、本発明の化合物は、そのままでも投与することができるが、他の薬学的に許容される担体、例えば分散補助剤、賦形剤等の担体と混合し、粉剤、液剤、カプセル剤、懸濁剤、乳剤、シロップ剤、エリキシル剤、顆粒剤、丸剤、錠剤、トローチ剤、リモネーデ剤等の経口剤又は注射剤等の剤形で使用することができる。これらの製剤は、公知の方法で製造することができる。 When the colchicine derivative of the present invention, a salt thereof or a solvate thereof is used as a pharmaceutical, the compound of the present invention can be administered as it is, but other pharmaceutically acceptable carriers such as a dispersion aid, Oral or injection such as powder, liquid, capsule, suspension, emulsion, syrup, elixir, granule, pill, tablet, troche, limonade, etc. Can be used in various dosage forms. These preparations can be produced by known methods.
　担体としては、例えば、マンニトール、乳糖、デキストラン等の水溶性の単糖類ないしオリゴ糖類もしくは多糖類；例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース等のゲル形成性又は水溶性のセルロース類；例えば、結晶性セルロース、α－セルロース、架橋カルボキシメチルセルロースナトリウム、及びそれらの誘導体等の水吸収性でかつ水難溶性のセルロース類；例えば、ヒドロキシプロピル澱粉、カルボキシメチル澱粉、架橋澱粉、アミロース、アミロペクチン、ペクチン及びそれらの誘導体等の水吸収性でかつ水難溶性の多糖類；例えば、アラビアガム、トラガントガム、グリコマンナン及びそれらの誘導体等の水吸収性でかつ水難溶性のガム類；例えば、ポリビニルピロリドン、架橋ポリアクリル酸及びその塩、架橋ポリビニルアルコール、ポリヒドロキシエチルメタクリレート及びそれらの誘導体等の架橋ビニル重合体類；リン脂質、コレステロール等のリポソーム等分子集合体を形成する脂質類等を挙げることができる。 Examples of the carrier include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose, and dextran; for example, gel-forming or water-soluble celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose; Water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, pectin and the like Water-absorbing and poorly water-soluble polysaccharides such as derivatives thereof; for example, water-absorbing and poorly water-soluble gums such as gum arabic, tragacanth gum, glycomannan and derivatives thereof; Cross-linked vinyl polymers such as cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; and lipids that form molecular aggregates such as liposomes such as phospholipids and cholesterol. it can.
　本発明の化合物の溶解性が低い場合には、可溶化処理を施すことができる。可溶化処理としては通常医薬に適用できる方法、例えば、ポリオキシエチレンアルコールエーテル類、ポリオキシエチレンアシルエステル類、ソルビタンアシルエステル類やポリオキシエチレンソルビタンアシルエステル類等の界面活性剤を添加する方法、ポリエチレングリコール等の水溶性高分子を使用する方法等が挙げられる。また、必要により、可溶性の塩にする方法、シクロデキストリン等を用いて包接化合物を形成させる方法等も使用できる。 When the solubility of the compound of the present invention is low, a solubilization treatment can be performed. As a solubilization treatment, a method that can be generally applied to a medicine, for example, a method of adding a surfactant such as polyoxyethylene alcohol ethers, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, Examples thereof include a method using a water-soluble polymer such as polyethylene glycol. Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, and the like can be used.
　本発明の抗癌剤の対象となる癌種としては、頭頚部癌、食道癌、胃癌、結腸癌、直腸癌、肝臓癌、胆嚢・胆管癌、膵臓癌、肺癌、乳癌、卵巣癌、子宮頚癌、子宮体癌、腎癌、膀胱癌、前立腺癌、精巣腫瘍、骨・軟部肉腫、白血病、悪性リンパ腫、多発性骨髄腫、皮膚癌、脳腫瘍等が挙げられる。 Examples of cancer types to be targeted by the anticancer agent of the present invention include head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, Examples include endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor and the like.
　本発明の医薬の投与量は、投与法や患者の症状等に合わせて適宜調整すればよいが、成人１日あたり１ｍｇ～１０ｇ、さらに１００ｍｇ～１０ｇ、特に５００ｍｇ～１０ｇ投与するのが好ましい。 The dosage of the medicament of the present invention may be appropriately adjusted according to the administration method, patient's symptoms, etc., but it is preferable to administer 1 mg to 10 g, further 100 mg to 10 g, particularly 500 mg to 10 g per day for an adult.
　次に本発明を実施例を挙げてさらに詳細に説明するが、これは単に例示であって本発明を限定するものではない。 Next, the present invention will be described in more detail with reference to examples, but this is merely an example and does not limit the present invention.
参考例１
４－ホルミルコルヒチンの合成
　コルヒチン100 mg （0.25 mmol）をジクロロメタン 2.5 mLに溶解し、氷冷下塩化スズ（IV）87.8μL （0.75 mmol, 3 eq）、ジクロロメチルメチルエーテル0.3 mL （3.0 mmol, 12 eq）を順に滴下し、0℃、アルゴン雰囲気下で30分攪拌した後、室温まで昇温しさらに12.5時間攪拌した。反応液に氷、クロロホルムを加え1時間攪拌し、分液漏斗にあけて有機層を分取した後、10%水酸化ナトリウム次いで水で洗浄し、無水硫酸マグネシウムで乾燥後、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10%→ 15%→ 20%メタノール/ 酢酸エチル）にて精製し、表題の化合物134.4 mg (収率 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：10.46 (1H, s, -CHO), 7.55 (1H, br-d, J=6.6Hz, -NH), 7.52 (1H, s, H-8), 7.23 (1H, d, J=10.8Hz, H-12), 6.85 (1H, d, J=10.8Hz, H-11), 4.54 (1H, ddd, J=12.3, 6.2, 6.2Hz, H-7), 4.06 (3H, s, -OMe), 4.02 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.87 (1H, dd, J=13.3, 4.7Hz, H-5β), 3.69 (3H, s, -OMe),2.34 (1H, dddd, J=12.7, 12.7, 6.4, 6.4Hz, H-6β), 2.01 (3H, s, -NHCOCH 3 ), 2.00 (1H, ddd, J=13.2, 13.2, 6.7Hz, H-5α), 1.81 (1H, ddd, J=12.2, 12.2, 4.9Hz, H-6α).
EI-MS m/z (%)：427 (M+, 50.0), 340(100.0). Reference example 1
Synthesis of 4-formylcolchicine 100 mg (0.25 mmol) of colchicine was dissolved in 2.5 mL of dichloromethane, and 87.8 μL (0.75 mmol, 3 eq) of tin (IV) chloride under ice cooling, 0.3 mL (3.0 mmol, 12 eq) of dichloromethyl methyl ether eq) was added dropwise in order, and the mixture was stirred at 0 ° C. in an argon atmosphere for 30 minutes, then warmed to room temperature and further stirred for 12.5 hours. Ice and chloroform were added to the reaction mixture, and the mixture was stirred for 1 hour. After opening the separatory funnel, the organic layer was separated, washed with 10% sodium hydroxide and then with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. And vacuum dried. The obtained residue was purified by silica gel column chromatography (10% → 15% → 20% methanol / ethyl acetate) to obtain 134.4 mg (quantitative yield) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 10.46 (1H, s, -CHO), 7.55 (1H, br-d, J = 6.6 Hz, -NH), 7.52 (1H, s, H- 8), 7.23 (1H, d, J = 10.8Hz, H-12), 6.85 (1H, d, J = 10.8Hz, H-11), 4.54 (1H, ddd, J = 12.3, 6.2, 6.2Hz, H-7), 4.06 (3H, s, -OMe), 4.02 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.87 (1H, dd, J = 13.3, 4.7Hz, H- 5β), 3.69 (3H, s, -OMe), 2.34 (1H, dddd, J = 12.7, 12.7, 6.4, 6.4Hz, H-6β), 2.01 (3H, s, -NHCO CH 3 ), 2.00 (1H , ddd, J = 13.2, 13.2, 6.7Hz, H-5α), 1.81 (1H, ddd, J = 12.2, 12.2, 4.9Hz, H-6α).
EI-MS m / z (%): 427 (M + , 50.0), 340 (100.0).
実施例１
４－ニトロコルヒチンの合成
　硝酸ニアンモニウムセリウム（IV）（CAN）14.3 mg（0.026 mmol, 1.05 eq）をジクロロメタン0.5 mLに溶解し、コルヒチン10 mg （0.025 mmol）、トリフルオロ酢酸無水物12.2 μL （0.0875 mmol, 3.5 eq）を加え、室温で16時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで4回抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10%メタノール/ 酢酸エチル及び5%メタノール/ クロロホルム）にて精製し、表題の化合物1.6 mg（収率 15%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.47 (1H, s, H-8), 7.25 (1H, d, J=11.0Hz, H-12),7.10 (1H, br-d, J=6.7Hz, -NH), 6.84 (1H, d, J=10.8Hz, H-11), 4.61 (1H, ddd, J=12.1, 6.1, 6.1Hz, H-7), 4.04 (3H, s, -OMe), 4.03 (3H, s, -OMe), 4.01 (3H, s, -OMe), 3.68 (3H, s, -OMe), 2.56 (1H, dd, J=13.6, 5.0Hz, H-5β), 2.34 (1H, dddd, J=12.8, 12.8, 6.4, 6.4Hz, H-6β), 2.33 (1H, ddd, J=13.3, 13.3, 6.6Hz, H-5α), 2.02 (3H, s, -NHCOCH 3 ), 1.83 (1H, ddd, J=12.0, 12.0, 6.0Hz, H-6α).
EI-MS m/z (%)：444 (M+, 35.5), 57(100.0) Example 1
Synthesis of 4-nitrocolchicine 14.3 mg (0.026 mmol, 1.05 eq) of diammonium cerium (IV) nitrate (CAN) was dissolved in 0.5 mL of dichloromethane, and 10 mg (0.025 mmol) of colchicine, 12.2 μL of trifluoroacetic anhydride (0.0875 mmol, 3.5 eq) was added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 4 times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried in vacuo. The obtained residue was purified by silica gel column chromatography (10% methanol / ethyl acetate and 5% methanol / chloroform) to obtain 1.6 mg (yield 15%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.47 (1H, s, H-8), 7.25 (1H, d, J = 11.0 Hz, H-12), 7.10 (1H, br-d, J = 6.7Hz, -NH), 6.84 (1H, d, J = 10.8Hz, H-11), 4.61 (1H, ddd, J = 12.1, 6.1, 6.1Hz, H-7), 4.04 (3H, s , -OMe), 4.03 (3H, s, -OMe), 4.01 (3H, s, -OMe), 3.68 (3H, s, -OMe), 2.56 (1H, dd, J = 13.6, 5.0Hz, H- 5β), 2.34 (1H, dddd, J = 12.8, 12.8, 6.4, 6.4Hz, H-6β), 2.33 (1H, ddd, J = 13.3, 13.3, 6.6Hz, H-5α), 2.02 (3H, s , -NHCO CH 3 ), 1.83 (1H, ddd, J = 12.0, 12.0, 6.0Hz, H-6α).
EI-MS m / z (%): 444 (M + , 35.5), 57 (100.0)
実施例２
４－ヒドロキシコルヒチンの合成
　４－ホルミルコルヒチン15.7 mg（0.037 mmol）をメタノール0.37 mLに溶解し、80%モノペルオキシフタル酸　マグネシウム（MMPP）22.3 mg（0.036 mmol, 3 eq）を加え、室温で4時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えクエンチし、1N塩酸で酸性とし、クロロホルムで4回抽出した。有機層を分取し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（3%メタノール/ クロロホルム）にて精製し、表題の化合物5.7 mg（収率 37%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.46 (1H, s, H-8), 7.32 (1H, d, J=10.6Hz, H-12),6.86 (1H, br-d, J=8.4Hz, -NH), 6.83 (1H, d, J=11.2Hz, H-11), 5.68 (1H, br-s, -OH), 4.63 (1H, ddd, J=12.3, 6.3, 6.3Hz, H-7), 4.02 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.58 (3H, s, -OMe), 3.15 (1H, dd, J=13.7, 5.9Hz, H-5β),2.25 (1H, dddd, J=12.6, 12.6, 6.3, 6.3Hz, H-6β), 2.00 (3H, s, -NHCOCH 3 ), 1.97(1H, ddd, J=13.4, 13.4, 6.6Hz, H-5α), 1.78 (1H, ddd, J=11.9, 11.9, 5.9Hz, H-6α).
EI-MS m/z (%)：415 (M+, 100.0), 328 (55.8), 313 (65.5). Example 2
Synthesis of 4-hydroxycolchicine Dissolve 15.7 mg (0.037 mmol) of 4-formylcolchicine in 0.37 mL of methanol, add 22.3 mg (0.036 mmol, 3 eq) of 80% magnesium monoperoxyphthalate (MMPP), and then at room temperature for 4 hours. Stir. The reaction solution was quenched by adding saturated aqueous sodium hydrogen carbonate solution, acidified with 1N hydrochloric acid, and extracted four times with chloroform. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (3% methanol / chloroform) to obtain 5.7 mg (yield 37%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.46 (1H, s, H-8), 7.32 (1H, d, J = 10.6 Hz, H-12), 6.86 (1H, br-d, J = 8.4Hz, -NH), 6.83 (1H, d, J = 11.2Hz, H-11), 5.68 (1H, br-s, -OH), 4.63 (1H, ddd, J = 12.3, 6.3, 6.3 Hz, H-7), 4.02 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.58 (3H, s, -OMe), 3.15 (1H , dd, J = 13.7, 5.9Hz, H-5β), 2.25 (1H, dddd, J = 12.6, 12.6, 6.3, 6.3Hz, H-6β), 2.00 (3H, s, -NHCO CH 3 ), 1.97 (1H, ddd, J = 13.4, 13.4, 6.6Hz, H-5α), 1.78 (1H, ddd, J = 11.9, 11.9, 5.9Hz, H-6α).
EI-MS m / z (%): 415 (M + , 100.0), 328 (55.8), 313 (65.5).
参考例２
コルヒチン－４－カルボン酸の合成
　４－ホルミルコルヒチン170 mg（0.4 mmol）をt-ブタノール2.0 mLと水1.0 mLの混液に溶解し、氷冷下２－メチル－２－ブテン（2Mテトラヒドロフラン溶液）3 mL（6.0 mmol, 15 eq）、亜塩素酸ナトリウム181 mg（2.0 mmol, 5 eq）、リン酸ニ水素ナトリウム480 mg（4.0 mmol, 10 eq）を順に加え、室温で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えてクエンチし、10%メタノール/ クロロホルムで4回抽出した。有機層を飽和食塩水で洗浄、MgSO4乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10% [10% 酢酸含有メタノール] / クロロホルム）にて精製し、表題の化合物174.6 mg（収率 99%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.65 (1H, s, H-8), 7.44 (1H, br-s, -NH), 7.32 (1H, d, J=10.8Hz, H-12), 6.92 (1H, d, J=11.0Hz, H-11), 4.64 (1H, ddd, J=12.2, 6.3,6.3Hz, H-7), 4.03 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.96 (3H, s, -OMe), 3.65 (3H, s, -OMe), 2.81 (1H, dd, J=13.7, 4.6Hz, H-5β), 2.33 (1H, dddd, J=12.4, 12.4,6.2, 6.2Hz, H-6β), 2.18 (1H, ddd, J=13.1, 13.1, 6.2Hz, H-5α), 1.99 (3H, s, -NHCOCH 3 ), 1.81 (1H, ddd, J=11.6, 11.6, 5.6Hz, H-6α).
EI-MS m/z (%)：443 (M+, 44.7), 370 (80.0), 338 (100.0). Reference example 2
Synthesis of colchicine-4-carboxylic acid 170 mg (0.4 mmol) of 4-formylcolchicine was dissolved in a mixture of 2.0 mL of t-butanol and 1.0 mL of water, and 2-methyl-2-butene (2M tetrahydrofuran solution) 3 under ice-cooling. mL (6.0 mmol, 15 eq), sodium chlorite 181 mg (2.0 mmol, 5 eq) and sodium dihydrogen phosphate 480 mg (4.0 mmol, 10 eq) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was quenched by adding a saturated aqueous ammonium chloride solution, and extracted four times with 10% methanol / chloroform. The organic layer was washed with saturated brine, dried over MgSO 4 , filtered, evaporated under reduced pressure, and dried in vacuo. The obtained residue was purified by silica gel column chromatography (10% [10% acetic acid-containing methanol] / chloroform) to obtain 174.6 mg (yield 99%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.65 (1H, s, H-8), 7.44 (1H, br-s, -NH), 7.32 (1H, d, J = 10.8Hz, H -12), 6.92 (1H, d, J = 11.0Hz, H-11), 4.64 (1H, ddd, J = 12.2, 6.3,6.3Hz, H-7), 4.03 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.96 (3H, s, -OMe), 3.65 (3H, s, -OMe), 2.81 (1H, dd, J = 13.7, 4.6Hz, H-5β), 2.33 ( 1H, dddd, J = 12.4, 12.4,6.2, 6.2Hz, H-6β), 2.18 (1H, ddd, J = 13.1, 13.1, 6.2Hz, H-5α), 1.99 (3H, s, -NHCO CH 3 ), 1.81 (1H, ddd, J = 11.6, 11.6, 5.6Hz, H-6α).
EI-MS m / z (%): 443 (M + , 44.7), 370 (80.0), 338 (100.0).
実施例３
４－フルオロコルヒチンの合成
　コルヒチン30 mg（0.075 mmol）をギ酸0.75 mLに溶解し、N-フルオロベンゼンスルホンイミド（NFSi）47.3 mg（0.15 mmol, 2 eq）を加えて、アルゴン雰囲気下70℃にて12時間攪拌した。その後、NFSi 47.3 mg (0.15 mmol, 2 eq)を加えて6.5時間撹拌した。さらにNFSi 47.3 mg (0.15 mmol, 2 eq)、ギ酸0.5 mLを追加し、6.5時間撹拌した。室温まで放冷し、反応液に飽和チオ硫酸ナトリウム水溶液を加えて数分間攪拌した後、水酸化ナトリウムを加えて塩基性にした。クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10% → 15%メタノール/ 酢酸エチル）にて精製し、表題の化合物4.5 mg（収率 15%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.48 (1H, H-8), 7.31 (1H, d, J=10.6 Hz, H-12), 7.04 (1H, br-d, J=4.8Hz, -NH), 6.84 (1H, d, J=10.8Hz, H-11), 4.61(1H, ddd, J=12.2, 6.2, 6.2Hz, H-7), 4.01 (6H, s, -OMe), 4.00 (3H, s, -OMe), 3.61 (3H, s, -OMe), 3.07 (1H, dd, J=13.9, 6.0Hz, H-5β), 2.27 (1H, dddd, J=12.6, 12.6, 6.3, 6.3Hz, H-6β), 2.04 (1H, overlapped, H-5α), 2.00 (3H, s, -NHCOCH 3 ), 1.84(1H, ddd, J=12.2, 12.2, 6.6Hz, H-6α).
FAB-MS (NBA) m/z : 417 [M+H]+. Example 3
Synthesis of 4-fluorocolchicine 30 mg (0.075 mmol) of colchicine was dissolved in 0.75 mL of formic acid, 47.3 mg (0.15 mmol, 2 eq) of N-fluorobenzenesulfonimide (NFSi) was added, and the atmosphere was 70 ° C. under an argon atmosphere. Stir for 12 hours. Then, 47.3 mg (0.15 mmol, 2 eq) of NFSi was added and stirred for 6.5 hours. Furthermore, 47.3 mg (0.15 mmol, 2 eq) of NFSi and 0.5 mL of formic acid were added, and the mixture was stirred for 6.5 hours. The mixture was allowed to cool to room temperature, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for several minutes, and then made basic with sodium hydroxide. Extraction was performed 4 times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% → 15% methanol / ethyl acetate) to obtain 4.5 mg (yield 15%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, H-8), 7.31 (1H, d, J = 10.6 Hz, H-12), 7.04 (1H, br-d, J = 4.8Hz, -NH), 6.84 (1H, d, J = 10.8Hz, H-11), 4.61 (1H, ddd, J = 12.2, 6.2, 6.2Hz, H-7), 4.01 (6H, s,- OMe), 4.00 (3H, s, -OMe), 3.61 (3H, s, -OMe), 3.07 (1H, dd, J = 13.9, 6.0Hz, H-5β), 2.27 (1H, dddd, J = 12.6 , 12.6, 6.3, 6.3Hz, H-6β), 2.04 (1H, overlapped, H-5α), 2.00 (3H, s, -NHCO CH 3 ), 1.84 (1H, ddd, J = 12.2, 12.2, 6.6Hz , H-6α).
FAB-MS (NBA) m / z: 417 [M + H] + .
参考例３
４－クロロコルヒチンの合成
　コルヒチン200 mg（0.5 mmol）を酢酸0.25 mLに溶解し、N-クロロコハク酸イミド（NCS）133.5 mg（1.0 mmol, 2 eq）を加えて、アルゴン雰囲気下70℃にて3時間攪拌した。室温まで放冷し、反応液に飽和チオ硫酸ナトリウム水溶液を加えて数分間攪拌した後、飽和炭酸水素ナトリウム水溶液を加えて塩基性にした。クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10%メタノール/酢酸エチル）にて精製し、表題の化合物177.2 mg（収率 82%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.60 (1H, br-d, J=5.9Hz, -NH), 7.54 (1H, s, H-8), 7.30 (1H, d, J=10.6Hz, H-12), 6.86 (1H, d, J=11.0Hz, H-11), 4.55 (1H, ddd, J=12.3, 6.3, 6.3Hz, H-7), 4.02 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.63 (3H, s, -OMe), 3.26(1H, dd, J=13.5, 4.9Hz, H-5β), 2.30 (1H, dddd, J=12.7, 12.7, 6.3, 6.3Hz, H-6β), 2.16 (1H, ddd, J=13.4, 13.4, 6.3Hz, H-5α), 2.00 (3H, s, -NHCOCH 3 ), 1.85 (1H, ddd, J=12.3, 12.3, 5.6Hz, H-6α).
EI-MS m/z (%)： 433 (M+, 18.5), 435 ([M+2]+, 6.7), 91 (100.0). Reference example 3
Synthesis of 4-chlorocolchicine 200 mg (0.5 mmol) of colchicine was dissolved in 0.25 mL of acetic acid, 133.5 mg (1.0 mmol, 2 eq) of N-chlorosuccinimide (NCS) was added, and the mixture was added at 70 ° C. under an argon atmosphere. Stir for hours. The mixture was allowed to cool to room temperature, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for several minutes. Extraction was performed 4 times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% methanol / ethyl acetate) to give the title compound (177.2 mg, yield 82%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.60 (1H, br-d, J = 5.9 Hz, -NH), 7.54 (1H, s, H-8), 7.30 (1H, d, J = 10.6Hz, H-12), 6.86 (1H, d, J = 11.0Hz, H-11), 4.55 (1H, ddd, J = 12.3, 6.3, 6.3Hz, H-7), 4.02 (3H, s , -OMe), 4.00 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.63 (3H, s, -OMe), 3.26 (1H, dd, J = 13.5, 4.9Hz, H- 5β), 2.30 (1H, dddd, J = 12.7, 12.7, 6.3, 6.3Hz, H-6β), 2.16 (1H, ddd, J = 13.4, 13.4, 6.3Hz, H-5α), 2.00 (3H, s , -NHCO CH 3 ), 1.85 (1H, ddd, J = 12.3, 12.3, 5.6Hz, H-6α).
EI-MS m / z (%): 433 (M + , 18.5), 435 ([M + 2] + , 6.7), 91 (100.0).
参考例４
４－ブロモコルヒチンの合成
　コルヒチン10 mg（0.025 mmol）を酢酸0.25 mLに溶解し、N-ブロモコハク酸イミド（NBS）6.7 mg（0.05 mmol, 2 eq）を加えて、アルゴン雰囲気下70℃にて13時間攪拌した。室温まで放冷し、反応液に飽和チオ硫酸ナトリウム水溶液を加えて数分間攪拌した後、飽和炭酸水素ナトリウム水溶液を加えて塩基性にした。クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（5% → 10%メタノール/ クロロホルム）にて精製し、表題の化合物3.4 mg（収率 29%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.99 (1H, br-s, -NH), 7.58 (1H, s, H-8), 7.29 (1H, d, J=10.6Hz, H-12), 6.87 (1H, d, J=10.8Hz, H-11), 4.52 (1H, ddd, J=12.2, 6.2,6.2Hz, H-7), 4.02 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.95 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.25 (1H, dd, J=13.4, 5.2Hz, H-5β), 2.31 (1H, dddd, J=12.6, 12.6,6.3, 6.3Hz, H-6β), 2.24 (1H, ddd, J=13.4, 13.4, 6.1Hz, H-5α), 1.85 (3H, s, -NHCOCH 3 ), 1.74 (1H, ddd, J=11.9, 11.9, 5.8Hz, H-6α).
EI-MS m/z (%)：477 (M+, 4.3), 479 ([M+2]+). Reference example 4
Synthesis of 4-bromocolchicine 10 mg (0.025 mmol) of colchicine was dissolved in 0.25 mL of acetic acid, and 6.7 mg (0.05 mmol, 2 eq) of N-bromosuccinimide (NBS) was added. Stir for hours. The mixture was allowed to cool to room temperature, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for several minutes. Extraction was performed 4 times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (5% → 10% methanol / chloroform) to obtain 3.4 mg (yield 29%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.99 (1H, br-s, -NH), 7.58 (1H, s, H-8), 7.29 (1H, d, J = 10.6Hz, H -12), 6.87 (1H, d, J = 10.8Hz, H-11), 4.52 (1H, ddd, J = 12.2, 6.2, 6.2Hz, H-7), 4.02 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.95 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.25 (1H, dd, J = 13.4, 5.2Hz, H-5β), 2.31 ( 1H, dddd, J = 12.6, 12.6,6.3, 6.3Hz, H-6β), 2.24 (1H, ddd, J = 13.4, 13.4, 6.1Hz, H-5α), 1.85 (3H, s, -NHCO CH 3 ), 1.74 (1H, ddd, J = 11.9, 11.9, 5.8Hz, H-6α).
EI-MS m / z (%): 477 (M + , 4.3), 479 ([M + 2] + ).
参考例５
４－ヨードコルヒチンの合成
　コルヒチン100 mg（0.25 mmol）を酢酸2.5 mLに溶解し、N-ヨードコハク酸イミド（NIS）112.49 mg（0.5 mmol, 2 eq）を加えて、アルゴン雰囲気下70℃にて7時間攪拌した。室温まで放冷し、反応液に飽和チオ硫酸ナトリウム水溶液を加えて数分間攪拌した後、飽和炭酸水素ナトリウム水溶液を加えて塩基性にした。クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（5% → 10% メタノール/ クロロホルム）にて精製し、表題の化合物129.5 mg（収率 98.6%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.49 (1H, s, H-8), 7.26 (1H, d, J=10.6Hz, H-12),7.15 (1H, br-d, J=6.8Hz, -NH), 6.84 (1H, d, J=11.2Hz, H-11), 4.50 (1H, ddd, J=12.2, 6.2, 6.2Hz, H-7), 4.02 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.95 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.18 (1H, dd, J=13.5, 5.1Hz, H-5β), 2.43 (1H, ddd, J=13.7, 13.7, 6.0Hz, H-5α), 2.28 (1H, dddd, J=12.6, 12.6, 6.4, 6.4Hz, H-6β), 2.00 (3H, s, -NHCOCH 3 ), 1.75 (1H, ddd, J=11.8, 11.8, 5.7Hz, H-6α).
EI-MS m/z (%)：525 (M+, 68.6), 438 (100.0). Reference Example 5
Synthesis of 4-iodocolchicine 100 mg (0.25 mmol) of colchicine was dissolved in 2.5 mL of acetic acid, 112.49 mg (0.5 mmol, 2 eq) of N-iodosuccinimide (NIS) was added, and 7 at 7O 0 C under an argon atmosphere. Stir for hours. The mixture was allowed to cool to room temperature, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for several minutes. Extraction was performed 4 times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (5% → 10% methanol / chloroform) to obtain 129.5 mg (yield 98.6%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.49 (1H, s, H-8), 7.26 (1H, d, J = 10.6 Hz, H-12), 7.15 (1H, br-d, J = 6.8Hz, -NH), 6.84 (1H, d, J = 11.2Hz, H-11), 4.50 (1H, ddd, J = 12.2, 6.2, 6.2Hz, H-7), 4.02 (3H, s , -OMe), 3.97 (3H, s, -OMe), 3.95 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.18 (1H, dd, J = 13.5, 5.1Hz, H- 5β), 2.43 (1H, ddd, J = 13.7, 13.7, 6.0Hz, H-5α), 2.28 (1H, dddd, J = 12.6, 12.6, 6.4, 6.4Hz, H-6β), 2.00 (3H, s , -NHCO CH 3 ), 1.75 (1H, ddd, J = 11.8, 11.8, 5.7Hz, H-6α).
EI-MS m / z (%): 525 (M + , 68.6), 438 (100.0).
実施例４
４－アミノコルヒチンの合成
　コルヒチン-4-カルボン酸5.0 mg（0.011 mmol）をテトラヒドロフラン0.3 mLに溶解し、氷冷下トリエチルアミン2.3μL（0.0165 mmol, 1.5 eq）、ジフェニルリン酸アジド（DPPA）2.8 μL（0.013 mmol, 1.2 eq）を加え室温で4時間攪拌した。さらに水0.15 mLを加え、1時間煮沸還流した。反応液に飽和炭酸カリウム水溶液を加え、クロロホルムで4回抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10%メタノール/ クロロホルム）にて精製し、表題の化合物1.7 mg（収率 37%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.49 (1H, s, H-8), 7.33 (1H, d, J=10.8Hz, H-12),7.09 (1H, br-s, -NH), 6.85 (1H, d, J=10.8Hz, H-11), 4.65 (1H, ddd, J=12.1, 6.1,6.1Hz, H-7), 4.00 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.94 (3H, s, -OMe), 3.72 (2H, br-s, -NH2), 3.55 (3H, s, -OMe), 2.63 (1H, dd, J=14.0, 5.1Hz, H-5β), 2.26 (1H, dddd, J=12.6, 12.6, 6.3, 6.3Hz, H-6β), 2.12 (1H, ddd, J=13.9, 13.9, 6.1Hz, H-5α), 2.00 (3H, s, -NHCOCH 3 ), 1.80 (1H, ddd, J=11.7, 11.7, 5.6Hz, H-6α).
FAB-MS(NBA) m/z：415 [M+H]+. Example 4
Synthesis of 4-aminocolchicine 5.0 mg (0.011 mmol) of colchicine-4-carboxylic acid was dissolved in 0.3 mL of tetrahydrofuran, and 2.3 μL (0.0165 mmol, 1.5 eq) of triethylamine, 2.8 μL of diphenylphosphoric acid azide (DPPA) under ice-cooling ( 0.013 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 4 hours. Further, 0.15 mL of water was added, and the mixture was boiled and refluxed for 1 hour. A saturated aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted 4 times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% methanol / chloroform) to obtain 1.7 mg (yield 37%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.49 (1H, s, H-8), 7.33 (1H, d, J = 10.8 Hz, H-12), 7.09 (1H, br-s, -NH), 6.85 (1H, d, J = 10.8Hz, H-11), 4.65 (1H, ddd, J = 12.1, 6.1,6.1Hz, H-7), 4.00 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.94 (3H, s, -OMe), 3.72 (2H, br-s, -NH 2 ), 3.55 (3H, s, -OMe), 2.63 (1H, dd, J = 14.0, 5.1Hz, H-5β), 2.26 (1H, dddd, J = 12.6, 12.6, 6.3, 6.3Hz, H-6β), 2.12 (1H, ddd, J = 13.9, 13.9, 6.1Hz, H- 5α), 2.00 (3H, s, -NHCO CH 3 ), 1.80 (1H, ddd, J = 11.7, 11.7, 5.6Hz, H-6α).
FAB-MS (NBA) m / z: 415 [M + H] + .
参考例６
グロリオサミンＡの合成
　４－ヒドロキシ－２，３－（メチレンジオキシ）－２，３－ジデメトキシコルヒチン2.3 mg（0.0057 mmol）をアセトン0.3 mLに溶解し、炭酸カリウム3.6 mg（0.026 mmol, 5 eq）、ヨウ化メチル3.5 μL（0.057 mmol, 10 eq）を順に加え、50℃で8.5時間撹拌した。反応液に水を加えてクエンチし、クロロホルムで4回抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（4%メタノール/ クロロホルム）にて精製し、表題の化合物1.2 mg（収率 55%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.50 (1H, s, H-8), 7.77 (1H, br-d, J=7.7Hz, -NH), 7.26 (1H, d, J=10.6Hz, H-12), 6.85 (1H, d, J=10.8Hz, H-11), 6.03 (1H, d, J=1.5Hz, -OCH2O-), 6.02 (1H, d, J=1.5Hz, -OCH2O-), 4.62 (1H, ddd, J=12.1, 6.1, 6.1Hz,H-7), 4.01 (3H, s, -OMe), 3.92 (3H, s, -OMe), 3.69 (3H, s, -OMe), 3.11 (1H, dd,J=13.5, 6.0Hz, H-5β), 2.22 (1H, dddd, J=12.5, 12.5, 6.2, 6.2Hz, H-6β), 1.99 (3H, s, -NHCOCH 3 ), 1.90 (1H, ddd, J=13.2, 13.2, 6.7Hz, H-5α), 1.80 (1H, ddd, J=11.9, 11.9, 6.4Hz, H-6α).
EI-MS m/z (%) : 413 (M+, 91.5). Reference Example 6
Synthesis of Gloriosamine A 2.3 mg (0.0057 mmol) of 4-hydroxy-2,3- (methylenedioxy) -2,3-didemethoxycolchicine was dissolved in 0.3 mL of acetone, and 3.6 mg (0.026 mmol, 5 eq) of potassium carbonate ) And methyl iodide 3.5 μL (0.057 mmol, 10 eq) were sequentially added, and the mixture was stirred at 50 ° C. for 8.5 hours. The reaction solution was quenched by adding water, and extracted four times with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (4% methanol / chloroform) to obtain 1.2 mg (yield 55%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.50 (1H, s, H-8), 7.77 (1H, br-d, J = 7.7 Hz, -NH), 7.26 (1H, d, J = 10.6Hz, H-12), 6.85 (1H, d, J = 10.8Hz, H-11), 6.03 (1H, d, J = 1.5Hz, -OCH 2 O-), 6.02 (1H, d, J = 1.5Hz, -OCH 2 O-), 4.62 (1H, ddd, J = 12.1, 6.1, 6.1Hz, H-7), 4.01 (3H, s, -OMe), 3.92 (3H, s, -OMe) , 3.69 (3H, s, -OMe), 3.11 (1H, dd, J = 13.5, 6.0Hz, H-5β), 2.22 (1H, dddd, J = 12.5, 12.5, 6.2, 6.2Hz, H-6β) , 1.99 (3H, s, -NHCO CH 3 ), 1.90 (1H, ddd, J = 13.2, 13.2, 6.7Hz, H-5α), 1.80 (1H, ddd, J = 11.9, 11.9, 6.4Hz, H- 6α).
EI-MS m / z (%): 413 (M + , 91.5).
参考例７
４－ヒドロキシ－２，３－（メチレンジオキシ）－２，３－ジデメトキシコルヒチンの合成
　２，３－ジデメチルコルヒチン38 mg（0.102 mmol）をアセトニトリル1 mLに懸濁し、炭酸カリウム112.8 mg（0.816 mmol, 8 eq）、ブロモクロロメタン0.5 mL （過剰量）を加え、60℃で21時間撹拌した。反応液に水を加えてクエンチし、クロロホルムで3回抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（4%メタノール/ クロロホルム）にて精製し、２，３－（メチレンジオキシ）－２，３－ジデメトキシコルヒチン（コルニゲリン）21.4 mg（収率 55%）を得た。コルニゲリン20 mg（0.052 mmol）をジクロロメタン0.52 mLに溶解し、氷冷下塩化すず（IV）18.3 μL（0.156 mmol, 3 eq）、ジクロロメチルメチルエーテル56.5 μL（0.624 mmol, 12 eq）を順に滴下、0℃、アルゴン雰囲気下、30分攪拌した後、室温まで昇温しさらに7時間攪拌した。反応液に氷、クロロホルムを加え1時間攪拌し、分液漏斗にあけて有機層を分取した後、10%水酸化ナトリウム次いで、水で洗浄した。有機層を硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥し、得られた残渣をそのまま次の反応に用いた。４－ホルミル－２，３－（メチレンジオキシ）－ジデメトキシコルヒチン18 mg（0.044 mmol）をメタノール0.44 mLに溶解し、80%モノペルオキシフタル酸マグネシウム（MMPP）81.9 mg（0.132 mmol, 3 eq）を加え室温で18時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えクエンチし、1N塩酸で酸性とし、クロロホルムで4回抽出し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（4%メタノール/ クロロホルム）にて精製し、表題の化合物1.3 mg（収率 7%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.33 (1H, s, H-8), 7.32 (1H, d, J=9.0Hz, H-12), 6.92 (1H, d, J=11.0Hz, H-11), 6.02 (1H, d, J=1.3Hz, -OCH2O-), 6.00 (1H, d, J=1.3Hz, -OCH2O-), 4.63 (1H, ddd, J=12.7, 6.5, 6.5Hz, H-7), 4.01 (3H, s, -OMe), 3.64 (3H, s, -OMe), 3.14 (1H, dd, J=13.5, 6.1Hz, H-5β), 2.16 (1H, dddd, J=12.3, 12.3, 6.1, 6.1Hz, H-6β), 2.01 (3H, s, -NHCOCH 3 ), 1.87 (1H, ddd, J=13.0, 13.0, 6.7Hz, H-5α), 1.78 (1H, ddd, J=11.7, 11.7, 6.1Hz, H-6α).
EI-MS m/z (%) : 399 (M+, 75.3) Reference Example 7
Synthesis of 4-hydroxy-2,3- (methylenedioxy) -2,3-didemethoxycolchicine 38 mg (0.102 mmol) of 2,3-didemethylcolchicine was suspended in 1 mL of acetonitrile, and 112.8 mg of potassium carbonate (0.816 mmol, 8 eq) and 0.5 mL of bromochloromethane (excess) were added, and the mixture was stirred at 60 ° C. for 21 hours. The reaction solution was quenched by adding water, extracted three times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (4% methanol / chloroform), and 2,3- (methylenedioxy) -2,3-didemethoxycolchicine (cornigelin) 21.4 mg (55% yield) Got. Cornigerin 20 mg (0.052 mmol) is dissolved in 0.52 mL of dichloromethane, and tin chloride (IV) 18.3 μL (0.156 mmol, 3 eq) and dichloromethyl methyl ether 56.5 μL (0.624 mmol, 12 eq) are added dropwise in this order under ice-cooling. After stirring for 30 minutes in an argon atmosphere at 0 ° C., the mixture was warmed to room temperature and further stirred for 7 hours. Ice and chloroform were added to the reaction solution, and the mixture was stirred for 1 hour. The organic layer was separated by opening in a separatory funnel, and then washed with 10% sodium hydroxide and then with water. The organic layer was dried over magnesium sulfate, filtered, evaporated under reduced pressure, and dried in vacuo, and the resulting residue was used as such for the next reaction. 4-Formyl-2,3- (methylenedioxy) -didemethoxycolchicine 18 mg (0.044 mmol) is dissolved in 0.44 mL of methanol, and 80% magnesium monoperoxyphthalate (MMPP) 81.9 mg (0.132 mmol, 3 eq) And stirred at room temperature for 18 hours. The reaction solution was quenched by adding a saturated aqueous sodium hydrogen carbonate solution, acidified with 1N hydrochloric acid, extracted four times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (4% methanol / chloroform) to obtain 1.3 mg (yield 7%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.33 (1H, s, H-8), 7.32 (1H, d, J = 9.0 Hz, H-12), 6.92 (1H, d, J = 11.0Hz, H-11), 6.02 (1H, d, J = 1.3Hz, -OCH 2 O-), 6.00 (1H, d, J = 1.3Hz, -OCH 2 O-), 4.63 (1H, ddd, J = 12.7, 6.5, 6.5Hz, H-7), 4.01 (3H, s, -OMe), 3.64 (3H, s, -OMe), 3.14 (1H, dd, J = 13.5, 6.1Hz, H-5β ), 2.16 (1H, dddd, J = 12.3, 12.3, 6.1, 6.1Hz, H-6β), 2.01 (3H, s, -NHCO CH 3 ), 1.87 (1H, ddd, J = 13.0, 13.0, 6.7Hz , H-5α), 1.78 (1H, ddd, J = 11.7, 11.7, 6.1Hz, H-6α).
EI-MS m / z (%): 399 (M + , 75.3)
参考例８
４－メトキシ－１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチンの合成
　４－ヒドロキシ－１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチン7.0 mg（0.018 mmol）をアセトン0.28 mLに溶解し、炭酸カリウム12.4 mg（0.09 mmol, 5 eq）、ヨウ化メチル22.6 μL（0.18 mmol, 10 eq）を順に加え、室温で8時間、55℃で12時間、次いで70℃で8時間撹拌した。反応液に水を加えてクエンチし、クロロホルムで4回抽出、飽和食塩水で洗浄、硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（4%メタノール/ クロロホルム）にて精製し、表題の化合物2.0 mg（収率 27%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.41 (1H, s, H-8), 7.33 (1H, d, J=10.6Hz, H-12),6.80 (1H, d, J=10.8Hz, H-11), 6.52 (1H, br-d, J=7.3Hz, -NH), 6.03 (1H, d, J=1.5Hz, -OCH2O-), 5.89 (1H, d, J=1.5Hz, -OCH2O-), 4.71 (1H, ddd, J=12.3, 6.3, 6.3Hz,H-7), 4.08 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.77 (3H, s, -OMe), 3.11 (1H, dd,J=13.8, 5,9Hz, H-5β), 2.28 (1H, dddd, J=12.7, 12.7, 6.4, 6.4Hz, H-6β), 2.02 (1H,ddd, J=13.4, 13.4, 6.4Hz, H-5α), 2.00 (3H, s, -NHCOCH 3 ), 1.83 (1H, ddd, J=11.6, 11.6, 5.6Hz, H-6α).
EI-MS m/z (%) : 413 (M+, 67). Reference Example 8
Synthesis of 4-methoxy-1,2- (methylenedioxy) -1,2-didemethoxycolchicine 4-hydroxy-1,2- (methylenedioxy) -1,2-didemethoxycolchicine 7.0 mg (0.018 mmol) Is dissolved in 0.28 mL of acetone, and 12.4 mg (0.09 mmol, 5 eq) of potassium carbonate and 22.6 μL of methyl iodide (0.18 mmol, 10 eq) are added in that order. For 8 hours. The reaction solution was quenched by adding water, extracted four times with chloroform, washed with saturated brine, dried over magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (4% methanol / chloroform) to give the title compound (2.0 mg, yield 27%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.41 (1H, s, H-8), 7.33 (1H, d, J = 10.6 Hz, H-12), 6.80 (1H, d, J = 10.8Hz, H-11), 6.52 (1H, br-d, J = 7.3Hz, -NH), 6.03 (1H, d, J = 1.5Hz, -OCH 2 O-), 5.89 (1H, d, J = 1.5Hz, -OCH 2 O-), 4.71 (1H, ddd, J = 12.3, 6.3, 6.3Hz, H-7), 4.08 (3H, s, -OMe), 3.98 (3H, s, -OMe) , 3.77 (3H, s, -OMe), 3.11 (1H, dd, J = 13.8, 5,9Hz, H-5β), 2.28 (1H, dddd, J = 12.7, 12.7, 6.4, 6.4Hz, H-6β ), 2.02 (1H, ddd, J = 13.4, 13.4, 6.4Hz, H-5α), 2.00 (3H, s, -NHCO CH 3 ), 1.83 (1H, ddd, J = 11.6, 11.6, 5.6Hz, H -6α).
EI-MS m / z (%): 413 (M + , 67).
参考例９
４－ヒドロキシ－１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチンの合成
　１，２－ジデメチルコルヒチン100 mg（0.27 mmol）をアセトニトリル3 mLに懸濁し、炭酸カリウム298.5 mg（2.16 mmol, 8 eq）、ブロモクロロメタン1 mL（過剰量）を加え、60℃で19時間撹拌した。反応液に水を加えてクエンチし、クロロホルムで3回抽出、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。シリカゲルカラムクロマトグラフ法（5%メタノール/ クロロホルム）にて精製し、１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチン110.5 mg（収率 定量的）を得た。
　このもの60 mg（0.156 mmol）をジクロロメタン1.5 mLに溶解し、氷冷下塩化すず（IV）55 μL （0.468 mmol, 3 eq）、ジクロロメチルメチルエーテル0.17 mL（1.872 mmol, 12 eq）を順に滴下、0℃、アルゴン雰囲気下、30分攪拌した後、室温まで昇温しさらに6.5時間攪拌した。反応液に氷、クロロホルムを加え1時間攪拌、分液漏斗にあけて有機層を分取した後、10%水酸化ナトリウム次いで水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥し、得られた残渣をそのまま次の反応に用いた。４－ホルミル－１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチン39 mg（0.095 mmol）をメタノール0.95 mLに溶解し、80%モノペルオキシフタル酸　マグネシウム（MMPP）117.5 mg（0.19 mmol, 3 eq）を加え室温で18時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えクエンチし、1N塩酸で酸性とし、クロロホルムで4回抽出し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（4%メタノール/ クロロホルム）にて精製し、表題の化合物8 mg（収率 21%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.32 (1H, s, H-8), 7.43 (1H, d, J=10.8Hz, H-12),7.43 (1H, d, J=11.0Hz, H-11), 6.00 (1H, d, J=1.5Hz, -OCH2O-), 5.87 (1H, d, J=1.3Hz, -OCH2O-), 4.70 (1H, ddd, J=12.6, 6.5, 6.5Hz, H-7), 4.09 (3H, s, -OMe), 4.00(3H, s, -OMe), 3.15 (1H, dd, J=13.8, 6.0Hz, H-5β), 2.24 (1H, dddd, J=12.7, 12.7,6.4, 6.4Hz, H-6β), 2.00 (3H, s, -NHCOCH 3 ), 1.96 (1H, ddd, J=13.6, 13.6, 6.7Hz,H-5α), 1.84 (1H, ddd, J=11.8, 11.8, 6.0Hz, H-6α).
EI-MS m/z (%) : 399 (M+, 72.6). Reference Example 9
Synthesis of 4-hydroxy-1,2- (methylenedioxy) -1,2-didemethoxycolchicine 100 mg (0.27 mmol) of 1,2-didemethylcolchicine was suspended in 3 mL of acetonitrile, and 298.5 mg of potassium carbonate (2.16 mmol, 8 eq) and 1 mL of bromochloromethane (excess) were added, and the mixture was stirred at 60 ° C. for 19 hours. The reaction solution was quenched by adding water, extracted three times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The product was purified by silica gel column chromatography (5% methanol / chloroform) to obtain 110.5 mg (quantitative yield) of 1,2- (methylenedioxy) -1,2-didemethoxycolchicine.
Dissolve 60 mg (0.156 mmol) of this in 1.5 mL of dichloromethane, and add dropwise dropwise tin (IV) 55 μL (0.468 mmol, 3 eq) and 0.17 mL (1.872 mmol, 12 eq) of dichloromethyl methyl ether under ice-cooling. The mixture was stirred at 0 ° C. under an argon atmosphere for 30 minutes, then warmed to room temperature and further stirred for 6.5 hours. Ice and chloroform were added to the reaction solution, and the mixture was stirred for 1 hour, opened in a separatory funnel, the organic layer was separated, washed with 10% sodium hydroxide and then with water, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and vacuum dried The obtained residue was directly used in the next reaction. 4-Formyl-1,2- (methylenedioxy) -1,2-didemethoxycolchicine 39 mg (0.095 mmol) was dissolved in 0.95 mL of methanol, and 80% magnesium monoperoxyphthalate (MMPP) 117.5 mg (0.19 mmol) 3 eq) and stirred at room temperature for 18 hours. The reaction solution was quenched by adding a saturated aqueous sodium hydrogen carbonate solution, acidified with 1N hydrochloric acid, extracted four times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (4% methanol / chloroform) to obtain 8 mg (yield 21%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.32 (1H, s, H-8), 7.43 (1H, d, J = 10.8 Hz, H-12), 7.43 (1H, d, J = 11.0Hz, H-11), 6.00 (1H, d, J = 1.5Hz, -OCH 2 O-), 5.87 (1H, d, J = 1.3Hz, -OCH 2 O-), 4.70 (1H, ddd, J = 12.6, 6.5, 6.5Hz, H-7), 4.09 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.15 (1H, dd, J = 13.8, 6.0Hz, H-5β ), 2.24 (1H, dddd, J = 12.7, 12.7,6.4, 6.4Hz, H-6β), 2.00 (3H, s, -NHCO CH 3 ), 1.96 (1H, ddd, J = 13.6, 13.6, 6.7Hz , H-5α), 1.84 (1H, ddd, J = 11.8, 11.8, 6.0Hz, H-6α).
EI-MS m / z (%): 399 (M + , 72.6).
参考例１０
デアセチルコルヒチンの合成
　コルヒチン100 mg（0.25 mmol）をアセトニトリル2.5 mLに溶解し、ジメチルアミノピリジン（DMAP）30.5 mg（0.25 mmol, 1 eq）を加え、トリエチルアミン0.1 mL（0.75 mmol, 3 eq）、ニ炭酸ジ-t-ブチル0.29 mL（1.25 mmol, 5 eq）を順に滴下し、100℃で7.5時間煮沸還流した。反応液をクロロホルムで希釈し、飽和クエン酸水溶液で3回洗浄、得られた水層をクロロホルムで3回抽出後、有機層を合わせて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（1%メタノール/ 酢酸エチル）にて精製し、目的物のN－（t-ブトキシカルボニル）コルヒチン132.8 mg（収率 定量的）を得た。N－（t-ブトキシカルボニル）コルヒチン570 mg（1.14 mmol）をメタノール5mLに溶解し、1Mナトリウムメトキシド2.28 mL（2.28 mmol, 2eq）を滴下して室温で1時間攪拌した。反応液に飽和食塩水を加えてクエンチし、クロロホルムで4回抽出し、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をそのまま次の反応に用いた。N－（t-ブトキシカルボニル）デアセチルコルヒチン551 mg（1.20 mmol）をトリフルオル酢酸1.7 mL（22.8 mmol, 19 eq）に溶解し、室温で40分撹拌した。反応液に5M水酸化ナトリウムを加えて塩基性にし、クロロホルムで3回抽出し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10%メタノール/ クロロホルム）にて精製し、表題の化合物377 mg（収率 88%）を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]：7.74 (1H, s, H-8), 7.18 (1H, d, J=10.7Hz, H-12), 6.79 (1H, d, J=11.0Hz, H-11), 6.53 (1H, s, H-4), 3.99 (3H, s, -OMe), 3.90 (6H, s,-OMe X 2), 3.70 (1H, dd, J=11.0, 5.0 Hz, H-7), 3.65 (3H, s, -OMe), 2.47 (1H, dd,J=13.7, 6.3Hz, H-5β), 2.39 (1H, ddd, J=12.7, 12.7, 6.3Hz, H-5α), 2.30 (1H, dddd, J=12.2, 12.2, 6.1, 6.1Hz, H-6β), 1.60(1H, ddd, J=11.5, 11.5, 4.8Hz, H-6α).
EI-MS m/z (%)：357 (M+, 100.0), 312 (76.8), 298 (76.5). Reference Example 10
Synthesis of deacetylcolchicine 100 mg (0.25 mmol) of colchicine was dissolved in 2.5 mL of acetonitrile, 30.5 mg (0.25 mmol, 1 eq) of dimethylaminopyridine (DMAP) was added, 0.1 mL (0.75 mmol, 3 eq) of triethylamine, Di-t-butyl carbonate 0.29 mL (1.25 mmol, 5 eq) was sequentially added dropwise, and the mixture was boiled and refluxed at 100 ° C. for 7.5 hours. The reaction solution was diluted with chloroform and washed 3 times with saturated aqueous citric acid solution. The resulting aqueous layer was extracted 3 times with chloroform, and the organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and reduced pressure Distilled off and vacuum dried. The obtained residue was purified by silica gel column chromatography (1% methanol / ethyl acetate) to obtain 132.8 mg (quantitative yield) of the desired product, N- (t-butoxycarbonyl) colchicine. 570 mg (1.14 mmol) of N- (t-butoxycarbonyl) colchicine was dissolved in 5 mL of methanol, and 2.28 mL (2.28 mmol, 2 eq) of 1M sodium methoxide was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was quenched by adding saturated brine, extracted four times with chloroform, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was directly used in the next reaction. N- (t-butoxycarbonyl) deacetylcolchicine 551 mg (1.20 mmol) was dissolved in trifluoroacetic acid 1.7 mL (22.8 mmol, 19 eq) and stirred at room temperature for 40 minutes. The reaction mixture was basified with 5M sodium hydroxide, extracted with chloroform three times, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% methanol / chloroform) to give the title compound (377 mg, yield 88%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.74 (1H, s, H-8), 7.18 (1H, d, J = 10.7 Hz, H-12), 6.79 (1H, d, J = 11.0Hz, H-11), 6.53 (1H, s, H-4), 3.99 (3H, s, -OMe), 3.90 (6H, s, -OMe X 2), 3.70 (1H, dd, J = 11.0 , 5.0 Hz, H-7), 3.65 (3H, s, -OMe), 2.47 (1H, dd, J = 13.7, 6.3Hz, H-5β), 2.39 (1H, ddd, J = 12.7, 12.7, 6.3 Hz, H-5α), 2.30 (1H, dddd, J = 12.2, 12.2, 6.1, 6.1Hz, H-6β), 1.60 (1H, ddd, J = 11.5, 11.5, 4.8Hz, H-6α).
EI-MS m / z (%): 357 (M + , 100.0), 312 (76.8), 298 (76.5).
参考例１１
デアセチルコルヒチン塩酸塩の合成
　メタノール2 mLに氷冷下、アセチル　クロリド24 μL（0.34 mmol, 2 eq）を滴下して撹拌した。その溶液に、氷冷下、メタノール3 mLに溶解したデアセチルコルヒチン60 mg （0.17 mmol）を滴下し、1.5時間撹拌した。反応液を減圧留去、真空乾燥し、表題の化合物68.9 mgを得た。
1H-NMR(400MHz, CDCl3)δ[ppm]：7.76 (1H, s, H-8), 7.32 (1H, d, J=10.0Hz, H-12), 6.89 (1H, d, J=11.2Hz, H-11), 6.55 (1H, s, H-4), 4.25 (1H, br-s, H-7), 3.96 (3H, s, -OMe), 3.93 (3H, s, -OMe), 3.92 (3H, s, -OMe), 3.70 (3H, s, -OMe), 2.72 (2H, br-s), 2.51 (2H, overlapped). Reference Example 11
Synthesis of deacetylcolchicine hydrochloride To 2 mL of methanol, 24 μL (0.34 mmol, 2 eq) of acetyl chloride was added dropwise and stirred under ice-cooling. To the solution, 60 mg (0.17 mmol) of deacetyl colchicine dissolved in 3 mL of methanol was added dropwise under ice cooling, followed by stirring for 1.5 hours. The reaction solution was evaporated under reduced pressure and dried under vacuum to obtain 68.9 mg of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.76 (1H, s, H-8), 7.32 (1H, d, J = 10.0 Hz, H-12), 6.89 (1H, d, J = 11.2Hz, H-11), 6.55 (1H, s, H-4), 4.25 (1H, br-s, H-7), 3.96 (3H, s, -OMe), 3.93 (3H, s, -OMe ), 3.92 (3H, s, -OMe), 3.70 (3H, s, -OMe), 2.72 (2H, br-s), 2.51 (2H, overlapped).
実施例５
４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）コルヒチンの合成
　4-クロロコルヒチン10 mg（0.023 mmol）をアセトニトリル0.5 mLに溶解し、ジメチルアミノピリジン2.8 mg（0.023 mmol, 1 eq）を加え、トリエチルアミン9.6 μL（0.069 mmol, 3 eq）、ニ炭酸ジ-t-ブチル26.4 μL（0.115 mmol, 5 eq）を順に滴下し、100℃で10.5時間煮沸還流した。反応液をクロロホルムで希釈し、飽和クエン酸水溶液で3回洗浄、得られた水層をクロロホルムで3回抽出後、有機層を合わせて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（1% メタノール/ 酢酸エチル）にて精製し、表題の化合物9.2 mg（収率 75%）を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.56 (1H, s, H-8), 7.16 (1H, d, J = 10.7 Hz, H-12), 6.75 (1H, d, J = 11.0 Hz, H-11), 5.06 (1H, dd, J = 12.2, 6.1 Hz, H-7), 3.98 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.96 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.32 (1H, dd, J = 13.9, 4.9 Hz), 2.65-2.62 (1H, m), 2.30 (3H, s, -COCH3), 2.28-2.21(1H, m), 1.99-1.91 (1H, m), 1.57 (9H, s, -COOC(CH3)3)．
ESI-MS m/z：534 [M+H]+． Example 5
Synthesis of 4-chloro-N- (t-butoxycarbonyl) colchicine 10 mg (0.023 mmol) of 4-chlorocolchicine was dissolved in 0.5 mL of acetonitrile, 2.8 mg (0.023 mmol, 1 eq) of dimethylaminopyridine was added, and triethylamine 9.6 μL (0.069 mmol, 3 eq) and di-t-butyl dicarbonate 26.4 μL (0.115 mmol, 5 eq) were sequentially added dropwise, and the mixture was boiled and refluxed at 100 ° C. for 10.5 hours. The reaction solution was diluted with chloroform and washed 3 times with saturated aqueous citric acid solution. The resulting aqueous layer was extracted 3 times with chloroform, and the organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and reduced pressure Distilled off and vacuum dried. The obtained residue was purified by silica gel column chromatography (1% methanol / ethyl acetate) to give the title compound (9.2 mg, yield 75%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.56 (1H, s, H-8), 7.16 (1H, d, J = 10.7 Hz, H-12), 6.75 (1H, d, J = 11.0 Hz, H-11), 5.06 (1H, dd, J = 12.2, 6.1 Hz, H-7), 3.98 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.96 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.32 (1H, dd, J = 13.9, 4.9 Hz), 2.65-2.62 (1H, m), 2.30 (3H, s, -COCH 3 ), 2.28-2.21 (1H, m), 1.99-1.91 (1H, m), 1.57 (9H, s, -COOC (CH 3 ) 3 ).
ESI-MS m / z: 534 [M + H] + .
実施例６
４－クロロ－Ｎ－（t－ブトキシカルボニル）デアセチルコルヒチン
　4-クロロ-N-（t-ブトキシカルボニル）コルヒチン130 mg（0.24 mmol）をメタノール2.4 mLに溶解し、1M ナトリウムメトキシド 0.48 mL（0.48 mmol, 2 eq）を滴下して室温で6時間攪拌した。反応液に飽和食塩水を加えてクエンチし、クロロホルムで4回抽出、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（2% → 5% メタノール/ クロロホルム）にて精製し、表題の化合物105.6 mg（収率 89%）を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.51 (1H, s, H-8), 7.21 (1H, d, J = 10.7 Hz, H-12), 6.79 (1H, d, J = 10.7 Hz, H-11), 4.95 (1H, d, J = 7.8 Hz, -NH), 4.34-4.28 (1H, m, H-7), 4.00 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.23 (1H, dd, J = 13.3, 4.5 Hz), 2.30-2.11 (2H, m), 1.65-1.61 (1H,m), 1.38 (9H, s, -COOC(CH3)3)．
ESI-MS m/z：492 [M+H]+． Example 6
4-Chloro-N- (t-butoxycarbonyl) deacetylcolchicine 130 mg (0.24 mmol) of 4-chloro-N- (t-butoxycarbonyl) colchicine was dissolved in 2.4 mL of methanol and 0.48 mL (0.48 mL) of 1M sodium methoxide was dissolved. mmol, 2 eq) was added dropwise and stirred at room temperature for 6 hours. The reaction solution was quenched by adding saturated brine, extracted four times with chloroform, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (2% → 5% methanol / chloroform) to obtain 105.6 mg (yield 89%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.51 (1H, s, H-8), 7.21 (1H, d, J = 10.7 Hz, H-12), 6.79 (1H, d, J = 10.7 Hz, H-11), 4.95 (1H, d, J = 7.8 Hz, -NH), 4.34-4.28 (1H, m, H-7), 4.00 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.23 (1H, dd, J = 13.3, 4.5 Hz), 2.30-2.11 (2H, m), 1.65 -1.61 (1H, m), 1.38 (9H, s, -COOC (CH 3 ) 3 ).
ESI-MS m / z: 492 [M + H] + .
実施例７
４－クロロデアセチルコルヒチンの合成
　4-クロロ-N-（t-ブトキシカルボニル）デアセチルコルヒチン95 mg（0.19 mmol）をトリフルオロ酢酸0.27 mL（3.61 mmol, 19 eq）に溶解し、室温で20分撹拌した。反応液に5N水酸化ナトリウムを加えて塩基性にし、クロロホルムで3回抽出、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（5% → 10% メタノール/ クロロホルム）にて精製し、表題の化合物65 mg（収率 87%）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.75 (1H, s, H-8), 7.15 (1H, d, J=10.6Hz, H-12),6.79 (1H, d, J=10.8Hz, H-11), 4.01 (3H, s, -OMe), 3.96 (3H, s, -OMe), 3.95 (3H,s, -OMe), 3.62 (1H, overlapped, H-7), 3.61 (3H, s, -OMe), 3.19 (1H, dd, J=13.5,4.9Hz, H-5β), 2.29 (1H, dddd, J=12.6, 12.6, 4.2, 4.2Hz, H-6β), 2.16 (1H, ddd,J=13.4, 13.4, 6.1Hz, H-5α), 1.55 (1H, ddd, J=10.8, 10.8, 6.6Hz, H-6α).
EI-MS m/z (%)：391 (M+, 100.0), 393 ([M+2]+, 34.7). Example 7
Synthesis of 4-chlorodeacetylcolchicine 95 mg (0.19 mmol) of 4-chloro-N- (t-butoxycarbonyl) deacetylcolchicine is dissolved in 0.27 mL (3.61 mmol, 19 eq) of trifluoroacetic acid, and 20 minutes at room temperature. Stir. The reaction mixture was basified with 5N sodium hydroxide, extracted 3 times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (5% → 10% methanol / chloroform) to obtain 65 mg (yield 87%) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.75 (1H, s, H-8), 7.15 (1H, d, J = 10.6 Hz, H-12), 6.79 (1H, d, J = 10.8Hz, H-11), 4.01 (3H, s, -OMe), 3.96 (3H, s, -OMe), 3.95 (3H, s, -OMe), 3.62 (1H, overlapped, H-7), 3.61 (3H, s, -OMe), 3.19 (1H, dd, J = 13.5,4.9Hz, H-5β), 2.29 (1H, dddd, J = 12.6, 12.6, 4.2, 4.2Hz, H-6β), 2.16 (1H, ddd, J = 13.4, 13.4, 6.1Hz, H-5α), 1.55 (1H, ddd, J = 10.8, 10.8, 6.6Hz, H-6α).
EI-MS m / z (%): 391 (M + , 100.0), 393 ([M + 2] + , 34.7).
実施例８
４－クロロデアセチルコルヒチン塩酸塩の合成
　メタノール2 mLに氷冷下、アセチル　クロリド20 μL（0.28 mmol, 2 eq）を滴下して撹拌した。その溶液に、氷冷下、メタノール1.5 mLに溶解した4-クロロデアセチルコルヒチン55 mg（0.14 mmol）を滴下し、1.5時間撹拌した。反応液を減圧留去、真空乾燥し、表題の化合物61.5 mgを得た。
1H-NMR(400MHz, CDCl3)δ[ppm]：7.81 (1H, s, H-8), 7.35 (1H, d, J=10.6Hz, H-12), 6.96 (1H, d, J=10.8Hz, H-11), 4.21 (1H, br-s, H-7), 4.00 (6H, s, -OMe X 2), 3.98 (3H, s, -OMe), 3.65 (3H, s, -OMe), 3.29 (1H, br-dd, J=13.5, 5.5Hz), 2.62 (1H, m), 2.48 (1H, m), 2.23 (1H, m). Example 8
Synthesis of 4-chlorodeacetylcolchicine hydrochloride To 2 mL of methanol, 20 μL (0.28 mmol, 2 eq) of acetyl chloride was added dropwise and stirred under ice-cooling. To this solution, 55 mg (0.14 mmol) of 4-chlorodeacetylcolchicine dissolved in 1.5 mL of methanol was added dropwise under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was evaporated under reduced pressure and dried in vacuo to give 61.5 mg of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.81 (1H, s, H-8), 7.35 (1H, d, J = 10.6 Hz, H-12), 6.96 (1H, d, J = 10.8Hz, H-11), 4.21 (1H, br-s, H-7), 4.00 (6H, s, -OMe X 2), 3.98 (3H, s, -OMe), 3.65 (3H, s,- OMe), 3.29 (1H, br-dd, J = 13.5, 5.5Hz), 2.62 (1H, m), 2.48 (1H, m), 2.23 (1H, m).
実施例９
４－フルオロ－Ｎ－(ｔ-ブトキシカルボニル)コルヒチンの合成
　4-フルオロコルヒチン12 mg（0.029 mmol）をアセトニトリル0.5 mLに溶解し、ジメチルアミノピリジン3.5 mg（0.029 mmol, 1 eq）を加え、トリエチルアミン12 μL（0.087 mmol, 3 eq）、ニ炭酸ジ-t-ブチル33.3 μL（0.145 mmol, 5 eq）を順に滴下し、100℃で7.5時間煮沸還流した。反応液をクロロホルムで希釈し、飽和クエン酸水溶液で3回洗浄、得られた水層をクロロホルムで3回抽出後、有機層を合わせて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（1% メタノール/ 酢酸エチル）にて精製し、表題の化合物12.2 mg（収率 81%）を得た。 Example 9
Synthesis of 4-fluoro-N- (t-butoxycarbonyl) colchicine 12 mg (0.029 mmol) of 4-fluorocolchicine was dissolved in 0.5 mL of acetonitrile, 3.5 mg (0.029 mmol, 1 eq) of dimethylaminopyridine was added, and triethylamine 12 μL (0.087 mmol, 3 eq) and di-t-butyl dicarbonate 33.3 μL (0.145 mmol, 5 eq) were added dropwise in that order, and the mixture was boiled and refluxed at 100 ° C. for 7.5 hours. The reaction solution was diluted with chloroform and washed 3 times with saturated aqueous citric acid solution. The resulting aqueous layer was extracted 3 times with chloroform, and the organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and reduced pressure Distilled off and vacuum dried. The obtained residue was purified by silica gel column chromatography (1% methanol / ethyl acetate) to give the title compound (12.2 mg, yield 81%).
実施例１０
４－フルオロ－Ｎ－（t-ブトキシカルボニル）デアセチルコルヒチンの合成
　4-フルオロ-N-（t-ブトキシカルボニル）コルヒチン89 mg（0.17 mmol）をメタノール2mLに溶解し、1Mナトリウムメトキシド0.34 mL（0.34 mmol, 2 eq）を滴下して室温で1時間攪拌した。反応液に飽和食塩水を加えてクエンチし、クロロホルムで4回抽出、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥し、表題の化合物を得た。得られた化合物をそのまま次の反応に用いた。 Example 10
Synthesis of 4-fluoro-N- (t-butoxycarbonyl) deacetylcolchicine 89 mg (0.17 mmol) of 4-fluoro-N- (t-butoxycarbonyl) colchicine was dissolved in 2 mL of methanol, and 0.34 mL of 1M sodium methoxide ( 0.34 mmol, 2 eq) was added dropwise and stirred at room temperature for 1 hour. The reaction solution was quenched by adding saturated brine, extracted 4 times with chloroform, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum to give the title compound. The obtained compound was directly used in the next reaction.
実施例１１
４－フルオロデアセチルコルヒチンの合成
　4-フルオロ-N-（t-ブトキシカルボニル）デアセチルコルヒチン65 mg（0.14 mmol）をトリフルオロ酢酸0.2 mL（2.66 mmol, 19 eq）に溶解し、室温で40分撹拌した。反応液に5N水酸化ナトリウムを加えて塩基性にし、クロロホルムで3回抽出、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10% メタノール/ クロロホルム）にて精製し、表題の化合物55 mg（収率 定量的）を得た。
1H-NMR(400MHz, CDCl3)δ [ppm]：7.75 (1H, s, H-8), 7.19 (1H, d, J=10.6Hz, H-12), 6.79 (1H, d, J=10.8Hz, H-11), 4.01 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.97 (3H,s, -OMe), 3.69 (1H, dd, J=10.9, 6.3Hz, H-7), 3.59 (3H, s, -OMe), 3.00 (1H, dd, J=13.7, 6.2Hz, H-5β), 2.29 (1H, dddd, J=12.8, 12.8, 6.4, 6.4Hz, H-6β), 2.02 (1H,ddd, J=13.5, 13.5, 6.9Hz, H-5α), 1.59 (1H, ddd, J=11.7, 11.7, 7.0Hz, H-6α).
EI-MS m/z (%)：375 (M+, 68.4), 83 (100). Example 11
Synthesis of 4-fluoro deacetyl colchicine 65 mg (0.14 mmol) of 4-fluoro-N- (t-butoxycarbonyl) deacetyl colchicine was dissolved in 0.2 mL (2.66 mmol, 19 eq) of trifluoroacetic acid, and 40 minutes at room temperature. Stir. The reaction mixture was basified with 5N sodium hydroxide, extracted 3 times with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% methanol / chloroform) to obtain 55 mg (quantitative yield) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.75 (1H, s, H-8), 7.19 (1H, d, J = 10.6 Hz, H-12), 6.79 (1H, d, J = 10.8Hz, H-11), 4.01 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.69 (1H, dd, J = 10.9, 6.3Hz , H-7), 3.59 (3H, s, -OMe), 3.00 (1H, dd, J = 13.7, 6.2Hz, H-5β), 2.29 (1H, dddd, J = 12.8, 12.8, 6.4, 6.4Hz , H-6β), 2.02 (1H, ddd, J = 13.5, 13.5, 6.9Hz, H-5α), 1.59 (1H, ddd, J = 11.7, 11.7, 7.0Hz, H-6α).
EI-MS m / z (%): 375 (M + , 68.4), 83 (100).
実施例１２
４－フルオロデアセチルコルヒチン塩酸塩の合成
　メタノール1.5 mLに氷冷下、アセチル　クロリド21.3 μL（0.3 mmol, 2 eq）を滴下して撹拌した。その溶液に、氷冷下、メタノール1.5 mLに溶解した4－フルオロデアセチルコルヒチン55 mg（0.15 mmol）を滴下し、1.5時間撹拌した。反応液を減圧留去、真空乾燥し、表題の化合物44.5 mgを得た。
1H-NMR(400MHz, CDCl3)δ[ppm]：7.85 (1H, s, H-8), 7.42 (1H, d, J=10.8Hz, H-12), 7.00 (1H, d, J=10.8Hz, H-11), 4.27 (1H, br-s, H-7), 4.05 (3H, s, -OMe), 4.02 (3H,s, -OMe), 3.98 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.08 (1H, br-dd, J=14.0, 6.0Hz), 2.65 (1H, m), 2.52 (1H, m), 2.08 (1H, m). Example 12
Synthesis of 4-fluorodeacetylcolchicine hydrochloride 21.3 μL (0.3 mmol, 2 eq) of acetyl chloride was added dropwise to 1.5 mL of methanol under ice-cooling and stirred. To the solution was added dropwise 55 mg (0.15 mmol) of 4-fluorodeacetylcolchicine dissolved in 1.5 mL of methanol under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was evaporated under reduced pressure and dried under vacuum to obtain 44.5 mg of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.85 (1H, s, H-8), 7.42 (1H, d, J = 10.8 Hz, H-12), 7.00 (1H, d, J = 10.8Hz, H-11), 4.27 (1H, br-s, H-7), 4.05 (3H, s, -OMe), 4.02 (3H, s, -OMe), 3.98 (3H, s, -OMe) , 3.62 (3H, s, -OMe), 3.08 (1H, br-dd, J = 14.0, 6.0Hz), 2.65 (1H, m), 2.52 (1H, m), 2.08 (1H, m).
実施例１３
４－クロロ－Ｎ－プロピオニルデアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン10 mg（0.026 mmol）をジクロロメタン0.5 mLに溶解し、氷冷下ピリジン2.3 μL（0.029 mmol, 1.1 eq）、塩化プロピオニル2.3 μL（0.026 mmol, 1 eq）を順に滴下し、室温で1.5時間攪拌した。反応液に水を加えてクエンチし、飽和炭酸水素ナトリウム水溶液で塩基性にした。クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（10%メタノール/ 酢酸エチル及び5%メタノール/ クロロホルム）にて精製し、表題の化合物11.7 mg（収量 定量的）を得た。
1H-NMR（400MHz, CDCl3）δ [ppm]：7.49 (1H, s, H-8), 7.30 (1H, d, J=11.0Hz, H-12), 6.85 (1H, d, J=10.8Hz, H-11), 4.57 (1H, ddd, J=12.0, 6.1, 6.1Hz, H-7), 4.02 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.64 (3H, s, -OMe), 3.24 (1H, dd, J=13.5, 5.0Hz, H-5β), 2.29 (3H, m), 2.15 (1H, ddd, J=13.4, 13.4, 6.2Hz, H-5α), 1.80 (1H, ddd, J=11.9, 11.9, 5.9Hz, H-6α), 1.10 (3H, dd, J=7.6, 7.6Hz, -NHCOCH2 CH 3 ).
EI-MS m/z (%)： 446 (M+, 45.6), 448 ([M+2]+, 17.3), 55 (100.0). Example 13
Synthesis of 4-chloro-N-propionyl deacetyl colchicine 10 mg (0.026 mmol) of 4-chloro deacetyl colchicine was dissolved in 0.5 mL of dichloromethane, and 2.3 μL (0.029 mmol, 1.1 eq) of pyridine and 2.3 μL of propionyl chloride under ice cooling. (0.026 mmol, 1 eq) was added dropwise in order, and the mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by adding water and made basic with saturated aqueous sodium bicarbonate. The mixture was extracted 4 times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (10% methanol / ethyl acetate and 5% methanol / chloroform) to obtain 11.7 mg (quantitative yield) of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.49 (1H, s, H-8), 7.30 (1H, d, J = 11.0 Hz, H-12), 6.85 (1H, d, J = 10.8Hz, H-11), 4.57 (1H, ddd, J = 12.0, 6.1, 6.1Hz, H-7), 4.02 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.97 ( 3H, s, -OMe), 3.64 (3H, s, -OMe), 3.24 (1H, dd, J = 13.5, 5.0Hz, H-5β), 2.29 (3H, m), 2.15 (1H, ddd, J = 13.4, 13.4, 6.2Hz, H-5α), 1.80 (1H, ddd, J = 11.9, 11.9, 5.9Hz, H-6α), 1.10 (3H, dd, J = 7.6, 7.6Hz, -NHCOCH 2 CH 3 ).
EI-MS m / z (%): 446 (M + , 45.6), 448 ([M + 2] + , 17.3), 55 (100.0).
実施例１４
４－クロロ－Ｎ－ホルミルデアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン11.8 mg（0.030 mmol）をN,N-ジメチルホルムアミド0.4mLに溶解し、ぎ酸エチル0.2 mLを加え80℃で3時間攪拌した。その後120℃に昇温し、22時間攪拌した。反応液を減圧留去し、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（5%メタノール/ クロロホルム及び7%メタノール/ 酢酸エチル）にて精製し、表題の化合物12.5 mg（収量 99%）を得た。
1H-NMR（400MHz, CDCl3）δ [ppm]：8.20 (1H, s, -NHCOH), 7.57 (1H, br-d, J=6.8Hz, -NH), 7.53 (1H, s, H-8), 7.30 (1H, d, J=10.7Hz, H-12), 6.86 (1H, d, J=11.0Hz, H-11), 4.64 (1H, ddd, J=12.4, 6.3, 6.3Hz, H-7), 4.02 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.63 (3H, s, -OMe), 3.27 (1H, dd, J=13.3, 5.0Hz, H-5β), 2.30 (1H, dddd, J=12.6, 12.6, 6.2, 6.2Hz, H-6β), 2.18 (1H, ddd, J=13.3, 13.3, 6.1Hz, H-5α), 1.87 (1H, ddd, J=11.9, 11.9, 5.2Hz, H-6α).
EI-MS m/z (%)： 418 (M+, 30.1), 420 ([M+2]+, 12.8), 55 (100.0). Example 14
Synthesis of 4-chloro-N-formyldeacetylcolchicine Dissolve 11.8 mg (0.030 mmol) of 4-chlorodeacetylcolchicine in 0.4 mL of N, N-dimethylformamide, add 0.2 mL of ethyl formate, and stir at 80 ° C for 3 hours. did. Thereafter, the temperature was raised to 120 ° C. and stirred for 22 hours. The reaction solution was distilled off under reduced pressure and dried under vacuum. The obtained residue was purified by silica gel column chromatography (5% methanol / chloroform and 7% methanol / ethyl acetate) to give the title compound (12.5 mg, yield 99%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.20 (1H, s, -NHCO H ), 7.57 (1H, br-d, J = 6.8 Hz, -NH), 7.53 (1H, s, H -8), 7.30 (1H, d, J = 10.7Hz, H-12), 6.86 (1H, d, J = 11.0Hz, H-11), 4.64 (1H, ddd, J = 12.4, 6.3, 6.3Hz , H-7), 4.02 (3H, s, -OMe), 4.00 (3H, s, -OMe), 3.98 (3H, s, -OMe), 3.63 (3H, s, -OMe), 3.27 (1H, dd, J = 13.3, 5.0Hz, H-5β), 2.30 (1H, dddd, J = 12.6, 12.6, 6.2, 6.2Hz, H-6β), 2.18 (1H, ddd, J = 13.3, 13.3, 6.1Hz , H-5α), 1.87 (1H, ddd, J = 11.9, 11.9, 5.2Hz, H-6α).
EI-MS m / z (%): 418 (M + , 30.1), 420 ([M + 2] + , 12.8), 55 (100.0).
実施例１５
４－クロロ－Ｎ－（クロロアセチル）デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン24 mg（0.061 mmol）をジクロロメタン0.8 mLに溶解し、氷冷下トリエチルアミン13 μL（0.092 mmol, 1.5 eq）、塩化クロロアセチル5.8 μL（0.073 mmol, 1.2 eq）を順に加えて室温で30分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えてクエンチし、クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルカラムクロマトグラフ法（1% → 5% → 10%メタノール/ クロロホルム）にて精製し、表題の化合物31.3 mg（収量 定量的）を得た。
1H-NMR（400MHz, CDCl3）δ [ppm]：7.70 (1H, br-d, J=6.8Hz, -NH), 7.40 (1H, s, H-8), 7.28 (1H, d, J=10.7Hz, H-12), 6.84 (1H, d, J=10.7Hz, H-11), 4.55 (1H, ddd, J=12.1, 6.2, 6.2Hz, H-7), 4.09 (1H, d, J=14.9Hz, -CH 2 Cl), 4.02 (1H, d, J=14.9Hz, -CH 2 Cl), 4.01 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.62 (3H, s,-OMe), 3.28 (1H, dd, J=13.2, 4.4Hz, H-5β), 2.29 (1H, dddd, J=12.1, 12.1, 6.0, 6.0Hz, H-6β), 2.19 (1H, ddd, J=13.1, 13.1, 5.9Hz, H-5α), 1.89 (1H, ddd, J=11.6,11.6, 5.0Hz, H-6α)．
FAB-MS (NBA) m/z： 468 [M+H]+． Example 15
Synthesis of 4-chloro-N- (chloroacetyl) deacetylcolchicine 24 mg (0.061 mmol) of 4-chlorodeacetylcolchicine is dissolved in 0.8 mL of dichloromethane, and 13 μL (0.092 mmol, 1.5 eq) of triethylamine under ice cooling Chloroacetyl 5.8 microliters (0.073 mmol, 1.2 eq) was added in order, and it stirred at room temperature for 30 minutes. The reaction solution was quenched by adding saturated aqueous sodium hydrogen carbonate solution, extracted four times with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel column chromatography (1% → 5% → 10% methanol / chloroform) to obtain 31.3 mg of the title compound (quantitative yield).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.70 (1H, br-d, J = 6.8 Hz, -NH), 7.40 (1H, s, H-8), 7.28 (1H, d, J = 10.7Hz, H-12), 6.84 (1H, d, J = 10.7Hz, H-11), 4.55 (1H, ddd, J = 12.1, 6.2, 6.2Hz, H-7), 4.09 (1H, d , J = 14.9Hz, -CH 2 Cl), 4.02 (1H, d, J = 14.9Hz, -CH 2 Cl), 4.01 (3H, s, -OMe), 3.99 (3H, s, -OMe), 3.97 (3H, s, -OMe), 3.62 (3H, s, -OMe), 3.28 (1H, dd, J = 13.2, 4.4Hz, H-5β), 2.29 (1H, dddd, J = 12.1, 12.1, 6.0 , 6.0Hz, H-6β), 2.19 (1H, ddd, J = 13.1, 13.1, 5.9Hz, H-5α), 1.89 (1H, ddd, J = 11.6, 11.6, 5.0Hz, H-6α).
FAB-MS (NBA) m / z: 468 [M + H] + .
実施例１６
4-クロロ-N,N-ジメチルデアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(90 mg, 0.230 mmol)のギ酸(690 μL)溶液に、室温でホルムアルデヒド(37% in water, 460 μL)を加えた後、アルゴンガス雰囲気下、2.5時間煮沸環流した。室温まで放冷後、クロロホルムと飽和重曹水を加えた。有機層を取り、水層はさらにクロロホルムにて抽出した。有機層を合わせて、無水硫酸ナトリウムにて乾燥後、ろ過、ろ液を濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製、目的物画分を濃縮乾固して標記化合物(淡褐色固体, 55 mg, 0.130 mmol, 57%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.09 (1H, s), 7.18 (1H, d, J=10.7 Hz), 6.76 (1H, d, J=10.7 Hz), 3.99 (6H, s), 3.98 (3H, s), 3.57 (3H, s), 3.21-3.16 (1H, m), 2.59 (1H, dd, J=11.0, 5.9 Hz), 2.21-2.03 (2H, m), 2.16 (6H, br-s), 1.73-1.66 (1H, m).ESI-MS m/z: 420 [M+H]+. Example 16
Synthesis of 4-chloro-N, N-dimethyldeacetylcolchicine Add formaldehyde (37% in water, 460 μL) to a solution of 4-chlorodeacetylcolchicine (90 mg, 0.230 mmol) in formic acid (690 μL) at room temperature Then, the mixture was refluxed for 2.5 hours under an argon gas atmosphere. After cooling to room temperature, chloroform and saturated aqueous sodium hydrogen carbonate were added. The organic layer was taken and the aqueous layer was further extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) and the target fraction was concentrated to dryness to give the title compound (light brown solid, 55 mg, 0.130 mmol, 57%). Obtained.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.09 (1H, s), 7.18 (1H, d, J = 10.7 Hz), 6.76 (1H, d, J = 10.7 Hz), 3.99 (6H, s), 3.98 (3H, s), 3.57 (3H, s), 3.21-3.16 (1H, m), 2.59 (1H, dd, J = 11.0, 5.9 Hz), 2.21-2.03 (2H, m), 2.16 (6H, br-s), 1.73-1.66 (1H, m) .ESI-MS m / z: 420 [M + H] + .
実施例１７
4-クロロ-N,N-ジエチルデアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(50 mg, 0.128 mmol)のメタノール-酢酸混液(100:1, 1.9 mL)に氷冷、アルゴンガス雰囲気下にてアセトアルデヒド(25 μL, 0.128×3.5 mmol)及びシアノ水素化ホウ素ナトリウム(18 mg, 0.128×2.2 mmol)を加えた。本混合液を室温で3時間撹拌した後、飽和重曹水と酢酸エチルを加えた。有機層を取り、ブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、次いで減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(淡黄色固体, 30 mg, 0.067 mmol, 53%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.11 (1H, s), 7.19 (1H, d, J=10.7 Hz), 6.76 (1H, d, J=10.7 Hz), 3.99 (6H, s), 3.97 (3H, s), 3.58 (3H, s), 3.23-3.09 (2H, m), 2.82-2.31 (3H, m), 2.22-2.03 (2H, m), 1.81-1.60 (2H, m), 0.90 (6H, t, J=7.1Hz).
ESI-MS m/z: 448 [M+H]+. Example 17
Synthesis of 4-chloro-N, N-diethyl deacetyl colchicine 4-chlorodeacetyl colchicine (50 mg, 0.128 mmol) in methanol-acetic acid mixture (100: 1, 1.9 mL) under ice-cooling and argon gas atmosphere Acetaldehyde (25 μL, 0.128 × 3.5 mmol) and sodium cyanoborohydride (18 mg, 0.128 × 2.2 mmol) were added. The mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium hydrogen carbonate and ethyl acetate were added. The organic layer was taken, washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 30 mg, 0.067 mmol, 53%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.11 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 6.76 (1H, d, J = 10.7 Hz), 3.99 (6H, s), 3.97 (3H, s), 3.58 (3H, s), 3.23-3.09 (2H, m), 2.82-2.31 (3H, m), 2.22-2.03 (2H, m), 1.81-1.60 (2H, m), 0.90 (6H, t, J = 7.1Hz).
ESI-MS m / z: 448 [M + H] + .
実施例１８
4-クロロ-7-(ピペラジン-1-イル)-7-デ(アセチルアミノ)コルヒチンの合成
　4-クロロ-N,N-ジエチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡褐色固体, 30 mg, 0.065 mmol, 51%)を得た。アセトアルデヒドの代わりにグルタルアルデヒドを用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.20 (1H, s), 7.19 (1H, d, J=10.7 Hz), 6.75 (1H, d, J=10.7 Hz), 3.99 (6H, s), 3.97 (3H, s), 3.57 (3H, s), 3.21-3.16 (1H, m), 2.75-2.64 (1H, m), 2.22-2.02 (2H, m), 1.70-1.49 (11H, m).
ESI-MS m/z: 460 [M+H]+. Example 18
Synthesis of 4-chloro-7- (piperazin-1-yl) -7-de (acetylamino) colchicine In the same manner as the synthesis of 4-chloro-N, N-diethyldeacetylcolchicine, the title compound (light brown Solid, 30 mg, 0.065 mmol, 51%) was obtained. Instead of acetaldehyde, glutaraldehyde was used.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.20 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 6.75 (1H, d, J = 10.7 Hz), 3.99 (6H, s), 3.97 (3H, s), 3.57 (3H, s), 3.21-3.16 (1H, m), 2.75-2.64 (1H, m), 2.22-2.02 (2H, m), 1.70-1.49 (11H, m).
ESI-MS m / z: 460 [M + H] + .
実施例１９
N-(tert-ブチルオキシカルボニル)- 4-クロロ-N-メチルデアセチルコルヒチンの合成
　N-(tert-ブチルオキシカルボニル)- 4-クロロデアセチルコルヒチン(0.100 g, 0.203 mmol)のN,N-ジメチルホルムアミド(有機合成用, 2 mL)溶液に氷冷、アルゴンガス雰囲気下にて水素化ナトリウム(60% in oil, 16 mg, 0.203×2 mmol)を添加して、20分間撹拌した。さらにヨウ化メチル(86 mg, 0.203×3 mmol)を加えて、氷冷下30分間、次いで室温で一晩撹拌した。反応液に酢酸エチルと飽和塩化アンモニウム溶液を加えて、有機層を取った。有機層はブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルムメタノール)にて精製、目的物画分を濃縮乾固して標記化合物(淡褐色個体, 67 mg, 0.132 mmol, 65%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.27 (1H, s), 7.17 (1H, d, J=10.8Hz), 6.79 (1H, d,J=10.8 Hz), 4.68-4.57 (1H, m), 4.00 (3H, s), 3.97 (6H, s), 3.66 (3H, br-s), 3.34-3.29 (1H, m), 3.12 (3H, s), 2.24-2.10 (3H, m), 1.35 (9H, br-s).
ESI-MS m/z: 506 [M+H]+. Example 19
Synthesis of N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine N- (tert-butyloxycarbonyl) -4-chlorodeacetylcolchicine (0.100 g, 0.203 mmol) N, N- Sodium hydride (60% in oil, 16 mg, 0.203 × 2 mmol) was added to a dimethylformamide (for organic synthesis, 2 mL) solution under an ice-cooled, argon gas atmosphere, and the mixture was stirred for 20 minutes. Further, methyl iodide (86 mg, 0.203 × 3 mmol) was added, and the mixture was stirred for 30 minutes under ice cooling and then overnight at room temperature. Ethyl acetate and saturated ammonium chloride solution were added to the reaction solution, and the organic layer was taken. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform methanol), and the target fraction was concentrated to dryness to give the title compound (light brown solid, 67 mg, 0.132 mmol, 65%) It was.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.27 (1H, s), 7.17 (1H, d, J = 10.8 Hz), 6.79 (1H, d, J = 10.8 Hz), 4.68-4.57 ( 1H, m), 4.00 (3H, s), 3.97 (6H, s), 3.66 (3H, br-s), 3.34-3.29 (1H, m), 3.12 (3H, s), 2.24-2.10 (3H, m), 1.35 (9H, br-s).
ESI-MS m / z: 506 [M + H] + .
実施例２０
N-(tert-ブチルオキシカルボニル)- 4-クロロ-N-エチルデアセチルコルヒチンの合成
　N-(tert-ブチルオキシカルボニル)- 4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡褐色固体, 81 mg, 0.155 mmol, 51%)を得た。ヨウ化メチルの代わりにヨウ化エチルを用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.25 (1H, s), 7.17 (1H, d, J=10.7 Hz), 6.78 (1H, d, J=10.7 Hz), 4.73-4.65 (1H, m), 3.99 (3H, s), 3.97 (6H, s), 3.64 (3H, br-s), 3.34-3.20 (3H, m), 2.19-2.08 (3H, m), 1.35 (9H, br-s), 1.15 (3H, t, J=7.0 Hz).
ESI-MS m/z: 520 [M+H]+. Example 20
Synthesis of N- (tert-butyloxycarbonyl) -4-chloro-N-ethyldeacetylcolchicine The title compound (light brown solid, 81 mg, 0.155 mmol, 51%) was obtained. Ethyl iodide was used in place of methyl iodide.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.25 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 6.78 (1H, d, J = 10.7 Hz), 4.73-4.65 ( 1H, m), 3.99 (3H, s), 3.97 (6H, s), 3.64 (3H, br-s), 3.34-3.20 (3H, m), 2.19-2.08 (3H, m), 1.35 (9H, br-s), 1.15 (3H, t, J = 7.0 Hz).
ESI-MS m / z: 520 [M + H] + .
実施例２１
N-アリル-4-クロロ-N-(tert-ブチルオキシカルボニル)デアセチルコルヒチンの合成
　N-(tert-ブチルオキシカルボニル)-4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡褐色固体, 117 mg, 0.219 mmol, 54%)を得た。ヨウ化メチルの代わりに臭化アリルを用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.27 (1H, s), 7.18 (1H, d, J=10.8 Hz), 6.79 (1H, d, J=10.8 Hz), 5.87-5.77 (1H, m), 5.15-5.07 (2H, m), 4.80-4.68 (1H, m), 4.52 (1H, dd, J=16.8, 4.3 Hz), 4.00 (3H, s), 3.97 (6H, s), 3.84 (1H, dd, J=16.8, 5.5 Hz),3.65 (3H, s), 3.32-3.24 (1H, m), 2.20-2.02 (3H, m), 1.34 (9H, s).
ESI-MS m/z: 532 [M+H]+. Example 21
Synthesis of N-allyl-4-chloro-N- (tert-butyloxycarbonyl) deacetylcolchicine In the same manner as the synthesis of N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine The title compound (light brown solid, 117 mg, 0.219 mmol, 54%) was obtained. Allyl bromide was used in place of methyl iodide.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.27 (1H, s), 7.18 (1H, d, J = 10.8 Hz), 6.79 (1H, d, J = 10.8 Hz), 5.87-5.77 ( 1H, m), 5.15-5.07 (2H, m), 4.80-4.68 (1H, m), 4.52 (1H, dd, J = 16.8, 4.3 Hz), 4.00 (3H, s), 3.97 (6H, s) , 3.84 (1H, dd, J = 16.8, 5.5 Hz), 3.65 (3H, s), 3.32-3.24 (1H, m), 2.20-2.02 (3H, m), 1.34 (9H, s).
ESI-MS m / z: 532 [M + H] + .
実施例２２
N-(tert-ブチルオキシカルボニル)-4-クロロ-N-(２-メチルアリル)デアセチルコルヒチンの合成
　N-(tert-ブチルオキシカルボニル)-4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡褐色固体, 59 mg, 0.108 mmol, 27%)を得た。ヨウ化メチルの代わりに3-ブロモ-2-メチルプロペンを用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.32 (1H, s), 7.20 (1H, d, J=10.7 Hz), 6.80 (1H, d, J=10.7 Hz), 4.86-4.73 (1H, m), 4.82 (1H, s), 4.67 (1H, s), 4.48 (1H, d, J=18.0 Hz), 4.00 (3H, s), 3.98 (6H, s), 3.73 (1H, d, J=18.0 Hz), 3.66 (3H, br-s), 3.29-3.20 (1H, m), 2.20-1.96 (3H, m), 1.72 (3H, s), 1.32 (9H, s).
ESI-MS m/z: 644 [M+H]+. Example 22
Synthesis of N- (tert-butyloxycarbonyl) -4-chloro-N- (2-methylallyl) deacetylcolchicine Similar to the synthesis of N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine By the method, the title compound (light brown solid, 59 mg, 0.108 mmol, 27%) was obtained. 3-Bromo-2-methylpropene was used instead of methyl iodide.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.32 (1H, s), 7.20 (1H, d, J = 10.7 Hz), 6.80 (1H, d, J = 10.7 Hz), 4.86-4.73 ( 1H, m), 4.82 (1H, s), 4.67 (1H, s), 4.48 (1H, d, J = 18.0 Hz), 4.00 (3H, s), 3.98 (6H, s), 3.73 (1H, d , J = 18.0 Hz), 3.66 (3H, br-s), 3.29-3.20 (1H, m), 2.20-1.96 (3H, m), 1.72 (3H, s), 1.32 (9H, s).
ESI-MS m / z: 644 [M + H] + .
実施例２３
N-ベンジル-N-(tert-ブチルオキシカルボニル)-4-クロロデアセチルコルヒチンの合成
　N-(tert-ブチルオキシカルボニル)-4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(乳白色固体, 91 mg, 0.156 mmol, 51%)を得た。ヨウ化メチルの代わりに臭化ベンジルを用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.40 (1H, s), 7.33-7.16 (6H, m), 6.81 (1H, d, J=10.7 Hz), 5.26 (1H, d, J=17.1 Hz), 4.92-4.82 (1H, m), 4.48 (1H, d, J=17.1 Hz), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.67 (3H, s), 3.20-3.15 (1H, m), 2.16-1.86 (3H, m), 1.27 (9H, s).
ESI-MS m/z: 582 [M+H]+. Example 23
Synthesis of N-benzyl-N- (tert-butyloxycarbonyl) -4-chlorodeacetylcolchicine In the same manner as the synthesis of N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine The title compound (milky white solid, 91 mg, 0.156 mmol, 51%) was obtained. Benzyl bromide was used in place of methyl iodide.
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.40 (1H, s), 7.33-7.16 (6H, m), 6.81 (1H, d, J = 10.7 Hz), 5.26 (1H, d, J = 17.1 Hz), 4.92-4.82 (1H, m), 4.48 (1H, d, J = 17.1 Hz), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.67 (3H , s), 3.20-3.15 (1H, m), 2.16-1.86 (3H, m), 1.27 (9H, s).
ESI-MS m / z: 582 [M + H] + .
実施例２４
4-クロロ-N-メチルデアセチルコルヒチンの合成
　N-(tert-ブチルオキシカルボニル)-4-クロロ-N-メチルデアセチルコルヒチン(47 mg, 0.093 mmol)のジクロロメタン(750 μL)溶液に氷冷、アルゴンガス雰囲気下してトリフルオロ酢酸(300 μL)を添加した。本溶液を氷冷下にて5分間、次いで室温で2時間撹拌した。反応液を飽和重曹水で塩基性とした後、クロロホルムとブラインを加えた。有機層を取り、水層はクロロホルムで再び抽出した。有機層は合わせて、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製、目的物画分を濃縮乾固して標記化合物(淡褐色固体, 36 mg, 0.088 mmol, 95%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.71 (1H, s), 7.18 (1H, d, J=10.7 Hz), 6.78 (1H, d, J=10.7 Hz), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.20-3.16 (2H, m), 2.26 (3H, s), 2.23-2.09 (2H, m), 1.67-1.60 (1H, m).
ESI-MS m/z: 406 [M+H]+. Example 24
Synthesis of 4-chloro-N-methyldeacetylcolchicine N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine (47 mg, 0.093 mmol) in dichloromethane (750 μL) in ice-cooled, Trifluoroacetic acid (300 μL) was added under an argon gas atmosphere. The solution was stirred under ice-cooling for 5 minutes and then at room temperature for 2 hours. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and chloroform and brine were added. The organic layer was taken and the aqueous layer was extracted again with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol), and the target fraction was concentrated to dryness to give the title compound (light brown solid, 36 mg, 0.088 mmol, 95%). Obtained.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.71 (1H, s), 7.18 (1H, d, J = 10.7 Hz), 6.78 (1H, d, J = 10.7 Hz), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.20-3.16 (2H, m), 2.26 (3H, s), 2.23-2.09 (2H, m), 1.67 -1.60 (1H, m).
ESI-MS m / z: 406 [M + H] + .
実施例２５
4-クロロ-N-エチルデアセチルコルヒチンの合成
　4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡黄褐色固体, 44 mg, 0.104 mmol, 76%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.75 (1H, s), 7.17 (1H, d, J=10.7 Hz), 6.78 (1H, d, J=10.7 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.56 (3H, s), 3.32-3.27 (1H, m), 3.20-3.14 (1H, m), 2.60-2.51 (1H, m), 2.35-2.27 (1H, m), 2.22-2.08 (2H,m), 1.64-1.55 (1H, m), 1.04 (3H, t, J=7.1 Hz).
ESI-MS m/z: 420 [M+H]+. Example 25
Synthesis of 4-chloro-N-ethyldeacetylcolchicine In the same manner as the synthesis of 4-chloro-N-methyldeacetylcolchicine, the title compound (light tan solid, 44 mg, 0.104 mmol, 76%) was obtained. It was.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.75 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 6.78 (1H, d, J = 10.7 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.56 (3H, s), 3.32-3.27 (1H, m), 3.20-3.14 (1H, m), 2.60-2.51 (1H, m) , 2.35-2.27 (1H, m), 2.22-2.08 (2H, m), 1.64-1.55 (1H, m), 1.04 (3H, t, J = 7.1 Hz).
ESI-MS m / z: 420 [M + H] + .
実施例２６
4-クロロ-N-エチルデアセチルコルヒチンの別途合成法
　4-クロロデアセチルコルヒチン(0.150 g, 0.383 mmol)のジクロロメタン-酢酸混液(50:1, 7.7 mL)溶液に、室温、アルゴンガス雰囲気下にて、アセトアルデヒド(20.4 μL, 0.383×0.95 mmol)を加えて10分間撹拌した。本溶液にトリアセトキシ水素化ホウ素ナトリウム(0.179 mg, 0.383×2.2 mmol)を加えて、室温で一晩撹拌しいた後、酢酸エチルと飽和重曹水を添加した。有機層を取り、ブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(乳白色固体, 97 mg, 0.231 mmol, 60%)を得た。 Example 26
Separate synthesis method of 4-chloro-N-ethyldeacetylcolchicine To a solution of 4-chlorodeacetylcolchicine (0.150 g, 0.383 mmol) in dichloromethane-acetic acid (50: 1, 7.7 mL) at room temperature under argon gas atmosphere Then, acetaldehyde (20.4 μL, 0.383 × 0.95 mmol) was added and stirred for 10 minutes. To this solution was added sodium triacetoxyborohydride (0.179 mg, 0.383 × 2.2 mmol), and the mixture was stirred overnight at room temperature, and then ethyl acetate and saturated aqueous sodium hydrogen carbonate were added. The organic layer was taken, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 97 mg, 0.231 mmol, 60%).
実施例２７
4-クロロ-N-エチルデアセチルコルヒチン塩酸塩の合成法
　メタノール(2 mL)に氷冷、アルゴンガス雰囲気下にてアセチルクロリド(24.6 μL, 0.231×1.5 mmol)を添加して、氷冷下1時間撹拌した。本溶液に、4-クロロ-N-エチルデアセチルコルヒチン(97 mg)のメタノール(2 mL)溶液を加えた後、減圧下濃縮乾固した。残留物を少量のクロロホルムに溶かし、ヘキサンを加えて固体化した。析出物をろ取、ヘキサンで洗浄後、減圧乾燥して標記化合物(淡黄色固体, 0.105 g, 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 10.68 (1H, br-s), 10.57 (1H, br-s), 8.04 (1H, s), 7.48 (1H, d, J=11.0 Hz), 7.04 (1H, d, J=11.0 Hz), 4.08 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.90-3.83 (1H, m), 3.71 (3H, s), 3.38-3.11 (3H, m), 2.57-2.48 (2H, m), 2.25-2.14 (1H, m), 1.54 (3H, t, J=7.2 Hz). Example 27
Synthesis method of 4-chloro-N-ethyldeacetylcolchicine hydrochloride Methanol (2 mL) was ice-cooled and acetyl chloride (24.6 μL, 0.231 × 1.5 mmol) was added under an argon gas atmosphere. Stir for hours. To this solution was added a solution of 4-chloro-N-ethyldeacetylcolchicine (97 mg) in methanol (2 mL), and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in a small amount of chloroform and solidified by adding hexane. The precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to obtain the title compound (pale yellow solid, 0.105 g, quantitative).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 10.68 (1H, br-s), 10.57 (1H, br-s), 8.04 (1H, s), 7.48 (1H, d, J = 11.0 Hz ), 7.04 (1H, d, J = 11.0 Hz), 4.08 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.90-3.83 (1H, m), 3.71 (3H, s) , 3.38-3.11 (3H, m), 2.57-2.48 (2H, m), 2.25-2.14 (1H, m), 1.54 (3H, t, J = 7.2 Hz).
実施例２８
N-アリル-4-クロロデアセチルコルヒチンの合成
　4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡褐色固体, 44 mg, 0.104 mmol, 76%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.78 (1H, s), 7.18 (1H, d, J=10.7 Hz), 6.78 (1H, d, J=10.7 Hz), 5.85-5.75 (1H, m), 5.07-4.97 (2H, m), 4.01 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.55 (3H, s), 3.34 (1H, dd, J=11.0, 5.9 Hz), 3.26-3.17 (2H, m), 2.95 (1H, dd, J=14.2, 7.0 Hz), 2.24-2.10 (2H, m), 1.71-1.63 (1H, m).
ESI-MS m/z: 432 [M+H]+. Example 28
Synthesis of N-allyl-4-chlorodeacetylcolchicine In the same manner as the synthesis of 4-chloro-N-methyldeacetylcolchicine, the title compound (light brown solid, 44 mg, 0.104 mmol, 76%) was obtained. .
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.78 (1H, s), 7.18 (1H, d, J = 10.7 Hz), 6.78 (1H, d, J = 10.7 Hz), 5.85-5.75 ( 1H, m), 5.07-4.97 (2H, m), 4.01 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.55 (3H, s), 3.34 (1H, dd, J = 11.0, 5.9 Hz), 3.26-3.17 (2H, m), 2.95 (1H, dd, J = 14.2, 7.0 Hz), 2.24-2.10 (2H, m), 1.71-1.63 (1H, m).
ESI-MS m / z: 432 [M + H] + .
実施例２９
4-クロロ-N-(2-メチルアリル)デアセチルコルヒチンの合成
　4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(褐色固体, 30 mg, 0.068 mmol, 71%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.81 (1H, s), 7.17 (1H, d, J=10.7 Hz), 6.77 (1H, d, J=10.7 Hz), 4.75 (1H, s), 4.72 (1H, s), 4.00 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.56 (3H, s), 3.30-3.26 (1H, m), 3.21-3.16 (1H, m), 3.09 (1H, d, J=14.2 Hz),2.87 (1H, d, J=14.2 Hz), 2.23-2.10 (2H, m), 1.70-1.63 (1H, m), 1.68 (3H, s).
ESI-MS m/z: 446 [M+H]+. Example 29
Synthesis of 4-chloro-N- (2-methylallyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-methyldeacetylcolchicine, the title compound (brown solid, 30 mg, 0.068 mmol, 71%) Got.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.81 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 6.77 (1H, d, J = 10.7 Hz), 4.75 (1H, s), 4.72 (1H, s), 4.00 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.56 (3H, s), 3.30-3.26 (1H, m), 3.21-3.16 (1H, m), 3.09 (1H, d, J = 14.2 Hz), 2.87 (1H, d, J = 14.2 Hz), 2.23-2.10 (2H, m), 1.70-1.63 (1H, m), 1.68 ( 3H, s).
ESI-MS m / z: 446 [M + H] + .
実施例３０
N-ベンジル-4-クロロデアセチルコルヒチンの合成
　4-クロロ-N-メチルデアセチルコルヒチンの合成と同様の方法にて、標記化合物(乳白色固体, 40 mg, 0.084 mmol, 73%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.68 (1H, s), 7.25-7.13 (5H, m), 7.11 (1H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 3.90 (3H, s), 3.86 (3H, s), 3.85 (3H, s), 3.57 (1H, dd, J=13.8, 7.4 Hz), 3.41 (3H, s), 3.39-3.34 (1H, m), 3.15-2.91 (3H, m), 2.12-2.01 (2H, m), 1.61-1.55 (1H, m).
ESI-MS m/z: 482 [M+H]+. Example 30
Synthesis of N-benzyl-4-chlorodeacetylcolchicine In the same manner as the synthesis of 4-chloro-N-methyldeacetylcolchicine, the title compound (milky white solid, 40 mg, 0.084 mmol, 73%) was obtained.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.68 (1H, s), 7.25-7.13 (5H, m), 7.11 (1H, d, J = 10.7 Hz), 7.02 (1H, d , J = 10.7 Hz), 3.90 (3H, s), 3.86 (3H, s), 3.85 (3H, s), 3.57 (1H, dd, J = 13.8, 7.4 Hz), 3.41 (3H, s), 3.39 -3.34 (1H, m), 3.15-2.91 (3H, m), 2.12-2.01 (2H, m), 1.61-1.55 (1H, m).
ESI-MS m / z: 482 [M + H] + .
実施例３１
N-ベンジル-4-クロロデアセチルコルヒチン塩酸塩の合成
　N-ベンジル-4-クロロデアセチルコルヒチン(0.132 g, 0.274 mmol)のメタノール(1 mL)溶液に、氷冷、アルゴンガス雰囲気下にて10%HCl-メタノール(166μL, 0.274×1.5 mmol)を添加した。本溶液を減圧下、濃縮乾固して標記化合物(乳白色固体, 142 mg, 0.274 mmol, 定量的)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.13 (1H, s), 9.61 (1H, s), 7.45-7.29 (6H, m), 7.19 (2H, d, J=10.7 Hz), 7.10 (2H, d, J=10.7 Hz), 4.30-4.13 (2H, m), 3.93 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.72-3.64 (1H, m), 3.52 (3H, s), 3.17 (1H, dd, J=13.9, 4.9 Hz), 2.20-1.97 (3H, m). Example 31
Synthesis of N-benzyl-4-chlorodeacetylcolchicine hydrochloride To a solution of N-benzyl-4-chlorodeacetylcolchicine (0.132 g, 0.274 mmol) in methanol (1 mL) under ice-cooling and argon gas atmosphere, 10 % HCl-methanol (166 μL, 0.274 × 1.5 mmol) was added. This solution was concentrated to dryness under reduced pressure to obtain the title compound (milky white solid, 142 mg, 0.274 mmol, quantitative).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.13 (1H, s), 9.61 (1H, s), 7.45-7.29 (6H, m), 7.19 (2H, d, J = 10.7 Hz ), 7.10 (2H, d, J = 10.7 Hz), 4.30-4.13 (2H, m), 3.93 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.72-3.64 (1H, m), 3.52 (3H, s), 3.17 (1H, dd, J = 13.9, 4.9 Hz), 2.20-1.97 (3H, m).
実施例３２
4-クロロ-N-プロピルデアセチルコルヒチンの合成
　N-アリル-4-クロロデアセチルコルヒチン(36 mg, 0.0833 mmol)の酢酸エチル(860 μL)溶液に、氷冷、アルゴンガス雰囲気下にて、10%パラジウム炭素(8 mg)及び臭化亜鉛(11 mg)を加えた。反応容器内を脱気した後、水素ガスで置換した。本懸濁液を室温、水素ガス雰囲気下にて一晩撹拌した。不要物をマイクロフィルター(0.45μm)により除去、ろ液を減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製、目的物画分を濃縮乾固して標記化合物(淡黄褐色固体, 16 mg, 0.037 mmol, 44%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.77 (1H, s), 7.18 (1H, d, J=10.7 Hz), 6.78 (1H, d, J=10.7Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.29-3.25 (1H, m), 3.20-3.15 (1H, m), 2.50-2.43 (1H, m), 2.26-2.09 (3H, m), 1.66-1.59 (1H, m), 1.50-1.39 (2H, m), 0.85 (3H, t, J=7.4 Hz).
ESI-MS m/z: 434 [M+H]+. Example 32
Synthesis of 4-chloro-N-propyldeacetylcolchicine N-allyl-4-chlorodeacetylcolchicine (36 mg, 0.0833 mmol) in an ethyl acetate (860 μL) solution under ice-cooling and argon gas atmosphere % Palladium on carbon (8 mg) and zinc bromide (11 mg) were added. The inside of the reaction vessel was deaerated and then replaced with hydrogen gas. The suspension was stirred overnight at room temperature under a hydrogen gas atmosphere. Unnecessary substances were removed with a microfilter (0.45 μm), and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol), and the fraction of interest was concentrated to dryness to give the title compound (light tan solid, 16 mg, 0.037 mmol, 44%) Got.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.77 (1H, s), 7.18 (1H, d, J = 10.7 Hz), 6.78 (1H, d, J = 10.7 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.29-3.25 (1H, m), 3.20-3.15 (1H, m), 2.50-2.43 (1H, m) , 2.26-2.09 (3H, m), 1.66-1.59 (1H, m), 1.50-1.39 (2H, m), 0.85 (3H, t, J = 7.4 Hz).
ESI-MS m / z: 434 [M + H] + .
実施例３３
N-イソブチル-4-クロロデアセチルコルヒチンの合成
　N-プロピルデアセチルコルヒチンの合成と同様の方法にて、4-クロロ-N-(2-メチルアリル)デアセチルコルヒチンから、標記化合物(乳白色固体, 4 mg, 0.0090 mmol, 17%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.79 (1H, s), 7.17 (1H, d, J=10.7 Hz), 6.76 (1H, d, J=10.7 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.26-3.14 (2H, m), 2.32-2.07 (4H, m), 1.69-1.60 (1H, m), 1.30-1.25 (1H, m), 0.89 (3H, d, J=6.6 Hz), 0.85 (3H, d, J=6.6 Hz).
ESI-MS m/z: 448 [M+H]+. Example 33
Synthesis of N-isobutyl-4-chlorodeacetylcolchicine In the same manner as the synthesis of N-propyldeacetylcolchicine, the title compound (milky white solid, 4) was synthesized from 4-chloro-N- (2-methylallyl) deacetylcolchicine. mg, 0.0090 mmol, 17%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.79 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 6.76 (1H, d, J = 10.7 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.26-3.14 (2H, m), 2.32-2.07 (4H, m), 1.69-1.60 (1H, m) , 1.30-1.25 (1H, m), 0.89 (3H, d, J = 6.6 Hz), 0.85 (3H, d, J = 6.6 Hz).
ESI-MS m / z: 448 [M + H] + .
実施例３４
N-(アセトキシアセチル)-4-クロロデアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(0.150 g, 0.383 mmol)のジクロロメタン(5.7 mL)溶液に氷冷、アルゴンガス雰囲気下にてトリエチルアミン(64.1 μL , 0.3831×1.2 mmol)次いでアセトキシアセチルクロリド(45.3 μL, 0.383×1.1 mmol)を添加した。本溶液を氷冷下、10分間次いで室温で3時間撹拌した。酢酸エチルと10%クエン酸を加えた後、有機層を取った。有機層を飽和重曹水次いでブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社IsoleraOne, クロロホルム/メタノール)にて精製し、標記化合物(乳白色固体, 0.142 g, 0.238 mmol, 76%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.45 (1H, s), 7.31 (1H, d, J=10.7 Hz), 7.12 (1H, d, J=7.1 Hz), 6.86 (1H, d, J=10.7 Hz), 4.63-4.58 (1H, m), 4.60 (1H, d, J=15.7 Hz), 4.54 (1H, d, J=15.7 Hz), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.30-3.25 (1H, m), 2.32-2.14 (2H, m), 2.18 (3H, s), 1.90-1.83 (1H, m).
ESI-MS m/z: 492 [M+H]+. Example 34
Synthesis of N- (acetoxyacetyl) -4-chlorodeacetylcolchicine Trichloroamine (64.1 μL, 64.1 μL) in a solution of 4-chlorodeacetylcolchicine (0.150 g, 0.383 mmol) in dichloromethane (5.7 mL) under ice-cooling and argon gas atmosphere 0.3831 × 1.2 mmol) and then acetoxyacetyl chloride (45.3 μL, 0.383 × 1.1 mmol) was added. The solution was stirred under ice cooling for 10 minutes and then at room temperature for 3 hours. After adding ethyl acetate and 10% citric acid, the organic layer was taken. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage IsoleraOne, chloroform / methanol) to obtain the title compound (milky white solid, 0.142 g, 0.238 mmol, 76%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.45 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 7.12 (1H, d, J = 7.1 Hz), 6.86 (1H, d, J = 10.7 Hz), 4.63-4.58 (1H, m), 4.60 (1H, d, J = 15.7 Hz), 4.54 (1H, d, J = 15.7 Hz), 4.02 (3H, s), 3.99 ( 3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.30-3.25 (1H, m), 2.32-2.14 (2H, m), 2.18 (3H, s), 1.90-1.83 (1H, m).
ESI-MS m / z: 492 [M + H] + .
実施例３５
4-クロロ-N-(ヒドロキシアセチル)デアセチルコルヒチンの合成
　N-(アセトキシアセチル)-4-クロロデアセチルコルヒチン(0.161 g, 0.327 mmol)のメタノール(3.3 mL)溶液に、氷冷、アルゴンガス雰囲気下にてナトリウムメトキシド(5M in MeOH, 65.4μL, 0.327 mmol)を添加した後、氷冷下5分間、次いで室温で30分間撹拌した。反応液にブラインと10%クエン酸を加え、クロロホルム(×2)で抽出した。有機層は合わせて、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(乳白色固体, 0.147 g, 0.327 mmol, 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.68 (1H, s), 7.56 (1H, d, J=7.3 Hz), 7.34 (1H, d, J=10.7 Hz), 6.90 (1H, d, J=10.7 Hz), 4.66-4.59 (1H, m), 4.20 (1H, d, J=16.3 Hz), 4.04 (1H, d, J=16.3 Hz), 4.02 (3H, s), 3.99 (3H, s), 3.98 (3H, s), 3.62 (3H, s), 3.31-3.26 (1H, m), 2.33-2.14 (2H, m), 1.94-1.87 (1H, m).
ESI-MS m/z: 450 [M+H]+. Example 35
Synthesis of 4-chloro-N- (hydroxyacetyl) deacetylcolchicine N- (acetoxyacetyl) -4-chlorodeacetylcolchicine (0.161 g, 0.327 mmol) in methanol (3.3 mL) in ice-cooled, argon gas atmosphere Under the addition of sodium methoxide (5M in MeOH, 65.4 μL, 0.327 mmol), the mixture was stirred under ice-cooling for 5 minutes and then at room temperature for 30 minutes. Brine and 10% citric acid were added to the reaction solution, and the mixture was extracted with chloroform (× 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 0.147 g, 0.327 mmol, quantitative).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.68 (1H, s), 7.56 (1H, d, J = 7.3 Hz), 7.34 (1H, d, J = 10.7 Hz), 6.90 (1H, d, J = 10.7 Hz), 4.66-4.59 (1H, m), 4.20 (1H, d, J = 16.3 Hz), 4.04 (1H, d, J = 16.3 Hz), 4.02 (3H, s), 3.99 ( 3H, s), 3.98 (3H, s), 3.62 (3H, s), 3.31-3.26 (1H, m), 2.33-2.14 (2H, m), 1.94-1.87 (1H, m).
ESI-MS m / z: 450 [M + H] + .
参考例１２
Trans-4-ヒドロキシ(シクロヘキサン)カルボン酸ベンジルの合成
　Trans-４-ヒドロキシ(シクロヘキサン)カルボン酸(1.00 g, 6.94 mmol)のN,N-ジメチルホルムアミド(69 mL)溶液に、室温、アルゴンガス雰囲気下にて炭酸カリウム(0.959 g, 6.94 mmol)及び臭化ベンジル(825 μL, 6.94 mmol)を添加した。本懸濁液を室温で一晩撹拌した後、酢酸エチル-ヘキサン混液(1:1)を添加して不要物をろ去、次いで酢酸エチル-ヘキサン(1:1)で洗いこんだ。ろ液と洗浄液は合わせて、水(×3)次いでブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, ヘキサン/酢酸エチル)にて精製し、標記化合物(白色固体, 1.567 g, 6.69 mmol, 96%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.39-7.30 (5H, m), 5.11 (2H, s), 3.61 (1H, tt, J=10.9, 4.0 Hz), 2.31 (1H, tt, J=12.0, 3.5 Hz), 2.08-2.00 (4H, m), 1.58-1.47 (3H, m), 1.34-1.23 (2H, m). Reference Example 12
Synthesis of benzyl Trans-4-hydroxy (cyclohexane) carboxylate To a solution of Trans-4-hydroxy (cyclohexane) carboxylic acid (1.00 g, 6.94 mmol) in N, N-dimethylformamide (69 mL) at room temperature under an argon gas atmosphere Potassium carbonate (0.959 g, 6.94 mmol) and benzyl bromide (825 μL, 6.94 mmol) were added. The suspension was stirred overnight at room temperature, and then an ethyl acetate-hexane mixture (1: 1) was added to remove unnecessary substances, followed by washing with ethyl acetate-hexane (1: 1). The filtrate and the washing solution were combined, washed with water (× 3) and then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, hexane / ethyl acetate) to obtain the title compound (white solid, 1.567 g, 6.69 mmol, 96%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.39-7.30 (5H, m), 5.11 (2H, s), 3.61 (1H, tt, J = 10.9, 4.0 Hz), 2.31 (1H, tt , J = 12.0, 3.5 Hz), 2.08-2.00 (4H, m), 1.58-1.47 (3H, m), 1.34-1.23 (2H, m).
参考例１３
1-メチルピペリジン-4-イルオキシカルボニルクロリド塩酸塩の合成
　4-ヒドロキシ-1-メチルピペリジン(1 mL, 8.50 mmol)のアセトニトリル(17 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリホスゲン(2.52 g, 8.50 mmol)を加えて、室温に戻しながら一晩撹拌した。析出物をろ取、エーテル次いでヘキサンで洗浄した後、減圧乾燥して表記化合物(白色固体, 1.135 g, 62%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 12.94 (1H, br-s), 5.27-5.24 (1H, m), 3.47-3.41 (2H, m), 3.08-2.98 (2H, m), 2.83 (3H, d, J=4.9 Hz), 2.78-2.69 (2H, m), 2.24-2.18 (2H, m). Reference Example 13
Synthesis of 1-methylpiperidin-4-yloxycarbonyl chloride hydrochloride To a solution of 4-hydroxy-1-methylpiperidine (1 mL, 8.50 mmol) in acetonitrile (17 mL) under ice-cooling and argon gas atmosphere, triphosgene ( 2.52 g, 8.50 mmol) was added, and the mixture was stirred overnight while returning to room temperature. The precipitate was collected by filtration, washed with ether and then hexane, and then dried under reduced pressure to obtain the title compound (white solid, 1.135 g, 62%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 12.94 (1H, br-s), 5.27-5.24 (1H, m), 3.47-3.41 (2H, m), 3.08-2.98 (2H, m) , 2.83 (3H, d, J = 4.9 Hz), 2.78-2.69 (2H, m), 2.24-2.18 (2H, m).
参考例１４
1-(ベンジルオキシカルボニル)ピペリジン-4-イルオキシカルボニルクロリドの合成
　4-ヒドロキシ-1-(ベンジルオキシカルボニル)ピペリジン(2.00 g, 8.50 mmol)のアセトニトリル(17 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリホスゲン(2.52 g, 8.50 mmol)を加えて、室温に戻しながら一晩撹拌した。反応液を濃縮乾固して、標記化合物(微褐色澄明の粘性液, 2.47 g, 8.29 mmol, 98%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.40-7.30 (5H, m), 5.13 (2H, s), 5.06-5.00 (1H, m), 3.79-3.73 (2H, m), 3.43-3.37 (2H, m), 2.01-1.92 (2H, m), 1.84-1.74 (2H, m). Reference Example 14
Synthesis of 1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl chloride To a solution of 4-hydroxy-1- (benzyloxycarbonyl) piperidine (2.00 g, 8.50 mmol) in acetonitrile (17 mL), ice-cooled, argon gas Triphosgene (2.52 g, 8.50 mmol) was added under an atmosphere, and the mixture was stirred overnight while returning to room temperature. The reaction solution was concentrated to dryness to obtain the title compound (clear brown liquid, 2.47 g, 8.29 mmol, 98%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.40-7.30 (5H, m), 5.13 (2H, s), 5.06-5.00 (1H, m), 3.79-3.73 (2H, m), 3.43 -3.37 (2H, m), 2.01-1.92 (2H, m), 1.84-1.74 (2H, m).
参考例１５
Trans-4-(クロロカルボニルオキシ)シクロヘキサンカルボン酸ベンジルの合成
　Trans-4-ヒドロキシ(シクロヘキサン)カルボン酸ベンジルエステル(1.00 g, 4.27 mmol)のアセトニトリル(8.5 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリホスゲン(1.27g, 4.27 mmol)を加えて、室温に戻しながら一晩撹拌した。反応液を濃縮乾固して、標記化合物(白濁粘性液, 1.27 g, 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.39-7.31 (5H, m), 5.12 (2H, s), 4.83-4.76 (1H, m), 2.42-2.35 (1H, m), 2.18-2.08 (4H, m), 1.66-1.49 (4H, m). Reference Example 15
Synthesis of Trans-4- (chlorocarbonyloxy) cyclohexanecarboxylate benzyl Trans-4-hydroxy (cyclohexane) carboxylate benzyl ester (1.00 g, 4.27 mmol) in acetonitrile (8.5 mL) under ice-cooling and argon gas atmosphere Triphosgene (1.27 g, 4.27 mmol) was added and stirred overnight while returning to room temperature. The reaction mixture was concentrated to dryness to obtain the title compound (white cloudy viscous liquid, 1.27 g, quantitative).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.39-7.31 (5H, m), 5.12 (2H, s), 4.83-4.76 (1H, m), 2.42-2.35 (1H, m), 2.18 -2.08 (4H, m), 1.66-1.49 (4H, m).
参考例１６
チオモルホリン-4-カルボニルクロリドの合成
　チオモルホリン(500 μL, 5.28 mmol)のアセトニトリル(11 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリホスゲン(1.57 g, 5.28 mmol)を加えて、室温に戻しながら一晩撹拌した。反応液を濃縮乾固して、標記化合物(淡褐色澄明液, 0.860 g, 5.19 mmol, 98%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 4.01-3.98 (2H, m), 3.91-3.88 (2H, m), 2.70-2.68 (4H, m). Reference Example 16
Synthesis of thiomorpholine-4-carbonyl chloride To a solution of thiomorpholine (500 μL, 5.28 mmol) in acetonitrile (11 mL) was added triphosgene (1.57 g, 5.28 mmol) under ice-cooling and argon gas atmosphere, and the mixture was brought to room temperature. The mixture was stirred overnight while returning. The reaction solution was concentrated to dryness to obtain the title compound (light brown clear solution, 0.860 g, 5.19 mmol, 98%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 4.01-3.98 (2H, m), 3.91-3.88 (2H, m), 2.70-2.68 (4H, m).
参考例１７
チオモルホリン-4-カルボニルクロリド 1,1-ジオキシドの合成
　チオモルホリン 1,1-ジオキシド(0.500 g, 3.70 mmol)のアセトニトリル(7.4 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリホスゲン(1.10 g, 3.70 mmol)を加えて、室温に戻しながら一晩撹拌した。反応液を濃縮乾固して得られた固体にヘキサンを添加して超音波処理した。固体をろ取、ヘキサンで洗浄、減圧乾燥して、標記化合物(白色個体, 0.731 g, 3.70 mmol, 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 4.27-4.22 (2H, m), 4.15-4.10 (2H, m), 3.15-3.12 (4H, m). Reference Example 17
Synthesis of thiomorpholine-4-carbonyl chloride 1,1-dioxide Triphosgene (1.10 g) was added to a solution of thiomorpholine 1,1-dioxide (0.500 g, 3.70 mmol) in acetonitrile (7.4 mL) under ice-cooling and argon gas atmosphere. , 3.70 mmol) and stirred overnight while returning to room temperature. Hexane was added to the solid obtained by concentrating the reaction solution to dryness and sonicated. The solid was collected by filtration, washed with hexane, and dried under reduced pressure to obtain the title compound (white solid, 0.731 g, 3.70 mmol, quantitative).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 4.27-4.22 (2H, m), 4.15-4.10 (2H, m), 3.15-3.12 (4H, m).
参考例１８
1-メチルピペラジン-4-カルボニルクロリド塩酸塩の合成
　1-メチルピペラジン(500 μL, 4.54 mmol)のアセトニトリル(9 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリホスゲン(1.35 g, 4.54 mmol)を加えて、室温に戻しながら一晩撹拌した。反応液を濃縮乾固して得られた固体にジエチルエーテルを添加して超音波処理した。固体をろ取、ジエチルエーテル次いでヘキサンで洗浄、減圧乾燥して、標記化合物(白色個体, 0.904 g, 4.54 mmol, 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 13.7 (1H, br-s), 4.45 (2H, d, J=15.1 Hz), 4.12 (1H, t, J=12.6 Hz), 3.88 (1H, t, J=12.6 Hz), 3.60-3.52 (2H, m), 2.98-2.89 (2H, m), 2.87 (3H, d, J=4.6 Hz). Reference Example 18
Synthesis of 1-methylpiperazine-4-carbonyl chloride hydrochloride Triphosgene (1.35 g, 4.54 mmol) in a solution of 1-methylpiperazine (500 μL, 4.54 mmol) in acetonitrile (9 mL) under ice-cooling and argon gas atmosphere And stirred overnight while returning to room temperature. The reaction solution was concentrated to dryness, and diethyl ether was added to the resulting solid and sonicated. The solid was collected by filtration, washed with diethyl ether and then hexane, and dried under reduced pressure to obtain the title compound (white solid, 0.904 g, 4.54 mmol, quantitative).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 13.7 (1H, br-s), 4.45 (2H, d, J = 15.1 Hz), 4.12 (1H, t, J = 12.6 Hz), 3.88 ( 1H, t, J = 12.6 Hz), 3.60-3.52 (2H, m), 2.98-2.89 (2H, m), 2.87 (3H, d, J = 4.6 Hz).
実施例３６
4-クロロ-N-(1-メチルピペラジン-4-イルオキシカルボニル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)のジクロロメタン(1.5 mL)溶液に室温で、ピリジン(12.4 μL, 0.0766×2 mmol)及び1-メチルピペリジン-4-イルオキシカルボニルクロリド塩酸塩(25 mg, 0.0766×1.5 mmol)を添加した。本混合液を室温で一晩撹拌した後、クロロホルムと飽和重曹水を添加した。有機層を取り、水層はさらにクロロホルムにて抽出した。有機層は合わせて無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(淡黄色固体, 35 mg, 0.0654 mmol, 85%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.48 (1H, s), 7.24 (1H, d, J=10.7 Hz), 6.81 (1H, d, J=10.7 Hz), 5.43 (1H, d, J=6.6 Hz), 4.68-4.60 (1H, m), 4.37-4.30 (1H, m), 4.01(3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.59 (3H, s), 3.26 (1H, dd, J=13.4, 4.6 Hz), 2.85-2.73 (2H, m), 2.58-2.39 (2H, m), 2.43 (3H, s), 2.33-2.13 (2H, m), 2.08-1.98 (2H, m), 1.89-1.69 (3H, m).
ESI-MS m/z: 533 [M+H]+. Example 36
Synthesis of 4-chloro-N- (1-methylpiperazin-4-yloxycarbonyl) deacetylcolchicine A solution of 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) in dichloromethane (1.5 mL) at room temperature and pyridine (12.4 μL, 0.0766 × 2 mmol) and 1-methylpiperidin-4-yloxycarbonyl chloride hydrochloride (25 mg, 0.0766 × 1.5 mmol) were added. The mixture was stirred overnight at room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added. The organic layer was taken and the aqueous layer was further extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 35 mg, 0.0654 mmol, 85%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, s), 7.24 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 5.43 (1H, d, J = 6.6 Hz), 4.68-4.60 (1H, m), 4.37-4.30 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.59 (3H , s), 3.26 (1H, dd, J = 13.4, 4.6 Hz), 2.85-2.73 (2H, m), 2.58-2.39 (2H, m), 2.43 (3H, s), 2.33-2.13 (2H, m ), 2.08-1.98 (2H, m), 1.89-1.69 (3H, m).
ESI-MS m / z: 533 [M + H] + .
実施例３７
4-クロロ-N-[1-(ベンジルオキシカルボニル)ピペリジン-4-イルオキシカルボニル]デアセチルコルヒチンの合成
　4-クロロ-N-(1-メチルピペラジン-4-イルオキシカルボニル)デアセチルコルヒチンの合成と同様の方法にて、標記化合物(乳白色固体, 62 mg, 0.0952 mmol, 83%)を得た。1-メチルピペリジン-4-イルオキシカルボニルクロリド塩酸塩の代わりに1-(ベンジルオキシカルボニル)ピペリジン-4-イルオキシカルボニルクロリド(0.9 eq.)を用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.53 (1H, d, J=8.3 Hz), 7.38-7.30 (5H, m), 7.26 (1H, d, J=10.7 Hz), 6.82 (1H, d, J=10.7 Hz), 5.31 (1H, d, J=7.8 Hz), 5.11 (2H, s), 4.73-4.67 (1H, m), 4.37-4.30 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.79-3.69 (2H, m), 3.59 (3H, s), 3.28-3.20 (3H, m), 2.33-2.12 (2H, m), 1.86-1.50 (5H, m).
ESI-MS m/z: 653 [ M+H]+. Example 37
Synthesis of 4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl] deacetylcolchicine Synthesis of 4-chloro-N- (1-methylpiperazin-4-yloxycarbonyl) deacetylcolchicine In the same manner, the title compound (milky white solid, 62 mg, 0.0952 mmol, 83%) was obtained. Instead of 1-methylpiperidin-4-yloxycarbonyl chloride hydrochloride, 1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl chloride (0.9 eq.) Was used.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.53 (1H, d, J = 8.3 Hz), 7.38-7.30 (5H, m), 7.26 (1H, d, J = 10.7 Hz), 6.82 ( 1H, d, J = 10.7 Hz), 5.31 (1H, d, J = 7.8 Hz), 5.11 (2H, s), 4.73-4.67 (1H, m), 4.37-4.30 (1H, m), 4.01 (3H , s), 3.98 (3H, s), 3.97 (3H, s), 3.79-3.69 (2H, m), 3.59 (3H, s), 3.28-3.20 (3H, m), 2.33-2.12 (2H, m ), 1.86-1.50 (5H, m).
ESI-MS m / z: 653 [M + H] + .
実施例３８
4-クロロ-N-(ピペリジン-4-イルオキシカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-[1-(ベンジルオキシカルボニル)ピペリジン-4-イルオキシカルボニル]デアセチルコルヒチン(47 mg, 0.072 mmol)のメタノール-テトラヒドロフラン混液(2:1, 3 mL)に、氷冷、アルゴンガス雰囲気下にて20%水酸化パラジウム-炭素(10 mg)を添加した。反応容器内を減圧にて脱気、続く水素ガスによって置換した(本操作は３回繰り返した)。反応混合液を室温、水素ガス雰囲気下にて３時間激しく撹拌した。不要物をマイクロフィルター(0.45μm)により除去し、ろ液を濃縮乾固して標記化合物(褐色固体, 37 mg, quant.)を得た。
ESI-MS m/z: 519 [M+H]+. Example 38
Synthesis of 4-chloro-N- (piperidin-4-yloxycarbonyl) deacetylcolchicine 4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl] deacetylcolchicine (47 mg, 0.072 mmol) in methanol-tetrahydrofuran (2: 1, 3 mL) was added 20% palladium hydroxide-carbon (10 mg) under ice-cooling and argon gas atmosphere. The inside of the reaction vessel was deaerated under reduced pressure, and then replaced with hydrogen gas (this operation was repeated three times). The reaction mixture was vigorously stirred at room temperature under a hydrogen gas atmosphere for 3 hours. Unnecessary substances were removed by a microfilter (0.45 μm), and the filtrate was concentrated to dryness to obtain the title compound (brown solid, 37 mg, quant.).
ESI-MS m / z: 519 [M + H] + .
実施例３９
N-[trans-1-(ベンジルオキシカルボニル)シクロヘキサン-4-イルオキシカルボニル]-4-クロロデアセチルコルヒチンの合成
　4-クロロ-N-[1-(ベンジルオキシカルボニル)ピペリジン-4-イルオキシカルボニル]デアセチルコルヒチンの合成と同様の方法にて、標記化合物(淡黄色固体, 74 mg, 0.113 mmol, 82%)を得た。1-(ベンジルオキシカルボニル)ピペリジン-4-イルオキシカルボニルクロリドの代わりに、Trans-4-(クロロカルボニルオキシ)シクロヘキサンカルボン酸ベンジルエステル(0.9 eq.)を用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.50 (1H, s), 7.37-7.29 (5H, m), 7.25 (1H, d, J=10.7 Hz), 6.81 (1H, d, J=10.7 Hz), 5.12-5.09 (1H, m), 5.08 (2H, s), 4.50-4.43 (1H,m), 4.36-4.29 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.59 (3H, s), 3.25 (1H, dd, J=13.3, 4.5 Hz), 2.34-2.12 (3H, m), 2.05-1.95 (4H, m), 1.71-1.64 (1H, m), 1.57-1.45 (2H, m), 1.41-1.28 (2H, m).
ESI-MS m/z: 652 [M+H]+. Example 39
Synthesis of N- [trans-1- (benzyloxycarbonyl) cyclohexane-4-yloxycarbonyl] -4-chlorodeacetylcolchicine 4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl The title compound (light yellow solid, 74 mg, 0.113 mmol, 82%) was obtained in the same manner as in the synthesis of deacetylcolchicine. Trans-4- (chlorocarbonyloxy) cyclohexanecarboxylic acid benzyl ester (0.9 eq.) Was used in place of 1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl chloride.
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.50 (1H, s), 7.37-7.29 (5H, m), 7.25 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 5.12-5.09 (1H, m), 5.08 (2H, s), 4.50-4.43 (1H, m), 4.36-4.29 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.59 (3H, s), 3.25 (1H, dd, J = 13.3, 4.5 Hz), 2.34-2.12 (3H, m), 2.05-1.95 (4H, m), 1.71 -1.64 (1H, m), 1.57-1.45 (2H, m), 1.41-1.28 (2H, m).
ESI-MS m / z: 652 [M + H] + .
実施例４０
4-クロロ-N-(チオモルホリン-4-カルボニル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(50 mg, 0.128 mmol)のジクロロメタン(3.8 mL)溶液に、室温でトリエチルアミン(89 μL, 0.128×5.0 mmol)及びチオモルホリン-4-カルボニルクロリド(106 mg, 0.128×5.0 mmol)を添加した。本溶液をアルゴンガス雰囲気下、一晩煮沸環流した。反応液を室温まで放冷後、酢酸エチル及び10%クエン酸を添加して有機層を取った。有機層はさらに10%クエン酸次いでブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(微褐色固体, 47 mg,0.090 mmol, 70%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.80 (1H, s), 7.43 (1H, d, J=11.0 Hz), 6.96 (1H, d, J=11.0 Hz), 5.72 (1H, d, J=5.9 Hz), 4.57-4.51 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.80-3.65 (4H, m), 3.64 (3H, s), 3.25 (1H, dd, J=13.3, 5.2 Hz), 2.64-2.53 (4H, m), 2.33-2.24 (1H, m), 2.15-2.07 (1H, m), 1.94-1.86 (1H, m).
ESI-MS m/z: 521 [M+H]+. Example 40
Synthesis of 4-chloro-N- (thiomorpholine-4-carbonyl) deacetylcolchicine To a solution of 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (3.8 mL) at room temperature, triethylamine (89 μL, 0.128 × 5.0 mmol) and thiomorpholine-4-carbonyl chloride (106 mg, 0.128 × 5.0 mmol) were added. This solution was refluxed overnight under an argon gas atmosphere. The reaction solution was allowed to cool to room temperature, and then ethyl acetate and 10% citric acid were added to obtain an organic layer. The organic layer was further washed with 10% citric acid and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (fine brown solid, 47 mg, 0.090 mmol, 70%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.80 (1H, s), 7.43 (1H, d, J = 11.0 Hz), 6.96 (1H, d, J = 11.0 Hz), 5.72 (1H, d, J = 5.9 Hz), 4.57-4.51 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.80-3.65 (4H, m), 3.64 (3H , s), 3.25 (1H, dd, J = 13.3, 5.2 Hz), 2.64-2.53 (4H, m), 2.33-2.24 (1H, m), 2.15-2.07 (1H, m), 1.94-1.86 (1H , m).
ESI-MS m / z: 521 [M + H] + .
実施例４１
4-クロロ-N-(1,1-ジオキソチオモルホリン-4-カルボニル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(50 mg, 0.128 mmol)のジクロロメタン(有機合成用, 3.8 mL)溶液に、室温でトリエチルアミン(89 μL, 0.128×5.0 mmol)及びチオモルホリン-4-カルボニルクロリド 1,1-ジオキシド(0.202 g, 0.128×8.0 mmol)を添加した。本溶液をアルゴンガス雰囲気下、一晩煮沸環流した。反応液を室温まで放冷後、酢酸エチル及び10%クエン酸を添加して有機層を取った。有機層はさらに10%クエン酸次いでブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(淡褐色固体, 48 mg, 0.087 mmol, 68%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.76 (1H, s), 7.43 (1H, d, J=10.7Hz), 7.04 (1H, s), 6.98 (1H, d, J=10.7 Hz), 4.55-4.49 (1H, m), 4.04 (3H, s), 4.03-3.93 (4H, m), 4.00 (3H, s), 3.98 (3H, s), 3.64 (3H, s), 3.25 (1H, dd, J=13.5, 5.5 Hz), 3.02-2.97 (4H, m), 2.34-2.26 (1H, m), 2.17-2.06 (1H, m), 1.99-1.91 (1H, m).
ESI-MS m/z: 553 [M+H]+. Example 41
Synthesis of 4-chloro-N- (1,1-dioxothiomorpholine-4-carbonyl) deacetylcolchicine To a solution of 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (for organic synthesis, 3.8 mL) At room temperature, triethylamine (89 μL, 0.128 × 5.0 mmol) and thiomorpholine-4-carbonyl chloride 1,1-dioxide (0.202 g, 0.128 × 8.0 mmol) were added. This solution was refluxed overnight under an argon gas atmosphere. The reaction solution was allowed to cool to room temperature, and then ethyl acetate and 10% citric acid were added to obtain an organic layer. The organic layer was further washed with 10% citric acid and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 48 mg, 0.087 mmol, 68%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.76 (1H, s), 7.43 (1H, d, J = 10.7Hz), 7.04 (1H, s), 6.98 (1H, d, J = 10.7 Hz), 4.55-4.49 (1H, m), 4.04 (3H, s), 4.03-3.93 (4H, m), 4.00 (3H, s), 3.98 (3H, s), 3.64 (3H, s), 3.25 (1H, dd, J = 13.5, 5.5 Hz), 3.02-2.97 (4H, m), 2.34-2.26 (1H, m), 2.17-2.06 (1H, m), 1.99-1.91 (1H, m).
ESI-MS m / z: 553 [M + H] + .
実施例４２
4-クロロ-N-(1-メチルピペラジン-4-カルボニル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(50 mg, 0.128 mmol)のジクロロメタン(3.8 mL)溶液に、室温でトリエチルアミン(54 μL, 0.128×3.0 mmol)及び1-メチルピペラジン-4-カルボニルクロリド塩酸塩 (0.127 g, 0.128×5.0 mmol)を添加した。本溶液をアルゴンガス雰囲気下、6時間沸環流した。反応液を室温まで放冷後、クロロホルム及び飽和重曹水を添加して有機層を取った。水層はさらにクロロホルムで抽出した。有機層合わせてブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(淡褐色固体, 30 mg, 0.058 mmol, 45%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.52 (1H, s), 7.25 (1H, d, J=10.7 Hz), 6.80 (1H, d, J=10.7 Hz), 4.47-4.41 (1H, m), 3.98 (6H, s), 3.95 (3H, s), 3.79-3.66 (4H, m), 3.63 (3H, s), 3.24 (1H, dd, J=13.3, 4.3 Hz), 2.94-2.76 (4H, m), 2.60 (3H, s), 2.27-2.12 (2H, m), 1.96-1.86 (1H, m).
ESI-MS m/z: 518 [M+H]+. Example 42
Synthesis of 4-chloro-N- (1-methylpiperazine-4-carbonyl) deacetylcolchicine To a solution of 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (3.8 mL) at room temperature with triethylamine (54 μL, 0.128 × 3.0 mmol) and 1-methylpiperazine-4-carbonyl chloride hydrochloride (0.127 g, 0.128 × 5.0 mmol) were added. This solution was refluxed for 6 hours under an argon gas atmosphere. The reaction solution was allowed to cool to room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added to obtain an organic layer. The aqueous layer was further extracted with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 30 mg, 0.058 mmol, 45%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.52 (1H, s), 7.25 (1H, d, J = 10.7 Hz), 6.80 (1H, d, J = 10.7 Hz), 4.47-4.41 ( 1H, m), 3.98 (6H, s), 3.95 (3H, s), 3.79-3.66 (4H, m), 3.63 (3H, s), 3.24 (1H, dd, J = 13.3, 4.3 Hz), 2.94 -2.76 (4H, m), 2.60 (3H, s), 2.27-2.12 (2H, m), 1.96-1.86 (1H, m).
ESI-MS m / z: 518 [M + H] + .
実施例４３
N-ブチリル-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、 0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、 ブチリルクロリド (13 μl, 0.128 × 1 mmol) を加え、 室温に戻して40分撹拌した。反応液に水を加えをクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 52 mg, 0.113 mmol, 88%)を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.52 (1H, s), 7.30 (1H, d, J = 10.7 Hz), 6.85 (1H, d, J = 10.7 Hz), 6.79 (1H, d, J = 6.8 Hz), 4.61-4.55 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.25 (1H, dd, J = 12.8, 4.3 Hz), 2.25-2.23 (3H, m), 2.21-2.14 (1H, m), 1.81-1.77 (1H, m), 1.70-1.58 (3H, m), 0.92 (3H, t, J = 7.4 Hz)
ESI-MS m/z: 462 [M+H]+. Example 43
Synthesis of N-butyryl-4-chlorodeacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and butyryl chloride (13 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 40 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 52 mg, 0.113 mmol, 88%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.52 (1H, s), 7.30 (1H, d, J = 10.7 Hz), 6.85 (1H, d, J = 10.7 Hz), 6.79 (1H, d, J = 6.8 Hz), 4.61-4.55 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.25 (1H, dd , J = 12.8, 4.3 Hz), 2.25-2.23 (3H, m), 2.21-2.14 (1H, m), 1.81-1.77 (1H, m), 1.70-1.58 (3H, m), 0.92 (3H, t , J = 7.4 Hz)
ESI-MS m / z: 462 [M + H] + .
実施例４４
4-クロロ-N-イソブチリルデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した. そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、イソ酪酸クロリド(13 μl, 0.128 × 1 mmol) を加え, 室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 9 mg, 0.019 mmol, 15%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.48 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 10.7 Hz), 6.38 (1H, d, J = 6.6 Hz), 4.58-4.54 (1H, m), 4.01 (3H, s),3.99 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.25 (1H, dd, J = 12.6, 4.5 Hz), 2.48-2.47 (1H, m), 2.24-2.16 (2H, m), 1.82-1.77 (1H, m), 1.20 (3H, d, J = 6.8 Hz), 1.15 (3H, d, J = 6.6 Hz)
ESI-MS m/z: 462 [M+H]+. Example 44
Synthesis of 4-chloro-N-isobutyryl deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine ( 19 μl, 0.128 × 1.1 mmol) and isobutyric chloride (13 μl, 0.128 × 1 mmol) were added, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 9 mg, 0.019 mmol, 15%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 10.7 Hz), 6.38 (1H, d, J = 6.6 Hz), 4.58-4.54 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.25 (1H, dd , J = 12.6, 4.5 Hz), 2.48-2.47 (1H, m), 2.24-2.16 (2H, m), 1.82-1.77 (1H, m), 1.20 (3H, d, J = 6.8 Hz), 1.15 ( (3H, d, J = 6.6 Hz)
ESI-MS m / z: 462 [M + H] + .
実施例４５
4-クロロ-N- (シクロプロパンカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、シクロプロパンカルボニルクロリド (12 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 58 mg, 0.126 mmol, 99%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.71 (1H, s), 7.36 (1H, d, J = 10.7 Hz), 6.91 (1H, d, J = 10.7 Hz), 6.83 (1H, br.s), 4.64-4.58 (1H, m), 4.03 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.26 (1H, dd, J = 13.5, 5.0 Hz), 2.30-2.27 (1H, m), 2.18-2.10 (1H, m), 1.88-1.84 (1H, m), 1.56-1.52 (1H, m), 0.88-0.86 (2H, m), 0.75-0.73 (2H, m).
ESI-MS m/z: 460 [M+H]+. Example 45
Synthesis of 4-chloro-N- (cyclopropanecarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and cyclopropanecarbonyl chloride (12 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 58 mg, 0.126 mmol, 99%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.71 (1H, s), 7.36 (1H, d, J = 10.7 Hz), 6.91 (1H, d, J = 10.7 Hz), 6.83 (1H, br.s), 4.64-4.58 (1H, m), 4.03 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.26 (1H, dd, J = 13.5, 5.0 Hz), 2.30-2.27 (1H, m), 2.18-2.10 (1H, m), 1.88-1.84 (1H, m), 1.56-1.52 (1H, m), 0.88-0.86 (2H, m) , 0.75-0.73 (2H, m).
ESI-MS m / z: 460 [M + H] + .
実施例４６
4-クロロ-N-イソバレリルデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、イソバレリルクロリド (16 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 57 mg, 0.120 mmol, 94%)を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.47 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 6.24 (1H, d, J = 7.3 Hz), 4.61-4.57 (1H, m), 4.01 (3H, s),3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.25 (1H, dd, J = 13.4, 4.4 Hz), 2.27-2.04 (5H, m), 1.77-1.74 (2H, m), 0.95 (3H, d, J = 6.3 Hz), 0.92 (3H, d, J = 6.1Hz).
ESI-MS m/z: 476 [M+H]+. Example 46
Synthesis of 4-chloro-N-isovaleryl deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and isovaleryl chloride (16 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 57 mg, 0.120 mmol, 94%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.47 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 6.24 (1H, d, J = 7.3 Hz), 4.61-4.57 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.25 (1H, dd , J = 13.4, 4.4 Hz), 2.27-2.04 (5H, m), 1.77-1.74 (2H, m), 0.95 (3H, d, J = 6.3 Hz), 0.92 (3H, d, J = 6.1 Hz) .
ESI-MS m / z: 476 [M + H] + .
実施例４７
4-クロロ-N-ヘプタノイルデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、ヘプタノイルクロリド (20 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biorage Isorela One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 59 mg, 0.117 mmol, 92%)を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.48 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 10.7 Hz), 6.38 (1H, br.s), 4.58-4.55 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 2.26-2.11 (2H, m), 1.78-1.75 (1H, m), 1.62-1.54 (2H, m), 1.29-1.27 (8H, m), 0.88-0.84 (3H, m).
ESI-MS m/z: 504 [M+H]+. Example 47
Synthesis of 4-chloro-N-heptanoyl deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and heptanoyl chloride (20 microliters, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biorage Isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 59 mg, 0.117 mmol, 92%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 10.7 Hz), 6.38 (1H, br.s), 4.58-4.55 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 2.26-2.11 (2H, m) , 1.78-1.75 (1H, m), 1.62-1.54 (2H, m), 1.29-1.27 (8H, m), 0.88-0.84 (3H, m).
ESI-MS m / z: 504 [M + H] + .
実施例４８
4-クロロ-N- (シクロヘキサンカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、シクロヘキサンカルボニルクロリド (17 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 18 mg, 0.036 mmol, 28%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.47 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 6.23 (1H, d, J = 6.6 Hz), 4.58-4.52 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.25 (1H, dd, J = 12.8, 4.5 Hz), 2.26-2.12 (3H, m), 1.94-1.90 (2H, m), 1.82-1.76 (1H, m), 1.66-1.63 (2H, m), 1.50-1.15 (5H, m).
ESI-MS m/z: 502 [M+H]+. Example 48
Synthesis of 4-chloro-N- (cyclohexanecarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and cyclohexanecarbonyl chloride (17 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 18 mg, 0.036 mmol, 28%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.47 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 6.23 (1H, d, J = 6.6 Hz), 4.58-4.52 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.25 (1H, dd , J = 12.8, 4.5 Hz), 2.26-2.12 (3H, m), 1.94-1.90 (2H, m), 1.82-1.76 (1H, m), 1.66-1.63 (2H, m), 1.50-1.15 (5H , m).
ESI-MS m / z: 502 [M + H] + .
実施例４９
N-ベンゾイル-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (150 mg, 0.383 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (57 μl, 0.383 × 1.1 mmol)、ベンゾイルクロリド (44 μl, 0.383 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。
　有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isorela One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 146 mg, 0.294 mmol, 77%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.80-7.79 (2H, m), 7.63 (1H, s), 7.49-7.47 (1H, m), 7.41-7.37 (2H, m), 7.35 (1H, d, J = 10.7 Hz), 6.93 (1H, br.s), 6.88 (1H, d, J = 11.0 Hz), 4.80-4.78 (1H, m), 4.01 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.5, 5.2 Hz), 2.37-2.32 (1H, m), 2.25-2.22 (1H, m), 1.98-1.94 (1H, m).
ESI-MS m/z: 496 [M+H]+. Example 49
Synthesis of N-benzoyl-4-chlorodeacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (150 mg, 0.383 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (57 μl, 0.383 × 1.1 mmol) and benzoyl chloride (44 μl, 0.383 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 25 g, methanol / chloroform) to obtain the title compound (brown solid, 146 mg, 0.294 mmol, 77%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.80-7.79 (2H, m), 7.63 (1H, s), 7.49-7.47 (1H, m), 7.41-7.37 (2H, m), 7.35 (1H, d, J = 10.7 Hz), 6.93 (1H, br.s), 6.88 (1H, d, J = 11.0 Hz), 4.80-4.78 (1H, m), 4.01 (3H, s), 4.01 ( 3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.5, 5.2 Hz), 2.37-2.32 (1H, m), 2.25-2.22 (1H, m) , 1.98-1.94 (1H, m).
ESI-MS m / z: 496 [M + H] + .
実施例５０
4-クロロ-N-(フェニルアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (21 μl, 0.128 × 1.5 mmol)、フェニルアセチルクロリド (25 μl, 0.128 × 1.2 mmol) を加え、室温に戻して40分撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 44 mg, 0.086 mmol, 67%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.45 (1H, s), 7.38-7.26 (6H, m), 6.86 (1H, d, J = 10.7 Hz), 6.39 (1H, br.s), 4.57-4.51 (1H, m), 4.02 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.65-3.56 (2H, m), 3.61 (3H, s), 3.21-3.19 (1H, m), 2.16-2.08 (1H, m), 1.97-1.86 (1H, m), 1.74-1.70 (1H, m).
ESI-MS m/z: 510 [M+H]+. Example 50
Synthesis of 4-chloro-N- (phenylacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (21 μl, 0.128 × 1.5 mmol) and phenylacetyl chloride (25 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 40 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 44 mg, 0.086 mmol, 67%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.45 (1H, s), 7.38-7.26 (6H, m), 6.86 (1H, d, J = 10.7 Hz), 6.39 (1H, br.s ), 4.57-4.51 (1H, m), 4.02 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.65-3.56 (2H, m), 3.61 (3H, s), 3.21- 3.19 (1H, m), 2.16-2.08 (1H, m), 1.97-1.86 (1H, m), 1.74-1.70 (1H, m).
ESI-MS m / z: 510 [M + H] + .
実施例５１
4-クロロ-N- (ピリジン-3-イルカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (47 μl, 0.128 × 2.7 mmol)、ニコチン酸クロリド塩酸塩 (27 mg, 0.128 × 1.2 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (45 mg) を得たが、これには原料が20％含まれていた。そこでこのうち20 mg をジクロロメタン (0.8 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl)、ニコチン酸クロリド塩酸塩 (11 mg)を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 20 mg, 0.040 mmol, 71%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 9.27 (1H, s), 8.71 (1H, d, J = 3.7 Hz), 8.24 (1H, d, J = 8.3 Hz), 7.98 (1H, br.s), 7.54 (1H, s), 7.42 (1H, dd, J = 7.4, 5.2 Hz), 7.32 (1H, d, J = 10.7 Hz), 6.86 (1H, d, J = 11.0 Hz), 4.82-4.76 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.4, 4.9 Hz), 2.38-2.33 (1H, m), 2.25-2.22 (1H, m), 2.15-2.08 (1H, m).
ESI-MS m/z: 497 [M+H]+. Example 51
Synthesis of 4-chloro-N- (pyridin-3-ylcarbonyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. did. Triethylamine (47 microliters, 0.128 * 2.7 mmol) and nicotinic acid chloride hydrochloride (27 mg, 0.128 * 1.2 mmol) were added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (45 mg), which contained 20% of the starting material. Therefore, 20 mg of this was dissolved in dichloromethane (0.8 mL) and cooled to 0 ° C. Triethylamine (19 μl) and nicotinic acid chloride hydrochloride (11 mg) were added thereto, and the mixture was returned to room temperature and stirred for 3 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 20 mg, 0.040 mmol, 71%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 9.27 (1H, s), 8.71 (1H, d, J = 3.7 Hz), 8.24 (1H, d, J = 8.3 Hz), 7.98 (1H, br.s), 7.54 (1H, s), 7.42 (1H, dd, J = 7.4, 5.2 Hz), 7.32 (1H, d, J = 10.7 Hz), 6.86 (1H, d, J = 11.0 Hz), 4.82-4.76 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.4, 4.9 Hz) , 2.38-2.33 (1H, m), 2.25-2.22 (1H, m), 2.15-2.08 (1H, m).
ESI-MS m / z: 497 [M + H] + .
実施例５２
4-クロロ-N- (ピリジン-4-イルカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (47 μl, 0.128 × 2.7 mmol)、イソニコチン酸クロリド塩酸塩 (27 mg, 0.128 × 1.2 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 67 mg, 定量的)を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.65 (2H, d, J = 5.9 Hz), 8.28 (1H, br.s), 7.74 (2H, d, J = 5.9 Hz), 7.54 (1H, s), 7.36 (1H, d, J = 10.7 Hz), 6.90 (1H, d, J =11.0 Hz), 4.78-4.72 (1H, m), 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.71 (3H, s), 3.31 (1H, dd, J = 13.2, 4.6 Hz), 2.39-2.34 (1H, m), 2.24-2.20 (1H, m), 2.10-2.02 (1H, m).
ESI-MS m/z: 497 [M+H]+. Example 52
Synthesis of 4-chloro-N- (pyridin-4-ylcarbonyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. did. Triethylamine (47 μl, 0.128 × 2.7 mmol) and isonicotinic acid chloride hydrochloride (27 mg, 0.128 × 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 67 mg, quantitative).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.65 (2H, d, J = 5.9 Hz), 8.28 (1H, br.s), 7.74 (2H, d, J = 5.9 Hz), 7.54 ( 1H, s), 7.36 (1H, d, J = 10.7 Hz), 6.90 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.03 (3H, s), 4.01 (3H, s ), 3.98 (3H, s), 3.71 (3H, s), 3.31 (1H, dd, J = 13.2, 4.6 Hz), 2.39-2.34 (1H, m), 2.24-2.20 (1H, m), 2.10- 2.02 (1H, m).
ESI-MS m / z: 497 [M + H] + .
実施例５３
4-クロロ-N- (ピリジン-2-イルカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (160 mg, 0.408 mmol) をジクロロメタン (4 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (86 μl, 0.408 × 1.5 mmol)、ピコリン酸クロリド塩酸塩 (88 mg, 0.408 × 1.2 mmol) を加え、室温に戻して終夜撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 136 mg, 0.274 mmol, 67%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.60-8.58 (1H, m), 8.05 (1H, d, J = 7.8 Hz), 7.83 (1H, dd, J = 7.7, 6.5 Hz), 7.48-7.46 (1H, m), 7.45 (1H, s), 7.26 (1H, d, J = 10.2 Hz), 6.79 (1H, d, J = 10.7 Hz), 4.75-4.69 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.69 (3H, s), 3.33 (1H, dd, J = 12.7, 4.4 Hz), 2.41-2.23 (2H, m), 2.01-1.97 (1H, m).
ESI-MS m/z: 497 [M+H]+. Example 53
Synthesis of 4-chloro-N- (pyridin-2-ylcarbonyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (160 mg, 0.408 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0 ° C. did. Triethylamine (86 μl, 0.408 × 1.5 mmol) and picolinic acid chloride hydrochloride (88 mg, 0.408 × 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred overnight. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (yellow solid, 136 mg, 0.274 mmol, 67%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.60-8.58 (1H, m), 8.05 (1H, d, J = 7.8 Hz), 7.83 (1H, dd, J = 7.7, 6.5 Hz), 7.48-7.46 (1H, m), 7.45 (1H, s), 7.26 (1H, d, J = 10.2 Hz), 6.79 (1H, d, J = 10.7 Hz), 4.75-4.69 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.69 (3H, s), 3.33 (1H, dd, J = 12.7, 4.4 Hz), 2.41-2.23 (2H, m), 2.01-1.97 (1H, m).
ESI-MS m / z: 497 [M + H] + .
実施例５４
4-クロロ-N-(トリフルオロアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (6 mL) に溶解し、0℃に冷却した。そこへトリフルオロ酢酸無水物 (38 μl) を加え、0℃で30分撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 56 mg, 0.115 mmol, 90%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.64 (1H, br.s), 7.44 (1H, s), 7.34 (1H, d, J = 10.5 Hz), 7.34 (1H, d, J = 11.0 Hz), 4.64-4.58 (1H, m), 4.03 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.63 (3H, s), 3.31 (1H, dd, J = 13.8, 5.7 Hz), 2.41-2.33 (1H, m), 2.20-2.17 (1H, m), 2.09-2.01 (1H, m).
ESI-MS m/z: 488 [M+H]+. Example 54
Synthesis of 4-chloro-N- (trifluoroacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (6 mL) and cooled to 0 ° C. Trifluoroacetic anhydride (38 μl) was added thereto and stirred at 0 ° C. for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 56 mg, 0.115 mmol, 90%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.64 (1H, br.s), 7.44 (1H, s), 7.34 (1H, d, J = 10.5 Hz), 7.34 (1H, d, J = 11.0 Hz), 4.64-4.58 (1H, m), 4.03 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.63 (3H, s), 3.31 (1H, dd, J = 13.8, 5.7 Hz), 2.41-2.33 (1H, m), 2.20-2.17 (1H, m), 2.09-2.01 (1H, m).
ESI-MS m / z: 488 [M + H] + .
実施例５５
4-クロロ-N- (メトキシアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、メトキシアセチルクロリド (14 μl, 0.128 × 1.2 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 41 mg, 0.088 mmol, 69%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.40 (1H, s), 7.26-7.24 (1H, m), 7.00 (1H, d, J = 7.3 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.60-4.54 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.91 (1H, d, J = 15.1 Hz), 3.83 (1H, d, J = 15.1 Hz), 3.61 (3H, s), 3.46 (3H, s), 3.29-3.26 (1H, m), 2.25-2.18 (2H, m), 1.86-1.81 (1H, m).
ESI-MS m/z: 464 [M+H]+. Example 55
Synthesis of 4-chloro-N- (methoxyacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and methoxyacetyl chloride (14 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 41 mg, 0.088 mmol, 69%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.40 (1H, s), 7.26-7.24 (1H, m), 7.00 (1H, d, J = 7.3 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.60-4.54 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.91 (1H, d, J = 15.1 Hz), 3.83 (1H , d, J = 15.1 Hz), 3.61 (3H, s), 3.46 (3H, s), 3.29-3.26 (1H, m), 2.25-2.18 (2H, m), 1.86-1.81 (1H, m).
ESI-MS m / z: 464 [M + H] + .
実施例５６
4-クロロ-N- (フェノキシアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、フェノキシアセチルクロリド (17 μl, 0.128 × 1.2 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 36 mg, 0.068 mmol, 54%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.39 (1H, s), 7.35 (2H, dd, J = 8.1, 7.4 Hz), 7.26 (1H, d, J = 10.7 Hz), 7.06 (2H, t, J = 7.3 Hz), 6.95 (2H, d, J = 8.1 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.65-.4.59 (1H, m), 4.54 (1H, d, J = 15.1 Hz), 4.43 (1H, d, J = 14.9 Hz), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.64 (3H, s), 3.29-3.27 (1H, m), 2.25-2.20 (2H, m), 1.90-1.82 (1H, m).
ESI-MS m/z: 526 [M+H]+. Example 56
Synthesis of 4-chloro-N- (phenoxyacetyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and phenoxyacetyl chloride (17 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 36 mg, 0.068 mmol, 54%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.39 (1H, s), 7.35 (2H, dd, J = 8.1, 7.4 Hz), 7.26 (1H, d, J = 10.7 Hz), 7.06 ( 2H, t, J = 7.3 Hz), 6.95 (2H, d, J = 8.1 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.65-.4.59 (1H, m), 4.54 (1H, d, J = 15.1 Hz), 4.43 (1H, d, J = 14.9 Hz), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.64 (3H, s), 3.29-3.27 ( 1H, m), 2.25-2.20 (2H, m), 1.90-1.82 (1H, m).
ESI-MS m / z: 526 [M + H] + .
実施例５７
4-クロロ-N-[(メチルチオ)アセチル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、(メチルチオ)酢酸 (13 μl, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 31 mg, 0.065 mmol, 51%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.43 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 4.59-4.53 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.30-3.28 (1H, m), 3.25 (1H, d, J = 16.3 Hz), 3.17 (1H, d, J = 16.3 Hz), 2.28-2.20 (2H, m), 2.17 (3H, s), 1.89-1.86 (1H, m).
ESI-MS m/z: 480 [M+H]+. Example 57
Synthesis of 4-chloro-N-[(methylthio) acetyl] deacetylcolchicine Under argon atmosphere, (methylthio) acetic acid (13 μl, 0.128 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL). Cooled to ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 31 mg, 0.065 mmol, 51%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.43 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 4.59-4.53 ( 1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.30-3.28 (1H, m), 3.25 (1H, d, J = 16.3 Hz), 3.17 (1H, d, J = 16.3 Hz), 2.28-2.20 (2H, m), 2.17 (3H, s), 1.89-1.86 (1H, m).
ESI-MS m / z: 480 [M + H] + .
実施例５８
4-クロロ-N- [(4-ピリジルチオ)アセチル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、(4-ピリジルチオ)酢酸 (26 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 45 mg, 0.083 mmol, 65%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.50 (2H, d, J = 4.9 Hz), 7.94 (1H, d, J = 6.6 Hz), 7.36 (1H, s), 7.34 (2H, d, J = 4.9 Hz), 7.25 (1H, d, J = 11.0 Hz), 6.80 (1H, d, J = 11.0 Hz), 4.57-4.51 (1H, m), 3.99 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.96 (1H, d, J = 16.3 Hz), 3.77 (1H, d, J = 16.3 Hz), 3.61 (3H, s), 3.28-3.19 (1H, m), 2.16-2.11 (2H, m), 1.88-1.85 (1H, m).
ESI-MS m/z: 543 [M+H]+. Example 58
Synthesis of 4-chloro-N-[(4-pyridylthio) acetyl] deacetylcolchicine Under argon atmosphere, (4-pyridylthio) acetic acid (26 mg, 0.128 × 1.2 mmol) was added to N, N-dimethylformamide (1 mL). Dissolved and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 45 mg, 0.083 mmol, 65%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.50 (2H, d, J = 4.9 Hz), 7.94 (1H, d, J = 6.6 Hz), 7.36 (1H, s), 7.34 (2H, d, J = 4.9 Hz), 7.25 (1H, d, J = 11.0 Hz), 6.80 (1H, d, J = 11.0 Hz), 4.57-4.51 (1H, m), 3.99 (3H, s), 3.99 ( 3H, s), 3.97 (3H, s), 3.96 (1H, d, J = 16.3 Hz), 3.77 (1H, d, J = 16.3 Hz), 3.61 (3H, s), 3.28-3.19 (1H, m ), 2.16-2.11 (2H, m), 1.88-1.85 (1H, m).
ESI-MS m / z: 543 [M + H] + .
実施例５９
N- (4-ブロモブチリル) -4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ブロモ酪酸 (43 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して1時間撹拌した。反応液に水を加えてクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 27 mg, 0.070 mmol, 39%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.47 (1H, s), 7.30 (1H, d, J = 11.0 Hz), 6.85 (1H, d, J = 11.0 Hz), 6.65-6.64 (1H, br.s), 4.59-4.53 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.55 (1H, t, J = 6.2 Hz), 3.42 (1H, t, J = 6.5 Hz), 3.26 (1H, dd, J = 13.2, 4.4 Hz), 2.49-2.39 (1H, m), 2.29-2.11 (3H, m), 2,11-2.06 (1H, m), 1.80-1.75 (1H, m).
ESI-MS m/z: 540 [M+H]+. Example 59
Synthesis of N- (4-bromobutyryl) -4-chlorodeacetylcolchicine Dissolve 4-bromobutyric acid (43 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere at 0 ° C Cooled to. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 1 hour. The reaction solution was quenched by adding water, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 27 mg, 0.070 mmol, 39%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.47 (1H, s), 7.30 (1H, d, J = 11.0 Hz), 6.85 (1H, d, J = 11.0 Hz), 6.65-6.64 ( 1H, br.s), 4.59-4.53 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.55 (1H, t, J = 6.2 Hz), 3.42 (1H, t, J = 6.5 Hz), 3.26 (1H, dd, J = 13.2, 4.4 Hz), 2.49-2.39 (1H, m), 2.29-2.11 (3H, m), 2,11-2.06 (1H, m), 1.80-1.75 (1H, m).
ESI-MS m / z: 540 [M + H] + .
実施例６０
4-クロロ-N- (4-フルオロベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、4-フルオロベンゾイルクロリド (15 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。
　有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 45 mg, 0.088 mmol, 68%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.83-7.79 (2H, m), 7.57 (1H, s), 7.36 (1H, br.s), 7.34 (1H, d, J = 10.7 Hz), 7.01-6.99 (2H, m), 6.88 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.31 (1H, dd, J = 13.4, 5.4 Hz), 2.37-2.33 (1H, m), 2.24-2.20 (1H, m), 1.97-1.94 (1H, m)ESI-MS m/z: 514 [M+H]+. Example 60
Synthesis of 4-chloro-N- (4-fluorobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorocolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 4-fluorobenzoyl chloride (15 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 45 mg, 0.088 mmol, 68%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.83-7.79 (2H, m), 7.57 (1H, s), 7.36 (1H, br.s), 7.34 (1H, d, J = 10.7 Hz ), 7.01-6.99 (2H, m), 6.88 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.31 (1H, dd, J = 13.4, 5.4 Hz), 2.37-2.33 (1H, m), 2.24-2.20 (1H, m), 1.97-1.94 (1H, m) ESI-MS m / z: 514 [M + H] + .
実施例６１
4-クロロ-N- (3,5-ジフルオロベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3,5-ジフルオロベンゾイルクロリド (16 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (赤褐色固体, 50 mg, 0.094 mmol, 73%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.92 (1H, br.s), 7.63 (1H, s), 7.37 (1H, d, J = 11.0 Hz), 7.34-7.30 (2H, m), 6.92 (1H, d, J = 11.0 Hz), 6.85-6.83 (1H, m), 4.79-4.73 (1H, m), 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.69 (3H, s), 3.31 (1H, dd, J = 13.4, 5.1 Hz), 2.42-2.33 (1H, m), 2.23-2.20 (1H, m), 2.09-2.04 (1H, m).
ESI-MS m/z: 532 [M+H]+. Example 61
Synthesis of 4-chloro-N- (3,5-difluorobenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere and cool to 0 ° C. did. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3,5-difluorobenzoyl chloride (16 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (red brown solid, 50 mg, 0.094 mmol, 73%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.92 (1H, br.s), 7.63 (1H, s), 7.37 (1H, d, J = 11.0 Hz), 7.34-7.30 (2H, m ), 6.92 (1H, d, J = 11.0 Hz), 6.85-6.83 (1H, m), 4.79-4.73 (1H, m), 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.69 (3H, s), 3.31 (1H, dd, J = 13.4, 5.1 Hz), 2.42-2.33 (1H, m), 2.23-2.20 (1H, m), 2.09-2.04 (1H, m) .
ESI-MS m / z: 532 [M + H] + .
実施例６２
4-クロロ-N- (3,4,5-トリフルオロベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3,4,5-トリフルオロベンゾイルクロリド (17 μl, 0.128 × 1 mmol) を加え、室温に戻して30分撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (赤褐色固体, 38 mg,0.069 mmol, 54%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.26 (1H, br.s), 7.65 (1H, s), 7.49-7.47 (2H, m), 7.40 (1H, d, J = 10.7 Hz), 6.95 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.05 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.68 (3H, s), 3.31 (1H, dd, J = 13.5, 5.6 Hz), 2.39-2.35 (1H, m), 2.20.2.15 (2H, m).
ESI-MS m/z: 550 [M+H]+. Example 62
Synthesis of 4-chloro-N- (3,4,5-trifluorobenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere. Cooled to ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3,4,5-trifluorobenzoyl chloride (17 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (red brown solid, 38 mg, 0.069 mmol, 54%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.26 (1H, br.s), 7.65 (1H, s), 7.49-7.47 (2H, m), 7.40 (1H, d, J = 10.7 Hz ), 6.95 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.05 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.68 (3H, s) , 3.31 (1H, dd, J = 13.5, 5.6 Hz), 2.39-2.35 (1H, m), 2.20.2.15 (2H, m).
ESI-MS m / z: 550 [M + H] + .
実施例６３
4-クロロ-N- (4-メトキシベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、4-メトキシベンゾイルクロリド (26 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage isorela One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 56 mg, 0.106 mmol, 83%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.75 (2H, d, J = 8.5 Hz), 7.54 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.87 (2H, d, J = 9.0 Hz), 6.85 (1H, br.s), 6.84 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.83 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.3, 4.5 Hz), 2.38-2.29 (1H, m), 2.25-2.21 (1H, m), 1.92-1.89 (1H, m).
ESI-MS m/z: 526 [M+H]+. Example 63
Synthesis of 4-chloro-N- (4-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 4-methoxybenzoyl chloride (26 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 56 mg, 0.106 mmol, 83%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.75 (2H, d, J = 8.5 Hz), 7.54 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.87 (2H, d, J = 9.0 Hz), 6.85 (1H, br.s), 6.84 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.00 (3H, s), 4.00 (3H, s ), 3.97 (3H, s), 3.83 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.3, 4.5 Hz), 2.38-2.29 (1H, m), 2.25-2.21 ( 1H, m), 1.92-1.89 (1H, m).
ESI-MS m / z: 526 [M + H] + .
実施例６４
4-クロロ-N- (3,4,5-トリメトキシベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した. そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3,4,5-トリメトキシベンゾイルクロリド (30 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 68 mg,0.116 mmol, 91%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.75 (1H, s), 7.63 (1H, br.s), 7.40 (1H, d, J = 10.7 Hz), 7.07 (2H, s), 6.93 (1H, d, J = 11.0 Hz), 4.79-4.72 (1H, m), 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.84 (3H, s), 3.81 (3H, s), 3.81 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.5, 5.5 Hz), 2.42-2.33 (1H, m), 2.22-2.16 (1H, m), 2.09-2.03 (1H, m).
ESI-MS m/z: 586 [M+H]+. Example 64
Synthesis of 4-chloro-N- (3,4,5-trimethoxybenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere. The mixture was cooled to ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3,4,5-trimethoxybenzoyl chloride (30 mg, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 68 mg, 0.116 mmol, 91%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.75 (1H, s), 7.63 (1H, br.s), 7.40 (1H, d, J = 10.7 Hz), 7.07 (2H, s), 6.93 (1H, d, J = 11.0 Hz), 4.79-4.72 (1H, m), 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.84 (3H, s), 3.81 (3H, s), 3.81 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.5, 5.5 Hz), 2.42-2.33 (1H, m), 2.22-2.16 (1H, m ), 2.09-2.03 (1H, m).
ESI-MS m / z: 586 [M + H] + .
実施例６５
4-クロロ-N- (2-メトキシベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、2-メトキシベンゾイルクロリド (17 μl, 0.128 × 1 mmol) を加え、室温に戻して30分撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 49 mg, 0.093mmol, 73%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.35 (1H, d, J = 6.6 Hz), 8.01 (1H, dd, J = 7.7, 1.8 Hz), 7.51 (1H, s), 7.48-7.44 (1H, m), 7.28 (1H, d, J = 10.7 Hz), 7.04-7.00 (2H, m), 6.80 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, m), 4.05 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.2, 4.6 Hz), 2.40-2.31 (1H, m), 2.27-2.23 (1H, m), 1.89-1.85 (1H, m).
ESI-MS m/z: 526 [M+H]+. Example 65
Synthesis of 4-chloro-N- (2-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 2-methoxybenzoyl chloride (17 microliters, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 49 mg, 0.093 mmol, 73%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.35 (1H, d, J = 6.6 Hz), 8.01 (1H, dd, J = 7.7, 1.8 Hz), 7.51 (1H, s), 7.48- 7.44 (1H, m), 7.28 (1H, d, J = 10.7 Hz), 7.04-7.00 (2H, m), 6.80 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, m), 4.05 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.2, 4.6 Hz), 2.40- 2.31 (1H, m), 2.27-2.23 (1H, m), 1.89-1.85 (1H, m).
ESI-MS m / z: 526 [M + H] + .
実施例６６
4-クロロ-N- (3-メトキシベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3-メトキシベンゾイルクロリド (17 μl, 0.128 × 1 mmol) を加え、室温に戻して30分撹拌した。0分後、反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 53 mg, 0.101 mmol, 79%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.54 (1H, s), 7.34-7.31 (3H, m), 7.27 (1H, d, J = 10.7 Hz), 7.02-7.00 (1H, m), 6.96 (1H, d, J = 5.4 Hz), 6.85 (1H, d, J = 10.7 Hz), 4.01 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.80 (3H, s), 3.70 (3H, s), 3.31 (1H, dd, J = 13.3, 5.0 Hz), 2.39-2.30 (1H, m), 2.25-2.21 (1H, m), 1.95-1.89 (1H, m).
ESI-MS m/z: 526 [M+H]+. Example 66
Synthesis of 4-chloro-N- (3-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3-methoxybenzoyl chloride (17 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 30 minutes. After 0 minutes, water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 53 mg, 0.101 mmol, 79%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.54 (1H, s), 7.34-7.31 (3H, m), 7.27 (1H, d, J = 10.7 Hz), 7.02-7.00 (1H, m ), 6.96 (1H, d, J = 5.4 Hz), 6.85 (1H, d, J = 10.7 Hz), 4.01 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.80 (3H , s), 3.70 (3H, s), 3.31 (1H, dd, J = 13.3, 5.0 Hz), 2.39-2.30 (1H, m), 2.25-2.21 (1H, m), 1.95-1.89 (1H, m ).
ESI-MS m / z: 526 [M + H] + .
実施例６７
4-クロロ-N- [(フェニルチオ) アセチル] デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.2 mmol)、(フェニルチオ)アセチルクロリド (23 μl, 0.128 × 1.5 mmol) を加え、室温に戻して30分撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 41 mg, 0.076 mmol, 59%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.48 (1H, s), 7.35-7.32 (6H, m), 7.25-7.23 (1H, m), 6.87 (1H, d, J = 11.0 Hz), 4.54-4.49 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.72 (1H, d, J = 16.8 Hz), 3.63 (1H, d, J = 16.8 Hz), 3.60 (3H, s), 3.23 (1H, dd, J = 12.7, 4.6 Hz), 2.17-2.02 (2H, m), 1.79-1.76 (1H, m).
ESI-MS m/z: 542 [M+H]+. Example 67
Synthesis of 4-chloro-N-[(phenylthio) acetyl] deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.2 mmol) and (phenylthio) acetyl chloride (23 μl, 0.128 × 1.5 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 30 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 41 mg, 0.076 mmol, 59%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, s), 7.35-7.32 (6H, m), 7.25-7.23 (1H, m), 6.87 (1H, d, J = 11.0 Hz ), 4.54-4.49 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.72 (1H, d, J = 16.8 Hz), 3.63 (1H, d, J = 16.8 Hz), 3.60 (3H, s), 3.23 (1H, dd, J = 12.7, 4.6 Hz), 2.17-2.02 (2H, m), 1.79-1.76 (1H, m).
ESI-MS m / z: 542 [M + H] + .
実施例６８
4-クロロ-N- [3-(ジメチルアミノ)ベンゾイル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、3-(ジメチルアミノ)安息香酸 (25 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 37 mg, 0.069 mmol, 54%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.96 (1H, d, J = 7.3 Hz), 7.28 (1H, t, J = 7.9 Hz), 7.20-7.17 (3H, m), 7.13 (1H, d, J = 2.0 Hz), 7.05 (1H, d, J = 11.2 Hz), 6.89 (1H, dd, J = 8.1, 2.4 Hz), 4.51-4.45 (1H, m), 3.94 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.16 (1H, dd, J = 12.1, 5.5 Hz), 2.92 (6H, s), 2.21-2.10 (2H, m), 2.07-2.03 (1H, m).
ESI-MS m/z: 539 [M+H]+. Example 68
Synthesis of 4-chloro-N- [3- (dimethylamino) benzoyl] deacetylcolchicine Under argon atmosphere, 3- (dimethylamino) benzoic acid (25 mg, 0.128 × 1.2 mmol) was converted to N, N-dimethylformamide (1 (mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 37 mg, 0.069 mmol, 54%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.96 (1H, d, J = 7.3 Hz), 7.28 (1H, t, J = 7.9 Hz), 7.20-7.17 (3H, m), 7.13 (1H, d, J = 2.0 Hz), 7.05 (1H, d, J = 11.2 Hz), 6.89 (1H, dd, J = 8.1, 2.4 Hz), 4.51-4.45 (1H, m), 3.94 (3H , s), 3.89 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.16 (1H, dd, J = 12.1, 5.5 Hz), 2.92 (6H, s), 2.21-2.10 ( 2H, m), 2.07-2.03 (1H, m).
ESI-MS m / z: 539 [M + H] + .
実施例６９
4-クロロ-N- [4-(ジメチルアミノ)ベンゾイル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ジメチルアミノ安息香酸 (25 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 38 mg, 0.070 mmol, 55%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.71 (2H, d, J = 8.8 Hz), 7.50 (1H, s), 7.28 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 7.8 Hz), 6.80 (1H, d, J = 10.7 Hz), 6.73 (2H, d, J = 8.3 Hz), 4.78-4.72 (1H, m), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 12.9, 4.1 Hz), 3.01 (6H, s), 2.32-2.23 (2H, m), 1.95-1.88 (1H, m).
ESI-MS m/z: 539 [M+H]+. Example 69
Synthesis of 4-chloro-N- [4- (dimethylamino) benzoyl] deacetylcolchicine Under argon atmosphere, 4-dimethylaminobenzoic acid (25 mg, 0.128 × 1.2 mmol) was added to N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 38 mg, 0.070 mmol, 55%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.71 (2H, d, J = 8.8 Hz), 7.50 (1H, s), 7.28 (1H, d, J = 10.7 Hz), 6.83 ( 1H, d, J = 7.8 Hz), 6.80 (1H, d, J = 10.7 Hz), 6.73 (2H, d, J = 8.3 Hz), 4.78-4.72 (1H, m), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 12.9, 4.1 Hz), 3.01 (6H, s), 2.32-2.23 (2H, m) , 1.95-1.88 (1H, m).
ESI-MS m / z: 539 [M + H] + .
実施例７０
4-クロロ-N- (2-フルオロベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、2-フルオロベンゾイルクロリド (15 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 46 mg, 0.090mmol, 70%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.96-7.94 (1H, m), 7.55 (1H, s), 7.52-7.48 (1H, m), 7.33 (1H, d, J = 10.7 Hz), 7.26-7.14 (4H, m), 6.85 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, d, J = 10.7 Hz), 4.01 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.5, 5.2 Hz), 2.42-2.32 (1H, m), 2.27-2.21 (1H, m), 1.95-1.87 (1H, m).
ESI-MS m/z: 514 [M+H]+. Example 70
Synthesis of 4-chloro-N- (2-fluorobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 2-fluorobenzoyl chloride (15 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 46 mg, 0.090 mmol, 70%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.96-7.94 (1H, m), 7.55 (1H, s), 7.52-7.48 (1H, m), 7.33 (1H, d, J = 10.7 Hz ), 7.26-7.14 (4H, m), 6.85 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, d, J = 10.7 Hz), 4.01 (3H, s), 4.01 (3H, s) , 3.98 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.5, 5.2 Hz), 2.42-2.32 (1H, m), 2.27-2.21 (1H, m), 1.95-1.87 (1H, m).
ESI-MS m / z: 514 [M + H] + .
実施例７１
4-クロロ-N- (3-フルオロベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した. そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3-フルオロベンゾイルクロリド (15 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (赤褐色固体, 21 mg, 0.041mmol, 32%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.82 (1H, s), 7.66 (1H, d, J = 7.6 Hz), 7.55-7.53 (2H, m), 7.47 (1H, d, J = 10.7 Hz), 7.35-7.33 (1H, m), 7.15-7.13 (1H, m), 6.99 (1H, d, J = 11.0 Hz), 4.82-4.77 (1H, m), 4.05 (3H, s), 4.01 (3H, s), 3.99 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.1, 5.7 Hz), 2.41-2.32 (1H, m), 2.29-2.19 (1H, m), 2.16-2.08 (1H, m).
ESI-MS m/z: 514 [M+H]+. Example 71
Synthesis of 4-chloro-N- (3-fluorobenzoyl) deacetylcolchicineIn an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3-fluorobenzoyl chloride (15 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (reddish brown solid, 21 mg, 0.041 mmol, 32%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.82 (1H, s), 7.66 (1H, d, J = 7.6 Hz), 7.55-7.53 (2H, m), 7.47 (1H, d, J = 10.7 Hz), 7.35-7.33 (1H, m), 7.15-7.13 (1H, m), 6.99 (1H, d, J = 11.0 Hz), 4.82-4.77 (1H, m), 4.05 (3H, s) , 4.01 (3H, s), 3.99 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.1, 5.7 Hz), 2.41-2.32 (1H, m), 2.29-2.19 (1H , m), 2.16-2.08 (1H, m).
ESI-MS m / z: 514 [M + H] + .
実施例７２
4-クロロ-N- (2,4-ジフルオロベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、2,4-ジフルオロ安息香酸 (24 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 25 mg, 0.047 mmol, 37%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.02-7.96 (1H, m), 7.64 (1H, s), 7.38 (1H, d, J = 10.7 Hz), 7.20-7.17 (1H, m), 7.00-6.89 (3H, m), 4.78-4.71 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.69 (3H, s), 3.32 (1H, dd, J = 14.0, 4.8 Hz), 2.42-2.32 (1H, m), 2.24-2.21 (1H, m), 1.98-1.91 (1H, m).
ESI-MS m/z: 532 [M+H]+. Example 72
Synthesis of 4-chloro-N- (2,4-difluorobenzoyl) deacetylcolchicine Under argon atmosphere, 2,4-difluorobenzoic acid (24 mg, 0.128 × 1.2 mmol) was added to N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 25 mg, 0.047 mmol, 37%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.02-7.96 (1H, m), 7.64 (1H, s), 7.38 (1H, d, J = 10.7 Hz), 7.20-7.17 (1H, m ), 7.00-6.89 (3H, m), 4.78-4.71 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.69 (3H, s), 3.32 ( 1H, dd, J = 14.0, 4.8 Hz), 2.42-2.32 (1H, m), 2.24-2.21 (1H, m), 1.98-1.91 (1H, m).
ESI-MS m / z: 532 [M + H] + .
実施例７３
4-クロロ-N- (ピリジン-3-イルオキシアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、ピリジン-3-イルオキシ酢酸 (24 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 36 mg, 0.068 mmol, 53%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.47 (1H, s), 8.35 (1H, s), 7.47 (1H, d, J = 5.9 Hz), 7.39 (1H, s), 7.36-7.32 (2H, m), 7.26 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.65-4.62 (1H, m), 4.60 (1H, d, J = 14.9 Hz), 4.53 (1H, d, J = 14.6 Hz), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.29 (1H, dd, J = 12.4, 4.1 Hz), 2.32-2.20 (2H, m), 1.97-1.94 (1H, m).
ESI-MS m/z: 527 [M+H]+. Example 73
Synthesis of 4-chloro-N- (pyridin-3-yloxyacetyl) deacetylcolchicine Under argon atmosphere, pyridin-3-yloxyacetic acid (24 mg, 0.128 × 1.2 mmol) was mixed with N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 36 mg, 0.068 mmol, 53%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.47 (1H, s), 8.35 (1H, s), 7.47 (1H, d, J = 5.9 Hz), 7.39 (1H, s), 7.36-7.32 (2H, m), 7.26 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.65-4.62 (1H, m), 4.60 (1H, d, J = 14.9 Hz), 4.53 (1H, d, J = 14.6 Hz), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.29 (1H, dd, J = 12.4, 4.1 Hz), 2.32-2.20 (2H, m), 1.97-1.94 (1H, m).
ESI-MS m / z: 527 [M + H] + .
実施例７４
4-クロロ-N- (ピリジン-2-イルアセチル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、2-ピリジル酢酸塩酸塩 (27 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (21 μl, 0.128 × 1.2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg,0.128 mol) を加え、室温に戻して4時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、10% クエン酸水溶液、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 15 mg, 0.029 mmol, 23%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.01 (1H, d, J = 7.3 Hz), 8.52 (1H, d, J = 4.4 Hz), 7.81 (1H, t, J = 7.1 Hz), 7.38-7.32 (2H, m), 7.24 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.7 Hz), 4.27-4.21 (1H, m), 3.89 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.75 (2H, s), 3.49 (3H, s), 3.13 (1H, dd, 13.3, 5.0 Hz), 2.15-2.11 (1H, m), 2.02-1.98 (1H, m), 1.91-1.88 (1H, m).
ESI-MS m/z: 511 [M+H]+. Example 74
Synthesis of 4-chloro-N- (pyridin-2-ylacetyl) deacetylcolchicine Dissolve 2-pyridylacetic acid hydrochloride (27 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1 mL) under argon atmosphere And cooled to 0 ° C. Triethylamine (21 μl, 0.128 × 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate ( 21 mg, 0.128 × 1.2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 4 hours. Water was added to the reaction solution for quenching, ethyl acetate was added, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 15 mg, 0.029 mmol, 23%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.01 (1H, d, J = 7.3 Hz), 8.52 (1H, d, J = 4.4 Hz), 7.81 (1H, t, J = 7.1 Hz), 7.38-7.32 (2H, m), 7.24 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.7 Hz), 4.27-4.21 (1H, m ), 3.89 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.75 (2H, s), 3.49 (3H, s), 3.13 (1H, dd, 13.3, 5.0 Hz), 2.15 -2.11 (1H, m), 2.02-1.98 (1H, m), 1.91-1.88 (1H, m).
ESI-MS m / z: 511 [M + H] + .
実施例７５
4-クロロ-N- (ピリジン-3-イルアセチル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、3-ピリジル酢酸塩酸塩 (27 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (21 μl, 0.128 × 1.2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg,0.128 mol) を加え、室温に戻して4時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、10% クエン酸水溶液、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 8 mg, 0.016 mmol, 11%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.06 (1H, d, J = 7.3 Hz), 8.70 (2H, s), 8.22 (1H, d, J = 7.6 Hz), 7.81 (1H, t, J = 6.7 Hz), 7.13 (1H, d, J = 10.5 Hz), 7.12 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.27-4.20 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.78-3.77 (2H, m), 3.48 (3H, s), 3.12 (1H, dd, J = 13.2, 5.1 Hz), 2.18-2.09 (1H, m), 2.06-1.97 (1H, m), 1.92-1.85 (1H, m).
ESI-MS m/z: 511 [M+H]+. Example 75
Synthesis of 4-chloro-N- (pyridin-3-ylacetyl) deacetylcolchicine Dissolve 3-pyridylacetic acid hydrochloride (27 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere And cooled to 0 ° C. Triethylamine (21 μl, 0.128 × 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate ( 21 mg, 0.128 × 1.2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 4 hours. Water was added to the reaction solution for quenching, ethyl acetate was added, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 8 mg, 0.016 mmol, 11%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.06 (1H, d, J = 7.3 Hz), 8.70 (2H, s), 8.22 (1H, d, J = 7.6 Hz), 7.81 ( 1H, t, J = 6.7 Hz), 7.13 (1H, d, J = 10.5 Hz), 7.12 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.27-4.20 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.78-3.77 (2H, m), 3.48 (3H, s), 3.12 (1H, dd, J = 13.2, 5.1 Hz) , 2.18-2.09 (1H, m), 2.06-1.97 (1H, m), 1.92-1.85 (1H, m).
ESI-MS m / z: 511 [M + H] + .
実施例７６
4-クロロ-N- (メトキシカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、クロロぎ酸メチル (10 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isorela One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 48 mg, 0.107 mmol, 83%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.50 (1H, s), 7.24 (1H, d, J = 10.7 Hz), 6.80 (1H, d, J = 10.7 Hz), 5.27 (1H, d, J = 6.1 Hz), 4.37-4.30 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.60 (3H, s), 3.25 (1H, dd, J = 14.1, 5.1 Hz), 2.31-2.13 (2H, m), 1.73-1.65 (1H, m).
ESI-MS m/z: 450 [M+H]+. Example 76
Synthesis of 4-chloro-N- (methoxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and methyl chloroformate (10 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 48 mg, 0.107 mmol, 83%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.50 (1H, s), 7.24 (1H, d, J = 10.7 Hz), 6.80 (1H, d, J = 10.7 Hz), 5.27 (1H, d, J = 6.1 Hz), 4.37-4.30 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.60 (3H, s ), 3.25 (1H, dd, J = 14.1, 5.1 Hz), 2.31-2.13 (2H, m), 1.73-1.65 (1H, m).
ESI-MS m / z: 450 [M + H] + .
実施例７７
4-クロロ-N- (エトキシカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (260 mg, 0.664 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (109 μl, 0.664 × 1.2 mmol)、クロロぎ酸エチル (95 μl, 0.664 × 1.5 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 106 mg, 0.228 mmol, 34%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.53 (1H, s), 7.25 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 5.24 (1H, d, J = 7.3 Hz), 4.37-4.31 (1H, m), 4.01 (3H, s), 4.06-4.01 (2H, m), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.25 (1H, dd, J = 14.0, 5.2 Hz), 2.31-2.13 (2H, m), 1.72-1.68 (1H, m), 1.20 (3H, t, J = 7.1 Hz).
ESI-MS m/z: 464 [M+H]+. Example 77
Synthesis of 4-chloro-N- (ethoxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (260 mg, 0.664 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (109 μl, 0.664 × 1.2 mmol) and ethyl chloroformate (95 μl, 0.664 × 1.5 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (brown solid, 106 mg, 0.228 mmol, 34%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.53 (1H, s), 7.25 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 5.24 (1H, d, J = 7.3 Hz), 4.37-4.31 (1H, m), 4.01 (3H, s), 4.06-4.01 (2H, m), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H , s), 3.25 (1H, dd, J = 14.0, 5.2 Hz), 2.31-2.13 (2H, m), 1.72-1.68 (1H, m), 1.20 (3H, t, J = 7.1 Hz).
ESI-MS m / z: 464 [M + H] + .
実施例７８
4-クロロ-N- (イソプロピルオキシカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、クロロぎ酸イソプロピル (15 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g,メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 53 mg, 0.111 mmol, 87%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.52 (1H, s), 7.24 (1H, d, J = 10.7 Hz), 6.80 (1H, d, J = 10.7 Hz), 5.07 (1H, d, J = 7.3 Hz), 4.81-4.75 (1H, m), 4.37-4.31 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.25 (1H, dd, J = 13.2, 4.1 Hz), 2.25-2.16 (2H, m), 1.71-1.65 (1H, m), 1.21 (3H, d, J = 6.3 Hz), 1.18 (3H, d, J = 6.1 Hz).
ESI-MS m/z: 478 [M+H]+. Example 78
Synthesis of 4-chloro-N- (isopropyloxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and isopropyl chloroformate (15 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 53 mg, 0.111 mmol, 87%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.52 (1H, s), 7.24 (1H, d, J = 10.7 Hz), 6.80 (1H, d, J = 10.7 Hz), 5.07 (1H, d, J = 7.3 Hz), 4.81-4.75 (1H, m), 4.37-4.31 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H , s), 3.25 (1H, dd, J = 13.2, 4.1 Hz), 2.25-2.16 (2H, m), 1.71-1.65 (1H, m), 1.21 (3H, d, J = 6.3 Hz), 1.18 ( (3H, d, J = 6.1 Hz).
ESI-MS m / z: 478 [M + H] + .
実施例７９
4-クロロ-N- (イソブチルオキシカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、クロロぎ酸イソブチル (17 μl, 0.128 × 1 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 58 mg, 0.118 mmol, 92%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.57 (1H, s), 7.27 (1H, d, J = 10.5 Hz), 6.83 (1H, d, J = 10.7 Hz), 5.26 (1H, d, J = 6.8 Hz), 4.38-4.32 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.77-3.72 (2H, m), 3.60 (3H, s), 3.26 (1H, dd, J = 13.4, 4.9 Hz), 2.32-2.23 (1H, m), 2.18-2.15 (1H, m), 1.91-1.81 (1H, m), 1.76-1.68 (1H, m), 0.89 (6H, d, J = 6.6 Hz).
ESI-MS m/z: 492 [M+H]+. Example 79
Synthesis of 4-chloro-N- (isobutyloxycarbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and isobutyl chloroformate (17 microliters, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 58 mg, 0.118 mmol, 92%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.57 (1H, s), 7.27 (1H, d, J = 10.5 Hz), 6.83 (1H, d, J = 10.7 Hz), 5.26 (1H, d, J = 6.8 Hz), 4.38-4.32 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.77-3.72 (2H, m), 3.60 (3H , s), 3.26 (1H, dd, J = 13.4, 4.9 Hz), 2.32-2.23 (1H, m), 2.18-2.15 (1H, m), 1.91-1.81 (1H, m), 1.76-1.68 (1H , m), 0.89 (6H, d, J = 6.6 Hz).
ESI-MS m / z: 492 [M + H] + .
実施例８０
4-クロロ-N- (フェノキシカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、クロロぎ酸フェニル (16 μl, 0.128 × 1 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。
　有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 20 mg, 0.039 mmol, 31%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.64 (1H, s), 7.31-7.27 (3H, m), 7.18-7.15 (1H, m), 7.06-7.05 (2H, m), 6.83 (1H, d, J = 10.7 Hz), 5.63 (1H, d, J = 6.8 Hz), 4.45-4.39 (1H, m), 4.02 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.52 (3H, s), 3.30 (1H, dd, J = 13.5, 5.2 Hz), 2.41-2.32 (1H, m), 2.23-2.19 (1H, m), 1.83-1.78 (1H, m).
ESI-MS m/z: 512 [M+H]+. Example 80
Synthesis of 4-chloro-N- (phenoxycarbonyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and phenyl chloroformate (16 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 20 mg, 0.039 mmol, 31%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.64 (1H, s), 7.31-7.27 (3H, m), 7.18-7.15 (1H, m), 7.06-7.05 (2H, m), 6.83 (1H, d, J = 10.7 Hz), 5.63 (1H, d, J = 6.8 Hz), 4.45-4.39 (1H, m), 4.02 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.52 (3H, s), 3.30 (1H, dd, J = 13.5, 5.2 Hz), 2.41-2.32 (1H, m), 2.23-2.19 (1H, m), 1.83-1.78 (1H, m) .
ESI-MS m / z: 512 [M + H] + .
実施例８１
N-(ベンジルオキシカルボニル)-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (300 mg, 0.766 mmol) をジクロロメタン (6 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (115 μl, 0.766 × 1.1 mmol)、クロロぎ酸ベンジル (108 μl, 0.766 × 1 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。
　得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 105 mg, 0.200 mmol, 26%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.57 (1H, s), 7.34-7.30 (5H, m), 7.26 (1H, d, J = 10.5 Hz), 6.82 (1H, d, J = 10.5 Hz), 5.38 (1H, d, J = 6.8 Hz), 5.08 (1H, d, J = 12.0 Hz), 4.94 (1H, d, J = 12.2 Hz), 4.40-4.34 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.61 (3H, s), 3.25 (1H, dd, J = 12.7, 4.9 Hz), 2.32-2.25 (1H, m), 2.21-2.13 (1H, m), 1.76-1.69 (1H, m).
ESI-MS m/z: 526 [M+H]+. Example 81
Synthesis of N- (benzyloxycarbonyl) -4-chlorodeacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (300 mg, 0.766 mmol) was dissolved in dichloromethane (6 mL) and cooled to 0 ° C. Triethylamine (115 μl, 0.766 × 1.1 mmol) and benzyl chloroformate (108 μl, 0.766 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (white solid, 105 mg, 0.200 mmol, 26%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.57 (1H, s), 7.34-7.30 (5H, m), 7.26 (1H, d, J = 10.5 Hz), 6.82 (1H, d, J = 10.5 Hz), 5.38 (1H, d, J = 6.8 Hz), 5.08 (1H, d, J = 12.0 Hz), 4.94 (1H, d, J = 12.2 Hz), 4.40-4.34 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.61 (3H, s), 3.25 (1H, dd, J = 12.7, 4.9 Hz), 2.32-2.25 (1H, m) , 2.21-2.13 (1H, m), 1.76-1.69 (1H, m).
ESI-MS m / z: 526 [M + H] + .
実施例８２
4-クロロ-N-(メタンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、メタンスルホニルクロリド (12 μl, 0.128 × 1.2 mmol) を加え、0℃で1時間撹拌した。反応液に水を加えクエンチし、クロロホルムで抽出した。有機層を飽和重曹水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 57 mg, 0.121 mmol, 95%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.77 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.88 (1H, d, J = 10.7 Hz), 5.52 (1H, br.s), 4.36-4.30 (1H, m), 4.03 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.58 (3H, s), 3.27 (1H, dd, J = 14.1, 5.4 Hz), 2.89 (3H, s), 2.40-2.31 (1H, m), 2.15-2.12 (1H, m), 1.89-1.85 (1H, m).
ESI-MS m/z: 470 [M+H]+. Example 82
Synthesis of 4-chloro-N- (methanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and methanesulfonyl chloride (12 μl, 0.128 × 1.2 mmol) were added thereto and stirred at 0 ° C. for 1 hour. The reaction solution was quenched by adding water and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 57 mg, 0.121 mmol, 95%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.77 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.88 (1H, d, J = 10.7 Hz), 5.52 (1H, br.s), 4.36-4.30 (1H, m), 4.03 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.58 (3H, s), 3.27 (1H, dd, J = 14.1, 5.4 Hz), 2.89 (3H, s), 2.40-2.31 (1H, m), 2.15-2.12 (1H, m), 1.89-1.85 (1H, m).
ESI-MS m / z: 470 [M + H] + .
実施例８３
4-クロロ-N-(エタンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (198 mg, 0.505 mmol) をジクロロメタン (4 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (142 μl, 0.487 × 2 mmol)、エタンスルホニルクロリド (72 μl, 0.487 × 1.5 mmol) を加え、室温まで昇温させながら終夜撹拌した。反応液に水を加えクエンチし、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 243 mg, 0.502 mmol, 99%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.70 (1H, s), 7.26 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 11.0 Hz), 5.36 (1H, br.s), 4.33-4.27 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.58 (3H, s), 3.27 (1H, dd, J = 13.8, 5.2 Hz), 2.99-2.89 (2H, m), 2.36-2.31 (1H, m), 2.17-2.13 (1H, m), 1.91-1.83 (1H, m), 1.32 (3H, t, J = 7.4 Hz).
ESI-MS m/z: 484 [M+H]+. Example 83
Synthesis of 4-chloro-N- (ethanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (198 mg, 0.505 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0 ° C. Triethylamine (142 μl, 0.487 × 2 mmol) and ethanesulfonyl chloride (72 μl, 0.487 × 1.5 mmol) were added thereto, and the mixture was stirred overnight while raising the temperature to room temperature. The reaction solution was quenched by adding water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (yellow solid, 243 mg, 0.502 mmol, 99%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.70 (1H, s), 7.26 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 11.0 Hz), 5.36 (1H, br.s), 4.33-4.27 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.58 (3H, s), 3.27 (1H, dd, J = 13.8, 5.2 Hz), 2.99-2.89 (2H, m), 2.36-2.31 (1H, m), 2.17-2.13 (1H, m), 1.91-1.83 (1H, m), 1.32 (3H, t, J = (7.4 Hz).
ESI-MS m / z: 484 [M + H] + .
実施例８４
4-クロロ-N-(イソプロパンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、イソプロパンスルホニルクロリド (17 μl, 0.128 × 1.2 mmol) を加え、0℃で2時間撹拌した。反応液に水を加えクエンチし、0.1 N mol/L塩酸を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 6 mg, 0.012 mmol, 9%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.65 (1H, s), 7.26-7.23 (1H, m), 6.81 (1H, d, J = 11.0 Hz), 5.08 (1H, br.s), 4.30-4.24 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.26 (1H, dd, J = 13.5, 5.2 Hz), 3.04-2.97 (1H, m), 2.38-2.33 (1H, m), 2.22-2.11 (1H, m), 1.88-1.83 (1H, m), 1.32 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 6.8 Hz).
ESI-MS m/z: 498 [M+H]+. Example 84
Synthesis of 4-chloro-N- (isopropanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and isopropanesulfonyl chloride (17 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 2 hours. Water was added to the reaction solution to quench, 0.1 N mol / L hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 6 mg, 0.012 mmol, 9%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.65 (1H, s), 7.26-7.23 (1H, m), 6.81 (1H, d, J = 11.0 Hz), 5.08 (1H, br.s ), 4.30-4.24 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.57 (3H, s), 3.26 (1H, dd, J = 13.5, 5.2 Hz), 3.04-2.97 (1H, m), 2.38-2.33 (1H, m), 2.22-2.11 (1H, m), 1.88-1.83 (1H, m), 1.32 (3H, d, J = 6.8 Hz) , 1.27 (3H, d, J = 6.8 Hz).
ESI-MS m / z: 498 [M + H] + .
実施例８５
4-クロロ-N-(シクロプロパンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、シクロプロパンスルホニルクロリド (12 μl, 0.128 × 1.2 mmol) を加え、0℃で1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 36 mg, 0.073 mmol, 57%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.83 (1H, s), 7.28 (1H, d, J = 10.5 Hz), 6.85 (1H, d, J = 10.5 Hz), 5.18 (1H, br.s), 4.33-4.27 (1H, m), 4.02 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.61 (3H, s), 3.27 (1H, dd, J = 13.7, 5.6 Hz), 2.42-2.30 (2H, m), 2.16-2.13 (1H, m), 1.85-1.81 (1H, m), 1.09-1.05 (1H, m), 0.99-0.96 (1H, m), 0.87-0.79 (2H, m).
ESI-MS m/z: 496 [M+H]+. Example 85
Synthesis of 4-chloro-N- (cyclopropanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and cyclopropanesulfonyl chloride (12 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 36 mg, 0.073 mmol, 57%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.83 (1H, s), 7.28 (1H, d, J = 10.5 Hz), 6.85 (1H, d, J = 10.5 Hz), 5.18 (1H, br.s), 4.33-4.27 (1H, m), 4.02 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.61 (3H, s), 3.27 (1H, dd, J = 13.7, 5.6 Hz), 2.42-2.30 (2H, m), 2.16-2.13 (1H, m), 1.85-1.81 (1H, m), 1.09-1.05 (1H, m), 0.99-0.96 (1H, m) , 0.87-0.79 (2H, m).
ESI-MS m / z: 496 [M + H] + .
実施例８６
4-クロロ-N-(イソブタンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、イソブタンスルホニルクロリド (12 μl, 0.128 × 1.2 mmol) を加え、0℃で1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g,メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 56 mg, 0.109 mmol, 85%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.70 (1H, s), 7.26 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 10.7 Hz), 5.18 (1H, d, J = 5.1 Hz), 4.33-4.27 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.57 (3H, s), 3.26 (1H, dd, J = 14.0, 5.0 Hz), 2.88 (1H, dd, J = 14.0, 6.0 Hz), 2.74 (1H, dd, J = 14.0, 7.0 Hz), 2.38-2.29 (1H, m), 2.25-2.10 (2H, m), 1.88-1.82 (1H, m), 1.03 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz).
ESI-MS m/z: 512 [M+H]+. Example 86
Synthesis of 4-chloro-N- (isobutanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and isobutanesulfonyl chloride (12 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 56 mg, 0.109 mmol, 85%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.70 (1H, s), 7.26 (1H, d, J = 10.7 Hz), 6.84 (1H, d, J = 10.7 Hz), 5.18 (1H, d, J = 5.1 Hz), 4.33-4.27 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.57 (3H, s), 3.26 (1H, dd , J = 14.0, 5.0 Hz), 2.88 (1H, dd, J = 14.0, 6.0 Hz), 2.74 (1H, dd, J = 14.0, 7.0 Hz), 2.38-2.29 (1H, m), 2.25-2.10 ( 2H, m), 1.88-1.82 (1H, m), 1.03 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz).
ESI-MS m / z: 512 [M + H] + .
実施例８７
N-(ベンゼンスルホニル)-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、ベンゼンスルホニルクロリド (20 μl, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。反応液に水を加えクエンチし、クロロホルムで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isorela One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 30 mg, 0.056 mmol, 44%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.65-7.63 (2H, m), 7.47 (1H, t, J = 7.4 Hz), 7.37 (2H, t, J = 7.6 Hz), 7.28 (1H, s), 7.17 (1H, d, J = 10.5 Hz), 6.72 (1H, d, J = 11.0 Hz), 5.41 (1H, d, J = 7.8 Hz), 4.16-4.10 (1H, m), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.17 (1H, dd, J = 13.2, 4.6 Hz), 2.18-2.03 (2H, m), 1.74-1.71 (1H, m).
ESI-MS m/z: 532 [M+H]+. Example 87
Synthesis of N- (benzenesulfonyl) -4-chlorodeacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and benzenesulfonyl chloride (20 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 30 minutes. The reaction solution was quenched by adding water, extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 30 mg, 0.056 mmol, 44%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.65-7.63 (2H, m), 7.47 (1H, t, J = 7.4 Hz), 7.37 (2H, t, J = 7.6 Hz), 7.28 ( 1H, s), 7.17 (1H, d, J = 10.5 Hz), 6.72 (1H, d, J = 11.0 Hz), 5.41 (1H, d, J = 7.8 Hz), 4.16-4.10 (1H, m), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.17 (1H, dd, J = 13.2, 4.6 Hz), 2.18-2.03 (2H, m) , 1.74-1.71 (1H, m).
ESI-MS m / z: 532 [M + H] + .
実施例８８
4-クロロ-N- (p-トルエンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、p-トルエンスルホニルクロリド (29 mg, 0.128 × 1.2 mmol) を加え、0℃で2時間撹拌した。反応液に水を加えクエンチし、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 36 mg, 0.066 mmol, 52%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.51 (2H, d, J = 8.1 Hz), 7.31 (1H, s), 7.18 (1H, d, J = 10.5 Hz), 7.15 (2H, d, J = 7.8 Hz), 6.74 (1H, d, J = 10.7 Hz), 5.30 (1H, d, J = 7.1 Hz), 4.13-4.07 (1H, m), 4.00 (3H, s), 4.00 (3H, s), 3.98 (3H, s), 3.63 (3H, s), 3.17-3.15 (1H, m), 2.35 (3H, s), 2.11-2.06 (2H, m), 1.77-1.71 (1H, m).
ESI-MS m/z: 546 [M+H]+. Example 88
Synthesis of 4-chloro-N- (p-toluenesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (26 μl, 0.128 × 1.5 mmol) and p-toluenesulfonyl chloride (29 mg, 0.128 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 2 hours. The reaction solution was quenched by adding water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 36 mg, 0.066 mmol, 52%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.51 (2H, d, J = 8.1 Hz), 7.31 (1H, s), 7.18 (1H, d, J = 10.5 Hz), 7.15 (2H, d, J = 7.8 Hz), 6.74 (1H, d, J = 10.7 Hz), 5.30 (1H, d, J = 7.1 Hz), 4.13-4.07 (1H, m), 4.00 (3H, s), 4.00 ( 3H, s), 3.98 (3H, s), 3.63 (3H, s), 3.17-3.15 (1H, m), 2.35 (3H, s), 2.11-2.06 (2H, m), 1.77-1.71 (1H, m).
ESI-MS m / z: 546 [M + H] + .
実施例８９
4-クロロ-N- (2-チオフェンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (172 mg, 0.439 mmol) をジクロロメタン (3.5 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (92 μl, 0.439 × 1.5 mmol)、2-チオフェンスルホニルクロリド (121 mg, 0.439 × 1.5 mmol) を加え、室温で終夜撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isorela One, SNAP25 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 209 mg, 0.388 mmol, 88%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.46-7.43 (3H, m), 7.22 (1H, d, J = 10.5 Hz), 6.96 (1H, dd, J = 4.9, 3.7Hz), 6.78 (1H, d, J = 10.5 Hz), 5.54 (1H, br.s), 4.23-4.17 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 4.00 (3H, s), 3.63 (3H, s), 3.21-3.19 (1H, m), 2.14-2.09 (2H, m), 1.83-1.75 (1H, m).
ESI-MS m/z: 538 [M+H]+. Example 89
Synthesis of 4-chloro-N- (2-thiophensulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (172 mg, 0.439 mmol) was dissolved in dichloromethane (3.5 mL) and cooled to 0 ° C. Triethylamine (92 μl, 0.439 × 1.5 mmol) and 2-thiophenesulfonyl chloride (121 mg, 0.439 × 1.5 mmol) were added thereto and stirred at room temperature overnight. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 25 g, methanol / chloroform) to obtain the title compound (yellow solid, 209 mg, 0.388 mmol, 88%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.46-7.43 (3H, m), 7.22 (1H, d, J = 10.5 Hz), 6.96 (1H, dd, J = 4.9, 3.7 Hz), 6.78 (1H, d, J = 10.5 Hz), 5.54 (1H, br.s), 4.23-4.17 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 4.00 (3H, s) , 3.63 (3H, s), 3.21-3.19 (1H, m), 2.14-2.09 (2H, m), 1.83-1.75 (1H, m).
ESI-MS m / z: 538 [M + H] + .
実施例９０
4-クロロ-N-(トリフルオロメタンスルホニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへピリジン (15 μl, 0.128 × 1.5 mmol)、トリフルオロメタンスルホニルクロリド (16 μl, 0.128 × 1.2 mmol) を加え、0℃で3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 8 mg, 0.015 mmol, 12%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.00 (1H, br.s), 7.80 (1H, s), 7.35 (1H, d, J = 10.7 Hz), 6.93 (1H, d, J = 11.0 Hz), 4.31-4.28 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.53 (3H, s), 3.29 (1H, dd, J = 12.7, 5.6 Hz), 2.44-2.37 (1H, m), 2.17-2.11 (2H, m).
ESI-MS m/z: 524 [M+H]+. Example 90
Synthesis of 4-chloro-N- (trifluoromethanesulfonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Pyridine (15 μl, 0.128 × 1.5 mmol) and trifluoromethanesulfonyl chloride (16 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 8 mg, 0.015 mmol, 12%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.00 (1H, br.s), 7.80 (1H, s), 7.35 (1H, d, J = 10.7 Hz), 6.93 (1H, d, J = 11.0 Hz), 4.31-4.28 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.53 (3H, s), 3.29 (1H, dd, J = 12.7, 5.6 Hz), 2.44-2.37 (1H, m), 2.17-2.11 (2H, m).
ESI-MS m / z: 524 [M + H] + .
実施例９１
4-クロロ-N- (エチルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をメタノール-水 (2:1, 1.5 mL) に溶解し、0℃に冷却した。そこへイソシアン酸エチル (20 μl, 0.128 × 2 mmol) を加え、0℃で75分撹拌した。反応液をクロロホルムで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 36 mg, 0.078 mmol, 61%) を得た。
1H-NMR(500MHz, CDCl3) δ [ppm]: 7.79 (1H, s), 7.36 (1H, d, J = 10.6 Hz), 6.92 (1H, d, J = 10.6 Hz), 6.67 (1H, br.s), 4.54-4.49 (1H, m), 4.03 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.63 (3H,s), 3.24-3.15 (2H, m), 3.10-3.06 (1H, m), 2.30-2.27 (1H, m), 2.14-2.07 (1H, m), 1.72-1.65 (1H, m), 1.04 (3H, t, J = 7.2 Hz).
ESI-MS m/z: 463 [M+H]+. Example 91
Synthesis of 4-chloro-N- (ethylcarbamoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in methanol-water (2: 1, 1.5 mL) under an argon atmosphere at 0 ° C. Cooled to. Ethyl isocyanate (20 μl, 0.128 × 2 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 75 minutes. The reaction solution was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 36 mg, 0.078 mmol, 61%).
1 H-NMR (500 MHz, CDCl 3 ) δ [ppm]: 7.79 (1H, s), 7.36 (1H, d, J = 10.6 Hz), 6.92 (1H, d, J = 10.6 Hz), 6.67 (1H, br.s), 4.54-4.49 (1H, m), 4.03 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.63 (3H, s), 3.24-3.15 (2H, m) , 3.10-3.06 (1H, m), 2.30-2.27 (1H, m), 2.14-2.07 (1H, m), 1.72-1.65 (1H, m), 1.04 (3H, t, J = 7.2 Hz).
ESI-MS m / z: 463 [M + H] + .
実施例９２
4-クロロ-N- (イソプロピルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をメタノール-水 (2:1, 1.5 mL) に溶解し、0℃に冷却した。そこへイソシアン酸イソプロピル (25μl, 0.128 × 2 mmol) を加え、0℃で75分撹拌した。反応液をクロロホルムで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 59 mg, 0.124 mmol, 97%) を得た。
1H-NMR(500MHz, CDCl3) δ [ppm]: 7.94 (1H, s), 7.46 (1H, d, J = 10.9 Hz), 7.02 (1H, d, J = 10.9 Hz), 6.28 (1H, br.s), 4.57-4.53 (1H, m), 4.06 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.84-3.80 (1H, m), 3.62 (3H, s), 3.23 (1H, dd, J = 13.5, 4.9 Hz), 2.34-2.28 (1H, m), 2.12-2.05 (1H, m), 1.79-1.76 (1H, m), 1.08 (3H, d, J = 6.3 Hz), 1.05 (3H, d, J = 6.6 Hz).
ESI-MS m/z: 477 [M+H]+. Example 92
Synthesis of 4-chloro-N- (isopropylcarbamoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in methanol-water (2: 1, 1.5 mL) under an argon atmosphere at 0 ° C. Cooled to. The isopropyl isocyanate (25 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 59 mg, 0.124 mmol, 97%).
1 H-NMR (500 MHz, CDCl 3 ) δ [ppm]: 7.94 (1H, s), 7.46 (1H, d, J = 10.9 Hz), 7.02 (1H, d, J = 10.9 Hz), 6.28 (1H, br.s), 4.57-4.53 (1H, m), 4.06 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.84-3.80 (1H, m), 3.62 (3H, s) , 3.23 (1H, dd, J = 13.5, 4.9 Hz), 2.34-2.28 (1H, m), 2.12-2.05 (1H, m), 1.79-1.76 (1H, m), 1.08 (3H, d, J = 6.3 Hz), 1.05 (3H, d, J = 6.6 Hz).
ESI-MS m / z: 477 [M + H] + .
実施例９３
4-クロロ-N- (ヘキシルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をメタノール-水 (2:1, 1.5 mL) に溶解し、0℃に冷却した。そこへイソシアン酸ヘキシル (37 μl, 0.128 × 2 mmol) を加え、0℃で75分撹拌した。反応液をクロロホルムで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isorela One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 53 mg, 0.102 mmol, 80%) を得た。
1H-NMR(500MHz, CDCl3) δ [ppm]: 8.21 (1H, s), 7.61 (1H, d, J = 10.9 Hz), 7.15 (1H, d, J = 10.9 Hz), 6.78 (1H, br.s), 4.59-4.57 (1H, m), 4.10 (3H, s), 3.99 (3H, s), 3.98 (3H, s), 3.62 (3H, s), 3.25 (1H, dd, J = 14.3, 5.7 Hz), 3.18-3.12 (1H, m), 3.04-2.98 (1H, m), 2.40-2.32 (1H, m), 2.07-2.02 (1H, m), 1.92-1.84 (1H, m), 1.42-1.39 (2H, m), 1.26-1.20 (4H, m), 0.88-0.86 (2H, m), 0.82 (3H, t, J = 6.9 Hz).
ESI-MS m/z: 519 [M+H]+. Example 93
Synthesis of 4-chloro-N- (hexylcarbamoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in methanol-water (2: 1, 1.5 mL) under an argon atmosphere at 0 ° C. Cooled to. Hexyl isocyanate (37 μl, 0.128 × 2 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 75 minutes. The reaction solution was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 53 mg, 0.102 mmol, 80%).
1 H-NMR (500 MHz, CDCl 3 ) δ [ppm]: 8.21 (1H, s), 7.61 (1H, d, J = 10.9 Hz), 7.15 (1H, d, J = 10.9 Hz), 6.78 (1H, br.s), 4.59-4.57 (1H, m), 4.10 (3H, s), 3.99 (3H, s), 3.98 (3H, s), 3.62 (3H, s), 3.25 (1H, dd, J = 14.3, 5.7 Hz), 3.18-3.12 (1H, m), 3.04-2.98 (1H, m), 2.40-2.32 (1H, m), 2.07-2.02 (1H, m), 1.92-1.84 (1H, m) , 1.42-1.39 (2H, m), 1.26-1.20 (4H, m), 0.88-0.86 (2H, m), 0.82 (3H, t, J = 6.9 Hz).
ESI-MS m / z: 519 [M + H] + .
実施例９４
4-クロロ-N- (フェニルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (200 mg, 0.510 mmol) をジクロロメタン (4 mL) に溶解し、0℃に冷却した。そこへイソシアン酸フェニル (110 μl, 0.510 × 2 mmol) を加え、0℃で2時間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルクロマトグラフィー(Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 168 mg, 0.329 mmol, 65%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.19 (1H,s), 7.48 (1H, d, J = 10.7 Hz), 7.29-7.26 (2H, m), 7.16-7.14 (2H, m), 7.07 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 11.2 Hz), 6.92-6.90 (1H, m), 4.73-4.67 (1H, m), 4.03 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.65 (3H, s), 3.22 (1H, dd, J = 13.5, 5.2 Hz), 2.43-2.33 (1H, m), 2.12-2.04
(1H, m), 1.84-1.80 (1H, m).
ESI-MS m/z: 511 [M+H]+. Example 94
Synthesis of 4-chloro-N- (phenylcarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (200 mg, 0.510 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0 ° C. The phenyl isocyanate (110 microliters, 0.510 * 2 mmol) was added there, and it stirred at 0 degreeC for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (brown solid, 168 mg, 0.329 mmol, 65%). .
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.19 (1H, s), 7.48 (1H, d, J = 10.7 Hz), 7.29-7.26 (2H, m), 7.16-7.14 (2H, m ), 7.07 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 11.2 Hz), 6.92-6.90 (1H, m), 4.73-4.67 (1H, m), 4.03 (3H, s) , 4.00 (3H, s), 3.99 (3H, s), 3.65 (3H, s), 3.22 (1H, dd, J = 13.5, 5.2 Hz), 2.43-2.33 (1H, m), 2.12-2.04
(1H, m), 1.84-1.80 (1H, m).
ESI-MS m / z: 511 [M + H] + .
実施例９５
N-(ベンジルカルバモイル)-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をメタノール-水 (2:1, 1.5 mL) に溶解し、0℃に冷却した。そこへイソシアン酸ベンジル (32 μl, 0.128 × 2 mmol) を加え、0℃で75分撹拌した。反応液をクロロホルムで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 37 mg, 0.070 mmol, 55%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.01 (1H, s), 7.39 (1H,d, J = 10.7 Hz), 7.21-7.20 (4H, m), 7.17-7.12 (1H, m), 6.87 (1H, d, J = 10.7 Hz), 6.54 (1H, br.s), 4.64-4.60 (1H, m), 4.59 (1H, d, J = 15.1 Hz), 4.25 (1H, d, J = 15.1 Hz), 3.99 (3H, s), 3.98 (3H, s), 3.85 (3H, s), 3.65 (3H, s), 3.21 (1H, dd, J = 13.8, 5.2 Hz), 2.37-2.28 (1H, m), 2.11-2.03 (1H, m), 1.80-1.72 (1H, m).
ESI-MS m/z: 525 ([M+H]+. Example 95
Synthesis of N- (benzylcarbamoyl) -4-chlorodeacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in methanol-water (2: 1, 1.5 mL), and 0 ° C Cooled to. The benzyl isocyanate (32 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 37 mg, 0.070 mmol, 55%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.01 (1H, s), 7.39 (1H, d, J = 10.7 Hz), 7.21-7.20 (4H, m), 7.17-7.12 (1H, m ), 6.87 (1H, d, J = 10.7 Hz), 6.54 (1H, br.s), 4.64-4.60 (1H, m), 4.59 (1H, d, J = 15.1 Hz), 4.25 (1H, d, J = 15.1 Hz), 3.99 (3H, s), 3.98 (3H, s), 3.85 (3H, s), 3.65 (3H, s), 3.21 (1H, dd, J = 13.8, 5.2 Hz), 2.37- 2.28 (1H, m), 2.11-2.03 (1H, m), 1.80-1.72 (1H, m).
ESI-MS m / z: 525 ([M + H] + .
実施例９６
4-クロロ-N- (ジメチルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解した。そこへトリエチルアミン (26 μl, 0.128 × 1.5 mmol)、ジメチルカルバモイルクロリド (14 μl, 0.128 × 1.2 mmol) を加え、加熱還流した。4時間後、トリエチルアミン(26 μl, 0.128 × 1.5 mmol)、ジメチルカルバモイルクロリド (14 μl, 0.128 × 1.2 mmol) を追加した。18時間後、さらにトリエチルアミン(26 μl, 0.128 × 1.5 mmol)、ジメチルカルバモイルクロリド (14 μl, 0.128 × 1.2 mmol) を追加した。20時間後、水を加え反応をクエンチした。混合物に飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 58 mg, 0.125 mmol, 98%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.58 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 11.0 Hz), 5.03 (1H, d, J = 5.9 Hz), 4.51-4.45 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.95 (3H, s), 3.64 (3H, s), 3.25 (1H, dd, J = 13.1, 4.3 Hz), 2.92 (6H, s), 2.31-2.22 (1H, m), 2.18-2.14 (1H, m), 1.77-1.74 (1H, m).
ESI-MS m/z: 463 [M+H]+. Example 96
Synthesis of 4-chloro-N- (dimethylcarbamoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (26 μl, 0.128 × 1.5 mmol) and dimethylcarbamoyl chloride (14 μl, 0.128 × 1.2 mmol) were added thereto, and the mixture was heated to reflux. After 4 hours, triethylamine (26 μl, 0.128 × 1.5 mmol) and dimethylcarbamoyl chloride (14 μl, 0.128 × 1.2 mmol) were added. After 18 hours, triethylamine (26 μl, 0.128 × 1.5 mmol) and dimethylcarbamoyl chloride (14 μl, 0.128 × 1.2 mmol) were further added. After 20 hours, water was added to quench the reaction. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 58 mg, 0.125 mmol, 98%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.58 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 11.0 Hz), 5.03 (1H, d, J = 5.9 Hz), 4.51-4.45 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.95 (3H, s), 3.64 (3H, s), 3.25 (1H, dd , J = 13.1, 4.3 Hz), 2.92 (6H, s), 2.31-2.22 (1H, m), 2.18-2.14 (1H, m), 1.77-1.74 (1H, m).
ESI-MS m / z: 463 [M + H] + .
実施例９７
4-クロロ-N- (ジエチルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (301 mg, 0.768 mmol) をジクロロエタン (6 mL) に溶解した。そこへトリエチルアミン (215 μl, 0.768 × 2 mmol)、ジエチルカルバミン酸クロリド (146 μl, 0.768 ×1.5 mmol) を加え、3時間加熱還流した。反応液を放冷し、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム)で精製し、標記の化合物 (黄色固体, 168 mg, 0.342 mmol, 44%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.60 (1H, s), 7.31 (1H, d, J = 10.5 Hz), 6.84 (1H, d, J = 11.0 Hz), 4.85 (1H, d, J = 6.3 Hz), 4.55-4.49 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.64 (3H, s), 3.36-3.32 (2H, m), 3.28-3.19 (3H, m), 2.28-2.23 (1H, m), 2.17-2.14 (1H, m), 1.76-1.74 (1H, m), 1.14 (6H, t, J = 7.1 Hz).
ESI-MS m/z: 491 [M+H]+.  Example 97
Synthesis of 4-chloro-N- (diethylcarbamoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (301 mg, 0.768 mmol) was dissolved in dichloroethane (6 mL). Triethylamine (215 μl, 0.768 × 2 mmol) and diethylcarbamic acid chloride (146 μl, 0.768 × 1.5 mmol) were added thereto, and the mixture was heated to reflux for 3 hours. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (yellow solid, 168 mg, 0.342 mmol, 44%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.60 (1H, s), 7.31 (1H, d, J = 10.5 Hz), 6.84 (1H, d, J = 11.0 Hz), 4.85 (1H, d, J = 6.3 Hz), 4.55-4.49 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.64 (3H, s), 3.36-3.32 (2H , m), 3.28-3.19 (3H, m), 2.28-2.23 (1H, m), 2.17-2.14 (1H, m), 1.76-1.74 (1H, m), 1.14 (6H, t, J = 7.1 Hz ).
ESI-MS m / z: 491 [M + H] + .
実施例９８
4-クロロ-N- (モルフォリン-4-カルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解した。そこへトリエチルアミン (87 μl, 0.128 × 5 mmol)、モルフォリン-4-カルボニルクロリド (73 μl, 0.128 × 5 mmol) を加え、5時間加熱還流した。反応液を放冷し、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム)で精製し、標記の化合物 (黄色固体, 30 mg, 0.059 mmol, 46%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.61 (1H, s), 7.33 (1H, d, J = 10.7 Hz), 6.87 (1H, d, J = 11.0 Hz), 5.81 (1H, br.s), 4.55-4.49 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.66 (4H, t, J = 4.9 Hz), 3.64 (3H, s), 3.41 (4H, t, J = 4.5 Hz), 3.24 (1H, dd, J = 13.3, 5.2 Hz), 2.32-2.23 (1H, m), 2.15-2.12 (1H, m), 1.82-1.79 (1H, m).
ESI-MS m/z: 505 [M+H]+. Example 98
Synthesis of 4-chloro-N- (morpholine-4-carbonyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (87 μl, 0.128 × 5 mmol) and morpholine-4-carbonyl chloride (73 μl, 0.128 × 5 mmol) were added thereto, and the mixture was heated to reflux for 5 hours. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 30 mg, 0.059 mmol, 46%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.61 (1H, s), 7.33 (1H, d, J = 10.7 Hz), 6.87 (1H, d, J = 11.0 Hz), 5.81 (1H, br.s), 4.55-4.49 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.66 (4H, t, J = 4.9 Hz), 3.64 (3H , s), 3.41 (4H, t, J = 4.5 Hz), 3.24 (1H, dd, J = 13.3, 5.2 Hz), 2.32-2.23 (1H, m), 2.15-2.12 (1H, m), 1.82- 1.79 (1H, m).
ESI-MS m / z: 505 [M + H] + .
実施例９９
4-クロロ-N- (ピロリジン-1-カルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解した。そこへトリエチルアミン (87 μl, 0.128 × 5 mmol)、ピロリジン-1-カルボニルクロリド (73 μl, 0.128 × 5 mmol) を加え、終夜加熱還流した。反応液を放冷し、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 23 mg, 0.047 mmol, 36%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.24 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.7 Hz), 6.73 (1H, d, J = 7.3 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.52 (3H, s), 3.29-3.24 (2H, m), 3.21-3.15 (2H, m), 3.10 (1H, dd, J = 13.5, 5.0 Hz), 2.10-2.06 (1H, m), 1.97-1.91 (2H, m), 1.79-1.78 (4H, m).
ESI-MS m/z: 489 [M+H]+. Example 99
Synthesis of 4-chloro-N- (pyrrolidine-1-carbonyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (87 μl, 0.128 × 5 mmol) and pyrrolidine-1-carbonyl chloride (73 μl, 0.128 × 5 mmol) were added thereto, and the mixture was heated to reflux overnight. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 23 mg, 0.047 mmol, 36%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.24 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.7 Hz), 6.73 ( 1H, d, J = 7.3 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.52 (3H, s), 3.29-3.24 (2H, m), 3.21-3.15 (2H, m), 3.10 (1H, dd, J = 13.5, 5.0 Hz), 2.10-2.06 (1H, m), 1.97-1.91 (2H, m), 1.79-1.78 (4H, m).
ESI-MS m / z: 489 [M + H] + .
実施例１００
4-クロロ-N- (ピペリジン-1-カルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解した。そこへトリエチルアミン (87 μl, 0.128 × 5 mmol)、ピペリジン-1-カルボニルクロリド (80 μl, 0.128 × 5 mmol) を加え、終夜加熱還流した。反応液を放冷し、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 36 mg, 0.072 mmol, 56%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.18 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 11.0 Hz), 7.00 (1H, d, J = 7.1 Hz), 4.20-4.17 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.29-3.28 (4H, m), 3.10 (1H, dd, J = 13.5, 4.3 Hz), 2.09-2.06 (1H, m), 2.00-1.89 (2H, m), 1.56-1.50 (2H, m), 1.41-1.37 (4H, m).
ESI-MS m/z: 503 [M+H]+. Example 100
Synthesis of 4-chloro-N- (piperidine-1-carbonyl) deacetylcolchicine 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) under an argon atmosphere. Triethylamine (87 μl, 0.128 × 5 mmol) and piperidine-1-carbonyl chloride (80 μl, 0.128 × 5 mmol) were added thereto, and the mixture was heated to reflux overnight. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 36 mg, 0.072 mmol, 56%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.18 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 11.0 Hz), 7.00 ( 1H, d, J = 7.1 Hz), 4.20-4.17 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.29-3.28 (4H, m), 3.10 (1H, dd, J = 13.5, 4.3 Hz), 2.09-2.06 (1H, m), 2.00-1.89 (2H, m), 1.56-1.50 (2H, m), 1.41-1.37 (4H, m).
ESI-MS m / z: 503 [M + H] + .
実施例１０１
4-クロロ-N- (トリクロロアセチルカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (100 mg, 0.255 mol) をジクロロメタン (5 mL) に溶解し、0℃に冷却した。そこへイソシアン酸トリクロロアセチル(48ml, 0.255 × 1.6 mmol) を加え、0℃で20分撹拌した。反応液を濃縮し、得られた残渣をシリカゲルクロマトグラフィー(Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (赤褐色固体, 19 mg, 0.033 mmol, 13%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.40 (1H, br.s), 8.30 (1H, d, J = 6.3 Hz), 7.42 (1H, s), 7.25 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.50-4.44 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.61 (3H, s), 3.31 (1H, dd, J = 12.8, 4.8 Hz), 2.37-2.19 (2H, m), 1.90-1.87 (1H, m).
ESI-MS m/z: 579 [M+H]+. Example 101
Synthesis of 4-chloro-N- (trichloroacetylcarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (100 mg, 0.255 mol) was dissolved in dichloromethane (5 mL) and cooled to 0 ° C. Thereto was added trichloroacetyl isocyanate (48 ml, 0.255 × 1.6 mmol), and the mixture was stirred at 0 ° C. for 20 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (red-brown solid, 19 mg, 0.033 mmol, 13%). .
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.40 (1H, br.s), 8.30 (1H, d, J = 6.3 Hz), 7.42 (1H, s), 7.25 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.50-4.44 (1H, m), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.61 (3H , s), 3.31 (1H, dd, J = 12.8, 4.8 Hz), 2.37-2.19 (2H, m), 1.90-1.87 (1H, m).
ESI-MS m / z: 579 [M + H] + .
実施例１０２
4-クロロ-N- (ジメチルアミノアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、N,N-ジメチルグリシン (41 mg, 0.332 × 1.2 mmol) をN,N-ジメチルホルムアミド (2 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (76 mg, 0.332 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (54 mg, 0.332 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 107 mg, 0.224 mmol, 68%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.58 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.31-4.28 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.10 (1H, dd, J = 13.2, 5.6 Hz), 2.89 (2H, d, J = 8.3 Hz), 2.21 (6H, s), 2.10-2.06 (1H, m), 1.93-1.92 (1H, m).
ESI-MS m/z: 477 [M+H]+. Example 102
Synthesis of 4-chloro-N- (dimethylaminoacetyl) deacetylcolchicine Under argon atmosphere, N, N-dimethylglycine (41 mg, 0.332 × 1.2 mmol) was dissolved in N, N-dimethylformamide (2 mL). Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (76 mg, 0.332 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (54 mg, 0.332 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (yellow solid, 107 mg, 0.224 mmol, 68%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.58 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.03 ( 1H, d, J = 10.7 Hz), 4.31-4.28 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.10 (1H , dd, J = 13.2, 5.6 Hz), 2.89 (2H, d, J = 8.3 Hz), 2.21 (6H, s), 2.10-2.06 (1H, m), 1.93-1.92 (1H, m).
ESI-MS m / z: 477 [M + H] + .
実施例１０３
4-クロロ-N- (ジメチルアミノアセチル)デアセチルコルヒチン塩酸塩の合成
　氷冷下、メタノール (2 mL) にアセチルクロライド (24 ml, 0.224 × 1.5 mmol) を滴下して1時間撹拌した。そこへ4-クロロ-N-ジメチルアミノアセチル-デアセチルコルヒチン (107 mg, 0.224 mmol) のメタノール溶液 (2 ml) を滴下し、0℃で150分撹拌した。反応液を濃縮乾固し、真空乾燥して標記の化合物 (黄褐色固体, 106 mg, 0.206 mmol, 92%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.71 (1H, br.s), 9.40 (1H, d, J = 6.8 Hz), 7.16 (1H, d, J = 10.5 Hz), 7.10 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.33-4.27 (1H, m), 4.10 (1H, dd, J = 15.4, 4.9 Hz), 3.96-3.88 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.14 (1H, dd, J = 13.1, 5.0 Hz), 2.75 (6H, s), 2.18-2.13 (1H, m), 2.08-1.99 (1H, m), 1.93-1.83 (1H, m). Example 103
Synthesis of 4-chloro-N- (dimethylaminoacetyl) deacetylcolchicine hydrochloride Under ice-cooling, acetyl chloride (24 ml, 0.224 × 1.5 mmol) was added dropwise to methanol (2 mL), followed by stirring for 1 hour. A methanol solution (2 ml) of 4-chloro-N-dimethylaminoacetyl-deacetylcolchicine (107 mg, 0.224 mmol) was added dropwise thereto and stirred at 0 ° C. for 150 minutes. The reaction mixture was concentrated to dryness and dried in vacuo to give the title compound (tan solid, 106 mg, 0.206 mmol, 92%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.71 (1H, br.s), 9.40 (1H, d, J = 6.8 Hz), 7.16 (1H, d, J = 10.5 Hz), 7.10 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.33-4.27 (1H, m), 4.10 (1H, dd, J = 15.4, 4.9 Hz), 3.96-3.88 (1H, m) , 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.14 (1H, dd, J = 13.1, 5.0 Hz), 2.75 (6H, s), 2.18-2.13 (1H, m), 2.08-1.99 (1H, m), 1.93-1.83 (1H, m).
実施例１０４
4-クロロ-N- (ジエチルアミノアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、N,N-ジエチルグリシン (66.9 mg, 0.255 × 2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (98 mg, 0.255 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (69 mg, 0.255 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (100 mg, 0.255 mol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 51 mg, 0.101 mmol, 40%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.42 (1H, d, J = 7.8 Hz), 7.13 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.7 Hz), 4.33-4.26 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.32-3.30 (2H, m), 3.10 (1H, dd, J = 13.1, 5.5 Hz), 2.98 (2H, d, J = 8.5 Hz), 2.53 (2H, d, J = 7.1 Hz), 2.15-2.01 (2H, m), 1.94-1.89 (1H, m), 0.99 (6H, t, J = 7.1 Hz).
ESI-MS m/z: 505 [M+H]+. Example 104
Synthesis of 4-chloro-N- (diethylaminoacetyl) deacetylcolchicine Under argon atmosphere, N, N-diethylglycine (66.9 mg, 0.255 × 2 mmol) was dissolved in N, N-dimethylformamide (1.5 mL). Cooled to ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (98 mg, 0.255 × 2 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.255 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (100 mg, 0.255 mol) was added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (white solid, 51 mg, 0.101 mmol, 40%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.42 (1H, d, J = 7.8 Hz), 7.13 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 4.33-4.26 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.32-3.30 (2H, m), 3.10 (1H, dd, J = 13.1, 5.5 Hz), 2.98 (2H, d, J = 8.5 Hz), 2.53 (2H, d, J = 7.1 Hz), 2.15-2.01 (2H, m), 1.94-1.89 (1H, m), 0.99 (6H, t, J = 7.1 Hz).
ESI-MS m / z: 505 [M + H] + .
実施例１０５
N- (t-ブチルオキシカルボニルアミノアセチル)-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、N-(t-ブチルオキシカルボニル)グリシン (64 mg, 0.306 × 1.2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (70 mg, 0.306 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (50 mg, 0.306 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (120 mg, 0.306 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 153 mg, 0.279 mmol, 94%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.61 (1H, d, J = 7.3 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 6.89 (1H, t, J = 6.0 Hz), 4.25-4.24 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.63 (1H, dd, J = 16.8, 6.3 Hz), 3.56-3.54 (1H, m), 3.54 (3H, s), 3.11 (1H, dd, J = 12.9, 5.4 Hz), 2.13-2.09 (1H, m), 1.96-1.89 (1H, m), 1.35 (9H, s).
ESI-MS m/z: 549 [M+H]+. Example 105
Synthesis of N- (t-butyloxycarbonylaminoacetyl) -4-chlorodeacetylcolchicine N- (t-butyloxycarbonyl) glycine (64 mg, 0.306 × 1.2 mmol) was converted to N, N-dimethylformamide under argon atmosphere Dissolved in (1.5 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (70 mg, 0.306 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (50 mg, 0.306 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (120 mg, 0.306 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (white solid, 153 mg, 0.279 mmol, 94%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.61 (1H, d, J = 7.3 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 6.89 (1H, t, J = 6.0 Hz), 4.25-4.24 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s ), 3.63 (1H, dd, J = 16.8, 6.3 Hz), 3.56-3.54 (1H, m), 3.54 (3H, s), 3.11 (1H, dd, J = 12.9, 5.4 Hz), 2.13-2.09 ( 1H, m), 1.96-1.89 (1H, m), 1.35 (9H, s).
ESI-MS m / z: 549 [M + H] + .
実施例１０６
4-クロロ-N-(アミノアセチル)デアセチルコルヒチン トリフルオロ酢酸塩の合成
　アルゴン雰囲気下、N-(t-ブチルオキシカルボニルアミノアセチル)-4-クロロ-デアセチルコルヒチン (50 mg, 0.091 mmol) をジクロロメタン (750 μl) に溶解し、0℃に冷却した。そこへトリフルオロ酢酸 (291 μl, 3.2 mL/mmol) を加え、室温に戻して1時間撹拌した。反応液を濃縮乾固し、真空乾燥して、標記の化合物 (褐色固体, 88 mg, 定量的) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.10 (1H, d, J = 7.1 Hz), 7.95-7.92 (3H, m), 7.16 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.05 (1H, d, J = 11.0 Hz), 4.26-4.22 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.69-3.61 (2H, m), 3.53 (3H, s), 3.14 (1H, dd, J = 13.3, 5.0 Hz), 2.17-2.13 (1H, m), 2.05-1.95 (1H, m), 1.88-1.83 (1H, m).
ESI-MS m/z: 449 [M+H]+. Example 106
Synthesis of 4-chloro-N- (aminoacetyl) deacetylcolchicine trifluoroacetate Under argon atmosphere, N- (t-butyloxycarbonylaminoacetyl) -4-chloro-deacetylcolchicine (50 mg, 0.091 mmol) Dissolved in dichloromethane (750 μl) and cooled to 0 ° C. Trifluoroacetic acid (291 μl, 3.2 mL / mmol) was added thereto, and the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was concentrated to dryness and dried in vacuo to give the title compound (brown solid, 88 mg, quantitative).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.10 (1H, d, J = 7.1 Hz), 7.95-7.92 (3H, m), 7.16 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.05 (1H, d, J = 11.0 Hz), 4.26-4.22 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.69 -3.61 (2H, m), 3.53 (3H, s), 3.14 (1H, dd, J = 13.3, 5.0 Hz), 2.17-2.13 (1H, m), 2.05-1.95 (1H, m), 1.88-1.83 (1H, m).
ESI-MS m / z: 449 [M + H] + .
実施例１０７
4-クロロ-N- (ピロリジン-1-イルアセチル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、ピロリジン-1-イル酢酸 (15.8 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 20 mg, 0.040 mmol, 31%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.52 (1H, d, J = 7.8 Hz), 7.15 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.7 Hz), 4.29-4.26 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.35-3.31 (1H, m), 3.10 (1H, dd, J = 13.7, 6.3 Hz), 3.07 (2H, s), 2.51-2.49 (3H, m), 2.11-2.03 (2H, m), 1.93-1.91 (1H, m), 1.71 (4H, br.s).
ESI-MS m/z: 503 [M+H]+.
HPLC測定条件 Example 107
Synthesis of 4-chloro-N- (pyrrolidin-1-ylacetyl) deacetylcolchicine Dissolve pyrrolidin-1-ylacetic acid (15.8 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1.5 mL) under argon atmosphere And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (white solid, 20 mg, 0.040 mmol, 31%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.52 (1H, d, J = 7.8 Hz), 7.15 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 4.29-4.26 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.35-3.31 (1H, m), 3.10 (1H, dd, J = 13.7, 6.3 Hz), 3.07 (2H, s), 2.51-2.49 (3H, m), 2.11-2.03 (2H, m), 1.93-1.91 (1H , m), 1.71 (4H, br.s).
ESI-MS m / z: 503 [M + H] + .
HPLC measurement conditions
実施例１０８
4-クロロ-N- (ピペリジン-1-イルアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、ピペリジン-1-イル酢酸 (15.8 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 48 mg, 0.093 mmol, 73%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.45 (1H. br.s), 7.14 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.7 Hz), 4.32-4.27 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.38 (1H, dd, J = 13.7, 6.6 Hz), 3.11 (1H, dd, J = 13.5, 5.2 Hz), 2.90 (2H, br.s), 2.37 (3H, br.s), 2.13-2.07 (1H, m), 2.01-1.91 (2H, m), 1.55-1.51 (4H, m), 1.38-1.37 (2H, m).
ESI-MS m/z: 517 [M+H]+. Example 108
Synthesis of 4-chloro-N- (piperidin-1-ylacetyl) deacetylcolchicine Dissolve piperidin-1-ylacetic acid (15.8 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1.5 mL) under argon atmosphere And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (white solid, 48 mg, 0.093 mmol, 73%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.45 (1H. Br.s), 7.14 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d , J = 10.7 Hz), 4.32-4.27 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.38 (1H, dd, J = 13.7, 6.6 Hz), 3.11 (1H, dd, J = 13.5, 5.2 Hz), 2.90 (2H, br.s), 2.37 (3H, br.s), 2.13-2.07 (1H, m), 2.01 -1.91 (2H, m), 1.55-1.51 (4H, m), 1.38-1.37 (2H, m).
ESI-MS m / z: 517 [M + H] + .
実施例１０９
4-クロロ-N- (3-カルボキシプロピオニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (80 mg, 0.204 mmol) をジメチルスルホキシド (510 μl) に溶解した。そこへN-メチルモルフォリン (88 μl, 0.204 × 5 mmol)、こはく酸無水物 (24 mg, 0.204 ×1.1 mmol) を加え、室温で1時間撹拌した。反応液に酢酸エチルを加え、飽和クエン酸水溶液、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 60 mg, 0.122 mmol, 60%) を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.75 (1H, d, J = 7.1 Hz), 7.16 (1H, s), 7.13 (1H, d, J = 10.5 Hz), 7.03 (1H, d, J = 11.0 Hz), 4.25-4.19 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.10 (1H, dd, J = 13.4, 5.4 Hz), 2.35 (2H, t, J = 6.5 Hz), 2.26 (2H, t, J = 6.6 Hz), 2.12-2.08 (1H, m), 1.97-1.92 (1H, m), 1.87-1.78 (1H, m).
ESI-MS m/z: 492 [M+H]+. Example 109
Synthesis of 4-chloro-N- (3-carboxypropionyl) deacetylcolchicine 4-chlorodeacetylcolchicine (80 mg, 0.204 mmol) was dissolved in dimethyl sulfoxide (510 μl) under an argon atmosphere. N-methylmorpholine (88 microliters, 0.204 * 5 mmol) and succinic anhydride (24 mg, 0.204 * 1.1 mmol) were added there, and it stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous citric acid solution and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 60 mg, 0.122 mmol, 60%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.75 (1H, d, J = 7.1 Hz), 7.16 (1H, s), 7.13 (1H, d, J = 10.5 Hz), 7.03 ( 1H, d, J = 11.0 Hz), 4.25-4.19 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.10 (1H , dd, J = 13.4, 5.4 Hz), 2.35 (2H, t, J = 6.5 Hz), 2.26 (2H, t, J = 6.6 Hz), 2.12-2.08 (1H, m), 1.97-1.92 (1H, m), 1.87-1.78 (1H, m).
ESI-MS m / z: 492 [M + H] + .
実施例１１０
4-クロロ-N- [3-(メトキシカルボニル)プロピオニル] デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロ-N-(4-カルボキシプロピオニル)-デアセチルコルヒチン (56 mg, 0.114 mmol) をトルエン (2.3 mL) に溶解した。そこへメタノール (570 μl, 5ml/mmol)、トリメチルシリルジアゾメタン (949 μl, 0.096 × 5 mmol, 0.6 M ヘキサン溶液) を加え、室温で1時間撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isorela One, SNAP 10 g,メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 34 mg, 0.067 mmol,59%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.52 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.86 (1H, d, J = 10.7 Hz), 6.68 (1H, d, J = 7.8 Hz), 4.59-4.53 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.69 (3H, s), 3.61 (3H, s), 3.26 (1H, dd, J = 12.7, 4.6 Hz), 2.69-2.52 (4H, m), 2.30-2.11 (2H, m), 1.85-1.78 (1H, m).
ESI-MS m/z: 506 [M+H]+. Example 110
Synthesis of 4-chloro-N- [3- (methoxycarbonyl) propionyl] deacetylcolchicine Under an argon atmosphere, 4-chloro-N- (4-carboxypropionyl) -deacetylcolchicine (56 mg, 0.114 mmol) was dissolved in toluene (56 mg, 0.114 mmol). 2.3 mL). Methanol (570 μl, 5 ml / mmol) and trimethylsilyldiazomethane (949 μl, 0.096 × 5 mmol, 0.6 M hexane solution) were added thereto, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel chromatography (Biotage Isorela One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 34 mg, 0.067 mmol, 59%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.52 (1H, s), 7.31 (1H, d, J = 10.7 Hz), 6.86 (1H, d, J = 10.7 Hz), 6.68 (1H, d, J = 7.8 Hz), 4.59-4.53 (1H, m), 4.01 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.69 (3H, s), 3.61 (3H, s ), 3.26 (1H, dd, J = 12.7, 4.6 Hz), 2.69-2.52 (4H, m), 2.30-2.11 (2H, m), 1.85-1.78 (1H, m).
ESI-MS m / z: 506 [M + H] + .
実施例１１１
4-クロロ-N- (4-カルボキシブチリル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (100 mg, 0.255 mmol) をジメチルスルホキシド (638 μl) に溶解した。そこへN-メチルモルフォリン (110 μl, 0.225 × 5 mmol)、グルタル酸無水物 (32 mg, 0.255 ×1.1 mmol) を加え、室温で40分撹拌した。反応液に酢酸エチルを加え、飽和クエン酸水溶液、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 112 mg, 0.241 mmol, 95%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.87 (1H, s), 7.77 (1H, br.s), 7.44 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.5 Hz), 4.58-4.52 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.27 (1H, dd, J = 13.1, 4.8 Hz), 2.53-2.34 (6H, m), 2.26-2.23 (1H, m), 2.18-2.10 (1H, m), 2.01-2.00 (1H, m).
ESI-MS m/z: 506 [M+H]+. Example 111
Synthesis of 4-chloro-N- (4-carboxybutyryl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (100 mg, 0.255 mmol) was dissolved in dimethyl sulfoxide (638 μl). Thereto were added N-methylmorpholine (110 μl, 0.225 × 5 mmol) and glutaric anhydride (32 mg, 0.255 × 1.1 mmol), and the mixture was stirred at room temperature for 40 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous citric acid solution and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (light yellow solid, 112 mg, 0.241 mmol, 95%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.87 (1H, s), 7.77 (1H, br.s), 7.44 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.5 Hz), 4.58-4.52 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.60 (3H, s), 3.27 (1H, dd, J = 13.1, 4.8 Hz), 2.53-2.34 (6H, m), 2.26-2.23 (1H, m), 2.18-2.10 (1H, m), 2.01-2.00 (1H, m).
ESI-MS m / z: 506 [M + H] + .
実施例１１２
4-クロロ-N- [4-(メトキシカルボニル)ブチリル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロ-N-(1-カルボキシブチリル)-デアセチルコルヒチン (87 mg, 0.172 mmol) をトルエン(3.4 mL) に溶解した。そこへメタノール (860 μl, 5 mL/mmol)、トリメチルシリルジアゾメタン (1.43 mL, 0.172 × 5 mmol, 0.6 M ヘキサン溶液)を加え、室温で20分撹拌した。反応液に水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 67 mg, 0.129 mmol, 75%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 7.54 (1H, s), 7.33 (1H, d, J = 10.7 Hz), 6.88 (1H, d, J = 10.7 Hz), 6.55 (1H, d, J = 6.6 Hz), 4.59-4.53 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.67 (3H, s), 3.62 (3H, s), 3.26 (1H, dd, J = 13.3, 4.3 Hz), 2.40-2.27 (4H, m), 2.25-2.11 (2H, m), 1.95-1.88 (3H, m).
ESI-MS m/z: 520 [M+H]+. Example 112
Synthesis of 4-chloro-N- [4- (methoxycarbonyl) butyryl] deacetylcolchicine Under argon atmosphere, 4-chloro-N- (1-carboxybutyryl) -deacetylcolchicine (87 mg, 0.172 mmol) was toluene Dissolved in (3.4 mL). Methanol (860 μl, 5 mL / mmol) and trimethylsilyldiazomethane (1.43 mL, 0.172 × 5 mmol, 0.6 M hexane solution) were added thereto, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 67 mg, 0.129 mmol, 75%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.54 (1H, s), 7.33 (1H, d, J = 10.7 Hz), 6.88 (1H, d, J = 10.7 Hz), 6.55 (1H, d, J = 6.6 Hz), 4.59-4.53 (1H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.67 (3H, s), 3.62 (3H, s ), 3.26 (1H, dd, J = 13.3, 4.3 Hz), 2.40-2.27 (4H, m), 2.25-2.11 (2H, m), 1.95-1.88 (3H, m).
ESI-MS m / z: 520 [M + H] + .
実施例１１３
N-(trans-1-カルボキシシクロヘキサン-4-イルオキシカルボニル)-4-クロロデアセチルコルヒチンの合成
　N-[trans-1-(ベンジルオキシカルボニル)シクロヘキサン-4-イルオキシカルボニル]-4-クロロデアセチルコルヒチン(66 mg, 0.101 mmol)の酢酸エチル(2 mL)溶液に氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(7 mg)を添加した。本反応液を室温、水素ガス雰囲気下にて一晩撹拌した後、不溶物をろ去、次いで酢酸エチルにて洗いこんだ。ろ液と洗浄液は合わせて濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 20 mg, 0.0354 mmol, 35%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.50 (1H, s), 7.25 (1H, d, J=6.81 (1H, d, J=10.7 Hz), 5.10 (1H, d, J=7.6 Hz), 4.51-4.45 (1H, m), 4.36-4.30 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.59 (3H, s), 3.25 (1H, dd, J=13.3, 4.3 Hz), 2.34-2.12 (3H, m), 2.08-1.96 (4H, m), 1.71-1.64 (1H, m), 1.56-1.46 (2H, m), 1.43-1.28 (2H, m).
ESI-MS m/z: 562 [M+H]+. Example 113
Synthesis of N- (trans-1-carboxycyclohexane-4-yloxycarbonyl) -4-chlorodeacetylcolchicine N- [trans-1- (benzyloxycarbonyl) cyclohexane-4-yloxycarbonyl] -4-chlorode To a solution of acetylcolchicine (66 mg, 0.101 mmol) in ethyl acetate (2 mL) was added 10% palladium-carbon (7 mg) under ice cooling and argon gas atmosphere. The reaction solution was stirred overnight at room temperature in a hydrogen gas atmosphere, and then insoluble matters were removed by filtration, followed by washing with ethyl acetate. The filtrate and the washing solution were combined and concentrated to dryness. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 20 mg, 0.0354 mmol, 35%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.50 (1H, s), 7.25 (1H, d, J = 6.81 (1H, d, J = 10.7 Hz), 5.10 (1H, d, J = 7.6 Hz), 4.51-4.45 (1H, m), 4.36-4.30 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.59 (3H, s), 3.25 (1H, dd, J = 13.3, 4.3 Hz), 2.34-2.12 (3H, m), 2.08-1.96 (4H, m), 1.71-1.64 (1H, m), 1.56-1.46 (2H, m), 1.43-1.28 (2H, m).
ESI-MS m / z: 562 [M + H] + .
実施例１１４
4-クロロ-N-(ピリジン-3-イルオキシカルボニル)デアセチルコルヒチンの合成
　3-ヒドロキシピリジン(50 mg, 0.526 mmol)のジクロロメタン溶液(1.1 mL)に氷冷、アルゴンガス雰囲気下にてピリジン(55 μL, 0.526×1.3 mmol)及びトリホスゲン(156 mg, 0.526 mmol)を添加して、氷冷下、10分間、次いで室温にて3時間撹拌した。反応液を減圧下、濃縮乾固して得た残留物をジクロロメタン(2 mL)に溶かし、ピリジン(18.6μL, 0.0766×3 mmol)及び4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)を添加した。本混合液を室温で一晩撹拌した後、クロロホルムと飽和重曹水を添加した。有機層を取り、水層はさらにクロロホルムにて抽出した。有機層は合わせて無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 32 mg, 0.0629 mmol, 82%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.34 (2H, br-s), 7.58 (1H, s), 7.48 (1H, d, J=7.3Hz), 7.26 (2H, br-s), 7.21 (2H, d, J=10.7 Hz), 6.78 (1H, d, J=10.7 Hz), 6.57 (1H, d, J=6.6 Hz), 4.38-4.32 (1H, m), 3.95 (3H, s), 3.91 (3H, s), 3.91 (3H, s), 3.49 (3H, s), 3.24 (1H, dd, J=13.8, 5.5 Hz), 2.37-2.29 (1H, m), 2.19-2.11 (1H, m), 1.89-1.81 (1H, m).
ESI-MS m/z: 513 [M+H]+. Example 114
Synthesis of 4-chloro-N- (pyridin-3-yloxycarbonyl) deacetylcolchicine A solution of 3-hydroxypyridine (50 mg, 0.526 mmol) in dichloromethane (1.1 mL) under ice-cooling and pyridine ( 55 μL, 0.526 × 1.3 mmol) and triphosgene (156 mg, 0.526 mmol) were added, and the mixture was stirred under ice-cooling for 10 minutes and then at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, the residue obtained was dissolved in dichloromethane (2 mL), and pyridine (18.6 μL, 0.0766 × 3 mmol) and 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) were added. did. The mixture was stirred overnight at room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added. The organic layer was taken and the aqueous layer was further extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 32 mg, 0.0629 mmol, 82%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.34 (2H, br-s), 7.58 (1H, s), 7.48 (1H, d, J = 7.3Hz), 7.26 (2H, br-s ), 7.21 (2H, d, J = 10.7 Hz), 6.78 (1H, d, J = 10.7 Hz), 6.57 (1H, d, J = 6.6 Hz), 4.38-4.32 (1H, m), 3.95 (3H , s), 3.91 (3H, s), 3.91 (3H, s), 3.49 (3H, s), 3.24 (1H, dd, J = 13.8, 5.5 Hz), 2.37-2.29 (1H, m), 2.19- 2.11 (1H, m), 1.89-1.81 (1H, m).
ESI-MS m / z: 513 [M + H] + .
参考例１９
クロロギ酸-3-(ジメチルアミノ)プロピル塩酸塩の合成
　3-(ジメチルアミノ)プロピル(500 μL, 4.27 mmol)のアセトニトリル(9 mL)溶液に氷冷、アルゴンガス雰囲気下にてトリホスゲン(1.27 g, 4.27 mmol)を添加した。本反応液を徐々に室温に戻しながら、一晩撹拌した後、エーテルとヘキサンを加えた。析出物をろ取、エーテル次いでヘキサンで洗浄した後、減圧乾燥して標記の化合物(白色固体, 0.649 g, 3.21 mmol, 75%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 10.82 (1H,s), 4.17 (2H, t, J=6.1 Hz), 3.12-3.07 (2H, m), 2.73 (3H, s), 2.72 (3H, s), 2.08-2.01 (2H, m). Reference Example 19
Synthesis of chloroformate-3- (dimethylamino) propyl hydrochloride Triphosgene (1.27 g, 1.25 g) was added to a solution of 3- (dimethylamino) propyl (500 μL, 4.27 mmol) in acetonitrile (9 mL) under ice-cooling and argon gas atmosphere. 4.27 mmol) was added. The reaction solution was stirred overnight while gradually returning to room temperature, and then ether and hexane were added. The precipitate was collected by filtration, washed with ether and then hexane, and then dried under reduced pressure to obtain the title compound (white solid, 0.649 g, 3.21 mmol, 75%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 10.82 (1H, s), 4.17 (2H, t, J = 6.1 Hz), 3.12-3.07 (2H, m), 2.73 (3H, s), 2.72 (3H, s), 2.08-2.01 (2H, m).
実施例１１５
4-クロロ-N-[1-(ジメチルアミノ)プロピル-3-イルオキシカルボニル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)のジクロロメタン(2 mL)溶液に、クロロギ酸-3-(ジメチルアミノ)プロピル塩酸塩(100 mg, 0.0766×6.5 mmol)及びピリジン(211μL, 0.0766×16 mmol)を添加して、室温で一晩撹拌した。反応液に酢酸エチル及び飽和重曹水を加えて有機層を取った。有機層は、飽和重曹水次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 13 mg, 0.0249 mmol, 33%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.48 (1H, s), 7.22 (1H, d, J=10.7 Hz), 6.81 (1H, d, J=10.7 Hz), 6.60 (1H, br-s), 4.30-4.22 (2H, m), 4.02-3.95 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.58 (3H, s), 3.26 (1H, dd, J=13.7, 4.9 Hz), 3.17-3.10 (2H, m), 2.89 (6H, s), 2.34-2.13 (4H, m), 1.90-1.82 (1H, m).
ESI-MS m/z: 521 [M+H]+. Example 115
Synthesis of 4-chloro-N- [1- (dimethylamino) propyl-3-yloxycarbonyl] deacetylcolchicine Chloroformate was added to a solution of 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) in dichloromethane (2 mL). -3- (Dimethylamino) propyl hydrochloride (100 mg, 0.0766 × 6.5 mmol) and pyridine (211 μL, 0.0766 × 16 mmol) were added and stirred at room temperature overnight. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution to obtain an organic layer. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 13 mg, 0.0249 mmol, 33%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, s), 7.22 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 6.60 (1H, br-s), 4.30-4.22 (2H, m), 4.02-3.95 (1H, m), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.58 (3H, s) , 3.26 (1H, dd, J = 13.7, 4.9 Hz), 3.17-3.10 (2H, m), 2.89 (6H, s), 2.34-2.13 (4H, m), 1.90-1.82 (1H, m).
ESI-MS m / z: 521 [M + H] + .
実施例１１６
4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成
　3-(ピロリジン-1-イル)安息香酸(22 mg, 0.0766×1.5 mmol)のジメチルホルムアミド(1.5 mL)溶液に室温、アルゴンガス雰囲気下にて1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(22 mg , 0.0766×1.5 mmol)次いでヒドロキシベンゾトリアゾール一水和物(18 mg, 0.0766×1.5 mmol)を添加した。本溶液を30分間撹拌した後、4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)を添加し、室温で一晩撹拌した。酢酸エチルと飽和重曹水を加えた後、有機層を取った。有機層を飽和重曹水次いでブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡黄色固体, 18 mg, 0.0321 mmol, 42%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.48 (1H, s), 7.28 (1H, d, J=10.7 Hz), 7.22 (1H, t, J=8.2 Hz), 7.05-7.01 (2H, br-m), 6.93-6.86 (1H, br-m), 6.81 (1H, d, J=10.7 Hz), 6.78-6.73 (1H, br-m), 4.77-4.71 (1H, m), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (3H, s), 3.32-3.27 (5H, m), 2.38-2.19 (2H, m), 2.01-1.97 (4H, m), 1.94-1.86 (1H, m).
ESI-MS m/z: [M+H]+. Example 116
Synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine 3- (pyrrolidin-1-yl) benzoic acid (22 mg, 0.0766 × 1.5 mmol) in dimethylformamide (1.5 mL) The solution was stirred at room temperature under an argon gas atmosphere with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (22 mg, 0.0766 × 1.5 mmol) and then hydroxybenzotriazole monohydrate (18 mg, 0.0766 × 1.5 mmol) was added. After stirring this solution for 30 minutes, 4-chloro deacetyl colchicine (30 mg, 0.0766 mmol) was added, and it stirred at room temperature overnight. After adding ethyl acetate and saturated aqueous sodium hydrogen carbonate, the organic layer was taken. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 18 mg, 0.0321 mmol, 42%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.48 (1H, s), 7.28 (1H, d, J = 10.7 Hz), 7.22 (1H, t, J = 8.2 Hz), 7.05-7.01 ( 2H, br-m), 6.93-6.86 (1H, br-m), 6.81 (1H, d, J = 10.7 Hz), 6.78-6.73 (1H, br-m), 4.77-4.71 (1H, m), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (3H, s), 3.32-3.27 (5H, m), 2.38-2.19 (2H, m), 2.01-1.97 ( 4H, m), 1.94-1.86 (1H, m).
ESI-MS m / z: [M + H] + .
実施例１１７
4-クロロ-N-[4-(4-モルホリニルメチル)ベンゾイル]デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 41 mg, 0.0683 mmol, 89%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに4-(4-モルホリニルメチル)安息香酸を用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.75 (2H, d, J=7.8 Hz), 7.50 (1H, s), 7.36 (2H, d, J=7.8 Hz), 7.30 (1H, d, J=10.7 Hz), 6.83 (1H, d, J=10.7 Hz), 4.79-4.73 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 3.98 (3H, s), 3.74 (4H, t, J=4.3 Hz), 3.71 (3H, s), 3.56 (2H, s), 3.30 (1H, dd, J=13.2, 4.9 Hz), 2.49 (4H, s), 2.39-2.19 (2H, m), 2.00-1.92 (1H, m).
ESI-MS m/z: 595 [M+H]+. Example 117
Synthesis of 4-chloro-N- [4- (4-morpholinylmethyl) benzoyl] deacetylcolchicine Similar to the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine By the method, the title compound (light brown solid, 41 mg, 0.0683 mmol, 89%) was obtained. 4- (4-morpholinylmethyl) benzoic acid was used in place of 3- (pyrrolidin-1-yl) benzoic acid.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.75 (2H, d, J = 7.8 Hz), 7.50 (1H, s), 7.36 (2H, d, J = 7.8 Hz), 7.30 (1H, d, J = 10.7 Hz), 6.83 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 3.98 (3H, s), 3.74 (4H, t, J = 4.3 Hz), 3.71 (3H, s), 3.56 (2H, s), 3.30 (1H, dd, J = 13.2, 4.9 Hz), 2.49 (4H, s), 2.39-2.19 (2H, m), 2.00-1.92 (1H, m).
ESI-MS m / z: 595 [M + H] + .
実施例１１８
4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)のジクロロメタン(1.5 mL)溶液に、氷冷、アルゴンガス雰囲気下にて、チオホスゲン(6.12 μL, 0.0766×1.05 mmol)及びトリエチルアミン(25.6 μL, 0.0766×2.4 mmol)を添加して、同温度で2時間撹拌した。ジエチルアミン(15.8 μL, 0.0766×2 mmol)を添加した後、室温に徐々に戻しながら一晩撹拌した。反応液に酢酸エチル及び10%クエン酸を添加して、有機層を取った。有機層を飽和重曹水次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 33 mg, 0.0648mmol, 85%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.54 (1H, d, J=6.8Hz), 7.15 (1H, d, J=11.0 Hz), 7.08 (1H, s), 7.03 (1H, d, J=11.0 Hz), 5.02-4.95 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.72-3.64 (4H, m), 3.62 (3H, s), 3.12 (1H, dd, J=13.5, 5.5 Hz), 2.33-2.24 (1H, m), 2.15-2.07 (1H, m), 2.02-1.95 (1H, m), 1.09 (6H, t, J=7.0 Hz).
ESI-MS m/z: 507 [M+H]+. Example 118
Synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine To a solution of 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) in dichloromethane (1.5 mL) under ice-cooling and argon gas atmosphere, thiophosgene ( 6.12 μL, 0.0766 × 1.05 mmol) and triethylamine (25.6 μL, 0.0766 × 2.4 mmol) were added, and the mixture was stirred at the same temperature for 2 hours. Diethylamine (15.8 μL, 0.0766 × 2 mmol) was added, and the mixture was stirred overnight while gradually returning to room temperature. Ethyl acetate and 10% citric acid were added to the reaction solution, and the organic layer was taken. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 33 mg, 0.0648 mmol, 85%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.54 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 11.0 Hz), 7.08 (1H, s), 7.03 ( 1H, d, J = 11.0 Hz), 5.02-4.95 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.72-3.64 (4H, m), 3.62 (3H, s), 3.12 (1H, dd, J = 13.5, 5.5 Hz), 2.33-2.24 (1H, m), 2.15-2.07 (1H, m), 2.02-1.95 (1H, m), 1.09 (6H , t, J = 7.0 Hz).
ESI-MS m / z: 507 [M + H] + .
実施例１１９
4-クロロ-N-(ピロリジン-1-チオカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 28 mg, 0.0550 mmol, 72%)を得た。ジエチルアミンの代わりにピロリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.55 (1H, d, J=7.3 Hz), 7.15 (1H, d, J=10.7 Hz), 7.12 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.94-4.87 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.61 (3H, s), 3.58-3.45 (4H, m), 3.12 (1H, dd, J=13.4, 5.1 Hz), 2.25-1.84 (7H, m).
ESI-MS m/z: 505 [M+H]+. Example 119
Synthesis of 4-chloro-N- (pyrrolidine-1-thiocarbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine, the title compound (light yellow solid, 28 mg, 0.0550 mmol, 72%). Pyrrolidine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.55 (1H, d, J = 7.3 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.12 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.94-4.87 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.61 (3H, s), 3.58-3.45 (4H, m), 3.12 (1H, dd, J = 13.4, 5.1 Hz), 2.25-1.84 (7H, m).
ESI-MS m / z: 505 [M + H] + .
実施例１２０
4-クロロ-N-(ピペリジン-1-チオカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 28 mg, 0.0536 mmol, 70%)を得た。ジエチルアミンの代わりにピペリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.85 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.96-4.90 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.86-3.76 (4H, m), 3.63 (3H, s), 3.12 (1H, dd, J=13.1, 5.2 Hz), 2.23-1.96 (3H, m), 1.64-1.58 (2H, m), 1.50-1.44 (4H, m).
ESI-MS m/z: 519 [M+H]+. Example 120
Synthesis of 4-chloro-N- (piperidine-1-thiocarbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine, the title compound (milky white solid, 28 mg, 0.0536 mmol, 70%). Piperidine was used instead of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.85 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.96-4.90 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.86-3.76 (4H, m), 3.63 (3H, s), 3.12 (1H, dd, J = 13.1, 5.2 Hz), 2.23-1.96 (3H, m), 1.64-1.58 (2H, m), 1.50-1.44 (4H, m).
ESI-MS m / z: 519 [M + H] + .
実施例１２１
4-クロロ-N-(モルホリン-4-チオカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 28 mg, 0.0536 mmol, 70%)を得た。ジエチルアミンの代わりにモルホリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.03 (1H, d, J=7.1 Hz), 7.16 (1H, d, J=10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.92-4.86 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.87-3.75 (4H, m), 3.62 (3H, s), 3.59 (4H, t, J=4.8 Hz), 3.12 (1H, dd, J=12.2, 5.1 Hz), 2.21-1.99 (3H, m).
ESI-MS m/z: 521 [M+H]+. Example 121
Synthesis of 4-chloro-N- (morpholine-4-thiocarbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine, the title compound (milky white solid, 28 mg, 0.0536 mmol, 70%). Morpholine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.03 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.92-4.86 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.87-3.75 (4H, m), 3.62 (3H, s), 3.59 (4H, t, J = 4.8 Hz), 3.12 (1H, dd, J = 12.2, 5.1 Hz), 2.21-1.99 (3H, m).
ESI-MS m / z: 521 [M + H] + .
実施例１２２
4-クロロ-N-(チオモルホリン-4-チオカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 27 mg, 0.0504 mmol, 66%)を得た。ジエチルアミンの代わりにチオモルホリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.97 (1H, d, J=6.8 Hz), 7.16 (1H, d, J=10.7 Hz), 7.04 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.95-4.89 (1H, m), 4.21-4.09 (4H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J=12.4, 4.9 Hz), 2.60 (4H, t, J=4.9 Hz), 2.23-2.00 (3H, m).
ESI-MS m/z: 537 [M+H]+. Example 122
Synthesis of 4-chloro-N- (thiomorpholine-4-thiocarbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine, the title compound (milky white solid, 27 mg, 0.0504 mmol, 66%). Thiomorpholine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.97 (1H, d, J = 6.8 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.04 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.95-4.89 (1H, m), 4.21-4.09 (4H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J = 12.4, 4.9 Hz), 2.60 (4H, t, J = 4.9 Hz), 2.23-2.00 (3H, m).
ESI-MS m / z: 537 [M + H] + .
実施例１２３
4-クロロ-N-(1,1-ジオキソチオモルホリン-4-チオカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 30 mg, 0.0522 mmol, 68%)を得た。ジエチルアミンの代わりにチオモルホリン 1,1-ジオキシドを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.38 (1H, d, J=6.6 Hz), 7.17 (1H, d, J=10.7 Hz), 7.04 (1H, s), 7.04 (1H, d, J=10.7 Hz), 4.83-4.77 (1H, m), 4.38-4.31 (2H, m), 4.25-4.18 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.64 (3H, s), 3.28-3.21 (2H, m), 3.15-3.08 (2H, m), 2.17-2.08 (3H, m).
ESI-MS m/z: 569 [M+H]+. Example 123
Synthesis of 4-chloro-N- (1,1-dioxothiomorpholine-4-thiocarbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine, the title (Milky white solid, 30 mg, 0.0522 mmol, 68%) was obtained. Thiomorpholine 1,1-dioxide was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.38 (1H, d, J = 6.6 Hz), 7.17 (1H, d, J = 10.7 Hz), 7.04 (1H, s), 7.04 ( 1H, d, J = 10.7 Hz), 4.83-4.77 (1H, m), 4.38-4.31 (2H, m), 4.25-4.18 (2H, m), 3.90 (3H, s), 3.89 (3H, s) , 3.88 (3H, s), 3.64 (3H, s), 3.28-3.21 (2H, m), 3.15-3.08 (2H, m), 2.17-2.08 (3H, m).
ESI-MS m / z: 569 [M + H] + .
実施例１２４
4-クロロ-N-(1-メチルピペラジン-4-チオカルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-(ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 27 mg, 0.0504 mmol, 66%)を得た。ジエチルアミンの代わりに1-メチルピペラジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.98 (1H, d, J=6.8 Hz), 7.15 (1H, d, J=10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.93-4.87 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.88-3.77 (4H, m), 3.62 (3H, s), 3.12 (1H, dd, J=12.6, 4.8 Hz), 2.31 (4H, t, J=4.8 Hz), 2.21-1.97 (3H, m), 2.18 (3H, s).
ESI-MS m/z: 534 [M+H]+. Example 124
Synthesis of 4-chloro-N- (1-methylpiperazine-4-thiocarbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine, the title compound (milky white Solid, 27 mg, 0.0504 mmol, 66%). 1-methylpiperazine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.98 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.93-4.87 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.88-3.77 (4H, m), 3.62 (3H, s), 3.12 (1H, dd, J = 12.6, 4.8 Hz), 2.31 (4H, t, J = 4.8 Hz), 2.21-1.97 (3H, m), 2.18 (3H, s).
ESI-MS m / z: 534 [M + H] + .
実施例１２５
(S)-4-クロロ-N-(2-アセトキシプロピオニル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(100 mg, 0.255 mmol)のジクロロメタン(5 mL)に、氷冷、アルゴンガス雰囲気下にて、(S)-2-アセトキシプロピオン酸クロリド(35.5 μL, 0.255×1.1 mmol)及びトリエチルアミン(39.1 μL, 0.255×1.1 mmol)を添加して、徐々に室温に戻しながら一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 123 mg, 0.243 mmol, 95%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.80 (1H, d, J=7.3 Hz), 7.14 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.93 (1H, q, J=6.7 Hz), 4.27-4.21 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.53 (3H, s), 3.13 (1H, dd, J=12.3, 3.8 Hz), 2.16-2.08 (1H, m), 2.02 (3H, s), 1.99-1.90 (2H, m), 1.33 (3H, d, J=6.7 Hz).
ESI-MS m/z: 506 [M+H]+. Example 125
Synthesis of (S) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine 4-chlorodeacetylcolchicine (100 mg, 0.255 mmol) in dichloromethane (5 mL) under ice cooling and argon gas atmosphere Then, (S) -2-acetoxypropionic acid chloride (35.5 μL, 0.255 × 1.1 mmol) and triethylamine (39.1 μL, 0.255 × 1.1 mmol) were added, and the mixture was stirred overnight while gradually returning to room temperature. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 123 mg, 0.243 mmol, 95%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.80 (1H, d, J = 7.3 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.93 (1H, q, J = 6.7 Hz), 4.27-4.21 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.53 (3H, s ), 3.13 (1H, dd, J = 12.3, 3.8 Hz), 2.16-2.08 (1H, m), 2.02 (3H, s), 1.99-1.90 (2H, m), 1.33 (3H, d, J = 6.7 Hz).
ESI-MS m / z: 506 [M + H] + .
実施例１２６
(S)-4-クロロ-N-(2-ヒドロキシプロピオニル)デアセチルコルヒチンの合成
　(S)-4-クロロ-N-(2-アセトキシプロピオニル)デアセチルコルヒチン(123 mg, 0.250 mmol)のメタノール(2.5 mL)溶液に室温で、ナトリウムメトキシド(3mg, 0.250×0.2 mmol)を加えて、室温で1時間撹拌した。反応液にクロロホルム及びブラインを加えて有機層を取った。有機層は無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 107 mg, 0.231 mmol, 0.231 mmol)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.50 (1H, d, J=7.6 Hz), 7.16 (1H, s), 7.12 (1H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 5.58 (1H, d, J=5.4 Hz), 4.29-4.22 (1H, m), 4.02 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.53 (3H, ), 3.10 (1H, dd, J=12.4, 6.1 Hz), 2.14-2.06 (2H, m), 1.93-1.84 (1H, m), 1.17 (3H, d, J=6.8 Hz).
ESI-MS m/z: 464 [M+H]+. Example 126
Synthesis of (S) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine (S) -4-Chloro-N- (2-acetoxypropionyl) deacetylcolchicine (123 mg, 0.250 mmol) in methanol ( 2.5 mL) sodium methoxide (3 mg, 0.250 × 0.2 mmol) was added to the solution at room temperature, and the mixture was stirred at room temperature for 1 hour. Chloroform and brine were added to the reaction solution to take an organic layer. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 107 mg, 0.231 mmol, 0.231 mmol).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.50 (1H, d, J = 7.6 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 5.58 (1H, d, J = 5.4 Hz), 4.29-4.22 (1H, m), 4.02 (1H, m), 3.91 (3H, s), 3.88 (6H, s ), 3.53 (3H,), 3.10 (1H, dd, J = 12.4, 6.1 Hz), 2.14-2.06 (2H, m), 1.93-1.84 (1H, m), 1.17 (3H, d, J = 6.8 Hz ).
ESI-MS m / z: 464 [M + H] + .
実施例１２７
(R)-4-クロロ-N-(2-アセトキシプロピオニル)デアセチルコルヒチンの合成
　(S)-4-クロロ-N-(2-ヒドロキシプロピオニル)デアセチルコルヒチン(100 mg, 0.216mmol)のトルエン(4.3 mL)溶液に、氷冷、アルゴンガス雰囲気下にて酢酸(14.8 μL, 0.216×1.2 mmol)及びトリフェニルホスフィン(170 mg, 0.216×3 mmol)を添加し、次いでアゾジカルボン酸ジエチル(2.2 mol/L in toluene, 295 μL, 0.216×3 mmol)を滴下した後、徐々に室温に戻しながら一晩撹拌した。反応液をフラッシュクロマトグラフ法にて精製し、標記の化合物(131 mg)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.76 (1H, d, J=7.3 Hz), 7.17 (1H, s), 7.12 (1H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 4.93 (1H, q, J=6.8 Hz), 4.22-4.15 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.14-3.08 (1H, m), 2.15-2.07 (1H, m), 2.03 (3H, s), 1.96-1.88 (2H, m), 1.29 (3H, d, J=6.8 Hz).
ESI-MS m/z: 506 [M+H]+. Example 127
Synthesis of (R) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine (S) -4-Chloro-N- (2-hydroxypropionyl) deacetylcolchicine (100 mg, 0.216 mmol) in toluene ( 4.3 mL) acetic acid (14.8 μL, 0.216 × 1.2 mmol) and triphenylphosphine (170 mg, 0.216 × 3 mmol) were added to the solution under ice-cooling and argon gas atmosphere, and then diethyl azodicarboxylate (2.2 mol) / L in toluene, 295 μL, 0.216 × 3 mmol) was added dropwise, and the mixture was stirred overnight while gradually returning to room temperature. The reaction solution was purified by flash chromatography to obtain the title compound (131 mg).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.76 (1H, d, J = 7.3 Hz), 7.17 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 4.93 (1H, q, J = 6.8 Hz), 4.22-4.15 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s ), 3.54 (3H, s), 3.14-3.08 (1H, m), 2.15-2.07 (1H, m), 2.03 (3H, s), 1.96-1.88 (2H, m), 1.29 (3H, d, J = 6.8 Hz).
ESI-MS m / z: 506 [M + H] + .
実施例１２８
(R)-4-クロロ-N-(2-ヒドロキシプロピオニル)デアセチルコルヒチンの合成
　(S)-4-クロロ-N-(2-ヒドロキシプロピオニル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 42 mg, 0.0905 mmol, 2工程64%)を得た。(S)-4-クロロ-N-(2-アセトキシプロピオニル)デアセチルコルヒチンの代わりに(R)-4-クロロ-N-(2-アセトキシプロピオニル)デアセチルコルヒチンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.48 (1H, d, J=7.6 Hz), 7.15 (1H, s), 7.12 (1H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 5.52 (1H, d, J=5.1 Hz), 4.27-4.20 (1H, m), 4.00-3.93 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.10 (1H, dd, J=12.7, 5.9 Hz), 2.15-2.04 (2H, m), 1.95-1.85 (1H, m), 1.17 (3H, d, J=6.6 Hz).
ESI-MS m/z: 464 [M+H]+. Example 128
Synthesis of (R) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine In the same manner as the synthesis of (S) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine, the title (Milky white solid, 42 mg, 0.0905 mmol, 2 steps 64%) was obtained. Instead of (S) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine, (R) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.48 (1H, d, J = 7.6 Hz), 7.15 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 5.52 (1H, d, J = 5.1 Hz), 4.27-4.20 (1H, m), 4.00-3.93 (1H, m), 3.91 (3H, s), 3.88 (3H , s), 3.88 (3H, s), 3.54 (3H, s), 3.10 (1H, dd, J = 12.7, 5.9 Hz), 2.15-2.04 (2H, m), 1.95-1.85 (1H, m), 1.17 (3H, d, J = 6.6 Hz).
ESI-MS m / z: 464 [M + H] + .
実施例１２９
4-クロロ-N-(2-ヒドロキシ-2-メチルプロピオニル)デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 37 mg, 0.0766 mmol, 定量的)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに2-ヒドロキシ-2-メチルプロピオン酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.37 (1H, d, J=7.3 Hz), 7.17 (1H, s), 7.12 (1H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 5.49 (1H, s), 4.24-4.17 (1H, m), 3.92 (3H, s), 3.88 (6H, s), 3.54 (3H, s), 3.10 (1H, dd, J=12.2, 5.4 Hz), 2.18-2.06 (2H, m), 1.94-1.85 (1H, m), 1.21 (3H, s), 1.20 (3H, s).
ESI-MS m/z: 478 [M+H]+. Example 129
Synthesis of 4-chloro-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine In the same way as the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 37 mg, 0.0766 mmol, quantitative) was obtained. Instead of 3- (pyrrolidin-1-yl) benzoic acid, 2-hydroxy-2-methylpropionic acid was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.37 (1H, d, J = 7.3 Hz), 7.17 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 5.49 (1H, s), 4.24-4.17 (1H, m), 3.92 (3H, s), 3.88 (6H, s), 3.54 (3H, s), 3.10 (1H , dd, J = 12.2, 5.4 Hz), 2.18-2.06 (2H, m), 1.94-1.85 (1H, m), 1.21 (3H, s), 1.20 (3H, s).
ESI-MS m / z: 478 [M + H] + .
実施例１３０
4-クロロ-N-(3-ヒドロキシ-2,2-ジメチルプロピオニル)デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 39 mg, 0.0766 mmol, 定量的)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに3-ヒドロキシ-2,2-ジメチルプロピオン酸を用いた。
1H-NMR(400MHz, CDCl6)δ[ppm]: 7.65 (1H, br-s), 7.41 (1H, d, J=11.0 Hz), 7.32 (1H, br-s), 6.95 (1H, d, J=11.0 Hz), 4.58-4.51 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (1H, d, J=11.0 Hz), 3.64 (3H, s), 3.57 (1H, d, J=11.0 Hz), 2.31-2.09 (2H, m), 1.87-1.79 (1H, m), 1.22 (3H, s), 1.14 (3H, s).
ESI-MS m/z: 492 [M+H]+. Example 130
Synthesis of 4-chloro-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine Similar method to the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine Gave the title compound (milky white solid, 39 mg, 0.0766 mmol, quantitative). Instead of 3- (pyrrolidin-1-yl) benzoic acid, 3-hydroxy-2,2-dimethylpropionic acid was used.
1 H-NMR (400MHz, CDCl 6 ) δ [ppm]: 7.65 (1H, br-s), 7.41 (1H, d, J = 11.0 Hz), 7.32 (1H, br-s), 6.95 (1H, d , J = 11.0 Hz), 4.58-4.51 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.70 (1H, d, J = 11.0 Hz), 3.64 (3H, s), 3.57 (1H, d, J = 11.0 Hz), 2.31-2.09 (2H, m), 1.87-1.79 (1H, m), 1.22 (3H, s), 1.14 (3H, s).
ESI-MS m / z: 492 [M + H] + .
実施例１３１
4-クロロ-N-[2,2-ビス(ヒドロキシメチル)プロピオニル]デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 30 mg, 0.0589 mmol, 77%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに2,2-ビス(ヒドロキシメチル)プロピオン酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.03 (1H, d, J=7.1 Hz), 7.15 (1H, s), 7.11 (1H, d, J=10.7 Hz), 7.01 (1H, d, J=10.7 Hz), 4.72 (1H, t, J=5.2 Hz), 4.62 (1H, t, J= 5.2 Hz), 4.28-4.21 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.55 (3H, s), 3.48 (2H, d, J=5.4 Hz), 3.43 (2H, dd, J=5.1, 2.2 Hz), 3.10 (1H, dd, J=13.4, 4.9 Hz), 2.15-2.06 (1H, m), 2.02-1.91 (2H, m), 1.00 (3H, s).
ESI-MS m/z: 508 [M+H]+. Example 131
Synthesis of 4-chloro-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine Gave the title compound (milky white solid, 30 mg, 0.0589 mmol, 77%). 2,2-bis (hydroxymethyl) propionic acid was used instead of 3- (pyrrolidin-1-yl) benzoic acid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.03 (1H, d, J = 7.1 Hz), 7.15 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.01 ( 1H, d, J = 10.7 Hz), 4.72 (1H, t, J = 5.2 Hz), 4.62 (1H, t, J = 5.2 Hz), 4.28-4.21 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.55 (3H, s), 3.48 (2H, d, J = 5.4 Hz), 3.43 (2H, dd, J = 5.1, 2.2 Hz), 3.10 (1H, dd, J = 13.4, 4.9 Hz), 2.15-2.06 (1H, m), 2.02-1.91 (2H, m), 1.00 (3H, s).
ESI-MS m / z: 508 [M + H] + .
実施例１３２
4-クロロ-N-(1-アセチルピペリジン-4-カルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体,27 mg, 0.0492 mmol, 64%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに1-アセチルピペリジン-4-カルボン酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.61-8.58 (1H, m), 7.12 (1H, d, J=10.7 Hz), 7.10 (1H, d, J=2.4 Hz), 7.02 (1H, d, J=10.7 Hz), 4.35-4.29 (1H, m), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.85-3.75 (1H, m), 3.53 (3H, s), 3.11 (1H, dd, J=13.4, 5.4 Hz), 3.07-2.98 (1H, m), 2.59-2.43 (2H, m), 2.15-2.07 (1H, m), 2.01-1.81 (2H, m), 1.96 (3H, d, J=1.0 Hz), 1.75-1.59 (2H, m), 1.48-1.27 (2H, m).
ESI-MS m/z: 545 [M+H]+. Example 132
Synthesis of 4-chloro-N- (1-acetylpiperidine-4-carbonyl) deacetylcolchicine In the same way as the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 27 mg, 0.0492 mmol, 64%) was obtained. Instead of 3- (pyrrolidin-1-yl) benzoic acid, 1-acetylpiperidine-4-carboxylic acid was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.61-8.58 (1H, m), 7.12 (1H, d, J = 10.7 Hz), 7.10 (1H, d, J = 2.4 Hz), 7.02 (1H, d, J = 10.7 Hz), 4.35-4.29 (1H, m), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s) , 3.85-3.75 (1H, m), 3.53 (3H, s), 3.11 (1H, dd, J = 13.4, 5.4 Hz), 3.07-2.98 (1H, m), 2.59-2.43 (2H, m), 2.15 -2.07 (1H, m), 2.01-1.81 (2H, m), 1.96 (3H, d, J = 1.0 Hz), 1.75-1.59 (2H, m), 1.48-1.27 (2H, m).
ESI-MS m / z: 545 [M + H] + .
実施例１３３
4-クロロ-N-(1-ベンゾイルピペリジン-4-カルボニル)デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 42 mg, 0.0684 mmol, 89%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに1-ベンゾイルピペリジン-4-カルボン酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.63 (1H, d, J=7.1 Hz), 7.45-7.32 (5H, m), 7.13 (1H, d, J=10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.50-4.37 (1H, m), 4.25-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.66-3.51 (1H, m), 3.54 (3H, s), 3.14-2.74 (2H, m), 3.11 (1H, dd, J=13.2, 5.4 Hz), 2.57-2.51 (1H, m), 2.15-2.07 (1H, m), 2.01-1.36 (6H, m).
ESI-MS m/z: 607 [M+H]+. Example 133
Synthesis of 4-chloro-N- (1-benzoylpiperidine-4-carbonyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 42 mg, 0.0684 mmol, 89%) was obtained. Instead of 3- (pyrrolidin-1-yl) benzoic acid, 1-benzoylpiperidine-4-carboxylic acid was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.63 (1H, d, J = 7.1 Hz), 7.45-7.32 (5H, m), 7.13 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.50-4.37 (1H, m), 4.25-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s) , 3.88 (3H, s), 3.66-3.51 (1H, m), 3.54 (3H, s), 3.14-2.74 (2H, m), 3.11 (1H, dd, J = 13.2, 5.4 Hz), 2.57-2.51 (1H, m), 2.15-2.07 (1H, m), 2.01-1.36 (6H, m).
ESI-MS m / z: 607 [M + H] + .
実施例１３４
4-クロロ-N-[1-(tert-ブチルオキシカルボニル)ピペリジン-4-カルボニル]デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 48 mg, 0.0798 mmol, 62%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに1-(tert-ブチルオキシカルボニル)ピペリジン-4-カルボン酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.60 (1H, d, J=7.3 Hz), 7.13 (1H, d, J=10.7 Hz), 7.09 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.23-4.17 (1H, m), 3.96-3.86 (2H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.10 (1H, dd, J=12.9, 5.4 Hz), 2.79-2.67 (1H, m), 2.53-2.48 (1H, m), 2.43-2.35 (1H, m), 2.15-2.07 (1H, m), 2.00-1.80 (2H, m), 1.64 (2H, dd, J=32.4, 11.2), 1.40-1.24 (2H, m), 1.37 (9H, s).
ESI-MS m/z: 603 [M+H]+. Example 134
Synthesis of 4-chloro-N- [1- (tert-butyloxycarbonyl) piperidine-4-carbonyl] deacetylcolchicine Synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine In the same manner as described above, the title compound (pale yellow solid, 48 mg, 0.0798 mmol, 62%) was obtained. Instead of 3- (pyrrolidin-1-yl) benzoic acid, 1- (tert-butyloxycarbonyl) piperidine-4-carboxylic acid was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.23-4.17 (1H, m), 3.96-3.86 (2H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.10 (1H, dd, J = 12.9, 5.4 Hz), 2.79-2.67 (1H, m), 2.53-2.48 (1H, m), 2.43-2.35 (1H, m), 2.15-2.07 (1H, m), 2.00-1.80 (2H, m), 1.64 (2H, dd, J = 32.4, 11.2), 1.40-1.24 (2H, m), 1.37 (9H, s).
ESI-MS m / z: 603 [M + H] + .
実施例１３５
4-クロロ-N-(ピペリジン-4-カルボニル)デアセチルコルヒチン トリフルオロ酢酸塩の合成
　4-クロロ-N-[1-(tert-ブチルオキシカルボニル)ピペリジン-4-カルボニル]デアセチルコルヒチン(30 mg, 0.0797 mmol)のジクロロメタン(1 mL)溶液に、氷冷下、トリフルオロ酢酸(400 μL )を添加して、氷冷下にて5分間、次いで室温で2時間撹拌した。反応液を濃縮乾固した後、残留物にエーテルとヘキサンを加えて超音波処理した。析出物をろ取、ヘキサンによる洗浄、次いで減圧乾燥し、標記の化合物(乳白色固体,27 mg, 0.0433 mmol,87%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.71 (1H, d, J=7.3 Hz), 8.47 (1H, br-s), 8.19 (1H, br-s), 7.14 (1H, d, J=10.7 Hz), 7.08 (1H, s), 7.04 (1H, d, J=10.7 Hz), 4.25-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.55 (3H, s), 3.28 (2H, t, J=12.1 Hz), 3.11 (1H, dd, J=13.4, 4.9 Hz), 2.96-2.83 (2H, m), 2.56-2.48 (1H, m), 2.16-2.07 (1H, m), 2.01-1.77 (4H, m), 1.67-1.57 (2H, m).
ESI-MS m/z: 503 [M+H]+. Example 135
4-Chloro-N- (piperidine-4-carbonyl) deacetylcolchicine Synthesis of trifluoroacetate 4-chloro-N- [1- (tert-butyloxycarbonyl) piperidine-4-carbonyl] deacetylcolchicine (30 mg , 0.0797 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (400 μL) under ice cooling, and the mixture was stirred under ice cooling for 5 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated to dryness, and ether and hexane were added to the residue and sonicated. The precipitate was collected by filtration, washed with hexane, and then dried under reduced pressure to obtain the title compound (milky white solid, 27 mg, 0.0433 mmol, 87%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.71 (1H, d, J = 7.3 Hz), 8.47 (1H, br-s), 8.19 (1H, br-s), 7.14 (1H , d, J = 10.7 Hz), 7.08 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.25-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s) , 3.88 (3H, s), 3.55 (3H, s), 3.28 (2H, t, J = 12.1 Hz), 3.11 (1H, dd, J = 13.4, 4.9 Hz), 2.96-2.83 (2H, m), 2.56-2.48 (1H, m), 2.16-2.07 (1H, m), 2.01-1.77 (4H, m), 1.67-1.57 (2H, m).
ESI-MS m / z: 503 [M + H] + .
実施例１３６
4-クロロ-N-[3-(ジメチルアミノメチル)ベンゾイル]デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 35 mg, 0.0638 mmol, 83%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに3-(ジメチルアミノメチル)安息香酸塩酸塩を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.08 (1H, d, J=7.3 Hz), 7.81-7.78 (2H, m), 7.48-7.41 (2H, m), 7.21 (1H, s), 7.17 (1H, d, J=10.7 Hz), 7.05 (1H, d, J=10.7 Hz), 4.53-4.46 (1H, m), 3.94 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.44 (2H, s), 3.17 (1H, dd, J=12.2, 5.6 Hz), 2.21-1.98 (3H, m), 2.15 (6H, s).
ESI-MS m/z: 553 [M+H]+. Example 136
Synthesis of 4-chloro-N- [3- (dimethylaminomethyl) benzoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 35 mg, 0.0638 mmol, 83%) was obtained. Instead of 3- (pyrrolidin-1-yl) benzoic acid, 3- (dimethylaminomethyl) benzoic acid hydrochloride was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.08 (1H, d, J = 7.3 Hz), 7.81-7.78 (2H, m), 7.48-7.41 (2H, m), 7.21 (1H , s), 7.17 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.53-4.46 (1H, m), 3.94 (3H, s), 3.89 (3H, s) , 3.89 (3H, s), 3.60 (3H, s), 3.44 (2H, s), 3.17 (1H, dd, J = 12.2, 5.6 Hz), 2.21-1.98 (3H, m), 2.15 (6H, s ).
ESI-MS m / z: 553 [M + H] + .
参考例２０
3-(トリフェニルメチルオキシ)プロパノールの合成
　1,3-プロパンジオール(2.0 mL, 27.6 mmol)のジクロロメタン(140 mL)溶液に、氷冷、アルゴンガス雰囲気下にてトリエチルアミン(4.04 mL, 27.6×1.05 mmol)及びトリフェニルメチルクロリド(7.69 g, 27.6 mmol)を添加して、徐々に室温に戻しながら一晩撹拌した。反応液にクロロホルム及び水を添加して、有機層を取った。有機層は水次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, ヘキサン/酢酸エチル/クロロホルム)にて精製し、標記の化合物(白色固体, 4.59 g, 14.4 mmol, 52%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.45-7.41 (6H, m), 7.33-7.22 (9H, m), 3.77 (2H, t, J=5.9 Hz), 3.28 (2H, t, J=5.9 Hz), 1.89-1.84 (2H, m). Reference Example 20
Synthesis of 3- (triphenylmethyloxy) propanol To a solution of 1,3-propanediol (2.0 mL, 27.6 mmol) in dichloromethane (140 mL) under ice-cooling and argon gas atmosphere, triethylamine (4.04 mL, 27.6 × 1.05) mmol) and triphenylmethyl chloride (7.69 g, 27.6 mmol) were added, and the mixture was stirred overnight while gradually returning to room temperature. Chloroform and water were added to the reaction solution, and the organic layer was taken. The organic layer was washed with water and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, hexane / ethyl acetate / chloroform) to obtain the title compound (white solid, 4.59 g, 14.4 mmol, 52%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.45-7.41 (6H, m), 7.33-7.22 (9H, m), 3.77 (2H, t, J = 5.9 Hz), 3.28 (2H, t , J = 5.9 Hz), 1.89-1.84 (2H, m).
参考例２１
3-(トリフェニルメチルオキシ)プロピオンアルデヒドの合成
　塩化オキサリル(862 μL, 6.28×1.6 mmol)のジクロロメタン(15 mL)溶液に、-78℃付近、アルゴンガス雰囲気下にて、ジメチルスルホキシド(1.56 mL, 6.28×3.5 mmol)のジクロロメタン(2.5 mL)溶液を滴下した。-78℃付近で10分間撹拌した後、3-(トリフェニルメチルオキシ)プロパノール(2.00 g, 6.28 mmol)のジクロロメタン(9 mL)溶液を滴下した。-78℃付近で10分間撹拌した後、トリエチルアミン(3.50 mL, 6.28×4 mmol)を滴下した。次いで、ゆっくりと室温に戻し、クロロホルムと水を添加した。有機層を取り、ブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をヘキサンで再結晶して、標記の化合物(白色固体, 1.633 g, 5.16 mmol, 82%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 9.76 (1H, t, J=2.2 Hz), 7.44-7.40 (6H, m), 7.33-7.22 (9H, m), 3.47 (2H, t, J=6.1 Hz), 2.64 (2H, td, J=6.1, 2.2 Hz). Reference Example 21
Synthesis of 3- (triphenylmethyloxy) propionaldehyde To a solution of oxalyl chloride (862 μL, 6.28 × 1.6 mmol) in dichloromethane (15 mL) at about −78 ° C. under an argon gas atmosphere, dimethyl sulfoxide (1.56 mL, 6.28 × 3.5 mmol) in dichloromethane (2.5 mL) was added dropwise. After stirring at around −78 ° C. for 10 minutes, a solution of 3- (triphenylmethyloxy) propanol (2.00 g, 6.28 mmol) in dichloromethane (9 mL) was added dropwise. After stirring at around −78 ° C. for 10 minutes, triethylamine (3.50 mL, 6.28 × 4 mmol) was added dropwise. Subsequently, the temperature was slowly returned to room temperature, and chloroform and water were added. The organic layer was taken, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized from hexane to obtain the title compound (white solid, 1.633 g, 5.16 mmol, 82%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 9.76 (1H, t, J = 2.2 Hz), 7.44-7.40 (6H, m), 7.33-7.22 (9H, m), 3.47 (2H, t , J = 6.1 Hz), 2.64 (2H, td, J = 6.1, 2.2 Hz).
参考例２２
3-(トリフェニルメチルオキシ)プロピオン酸の合成
　3-(トリフェニルメチルオキシ)プロピオンアルデヒド(1.20 g, 3.79 mmol)のアセトン(19.5 mL)-水(3.8 mL)混液に氷冷下、過マンガンカリウム(0.599 g, 3.79 mmol)を数回に分けて添加した。反応液を室温で2時間撹拌した後、塩酸(1 mol/L)にてpH5付近に調製し、次いで10%チオ硫酸ナトリウムを添加して褐色を消去した。次いでクロロホルム、水及び塩酸(1 mol/L)を添加して、pH2付近に調製し、有機層を取った。水層は再びクロロホルムにて抽出した。有機層は合わせて、ブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物に酢酸エチル(10 mL)を加えて超音波処理した後、ヘキサン(10 mL)を加えて室温で一晩静置した。析出物をろ取、ヘキサンで洗浄、減圧乾燥して、標記の化合物(白色固体, 1.15 g, 3.47 mmol, 92%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.45-7.41 (6H, m), 7.32-7.21 (9H, m), 3.42 (2H, t, J=6.3 Hz), 2.62 (2H, t, J=6.3 Hz). Reference Example 22
Synthesis of 3- (triphenylmethyloxy) propionic acid 3- (triphenylmethyloxy) propionaldehyde (1.20 g, 3.79 mmol) in acetone (19.5 mL) -water (3.8 mL) mixed with potassium permanganate under ice-cooling (0.599 g, 3.79 mmol) was added in several portions. The reaction solution was stirred at room temperature for 2 hours, then adjusted to about pH 5 with hydrochloric acid (1 mol / L), and then 10% sodium thiosulfate was added to eliminate the brown color. Subsequently, chloroform, water and hydrochloric acid (1 mol / L) were added to adjust the pH to around 2, and the organic layer was taken. The aqueous layer was extracted again with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was sonicated with ethyl acetate (10 mL), hexane (10 mL) was added, and the mixture was allowed to stand overnight at room temperature. The precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to obtain the title compound (white solid, 1.15 g, 3.47 mmol, 92%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.45-7.41 (6H, m), 7.32-7.21 (9H, m), 3.42 (2H, t, J = 6.3 Hz), 2.62 (2H, t , J = 6.3 Hz).
実施例１３７
4-クロロ-N-[3-(トリフェニルメチルオキシ)プロピオニル]デアセチルコルヒチンの合成
　4-クロロ-N-[3-(ピロリジン-1-イル)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 118 mg, 0.168 mmol, 94%)を得た。3-(ピロリジン-1-イル)安息香酸の代わりに3-(トリフェニルメチルオキシ)プロピオン酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.78 (1H, d, J=7.3 Hz), 7.34-7.20 (16H, m), 7.13 (1H, d, J=10.7 Hz), 7.03 (1H, d, J=10.7 Hz), 4.35-4.28 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.18-3.09 (2H, m), 3.05-2.99 (1H, m), 2.53-2.39 (2H, m), 2.18-2.09 (1H, m), 2.02-1.83 (2H, m).
ESI-MS m/z: 706 [M+H]+. Example 137
Synthesis of 4-chloro-N- [3- (triphenylmethyloxy) propionyl] deacetylcolchicine In the same way as the synthesis of 4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine The title compound (milky white solid, 118 mg, 0.168 mmol, 94%) was obtained. Instead of 3- (pyrrolidin-1-yl) benzoic acid, 3- (triphenylmethyloxy) propionic acid was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.78 (1H, d, J = 7.3 Hz), 7.34-7.20 (16H, m), 7.13 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.35-4.28 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.18 -3.09 (2H, m), 3.05-2.99 (1H, m), 2.53-2.39 (2H, m), 2.18-2.09 (1H, m), 2.02-1.83 (2H, m).
ESI-MS m / z: 706 [M + H] + .
実施例１３８
4-クロロ-N-(3-ヒドロキシプロピオニル)デアセチルコルヒチンの合成
　4-クロロ-N-[3-(トリフェニルメチルオキシ)プロピオニル]デアセチルコルヒチン(95 mg, 0.135 mmol)のメタノール(0.5 mL)溶液に、室温でp-トルエンスルホン酸一水和物(5 mg, 0.135×0.2 mmol)を添加して、5時間撹拌した。反応液を濃縮乾固して、フラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡黄色固体, 54 mg, 0.116 mmol, 86%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.59 (1H, d, J=7.1 Hz), 7.13 (2H, s), 7.12 (2H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 4.54 (1H, t, J=5.2 Hz), 4.28-4.22 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.57-3.52 (2H, m), 3.53 (3H, s), 3.10 (1H, dd, J=13.7, 5.1 Hz), 2.35-2.23 (2H, m), 2.15-2.06 (1H, m), 1.99-1.80 (2H, m).
ESI-MS m/z: 464 [M+H]+. Example 138
Synthesis of 4-chloro-N- (3-hydroxypropionyl) deacetylcolchicine 4-chloro-N- [3- (triphenylmethyloxy) propionyl] deacetylcolchicine (95 mg, 0.135 mmol) in methanol (0.5 mL) To the solution, p-toluenesulfonic acid monohydrate (5 mg, 0.135 × 0.2 mmol) was added at room temperature and stirred for 5 hours. The reaction solution was concentrated to dryness and purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 54 mg, 0.116 mmol, 86%). .
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, d, J = 7.1 Hz), 7.13 (2H, s), 7.12 (2H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 4.54 (1H, t, J = 5.2 Hz), 4.28-4.22 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s ), 3.57-3.52 (2H, m), 3.53 (3H, s), 3.10 (1H, dd, J = 13.7, 5.1 Hz), 2.35-2.23 (2H, m), 2.15-2.06 (1H, m), 1.99-1.80 (2H, m).
ESI-MS m / z: 464 [M + H] + .
実施例１３９
4-クロロ-N-(メタンスルホニルアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、メタンスルホニル酢酸 (21 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 17 mg, 0.033 mmol, 29%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.67 (1H, br.s), 7.73 (1H, s), 7.36 (1H, d, J = 10.7 Hz), 6.92 (1H, d, J = 10.7 Hz), 4.63-4.56 (1H, m), 4.15 (1H, d, J = 14.6 Hz), 4.06 (1H, d, J = 14.6 Hz), 4.03 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.63 (3H , s), 3.25 (1H, dd, J = 13.4, 5.1 Hz), 3.08 (3H, s), 2.34-2.25 (1H, m), 2.16-2.13 (1H, m), 1.93-1.84 (1H, m).
ESI-MS m/z: 512 ([M+H]+) Example 139
Synthesis of 4-chloro-N- (methanesulfonylacetyl) deacetylcolchicine Methanesulfonylacetic acid (21 mg, 0.128 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL) under an argon atmosphere, and the solution was brought to 0 ° C. Cooled down. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 17 mg, 0.033 mmol, 29%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.67 (1H, br.s), 7.73 (1H, s), 7.36 (1H, d, J = 10.7 Hz), 6.92 (1H, d, J = 10.7 Hz), 4.63-4.56 (1H, m), 4.15 (1H, d, J = 14.6 Hz), 4.06 (1H, d, J = 14.6 Hz), 4.03 (3H, s), 4.00 (3H, s ), 3.99 (3H, s), 3.63 (3H, s), 3.25 (1H, dd, J = 13.4, 5.1 Hz), 3.08 (3H, s), 2.34-2.25 (1H, m), 2.16-2.13 ( 1H, m), 1.93-1.84 (1H, m).
ESI-MS m / z: 512 ([M + H] + )
実施例１４０
4-クロロ-N-[3-(ジメチルアミノ)プロピオニル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、3-ジメチルアミノプロピオン酸塩酸塩 (39 mg, 0.128 × 2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (49 mg, 0.128 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (35 mg, 0.128 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (乳白色固体, 27 mg, 0.055 mmol, 43%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.64 (1H, d, 7.1 Hz), 7.13 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.02 (1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.11 (1H, dd, J = 13.4, 5.1 Hz), 2.43-2.37 (2H, m), 2.31-2.27 (2H, m), 2.11 (3H, s), 2.10-2.08 (1H, m), 1.99-1.90 (1H, m), 1.86-1.78 (1H, m).
ESI-MS m/z: 491 ([M+H]+) Example 140
Synthesis of 4-chloro-N- [3- (dimethylamino) propionyl] deacetylcolchicine Under argon atmosphere, 3-dimethylaminopropionate hydrochloride (39 mg, 0.128 × 2 mmol) was converted to N, N-dimethylformamide (1 (mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 × 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (milky white solid, 27 mg, 0.055 mmol, 43%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.64 (1H, d, 7.1 Hz), 7.13 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.02 (1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.11 (1H, dd , J = 13.4, 5.1 Hz), 2.43-2.37 (2H, m), 2.31-2.27 (2H, m), 2.11 (3H, s), 2.10-2.08 (1H, m), 1.99-1.90 (1H, m ), 1.86-1.78 (1H, m).
ESI-MS m / z: 491 ([M + H] + )
実施例１４１
4-クロロ-N-[3-(ジエチルアミノ)プロピオニル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、3-ジエチルアミノプロピオン酸塩酸塩 (47 mg, 0.128 × 2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (49 mg, 0.128 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (35 mg, 0.128 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (乳白色固体, 34 mg, 0.066 mmol, 51%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.70 (1H, d, J = 6.6 Hz), 7.13 (1H, s), 7.12 (1H, d, J= 11.0 Hz), 7.02 (1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 13.5, 5.2 Hz), 2.64-2.55 (2H, m), 2.51-2.40 (4H, m), 2.27-2.22 (2H, m), 2.13-2.10 (1H, m), 1.99-1.92 (1H, m), 1.85-1.78 (1H, m), 0.93 (6H, t, J = 6.7 Hz).
ESI-MS m/z: 519 ([M+H]+) Example 141
Synthesis of 4-chloro-N- [3- (diethylamino) propionyl] deacetylcolchicine Under argon atmosphere, 3-diethylaminopropionate hydrochloride (47 mg, 0.128 × 2 mmol) was added to N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 × 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (milky white solid, 34 mg, 0.066 mmol, 51%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.70 (1H, d, J = 6.6 Hz), 7.13 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.02 ( 1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.11 (1H , dd, J = 13.5, 5.2 Hz), 2.64-2.55 (2H, m), 2.51-2.40 (4H, m), 2.27-2.22 (2H, m), 2.13-2.10 (1H, m), 1.99-1.92 (1H, m), 1.85-1.78 (1H, m), 0.93 (6H, t, J = 6.7 Hz).
ESI-MS m / z: 519 ([M + H] + )
実施例１４２
4-クロロ-N-(３－ピペリジノプロピオニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、1-ピペリジンプロピオン酸 (40 mg, 0.128 × 2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (49 mg, 0.128 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (35 mg, 0.128 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 20 mg, 0.038 mmol, 29%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.71 (1H, d, J = 7.3 Hz), 7.12 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.11 (1H, dd, J = 13.4, 5.1 Hz), 2.43 (2H, t, J = 7.0 Hz), 2.31-2.26 (6H, m), 2.13-2.10 (1H, m), 2.00-1.91 (1H, m), 1.83-1.80 (1H, m), 1.48-1.47 (4H, m), 1.37-1.35 (2H, m).
ESI-MS m/z: 531 ([M+H]+) Example 142
Synthesis of 4-chloro-N- (3-piperidinopropionyl) deacetylcolchicine Dissolve 1-piperidinepropionic acid (40 mg, 0.128 × 2 mmol) in N, N-dimethylformamide (1 mL) under argon atmosphere And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 × 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 20 mg, 0.038 mmol, 29%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.71 (1H, d, J = 7.3 Hz), 7.12 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 ( 1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.11 (1H , dd, J = 13.4, 5.1 Hz), 2.43 (2H, t, J = 7.0 Hz), 2.31-2.26 (6H, m), 2.13-2.10 (1H, m), 2.00-1.91 (1H, m), 1.83-1.80 (1H, m), 1.48-1.47 (4H, m), 1.37-1.35 (2H, m).
ESI-MS m / z: 531 ([M + H] + )
実施例１４３
N-[N'-(t-ブチルオキシカルボニル)-N'-メチルアミノアセチル]-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、t-ブチルオキシカルボニルサルコシン (96 mg, 0.255 × 2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (98 mg, 0.255 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (69 mg, 0.255 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (100 mg, 0.255 mmol) を加え、室温に戻して90分撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 71 mg, 0.126 mmol, 50%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.67, 8.64 (total 1H, each d, J = 7.8 Hz), 7.13 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.02 (1H, d, J = 10.5 Hz), 4.29-4.23 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.32-3.30 (2H, m), 3.11 (1H, dd, J = 13.4, 5.1 Hz), 2.74, 2.72 (total 3H, each s), 2.13-2.10 (1H, m), 1.99-1.93 (1H, m), 1.91-1.82 (1H, m), 1.36, 1.29 (total 6H, each s).
ESI-MS m/z: 563 ([M+H]+) Example 143
Synthesis of N- [N '-(t-butyloxycarbonyl) -N'-methylaminoacetyl] -4-chlorodeacetylcolchicine Under argon atmosphere, t-butyloxycarbonylsarcosine (96 mg, 0.255 × 2 mmol) Dissolved in N, N-dimethylformamide (1.5 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (98 mg, 0.255 × 2 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.255 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (100 mg, 0.255 mmol) was added there, and it returned to room temperature, and stirred for 90 minutes. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 71 mg, 0.126 mmol, 50%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.67, 8.64 (total 1H, each d, J = 7.8 Hz), 7.13 (1H, d, J = 10.5 Hz), 7.11 (1H, s ), 7.02 (1H, d, J = 10.5 Hz), 4.29-4.23 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s) , 3.32-3.30 (2H, m), 3.11 (1H, dd, J = 13.4, 5.1 Hz), 2.74, 2.72 (total 3H, each s), 2.13-2.10 (1H, m), 1.99-1.93 (1H, m), 1.91-1.82 (1H, m), 1.36, 1.29 (total 6H, each s).
ESI-MS m / z: 563 ([M + H] + )
実施例１４４
N-[N'-ベンジル-N'-（t-ブチルオキシカルボニル)アミノアセチル]-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、N-ベンジル-N-t-ブチルオキシカルボニルグリシン (135 mg, 0.255× 2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (98 mg, 0.255 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (69 mg, 0.255 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (100 mg, 0.255 mmol) を加え、室温に戻して90分撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 87 mg, 0.136 mmol, 57%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.64, 8.60 (total 1H, each d, J = 6.8 Hz), 7.36-7.31 (2H, m), 7.28-7.20 (3H, m), 7.15-7.12 (2H, m), 7.03 (1H, d, J = 11.0 Hz), 4.37-4.19 (3H, m), 3.92 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.85-3.66 (2H, m), 3.56 (3H, s), 3.10 (1H, dd, J = 13.4, 5.1 Hz), 2.16-2.07 (1H, m), 1.99-1.91 (1H, m), 1.87-1.79 (1H, m), 1.33 (9H, s).
ESI-MS m/z: 639 ([M+H]+) Example 144
Synthesis of N- [N'-benzyl-N '-(t-butyloxycarbonyl) aminoacetyl] -4-chlorodeacetylcolchicine Under argon atmosphere, N-benzyl-Nt-butyloxycarbonylglycine (135 mg, 0.255 × 2 mmol) was dissolved in N, N-dimethylformamide (1.5 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (98 mg, 0.255 × 2 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.255 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (100 mg, 0.255 mmol) was added there, and it returned to room temperature, and stirred for 90 minutes. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 87 mg, 0.136 mmol, 57%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.64, 8.60 (total 1H, each d, J = 6.8 Hz), 7.36-7.31 (2H, m), 7.28-7.20 (3H, m) , 7.15-7.12 (2H, m), 7.03 (1H, d, J = 11.0 Hz), 4.37-4.19 (3H, m), 3.92 (3H, s), 3.89 (3H, s), 3.89 (3H, s ), 3.85-3.66 (2H, m), 3.56 (3H, s), 3.10 (1H, dd, J = 13.4, 5.1 Hz), 2.16-2.07 (1H, m), 1.99-1.91 (1H, m), 1.87-1.79 (1H, m), 1.33 (9H, s).
ESI-MS m / z: 639 ([M + H] + )
実施例１４５
4-クロロ-N-(1-メチルピペリジン-4-イルカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、1-メチルピペリジン-4-カルボン酸塩酸塩 (46 mg, 0.128 × 2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した. そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (49 mg, 0.128 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (35 mg, 0.128 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して150分撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 17 mg, 0.033 mmol, 26%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.54 (1H, d, J = 7.3 Hz), 7.12 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.10 (1H, dd, J = 13.8, 5.5 Hz), 2.76-2.70 (2H, m), 2.17-2.06 (2H, m), 2.11 (3H, s), 1.97-1.92 (1H, m), 1.88-1.77 (3H, m), 1.67-1.64 (1H, m), 1.53-1.48 (3H, m).
ESI-MS m/z: 517 ([M+H]+) Example 145
Synthesis of 4-chloro-N- (1-methylpiperidin-4-ylcarbonyl) deacetylcolchicine Under argon atmosphere, 1-methylpiperidine-4-carboxylic acid hydrochloride (46 mg, 0.128 × 2 mmol) was converted to N, N Dissolved in 1-dimethylformamide (1 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 × 2 mmol), 1-hydroxybenzo Triazole monohydrate (35 mg, 0.128 × 2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 min. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 150 minutes. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 17 mg, 0.033 mmol, 26%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.54 (1H, d, J = 7.3 Hz), 7.12 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.10 (1H , dd, J = 13.8, 5.5 Hz), 2.76-2.70 (2H, m), 2.17-2.06 (2H, m), 2.11 (3H, s), 1.97-1.92 (1H, m), 1.88-1.77 (3H , m), 1.67-1.64 (1H, m), 1.53-1.48 (3H, m).
ESI-MS m / z: 517 ([M + H] + )
実施例１４６
4-クロロ-N-[1-(ベンジルオキシカルボニル)ピペリジン-4-イルカルボニル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、1-(ベンジルオキシカルボニル)ピペリジン-4-カルボン酸 (134 mg,0.255 × 2 mmol) をN,N-ジメチルホルムアミド (1.5 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (98 mg, 0.255 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (69 mg, 0.255 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (100 mg, 0.255 mmol) を加え、室温に戻して150分撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 110 mg,0.173 mmol, 68%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.61 (1H, d, J = 7.1 Hz), 7.36-7.31 (5H, m), 7.13 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 5.05 (2H, s), 4.24-4.17 (1H, m), 4.01-3.98 (2H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.10 (1H, dd, J = 13.2, 5.1 Hz), 2.88-2.75 (2H, m), 2.44-2.41 (1H, m), 2.12-2.09 (1H, m), 2.00-1.91 (1H, m), 1.89-1.81 (1H, m), 1.71-1.64 (2H, m), 1.39-1.34 (2H, m).
ESI-MS m/z: 637 ([M+H]+) Example 146
Synthesis of 4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine 1- (benzyloxycarbonyl) piperidine-4-carboxylic acid (134 mg, 0.255 × 2) under argon atmosphere mmol) was dissolved in N, N-dimethylformamide (1.5 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (98 mg, 0.255 × 2 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.255 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (100 mg, 0.255 mmol) was added there, and it returned to room temperature, and stirred for 150 minutes. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 110 mg, 0.173 mmol, 68%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.61 (1H, d, J = 7.1 Hz), 7.36-7.31 (5H, m), 7.13 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 5.05 (2H, s), 4.24-4.17 (1H, m), 4.01-3.98 (2H, m), 3.91 (3H, s) , 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.10 (1H, dd, J = 13.2, 5.1 Hz), 2.88-2.75 (2H, m), 2.44-2.41 (1H , m), 2.12-2.09 (1H, m), 2.00-1.91 (1H, m), 1.89-1.81 (1H, m), 1.71-1.64 (2H, m), 1.39-1.34 (2H, m).
ESI-MS m / z: 637 ([M + H] + )
実施例１４７
4-クロロ-N-(N'-メチルアミノアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロ-N-(N'-t-ブチルオキシカルボニル-N'-メチルアミノアセチル)デアセチルコルヒチン (30 mg, 0.053 mmol) をジクロロメタン (426 μl) に溶解し、0℃に冷却した。そこへトリフルオロ酢酸 (171 μl) を加え、0℃で150分撹拌した。反応液を濃縮乾固し、クロロホルムに再溶解して飽和重曹水、飽和食塩水で洗浄した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 16 mg, 0.035 mmol, 65%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.66 (1H, d, J = 7.3 Hz), 7.13 (1H, d, J = 10.5 Hz), 7.12 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.31-4.25 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.17 (2H, s), 3.11 (1H, dd, J = 13.7, 3.4 Hz), 2.27 (3H, s), 2.16-2.08 (1H, m), 1.97-1.92 (2H, m).
ESI-MS m/z: 463 ([M+H]+) Example 147
Synthesis of 4-chloro-N- (N'-methylaminoacetyl) deacetylcolchicine Under an argon atmosphere, 4-chloro-N- (N'-t-butyloxycarbonyl-N'-methylaminoacetyl) deacetylcolchicine ( 30 mg, 0.053 mmol) was dissolved in dichloromethane (426 μl) and cooled to 0 ° C. Trifluoroacetic acid (171 μl) was added thereto and stirred at 0 ° C. for 150 minutes. The reaction solution was concentrated to dryness, redissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 16 mg, 0.035 mmol, 65%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.66 (1H, d, J = 7.3 Hz), 7.13 (1H, d, J = 10.5 Hz), 7.12 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.31-4.25 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.17 (2H , s), 3.11 (1H, dd, J = 13.7, 3.4 Hz), 2.27 (3H, s), 2.16-2.08 (1H, m), 1.97-1.92 (2H, m).
ESI-MS m / z: 463 ([M + H] + )
実施例１４８
N-(N'-ベンジルアミノアセチル)-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロ-N-(N'-ベンジル-N'-t-ブトキシカルボニルアミノアセチル)デアセチルコルヒチン (23 mg, 0.036 mmol) をジクロロメタン (288 μl) に溶解し、0℃に冷却した。そこへトリフルオロ酢酸 (115 μl) を加え、0℃で150分撹拌した。反応液を濃縮乾固し、クロロホルムに再溶解して飽和重曹水、飽和食塩水で洗浄した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 21 mg, 定量的) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.66 (1H, d, J = 7.1 Hz), 7.34-7.32 (4H, m), 7.26-7.24 (1H, m), 7.14 (1H, s), 7.14 (1H, d, J = 10.5 Hz), 7.04 (1H, d, J = 10.7 Hz), 4.29-4.23 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.71 (2H, s), 3.54 (3H, s), 3.19 (2H, s), 3.11 (1H, dd, J = 13.3, 4.3 Hz), 2.13-2.10 (1H, m), 1.97-1.89 (2H, m).
ESI-MS m/z: 539 ([M+H]+) Example 148
Synthesis of N- (N'-benzylaminoacetyl) -4-chlorodeacetylcolchicine Under an argon atmosphere, 4-chloro-N- (N'-benzyl-N'-t-butoxycarbonylaminoacetyl) deacetylcolchicine (23 mg, 0.036 mmol) was dissolved in dichloromethane (288 μl) and cooled to 0 ° C. Trifluoroacetic acid (115 μl) was added thereto, and the mixture was stirred at 0 ° C. for 150 minutes. The reaction solution was concentrated to dryness, redissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 21 mg, quantitative).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.66 (1H, d, J = 7.1 Hz), 7.34-7.32 (4H, m), 7.26-7.24 (1H, m), 7.14 (1H , s), 7.14 (1H, d, J = 10.5 Hz), 7.04 (1H, d, J = 10.7 Hz), 4.29-4.23 (1H, m), 3.92 (3H, s), 3.89 (3H, s) , 3.88 (3H, s), 3.71 (2H, s), 3.54 (3H, s), 3.19 (2H, s), 3.11 (1H, dd, J = 13.3, 4.3 Hz), 2.13-2.10 (1H, m ), 1.97-1.89 (2H, m).
ESI-MS m / z: 539 ([M + H] + )
実施例１４９
4-クロロ-N-[4-(ジメチルアミノ)ブチリル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ジメチルアミノ酪酸塩酸塩 (43 mg, 0.128 × 2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (49 mg, 0.128 × 2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (35 mg, 0.128 × 2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 35 mg, 0.069 mmol, 54%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.62 (1H, d, J = 7.1 Hz), 7.12 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.11 (1H, dd, J = 13.5, 5.0 Hz), 2.36-2.34 (2H, m), 2.24 (6H, s), 2.19-2.16 (2H, m), 2.13-2.07 (1H, m), 2.00-1.91 (1H, m), 1.87-1.79 (1H, m), 1.66-1.59 (2H, m).
ESI-MS m/z: 505 ([M+H]+) Example 149
Synthesis of 4-chloro-N- [4- (dimethylamino) butyryl] deacetylcolchicine Under argon atmosphere, 4-dimethylaminobutyric acid hydrochloride (43 mg, 0.128 × 2 mmol) was added to N, N-dimethylformamide (1 mL ) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg, 0.128 × 2 mmol), 1-hydroxybenzotriazole monohydrate (35 mg, 0.128 × 2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 35 mg, 0.069 mmol, 54%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.62 (1H, d, J = 7.1 Hz), 7.12 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.03 ( 1H, d, J = 11.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.11 (1H , dd, J = 13.5, 5.0 Hz), 2.36-2.34 (2H, m), 2.24 (6H, s), 2.19-2.16 (2H, m), 2.13-2.07 (1H, m), 2.00-1.91 (1H , m), 1.87-1.79 (1H, m), 1.66-1.59 (2H, m).
ESI-MS m / z: 505 ([M + H] + )
実施例１５０
4-クロロ-N-[2-(ジメチルアミノ)ベンゾイル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、2-(ジメチルアミノ)安息香酸 (25 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して終夜撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 24 mg, 0.045 mmol, 35%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.54 (1H, d, J = 7.3 Hz), 7.42-7.38 (2H, m), 7.33 (1H, s), 7.17-7.15 (2H, m), 7.06-6.99 (2H, m), 4.52-4.46 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.15 (1H, dd, J = 12.9, 3.7 Hz), 2.70 (6H, s), 2.17-2.14 (1H, m), 2.10-1.98 (2H, m).
ESI-MS m/z: 539 ([M+H]+) Example 150
Synthesis of 4-chloro-N- [2- (dimethylamino) benzoyl] deacetylcolchicine Under argon atmosphere, 2- (dimethylamino) benzoic acid (25 mg, 0.128 × 1.2 mmol) was converted to N, N-dimethylformamide (1 (mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred all night. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 24 mg, 0.045 mmol, 35%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.54 (1H, d, J = 7.3 Hz), 7.42-7.38 (2H, m), 7.33 (1H, s), 7.17-7.15 (2H , m), 7.06-6.99 (2H, m), 4.52-4.46 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.15 (1H, dd, J = 12.9, 3.7 Hz), 2.70 (6H, s), 2.17-2.14 (1H, m), 2.10-1.98 (2H, m).
ESI-MS m / z: 539 ([M + H] + )
実施例１５１
4-クロロ-N- (イソブチルチオカルバモイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸イソブチル (31 μl, 0.128 × 2 mmol) を加え、室温まで昇温させながら4時間撹拌した。反応液に10%クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 26 mg, 0.051 mmol, 40%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.00 (1H, br.s), 7.57 (1H, br.s), 7.14 (1H, d, J = 10.5 Hz), 7.06 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.79-4.70 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.21-3.11 (3H, m), 2.15-2.07 (2H, m), 1.84-1.76 (1H, m), 0.84 (6H, d, J = 6.3 Hz).
ESI-MS m/z: 507 ([M+H]+) Example 151
Synthesis of 4-chloro-N- (isobutylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. Thereto was added isobutyl isothiocyanate (31 μl, 0.128 × 2 mmol), and the mixture was stirred for 4 hours while warming to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 26 mg, 0.051 mmol, 40%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.00 (1H, br.s), 7.57 (1H, br.s), 7.14 (1H, d, J = 10.5 Hz), 7.06 (1H , s), 7.03 (1H, d, J = 10.7 Hz), 4.79-4.70 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.21-3.11 (3H, m), 2.15-2.07 (2H, m), 1.84-1.76 (1H, m), 0.84 (6H, d, J = 6.3 Hz).
ESI-MS m / z: 507 ([M + H] + )
実施例１５２
N-(ベンジルチオカルバモイル)-4-クロロデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸ベンジル (34 μl, 0.128 × 2 mmol) を加え、室温まで昇温させながら4時間撹拌した。反応液に10% クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 43 mg, 0.079 mmol, 62%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.19 (1H, br.s), 7.97 (1H, br.s), 7.31-7.30 (2H, m), 7.25-7.24 (3H, m), 7.15 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 11.0 Hz), 4.79-4.74 (1H, m), 4.65-4.60 (2H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J = 12.4, 4.6 Hz), 2.18-2.06 (2H, m), 1.93-1.86 (1H, m).
ESI-MS m/z: 541 ([M+H]+) Example 152
Synthesis of N- (benzylthiocarbamoyl) -4-chlorodeacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. Thereto was added benzyl isothiocyanate (34 μl, 0.128 × 2 mmol), and the mixture was stirred for 4 hours while warming to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 43 mg, 0.079 mmol, 62%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.19 (1H, br.s), 7.97 (1H, br.s), 7.31-7.30 (2H, m), 7.25-7.24 (3H, m), 7.15 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 11.0 Hz), 4.79-4.74 (1H, m), 4.65-4.60 (2H, m ), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J = 12.4, 4.6 Hz), 2.18-2.06 (2H, m), 1.93-1.86 (1H, m).
ESI-MS m / z: 541 ([M + H] + )
実施例１５３
4-クロロ-N-(シクロヘキシルチオカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸シクロヘキシル (35μl, 0.128 × 2 mmol) を加え、室温に戻して6時間撹拌した。反応液に10% クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 26 mg, 0.049 mmol, 38%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.86 (1H, d, J = 6.6 Hz), 7.48 (1H, br.s), 7.14 (1H, d, J = 10.7 Hz), 7.04 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.78-4.71 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.11 (1H, dd, J = 12.8, 4.5 Hz), 2.12-2.07 (2H, m), 1.88-1.77 (3H, m), 1.66-1.61 (2H, m), 1.53-1.50 (1H, m), 1.25-1.14 (6H, m).
ESI-MS m/z: 533 ([M+H]+) Example 153
Synthesis of 4-chloro-N- (cyclohexylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. The cyclohexyl isothiocyanate (35 microliters, 0.128 * 2 mmol) was added there, and it returned to room temperature, and stirred for 6 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 26 mg, 0.049 mmol, 38%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.86 (1H, d, J = 6.6 Hz), 7.48 (1H, br.s), 7.14 (1H, d, J = 10.7 Hz), 7.04 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.78-4.71 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.11 (1H, dd, J = 12.8, 4.5 Hz), 2.12-2.07 (2H, m), 1.88-1.77 (3H, m), 1.66-1.61 (2H, m), 1.53-1.50 (1H, m), 1.25-1.14 (6H, m).
ESI-MS m / z: 533 ([M + H] + )
実施例１５４
4-クロロ-N-[(2-ピペリジノエチル)チオカルバモイル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸2-ピペリジノエチル(42 μl, 0.128 × 2 mmol) を加え、室温まで昇温させながら終夜撹拌した。反応液に10% クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 33 mg, 0.059 mmol, 46%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.59 (1H, br.s), 7.94 (1H, br.s), 7.15 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.75-4.70 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.80-3.74 (2H, m), 3.61 (3H, s), 3.20-3.06 (2H, m), 3.12 (1H, dd, J = 12.7, 4.4 Hz), 2.96-2.81 (2H, m), 2.19-2.02 (2H, m), 1.97-1.88 (1H, m), 1.73-1.61 (4H, m), 1.42-1.33 (1H, m), 1.28-1.25 (3H, m).
ESI-MS m/z: 562 ([M+H]+) Example 154
Synthesis of 4-chloro-N-[(2-piperidinoethyl) thiocarbamoyl] deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and heated to 0 ° C. Cooled down. Thereto was added 2-piperidinoethyl isothiocyanate (42 μl, 0.128 × 2 mmol), and the mixture was stirred overnight while warming to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 33 mg, 0.059 mmol, 46%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, br.s), 7.94 (1H, br.s), 7.15 (1H, d, J = 10.7 Hz), 7.06 (1H , s), 7.03 (1H, d, J = 11.0 Hz), 4.75-4.70 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.80-3.74 ( 2H, m), 3.61 (3H, s), 3.20-3.06 (2H, m), 3.12 (1H, dd, J = 12.7, 4.4 Hz), 2.96-2.81 (2H, m), 2.19-2.02 (2H, m), 1.97-1.88 (1H, m), 1.73-1.61 (4H, m), 1.42-1.33 (1H, m), 1.28-1.25 (3H, m).
ESI-MS m / z: 562 ([M + H] + )
実施例１５５
4-クロロ-N-[[2-(4-モルフォリノ)エチル]チオカルバモイル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸2-(4-モルフォリノ)エチル (39 μl, 0.128 × 2 mmol) を加え、室温まで昇温させながら終夜撹拌した。反応液に10% クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 35 mg, 0.062 mmol, 49%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.29 (1H, d, J = 6.1 Hz), 7.45 (1H, br.s), 7.14 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.78-4.71 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.59-3.57 (4H, m), 3.51-3.42 (2H, m), 3.12 (1H, dd, J = 12.7, 4.6 Hz), 2.39-2.35 (6H, m), 2.17-2.02 (2H, m), 1.91-1.78 (1H, m).
ESI-MS m/z: 564 ([M+H]+) Example 155
Synthesis of 4-chloro-N-[[2- (4-morpholino) ethyl] thiocarbamoyl] deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (1 mL) under argon atmosphere And cooled to 0 ° C. Thereto was added 2- (4-morpholino) ethyl isothiocyanate (39 μl, 0.128 × 2 mmol), and the mixture was stirred overnight while warming to room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 35 mg, 0.062 mmol, 49%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.29 (1H, d, J = 6.1 Hz), 7.45 (1H, br.s), 7.14 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.78-4.71 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.59-3.57 (4H, m), 3.51-3.42 (2H, m), 3.12 (1H, dd, J = 12.7, 4.6 Hz), 2.39-2.35 (6H, m), 2.17-2.02 (2H, m), 1.91-1.78 (1H, m).
ESI-MS m / z: 564 ([M + H] + )
実施例１５６
4-クロロ-N-(3-ピリジルチオカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸3-ピリジル (29 μl, 0.128 × 2 mmol) を加え、室温に戻して4時間撹拌した。反応液に10%クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 51 mg, 0.097 mmol, 76%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.79 (1H, s), 8.67 (1H, d, J = 6.8 Hz), 8.57 (1H, d, J = 2.2 Hz), 8,28 (1H, d, J = 3.7 Hz), 7.94 (1H, d, J = 8.1 Hz), 7.32 (1H, dd, J = 8.2, 4.8 Hz), 7.17 (1H, d, J = 10.7 Hz), 7.14 (1H, s), 7.05 (1H, d, J = 11.0 Hz), 4.81-4.75 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.61 (3 H, s), 3.17-3.12 (1H, m), 2.19-2.13 (2H, m), 2.06-1.99 (1H, m).
ESI-MS m/z: 528 ([M+H]+) Example 156
Synthesis of 4-chloro-N- (3-pyridylthiocarbamoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 ° C. . Thereto was added 3-pyridyl isothiocyanate (29 μl, 0.128 × 2 mmol), and the mixture was returned to room temperature and stirred for 4 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 51 mg, 0.097 mmol, 76%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.79 (1H, s), 8.67 (1H, d, J = 6.8 Hz), 8.57 (1H, d, J = 2.2 Hz), 8, 28 (1H, d, J = 3.7 Hz), 7.94 (1H, d, J = 8.1 Hz), 7.32 (1H, dd, J = 8.2, 4.8 Hz), 7.17 (1H, d, J = 10.7 Hz), 7.14 (1H, s), 7.05 (1H, d, J = 11.0 Hz), 4.81-4.75 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.61 (3 H, s), 3.17-3.12 (1H, m), 2.19-2.13 (2H, m), 2.06-1.99 (1H, m).
ESI-MS m / z: 528 ([M + H] + )
実施例１５７
4-クロロ-N-[p-(ジメチルアミノ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (1 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸p- (ジメチルアミノ) フェニル (43 mg, 0.128 × 2 mmol) を加え、室温に戻して4時間撹拌した。反応液に10% クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 46 mg, 0.081 mmol, 63%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.40 (1H, s), 8.02 (1H, d, J = 6.6 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 6.68 (2H, d, J = 8.8 Hz), 4.84-4.79 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.61 (3H, s), 3.11 (1H, dd, J = 12.8, 5.5 Hz), 2.87 (6H, s), 2.13-2.09 (2H, m), 2.03-1.98 (1H, m).
ESI-MS m/z: 570 ([M+H]+) Example 157
Synthesis of 4-chloro-N- [p- (dimethylamino) phenylthiocarbamoyl] deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (1 mL). Cooled to ° C. Thereto was added p- (dimethylamino) phenyl isothiocyanate (43 mg, 0.128 × 2 mmol), and the mixture was returned to room temperature and stirred for 4 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 46 mg, 0.081 mmol, 63%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.40 (1H, s), 8.02 (1H, d, J = 6.6 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.14 ( 2H, d, J = 8.3 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 6.68 (2H, d, J = 8.8 Hz), 4.84-4.79 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.61 (3H, s), 3.11 (1H, dd, J = 12.8, 5.5 Hz), 2.87 (6H, s), 2.13 -2.09 (2H, m), 2.03-1.98 (1H, m).
ESI-MS m / z: 570 ([M + H] + )
実施例１５８
4-クロロ-N-(4-ニトロベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、4-ニトロベンゾイルクロリド (24 mg, 0.128 × 1 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 36 mg, 0.098 mmol,77%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.31 (1H, d, J = 8.3 Hz), 8.07-8.02 (2H, m), 7.95 (2H, d, J = 8.5 Hz), 7.64 (1H, s), 7.41 (1H, d, J = 10.7 Hz), 6.95 (1H, d, J = 10.7Hz), 4.80-4.74 (1H, m), 4.05 (3H, s), 4.02 (3H, s), 3.99 (3H, s), 3.72 (3H, s), 3.32 (1H, dd, J = 13.5, 5.5 Hz), 2.45-2.36 (1H, m), 2.22-2.19 (1H, m), 2.11-2.04 (1H, m).
ESI-MS m/z: 541 ([M+H]+) Example 158
Synthesis of 4-chloro-N- (4-nitrobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 4-nitrobenzoyl chloride (24 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 36 mg, 0.098 mmol, 77%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.31 (1H, d, J = 8.3 Hz), 8.07-8.02 (2H, m), 7.95 (2H, d, J = 8.5 Hz), 7.64 ( 1H, s), 7.41 (1H, d, J = 10.7 Hz), 6.95 (1H, d, J = 10.7 Hz), 4.80-4.74 (1H, m), 4.05 (3H, s), 4.02 (3H, s ), 3.99 (3H, s), 3.72 (3H, s), 3.32 (1H, dd, J = 13.5, 5.5 Hz), 2.45-2.36 (1H, m), 2.22-2.19 (1H, m), 2.11- 2.04 (1H, m).
ESI-MS m / z: 541 ([M + H] + )
実施例１５９
4-クロロ-N-(2-ナフトイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、2-ナフトイルクロリド (24 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 42 mg, 0.077 mmol, 60%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.26 (1H, d, J = 7.1 Hz), 8.53 (1H, s), 8.02-7.97 (4H, m), 7.65-7.59 (2H, m), 7.26 (1H, s), 7.19 (1H, d, J = 10.5 Hz), 7.06 (1H, d, J = 10.7 Hz), 4.58-4.52 (1H, m), 3.95 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.63 (3H, s), 3.19 (1H, dd, J = 11.5, 4.6 Hz), 2.19-2.12 (3H, m).
ESI-MS m/z: 546 ([M+H]+) Example 159
Synthesis of 4-chloro-N- (2-naphthoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 2-naphthoyl chloride (24 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 42 mg, 0.077 mmol, 60%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.26 (1H, d, J = 7.1 Hz), 8.53 (1H, s), 8.02-7.97 (4H, m), 7.65-7.59 (2H , m), 7.26 (1H, s), 7.19 (1H, d, J = 10.5 Hz), 7.06 (1H, d, J = 10.7 Hz), 4.58-4.52 (1H, m), 3.95 (3H, s) , 3.90 (3H, s), 3.89 (3H, s), 3.63 (3H, s), 3.19 (1H, dd, J = 11.5, 4.6 Hz), 2.19-2.12 (3H, m).
ESI-MS m / z: 546 ([M + H] + )
実施例１６０
4-クロロ-N-(2-ニトロベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、2-ニトロ安息香酸 (26 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して終夜撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 23 mg, 0.043 mmol, 33%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.04 (1H, d, J = 7.8 Hz), 7.71-7.63 (3H, m), 7.58-7.56 (1H, m), 7.35 (1H, d, J = 10.2 Hz), 6.88 (1H, d, J = 10.7 Hz), 6.86 (1H, br.s), 4.85-4.79 (1H, m), 4.02 (3H, s), 4.02 (3H, s), 4.02 (3H, s), 3.66 (3H, s), 3.31 (1H, dd, J = 13.7, 5.4 Hz), 2.44-2.34 (1H, m), 2.22-2.18 (1H, m), 1.95-1.81 (1H, m).
ESI-MS m/z: 541 ([M+H]+) Example 160
Synthesis of 4-chloro-N- (2-nitrobenzoyl) deacetylcolchicine Dissolve 2-nitrobenzoic acid (26 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere. Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred all night. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 23 mg, 0.043 mmol, 33%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.04 (1H, d, J = 7.8 Hz), 7.71-7.63 (3H, m), 7.58-7.56 (1H, m), 7.35 (1H, d , J = 10.2 Hz), 6.88 (1H, d, J = 10.7 Hz), 6.86 (1H, br.s), 4.85-4.79 (1H, m), 4.02 (3H, s), 4.02 (3H, s) , 4.02 (3H, s), 3.66 (3H, s), 3.31 (1H, dd, J = 13.7, 5.4 Hz), 2.44-2.34 (1H, m), 2.22-2.18 (1H, m), 1.95-1.81 (1H, m).
ESI-MS m / z: 541 ([M + H] + )
実施例１６１
4-クロロ-N-(4-メチルベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、p-トルイル酸 (21 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して終夜撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 28 mg, 0.055 mmol, 43%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.70 (2H, d, J = 8.1 Hz), 7.62 (1H, s), 7.35 (1H, d, J = 10.7 Hz), 7.19 (2H, d, J = 8.1 Hz), 6.90 (1H, br.s), 6.87 (1H, d, J = 10.7 Hz), 4.80-4.74 (1H, m), 4.01 (3H, s), 4.00 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.31 (1H, dd, J = 13.4, 5.1 Hz), 2.41-2.30 (1H, m), 2.37 (3H, s), 2.24-2.20 (1H, m), 1.96-1.93 (1H, m).
ESI-MS m/z: 510 ([M+H]+) Example 161
Synthesis of 4-chloro-N- (4-methylbenzoyl) deacetylcolchicine Under argon atmosphere, p-toluic acid (21 mg, 0.128 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL). Cooled to ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred all night. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 28 mg, 0.055 mmol, 43%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.70 (2H, d, J = 8.1 Hz), 7.62 (1H, s), 7.35 (1H, d, J = 10.7 Hz), 7.19 ( 2H, d, J = 8.1 Hz), 6.90 (1H, br.s), 6.87 (1H, d, J = 10.7 Hz), 4.80-4.74 (1H, m), 4.01 (3H, s), 4.00 (3H , s), 3.98 (3H, s), 3.70 (3H, s), 3.31 (1H, dd, J = 13.4, 5.1 Hz), 2.41-2.30 (1H, m), 2.37 (3H, s), 2.24- 2.20 (1H, m), 1.96-1.93 (1H, m).
ESI-MS m / z: 510 ([M + H] + )
実施例１６２
4-クロロ-N-(4-フェニルベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、4-フェニルベンゾイルクロリド (28 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 40 mg, 0.070 mmol, 55%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.12 (1H, d, J = 7.1 Hz), 7.99 (2H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 7.3 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.41 (1H, t, J = 7.2 Hz), 7.23 (1H, s), 7.18 (1H, d, J = 10.5 Hz), 7.06 (1H, d, J = 11.0 Hz), 4.55-4.49 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.62 (3H, s), 3.18 (1H, dd, J = 12.0, 4.9 Hz), 2.23-2.06 (3H, m).
ESI-MS m/z: 572 ([M+H]+) Example 162
Synthesis of 4-chloro-N- (4-phenylbenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 4-phenyl benzoyl chloride (28 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 40 mg, 0.070 mmol, 55%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.12 (1H, d, J = 7.1 Hz), 7.99 (2H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 7.3 Hz), 7.50 (2H, t, J = 7.6 Hz), 7.41 (1H, t, J = 7.2 Hz), 7.23 (1H, s), 7.18 (1H, d, J = 10.5 Hz), 7.06 (1H, d, J = 11.0 Hz), 4.55-4.49 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.62 (3H, s), 3.18 (1H, dd, J = 12.0, 4.9 Hz), 2.23-2.06 (3H, m).
ESI-MS m / z: 572 ([M + H] + )
実施例１６３
4-クロロ-N-(3,5-ジニトロベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3,5-ジニトロベンゾイルクロリド (30 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 47 mg, 0.080 mmol, 63%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 9.91 (1H, d, J = 5.9 Hz), 8.95 (1H, t, J = 1.8 Hz), 8.63 (2H, s), 7.94 (1H, s), 7.54 (1H, d, J = 10.7 Hz), 7.14 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.12 (3H, s), 4.03 (3H, s), 3.98 (3H, s), 3.67 (3H, s), 3.37 (1H, dd, J = 12.2, 2.9 Hz), 2.49-2.42 (2H, m), 2.28-2.19 (1H, m).
ESI-MS m/z: 586 ([M+H]+) Example 163
Synthesis of 4-chloro-N- (3,5-dinitrobenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere and cool to 0 ° C. did. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3,5-dinitrobenzoyl chloride (30 mg, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 47 mg, 0.080 mmol, 63%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 9.91 (1H, d, J = 5.9 Hz), 8.95 (1H, t, J = 1.8 Hz), 8.63 (2H, s), 7.94 (1H, s), 7.54 (1H, d, J = 10.7 Hz), 7.14 (1H, d, J = 11.0 Hz), 4.78-4.72 (1H, m), 4.12 (3H, s), 4.03 (3H, s), 3.98 (3H, s), 3.67 (3H, s), 3.37 (1H, dd, J = 12.2, 2.9 Hz), 2.49-2.42 (2H, m), 2.28-2.19 (1H, m).
ESI-MS m / z: 586 ([M + H] + )
実施例１６４
4-クロロ-N-(3,5-ジメチルベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3,5-ジメチルベンゾイルクロリド (19 μl, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 35mg, 0.067 mmol, 52%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.64 (1H, s), 7.39 (2H, s), 7.36 (1H, d, J = 11.0 Hz), 7.12 (1H, s), 6.88 (1H, d, J = 11.0 Hz), 6.78 (1H, d, J = 6.8 Hz), 4.80-4.74 (1H, m), 4.01 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.69 (3H, s), 3,32 (1H, dd, J = 13.2, 5.1 Hz), 2.37-2.32 (1H, m), 2.32 (6H, s), 2.26-2.18 (1H, m), 1.98-1.93 (1H, m).
ESI-MS m/z: 524 ([M+H]+) Example 164
Synthesis of 4-chloro-N- (3,5-dimethylbenzoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. did. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3,5-dimethylbenzoyl chloride (19 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 35 mg, 0.067 mmol, 52%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.64 (1H, s), 7.39 (2H, s), 7.36 (1H, d, J = 11.0 Hz), 7.12 (1H, s), 6.88 ( 1H, d, J = 11.0 Hz), 6.78 (1H, d, J = 6.8 Hz), 4.80-4.74 (1H, m), 4.01 (3H, s), 4.01 (3H, s), 3.98 (3H, s ), 3.69 (3H, s), 3,32 (1H, dd, J = 13.2, 5.1 Hz), 2.37-2.32 (1H, m), 2.32 (6H, s), 2.26-2.18 (1H, m), 1.98-1.93 (1H, m).
ESI-MS m / z: 524 ([M + H] + )
実施例１６５
4-クロロ-N-(3-ニトロベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3-ニトロベンゾイルクロリド (27 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 59 mg, 0.109 mmol,85%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.90 (1H, d, J = 6.1 Hz), 8.57 (1H, s), 8.16 (1H, d, J = 8.1 Hz), 7.96 (1H, d, J = 7.6 Hz), 7.89 (1H, s), 7.47 (1H, d, J = 10.7 Hz), 7.34 (1H, t, J = 7.9 Hz), 7.03 (1H, d, J = 11.0 Hz), 4.83-4.77 (1H, m), 4.07 (3H, s), 4.02 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.33 (1H, dd, J = 13.4, 5.6 Hz), 2.47-2.38 (1H, m), 2.34-2.29 (1H, m), 2.27-2.17 (1H, m).
ESI-MS m/z: 541 ([M+H]+) Example 165
Synthesis of 4-chloro-N- (3-nitrobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 3-nitrobenzoyl chloride (27 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 59 mg, 0.109 mmol, 85%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.90 (1H, d, J = 6.1 Hz), 8.57 (1H, s), 8.16 (1H, d, J = 8.1 Hz), 7.96 (1H, d, J = 7.6 Hz), 7.89 (1H, s), 7.47 (1H, d, J = 10.7 Hz), 7.34 (1H, t, J = 7.9 Hz), 7.03 (1H, d, J = 11.0 Hz) , 4.83-4.77 (1H, m), 4.07 (3H, s), 4.02 (3H, s), 3.98 (3H, s), 3.70 (3H, s), 3.33 (1H, dd, J = 13.4, 5.6 Hz ), 2.47-2.38 (1H, m), 2.34-2.29 (1H, m), 2.27-2.17 (1H, m).
ESI-MS m / z: 541 ([M + H] + )
実施例１６６
4-クロロ-N-(3,5-ジメトキシベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3,5-ジメトキシベンゾイルクロリド (26 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 47 mg, 0.085mmol, 66%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.65 (1H, s), 7.38 (1H, d, J = 10.7 Hz), 7.01 (1H, d, J = 7.1 Hz), 6.93 (2H, s), 6.90 (1H, d, J = 10.7 Hz), 6.56 (1H, s), 4.77-4.71 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.79 (6H, s), 3.69 (3H, s), 3.31 (1H, dd, J = 13.3, 5.2 Hz), 2.40-2.30 (1H, m), 2.25-2.17 (1H, m), 2.02-1.95 (1H, m).
ESI-MS m/z: 556 ([M+H]+) Example 166
Synthesis of 4-chloro-N- (3,5-dimethoxybenzoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. did. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3,5-dimethoxybenzoyl chloride (26 mg, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 47 mg, 0.085 mmol, 66%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.65 (1H, s), 7.38 (1H, d, J = 10.7 Hz), 7.01 (1H, d, J = 7.1 Hz), 6.93 (2H, s), 6.90 (1H, d, J = 10.7 Hz), 6.56 (1H, s), 4.77-4.71 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 3.98 (3H, s ), 3.79 (6H, s), 3.69 (3H, s), 3.31 (1H, dd, J = 13.3, 5.2 Hz), 2.40-2.30 (1H, m), 2.25-2.17 (1H, m), 2.02- 1.95 (1H, m).
ESI-MS m / z: 556 ([M + H] + )
実施例１６７
4-クロロ-N-(2,4-ジメトキシベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した. そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、2,4-ジメトキシベンゾイルクロリド (26 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 33 mg, 0.059mmol, 46%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.29 (1H, d, J = 6.3 Hz), 7.98 (1H, d, J = 8.8 Hz), 7.64 (1H, s), 7.34 (1H, d, J = 10.7 Hz), 6.85 (1H, d, J = 10.7 Hz), 6.54 (1H, dd, J = 8.7, 2.1 Hz), 6.51 (1H, d, J = 2.0 Hz), 4.78-4.71 (1H, m), 4.02 (3H, s), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.85 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.2, 5.1 Hz), 2.40-2.31 (1H, m), 2.26-2.18 (1H, m), 1.93-1.84 (1H, m).
ESI-MS m/z: 556 ([M+H]+) Example 167
Synthesis of 4-chloro-N- (2,4-dimethoxybenzoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 2,4-dimethoxybenzoyl chloride (26 mg, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 33 mg, 0.059 mmol, 46%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.29 (1H, d, J = 6.3 Hz), 7.98 (1H, d, J = 8.8 Hz), 7.64 (1H, s), 7.34 ( 1H, d, J = 10.7 Hz), 6.85 (1H, d, J = 10.7 Hz), 6.54 (1H, dd, J = 8.7, 2.1 Hz), 6.51 (1H, d, J = 2.0 Hz), 4.78- 4.71 (1H, m), 4.02 (3H, s), 4.00 (3H, s), 4.00 (3H, s), 3.97 (3H, s), 3.85 (3H, s), 3.70 (3H, s), 3.30 (1H, dd, J = 13.2, 5.1 Hz), 2.40-2.31 (1H, m), 2.26-2.18 (1H, m), 1.93-1.84 (1H, m).
ESI-MS m / z: 556 ([M + H] + )
実施例１６８
4-クロロ-N-(2,4,6-トリメチルベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、2,4,6-トリメチルベンゾイルクロリド (21 μl, 0.128 × 1 mmol) を加え、室温に戻して90分撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 28 mg, 0.052 mmol, 41%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.50 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.86-6.81 (3H, m), 6.09 (1H, d, J = 7.8 Hz), 4.84-4.78 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 4.01 (3H, s), 3.69 (3H, s), 3.29 (1H ,dd, J = 13.2, 4.4 Hz), 2.33-2.16 (2H, m), 2.26 (9H, s), 1.80-1.73 (1H, m).
ESI-MS m/z: 538 ([M+H]+) Example 168
Synthesis of 4-chloro-N- (2,4,6-trimethylbenzoyl) deacetylcolchicine Dissolve 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) in dichloromethane (2 mL) under an argon atmosphere at 0 ° C. Cooled to. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 2,4,6-trimethylbenzoyl chloride (21 μl, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 90 minutes. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 28 mg, 0.052 mmol, 41%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.50 (1H, s), 7.29 (1H, d, J = 10.7 Hz), 6.86-6.81 (3H, m), 6.09 (1H, d, J = 7.8 Hz), 4.84-4.78 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 4.01 (3H, s), 3.69 (3H, s), 3.29 (1H, dd, J = 13.2, 4.4 Hz), 2.33-2.16 (2H, m), 2.26 (9H, s), 1.80-1.73 (1H, m).
ESI-MS m / z: 538 ([M + H] + )
実施例１６９
4-クロロ-N-(4-シアノベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、4-シアノベンゾイルクロリド (21 mg, 0.128 × 1 mmol) を加え、室温に戻して1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 51 mg, 0.098 mmol,77%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.45 (1H, d, J = 5.9 Hz), 7.93 (2H, d, J = 8.3 Hz), 7.71 (1H, s), 7.52 (2H, d, J = 8.1 Hz), 7.44 (1H, d, J = 11.0 Hz), 6.98 (1H, d, J = 11.0 Hz), 4.81-4.75 (1H, m), 4.06 (3H, s), 4.02 (3H, s), 3.99 (3H, s), 3.72 (3H, s), 3.31 (1H, dd, J = 13.2, 5.6 Hz), 2.44-2.35 (1H, m), 2.24-2.17 (1H, m), 2.16-2.06 (1H, m).
ESI-MS m/z: 521 ([M+H]+) Example 169
Synthesis of 4-chloro-N- (4-cyanobenzoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 microliters, 0.128 * 1.1 mmol) and 4-cyano benzoyl chloride (21 mg, 0.128 * 1 mmol) were added there, and it returned to room temperature, and stirred for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 51 mg, 0.098 mmol, 77%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.45 (1H, d, J = 5.9 Hz), 7.93 (2H, d, J = 8.3 Hz), 7.71 (1H, s), 7.52 (2H, d, J = 8.1 Hz), 7.44 (1H, d, J = 11.0 Hz), 6.98 (1H, d, J = 11.0 Hz), 4.81-4.75 (1H, m), 4.06 (3H, s), 4.02 ( 3H, s), 3.99 (3H, s), 3.72 (3H, s), 3.31 (1H, dd, J = 13.2, 5.6 Hz), 2.44-2.35 (1H, m), 2.24-2.17 (1H, m) , 2.16-2.06 (1H, m).
ESI-MS m / z: 521 ([M + H] + )
実施例１７０
4-クロロ-N-(3-ヒドロキシ-3-メチルブチリル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、β-ヒドロキシイソ吉草酸 (16 μl, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 33 mg, 0.067 mmol, 52%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.17 (1H, s), 7.13 (1H, d, J = 10.5 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.64 (1H, s), 4.29-4.23 (1H, m),3.92 (3H, s), 3.88 (3H, s), 3,88 (3H, s), 3.55 (3H, s), 3.11 (1H, dd, J = 13.2,4.9 Hz), 2.26 (2H, s), 2.15-2.07 (1H, m), 2.01-1.92 (1H, m), 1.89-1.81 (1H, m), 1.12 (3H, s), 1.11 (3H, s).
ESI-MS m/z: 492 ([M+H]+) Example 170
Synthesis of 4-chloro-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine Under argon atmosphere, β-hydroxyisovaleric acid (16 μl, 0.128 × 1.2 mmol) was added to N, N-dimethylformamide (1 mL). And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 33 mg, 0.067 mmol, 52%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.17 (1H, s), 7.13 (1H, d, J = 10.5 Hz), 7.03 ( 1H, d, J = 10.7 Hz), 4.64 (1H, s), 4.29-4.23 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3,88 (3H, s), 3.55 (3H, s), 3.11 (1H, dd, J = 13.2,4.9 Hz), 2.26 (2H, s), 2.15-2.07 (1H, m), 2.01-1.92 (1H, m), 1.89-1.81 (1H m), 1.12 (3H, s), 1.11 (3H, s).
ESI-MS m / z: 492 ([M + H] + )
実施例１７１
4-クロロ-N-[4-(ベンジルオキシ)ブチリル]デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ベンジルオキシ酪酸 (27 μl, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 36 mg, 0.063 mmol, 50%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.61 (1H, d, J = 7.1 Hz), 7.34-7.30 (4H, m), 7.28-7.24 (1H, m), 7.13 (1H, d, J = 10.5 Hz), 7.12 (1H, s), 7.03 (1H, d, J = 11.0Hz), 4.46 (1H, d, J = 12.0 Hz), 4.41 (1H, d, J = 12.0 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3,37 (2H, t, J = 6.5 Hz), 3.10 (1H, dd, J = 13.4, 5.1 Hz), 2.23 (2H, t, J = 6.8 Hz), 2.14-2.06 (1H, m), 1.98-1.88 (1H, m), 1.86-1.78 (1H, m), 1.75-1.68 (2H, m).
ESI-MS m/z: 568 ([M+H]+) Example 171
Synthesis of 4-chloro-N- [4- (benzyloxy) butyryl] deacetylcolchicine Under argon atmosphere, 4-benzyloxybutyric acid (27 μl, 0.128 × 1.2 mmol) was added to N, N-dimethylformamide (1 mL). Dissolved and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 36 mg, 0.063 mmol, 50%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.61 (1H, d, J = 7.1 Hz), 7.34-7.30 (4H, m), 7.28-7.24 (1H, m), 7.13 (1H , d, J = 10.5 Hz), 7.12 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 4.46 (1H, d, J = 12.0 Hz), 4.41 (1H, d, J = 12.0 Hz) ), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3,37 (2H, t, J = 6.5 Hz), 3.10 (1H, dd, J = 13.4, 5.1 Hz), 2.23 (2H, t, J = 6.8 Hz), 2.14-2.06 (1H, m), 1.98-1.88 (1H, m), 1.86-1.78 (1H, m), 1.75-1.68 (2H, m).
ESI-MS m / z: 568 ([M + H] + )
実施例１７２
4-クロロ-N-(2-シアノベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、2-シアノ安息香酸 (23 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 41 mg, 0.079 mmol, 62%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.96 (1H, d, J = 7.8 Hz), 7.72 (1H, d, J = 6.6 Hz), 7.64-7.53 (3H, m), 7.46 (1H, br.s), 7.35 (1H, d, J = 10.5 Hz), 6.89 (1H, d, J = 11.0 Hz), 4.86-4.80 (1H, m), 4.02 (3H, s), 4.01 (3H, s), 4.00 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.5, 5.5 Hz), 2.47-2.38 (1H, m), 2.26-2.18 (1H, m), 2.03-1.95 (1H, m)．
ESI-MS m/z: 521 ([M+H]+) Example 172
Synthesis of 4-chloro-N- (2-cyanobenzoyl) deacetylcolchicine Dissolve 2-cyanobenzoic acid (23 mg, 0.128 × 1.2 mmol) in N, N-dimethylformamide (1 mL) under an argon atmosphere. Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (tan solid, 41 mg, 0.079 mmol, 62%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.96 (1H, d, J = 7.8 Hz), 7.72 (1H, d, J = 6.6 Hz), 7.64-7.53 (3H, m), 7.46 ( 1H, br.s), 7.35 (1H, d, J = 10.5 Hz), 6.89 (1H, d, J = 11.0 Hz), 4.86-4.80 (1H, m), 4.02 (3H, s), 4.01 (3H , s), 4.00 (3H, s), 3.70 (3H, s), 3.32 (1H, dd, J = 13.5, 5.5 Hz), 2.47-2.38 (1H, m), 2.26-2.18 (1H, m), 2.03-1.95 (1H, m).
ESI-MS m / z: 521 ([M + H] + )
実施例１７３
4-クロロ-N-(3-シアノベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (19 μl, 0.128 × 1.1 mmol)、3-シアノベンゾイルクロリド (21 mg, 0.128 × 1 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 44 mg, 0.084 mmol, 66%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.33 (1H, br.s), 8.14 (1H, s), 7.98 (1H, d, J = 8.1 Hz), 7.67 (2H, s), 7.66-7.65 (2H, m), 7.42-7.40 (1H, m), 7.41 (1H, d, J = 11.0 Hz), 6.95 (1H, d, J = 10.7 Hz), 4.81-4.75 (1H, m), 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.71 (3H, s), 3.33 (1H, dd, J = 12.7, 5.4 Hz), 2.41-2.35 (1H, m), 2.26-2.15 (2H, m)．
ESI-MS m/z: 521 ([M+H]+) Example 173
Synthesis of 4-chloro-N- (3-cyanobenzoyl) deacetylcolchicine In an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (19 μl, 0.128 × 1.1 mmol) and 3-cyanobenzoyl chloride (21 mg, 0.128 × 1 mmol) were added thereto, and the mixture was returned to room temperature and stirred for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 44 mg, 0.084 mmol, 66%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.33 (1H, br.s), 8.14 (1H, s), 7.98 (1H, d, J = 8.1 Hz), 7.67 (2H, s), 7.66-7.65 (2H, m), 7.42-7.40 (1H, m), 7.41 (1H, d, J = 11.0 Hz), 6.95 (1H, d, J = 10.7 Hz), 4.81-4.75 (1H, m) , 4.03 (3H, s), 4.01 (3H, s), 3.98 (3H, s), 3.71 (3H, s), 3.33 (1H, dd, J = 12.7, 5.4 Hz), 2.41-2.35 (1H, m ), 2.26-2.15 (2H, m).
ESI-MS m / z: 521 ([M + H] + )
実施例１７４
4-クロロ-N-(2-エチル-2-ヒドロキシブチリル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、2-エチル-2-ヒドロキシ酪酸 (20 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 38 mg, 0.075 mmol, 59%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.32 (1H ,d, J = 7.8 Hz), 7.22 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 11.0 Hz), 4.97 (1H, s), 4.33-4.27 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.55 (3H, s), 3.10 (1H, dd, J = 12.9, 5.4 Hz), 2.20-2.06 (2H, m), 1.90-1.82 (1H, m), 1.67-1.54 (2H, m), 1.47-1.38 (2H, m), 0.76-0.69 (6H, m).
ESI-MS m/z: 506 ([M+H]+) Example 174
Synthesis of 4-chloro-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine Under argon atmosphere, 2-ethyl-2-hydroxybutyric acid (20 mg, 0.128 × 1.2 mmol) Dissolved in (1 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 38 mg, 0.075 mmol, 59%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.32 (1H, d, J = 7.8 Hz), 7.22 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.01 ( 1H, d, J = 11.0 Hz), 4.97 (1H, s), 4.33-4.27 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.55 (3H , s), 3.10 (1H, dd, J = 12.9, 5.4 Hz), 2.20-2.06 (2H, m), 1.90-1.82 (1H, m), 1.67-1.54 (2H, m), 1.47-1.38 (2H , m), 0.76-0.69 (6H, m).
ESI-MS m / z: 506 ([M + H] + )
実施例１７５
4-クロロ-N-(1-ヒドロキシシクロプロパンカルボニル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、1-ヒドロキシ-1-シクロプロパンカルボン酸 (16 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 28 mg, 0.059 mmol,50%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.66 (1H, d, J = 7.8 Hz), 7.26 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.7 Hz), 6.43 (1H, s), 4.35-4.28 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.51 (3H, s), 3.11 (1H, dd, J = 13.5, 5.5 Hz), 2.25-2.17 (1H, m), 2.14-2.06 (1H, m), 1.94-1.85 (1H, m), 0.96-0.79 (4H, m).
ESI-MS m/z: 476 ([M+H]+) Example 175
Synthesis of 4-chloro-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine 1-hydroxy-1-cyclopropanecarboxylic acid (16 mg, 0.128 × 1.2 mmol) was converted to N, N-dimethylformamide ( 1 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 28 mg, 0.059 mmol, 50%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.66 (1H, d, J = 7.8 Hz), 7.26 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 6.43 (1H, s), 4.35-4.28 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.51 (3H , s), 3.11 (1H, dd, J = 13.5, 5.5 Hz), 2.25-2.17 (1H, m), 2.14-2.06 (1H, m), 1.94-1.85 (1H, m), 0.96-0.79 (4H , m).
ESI-MS m / z: 476 ([M + H] + )
実施例１７６
4-クロロ-N-(3-フェニルベンゾイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、3-ビフェニルカルボン酸 (30 mg, 0.128 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (29 mg, 0.128 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (21 mg, 0.128 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) を加え、室温に戻して3時間撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 26 mg, 0.045 mmol, 36%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.18 (1H, d, J = 7.3 Hz), 8.18 (1H, t, J = 1.8 Hz), 7.86 (1H, dd, J = 7.8, 1.7 Hz), 7.75-7.73 (1H, m), 7.58 (1H, t, J = 7.7 Hz), 7.53-7.49 (1H, m), 7.44-7.39 (1H, m), 7.24 (1H, s), 7.19 (1H, d, J = 10.5 Hz), 7.06 (1H, d, J = 11.2 Hz), 4.56-4.50 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.89(3H, s), 3.62 (3H, s), 3.18 (1H, dd, J = 12.6, 4.0 Hz), 2.23-2.08 (3H, m).
ESI-MS m/z: 572 ([M+H]+) Example 176
Synthesis of 4-chloro-N- (3-phenylbenzoyl) deacetylcolchicine Under argon atmosphere, 3-biphenylcarboxylic acid (30 mg, 0.128 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL). Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.128 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (21 mg, 0.128 × 1.2 mmol) were added thereto, Stir at 0 ° C. for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mmol) was added there, and it returned to room temperature, and stirred for 3 hours. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 26 mg, 0.045 mmol, 36%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.18 (1H, d, J = 7.3 Hz), 8.18 (1H, t, J = 1.8 Hz), 7.86 (1H, dd, J = 7.8 , 1.7 Hz), 7.75-7.73 (1H, m), 7.58 (1H, t, J = 7.7 Hz), 7.53-7.49 (1H, m), 7.44-7.39 (1H, m), 7.24 (1H, s) , 7.19 (1H, d, J = 10.5 Hz), 7.06 (1H, d, J = 11.2 Hz), 4.56-4.50 (1H, m), 3.94 (3H, s), 3.90 (3H, s), 3.89 ( 3H, s), 3.62 (3H, s), 3.18 (1H, dd, J = 12.6, 4.0 Hz), 2.23-2.08 (3H, m).
ESI-MS m / z: 572 ([M + H] + )
実施例１７７
4-クロロ-N-(4-ヒドロキシブチリル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロ-N-(4-ベンジルオキシブチリル)デアセチルコルヒチン (41 mg, 0.072 mmol) をジクロロメタン (500 μl) に溶解し、-78℃に冷却した。そこへボロントリブロミド (1M ジクロロメタン溶液, 72 μl, 0.072 × 1 mmol) を加え、-78℃で30分撹拌した。反応液に飽和重曹水を加えクエンチし、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 14 mg, 0.029 mmol, 41%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.59 (1H, d, J = 7.1 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.46 (1H, t, J = 5.1 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.34-3.30 (2H, m), 3.10 (1H, dd, J = 13.5, 5.5 Hz), 2.17 (2H, t, J = 7.6 Hz), 2.13-2.06 (1H, m), 1.99-1.90 (1H, m), 1.87-1.79 (1H, m), 1.62-1.54 (2H, m).
ESI-MS m/z: 478 ([M+H]+) Example 177
Synthesis of 4-chloro-N- (4-hydroxybutyryl) deacetylcolchicine Under argon atmosphere, 4-chloro-N- (4-benzyloxybutyryl) deacetylcolchicine (41 mg, 0.072 mmol) was added to dichloromethane (500 μl) and cooled to -78 ° C. Boron tribromide (1M dichloromethane solution, 72 μl, 0.072 × 1 mmol) was added thereto, and the mixture was stirred at −78 ° C. for 30 minutes. The reaction solution was quenched by adding saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 14 mg, 0.029 mmol, 41%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, d, J = 7.1 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.46 (1H, t, J = 5.1 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s ), 3.53 (3H, s), 3.34-3.30 (2H, m), 3.10 (1H, dd, J = 13.5, 5.5 Hz), 2.17 (2H, t, J = 7.6 Hz), 2.13-2.06 (1H, m), 1.99-1.90 (1H, m), 1.87-1.79 (1H, m), 1.62-1.54 (2H, m).
ESI-MS m / z: 478 ([M + H] + )
実施例１７８
4-ブロモ-N-(t-ブチルオキシカルボニル)コルヒチンの合成
　4-ブロモコルヒチン(363 mg, 0.76 mmol)をアセトニトリル(18 mL)に溶解した。そこへジメチルアミノピリジン(93 mg, 0.76×1 mmol)、トリエチルアミン(0.318 mL, 0.76×3 mmol)、二炭酸-ジ-t-ブチル(0.873 mL, 0.76×5 mmol)を加えて7時間加熱還流した。反応後、クエン酸水溶液を加えた。クロロホルム抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄土色固体, 338 mg, 76.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.21 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.81 (1H, dd, J = 12.2, 5.9 Hz), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.56 (3H, s), 3.20 (1H, dd, J = 13.4, 5.1 Hz), 2.33-2.27 (1H, m), 2.25 (3H, s), 1.91-1.81 (1H, m), 1.49 (9H, s), 1.44-1.38 (1H, m).
ESI-MS m/z: 578 [M+H]+, 580 [M+2+H]+. Example 178
Synthesis of 4-bromo-N- (t-butyloxycarbonyl) colchicine 4-Bromocolchicine (363 mg, 0.76 mmol) was dissolved in acetonitrile (18 mL). Dimethylaminopyridine (93 mg, 0.76 × 1 mmol), triethylamine (0.318 mL, 0.76 × 3 mmol), dicarbonate-di-t-butyl (0.873 mL, 0.76 × 5 mmol) were added thereto, and the mixture was heated under reflux for 7 hours. did. After the reaction, an aqueous citric acid solution was added. Extracted with chloroform. Washed with saturated brine. Dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (ocher solid, 338 mg, 76.9%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.21 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.81 ( 1H, dd, J = 12.2, 5.9 Hz), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.56 (3H, s), 3.20 (1H, dd, J = 13.4, 5.1 Hz), 2.33-2.27 (1H, m), 2.25 (3H, s), 1.91-1.81 (1H, m), 1.49 (9H, s), 1.44-1.38 (1H, m).
ESI-MS m / z: 578 [M + H] + , 580 [M + 2 + H] + .
実施例１７９
4-ブロモ-N-(t-ブチルオキシカルボニル)デアセチルコルヒチンの合成
　4-ブロモ-N-(t-ブチルオキシカルボニル)コルヒチン(324 mg, 0.56 mmol)をメタノール(6.5 mL)に溶解した。そこへ1 mol/L水酸化ナトリウム水溶液(1.12 mL, 0.56×2 mmol)を加えて室温で5時間攪拌した。飽和食塩水を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 280 mg, 93.2%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.77 (1H, d, J = 7.8 Hz), 7.20 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.00-3.94 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.55 (3H, s), 3.08 (1H, dd, J = 13.2, 5.1 Hz), 2.18-2.10 (1H, m), 1.97-1.87 (1H, m), 1.83-1.74 (1H, m), 1.33 (9H, s).
ESI-MS m/z: 536 [M+H]+ , 538 [M+2+H]+. Example 179
Synthesis of 4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine 4-Bromo-N- (t-butyloxycarbonyl) colchicine (324 mg, 0.56 mmol) was dissolved in methanol (6.5 mL). 1 mol / L sodium hydroxide aqueous solution (1.12 mL, 0.56 * 2 mmol) was added there, and it stirred at room temperature for 5 hours. Saturated saline was added and the mixture was extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 280 mg, 93.2%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.77 (1H, d, J = 7.8 Hz), 7.20 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.03 ( 1H, d, J = 10.7 Hz), 4.00-3.94 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.55 (3H, s), 3.08 (1H , dd, J = 13.2, 5.1 Hz), 2.18-2.10 (1H, m), 1.97-1.87 (1H, m), 1.83-1.74 (1H, m), 1.33 (9H, s).
ESI-MS m / z: 536 [M + H] + , 538 [M + 2 + H] + .
実施例１８０
4-ブロモデアセチルコルヒチンの合成
　4-ブロモ-N-(t-ブチルオキシカルボニル)デアセチルコルヒチン(251 mg, 0.47 mmol)にトリフルオロ酢酸(0.663 mL, 0.47×19 mmol)を加え、室温で1時間攪拌した。1 mol/L水酸化ナトリウム水溶液でpH=14にし、クロロホルム:メタノール=5:1で抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 185 mg, 90.2%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.65 (1H, s), 7.06 (1H, d, J = 10.7 Hz), 6.99 (1H, d, J = 10.7 Hz), 3.88 (3H, s), 3.87 (3H, s), 3.85 (3H, s), 3.56 (3H, s), 3.37-3.34 (1H, m), 3.01 (1H, dd, J = 13.1, 4.8 Hz), 2.19-2.11 (1H, m), 2.09-1.93 (3H, m), 1.49-1.42 (1H, m).
ESI-MS m/z: 436 [M+H]+ , 438 [M+2+H]+. Example 180
Synthesis of 4-bromodeacetylcolchicine Add 4-trifluoro-N- (t-butyloxycarbonyl) deacetylcolchicine (251 mg, 0.47 mmol) to trifluoroacetic acid (0.663 mL, 0.47 × 19 mmol), and add 1 at room temperature. Stir for hours. The pH was adjusted to 14 with a 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with chloroform: methanol = 5: 1. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 185 mg, 90.2%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.65 (1H, s), 7.06 (1H, d, J = 10.7 Hz), 6.99 (1H, d, J = 10.7 Hz), 3.88 ( 3H, s), 3.87 (3H, s), 3.85 (3H, s), 3.56 (3H, s), 3.37-3.34 (1H, m), 3.01 (1H, dd, J = 13.1, 4.8 Hz), 2.19 -2.11 (1H, m), 2.09-1.93 (3H, m), 1.49-1.42 (1H, m).
ESI-MS m / z: 436 [M + H] + , 438 [M + 2 + H] + .
実施例１８１
4-ブロモ-N-プロピオニルデアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(37 mg, 0.084 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへプロピオニルクロリド(0.009 mL, 0.084×1.2 mmol)、トリエチルアミン(0.018 mL, 0.084×1.5 mmol)を加えて室温で2時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(白色固体, 40 mg, 96.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.55 (1H, d, J = 7.3 Hz), 7.14-7.11 (2H, m), 7.03 (1H, d, J = 11.0 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 13.8, 5.0 Hz), 2.23-2.12 (3H, m), 1.99-1.89 (1H, m), 1.84-1.77 (1H, m), 0.95 (3H, t, J = 7.6 Hz).
ESI-MS m/z: 492 [M+H]+ , 494 [M+2+H]+. Example 181
Synthesis of 4-bromo-N-propionyl deacetyl colchicine 4-Bromo deacetyl colchicine (37 mg, 0.084 mmol) was dissolved in dichloromethane (1.0 mL). Propionyl chloride (0.009 mL, 0.084 × 1.2 mmol) and triethylamine (0.018 mL, 0.084 × 1.5 mmol) were added thereto and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (white solid, 40 mg, 96.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.55 (1H, d, J = 7.3 Hz), 7.14-7.11 (2H, m), 7.03 (1H, d, J = 11.0 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 13.8, 5.0 Hz) , 2.23-2.12 (3H, m), 1.99-1.89 (1H, m), 1.84-1.77 (1H, m), 0.95 (3H, t, J = 7.6 Hz).
ESI-MS m / z: 492 [M + H] + , 494 [M + 2 + H] + .
実施例１８２
4-ブロモ-N-(シクロヘキサンカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(39 mg, 0.089 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへシクロヘキサンカルボニルクロリド(0.014 mL, 0.089×1.2 mmol)、トリエチルアミン(0.019 mL, 0.089×1.5 mmol)を加えて室温で2時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g,クロロホルム/メタノール)で精製し、標記の化合物(白色固体, 44 mg, 90.5%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.49 (1H, d, J = 7.6 Hz), 7.13-7.10 (2H, m), 7.02 (1H, d, J = 11.0 Hz), 4.21-4.14 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 13.4, 5.4 Hz), 2.23-2.14 (2H, m), 1.97-1.89 (1H, m), 1.87-1.78 (1H, m), 1.72-1.60 (5H, m), 1.30-1.19 (5H, m).
ESI-MS m/z: 546 [M+H]+ , 548 [M+2+H]+. Example 182
Synthesis of 4-bromo-N- (cyclohexanecarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (39 mg, 0.089 mmol) was dissolved in dichloromethane (1.0 mL). The cyclohexane carbonyl chloride (0.014 mL, 0.089 * 1.2 mmol) and the triethylamine (0.019 mL, 0.089 * 1.5 mmol) were added there, and it stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (white solid, 44 mg, 90.5%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.49 (1H, d, J = 7.6 Hz), 7.13-7.10 (2H, m), 7.02 (1H, d, J = 11.0 Hz), 4.21-4.14 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 13.4, 5.4 Hz) , 2.23-2.14 (2H, m), 1.97-1.89 (1H, m), 1.87-1.78 (1H, m), 1.72-1.60 (5H, m), 1.30-1.19 (5H, m).
ESI-MS m / z: 546 [M + H] + , 548 [M + 2 + H] + .
実施例１８３
4-ブロモ-N-ベンゾイルデアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(34 mg, 0.078 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへベンゾイルクロリド(0.011 mL, 0.078×1.2 mmol)、トリエチルアミン(0.018 mL, 0.078×1.5 mmol)を加えて室温で1時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 41 mg, 97.3%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.08 (1H, d, J = 7.3 Hz), 7.89-7.87 (2H, m), 7.58-7.55 (1H, m), 7.51-7.47 (2H, m), 7.20 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.50-4.44 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.3, 5.0 Hz), 2.30-2.21 (1H, m), 2.15-1.99 (2H, m).
ESI-MS m/z: 540 [M+H]+ , 542 [M+2+H]+. Example 183
Synthesis of 4-bromo-N-benzoyldeacetylcolchicine 4-Bromodeacetylcolchicine (34 mg, 0.078 mmol) was dissolved in dichloromethane (1.0 mL). Benzoyl chloride (0.011 mL, 0.078 × 1.2 mmol) and triethylamine (0.018 mL, 0.078 × 1.5 mmol) were added thereto and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 41 mg, 97.3%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.08 (1H, d, J = 7.3 Hz), 7.89-7.87 (2H, m), 7.58-7.55 (1H, m), 7.51-7.47 (2H, m), 7.20 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.50-4.44 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.3, 5.0 Hz), 2.30-2.21 (1H, m), 2.15-1.99 (2H, m).
ESI-MS m / z: 540 [M + H] + , 542 [M + 2 + H] + .
実施例１８４
4-ブロモ-N-(フェニルアセチル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(51 mg, 0.117 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへフェニルアセチルクロリド(0.019 mL, 0.117×1.2 mmol)、トリエチルアミン(0.024 mL, 0.117×1.5 mmol)を加えて室温で1時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 66 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.89 (1H, d, J = 7.3 Hz), 7.28-7.18 (5H, m), 7.16 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.5 Hz), 4.23-4.16 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.85 (3H, s), 3.49 (3H, s), 3.48 (2H, s), 3.12 (1H, dd, J = 13.4, 5.4 Hz), 2.25-2.16 (1H, m), 2.01-1.82 (2H, m).
ESI-MS m/z: 554 [M+H]+ , 556 [M+2+H]+. Example 184
Synthesis of 4-bromo-N- (phenylacetyl) deacetylcolchicine 4-Bromodeacetylcolchicine (51 mg, 0.117 mmol) was dissolved in dichloromethane (1.3 mL). Phenyl acetyl chloride (0.019 mL, 0.117 * 1.2 mmol) and triethylamine (0.024 mL, 0.117 * 1.5 mmol) were added there, and it stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 66 mg, quant.).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.89 (1H, d, J = 7.3 Hz), 7.28-7.18 (5H, m), 7.16 (1H, s), 7.11 (1H, d , J = 10.5 Hz), 7.02 (1H, d, J = 10.5 Hz), 4.23-4.16 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.85 (3H, s), 3.49 (3H, s), 3.48 (2H, s), 3.12 (1H, dd, J = 13.4, 5.4 Hz), 2.25-2.16 (1H, m), 2.01-1.82 (2H, m).
ESI-MS m / z: 554 [M + H] + , 556 [M + 2 + H] + .
実施例１８５
N-アリル-4-ブロモ-N-(t-ブチルオキシカルボニル)デアセチルコルヒチンの合成
　4-ブロモ-N-(t-ブチルオキシカルボニル)デアセチルコルヒチン(158 mg, 0.29 mmol)をN,N-ジメチルホルムアミド (3.2 mL)に溶解した。そこへ50%水素化ナトリウム(28 mg, 0.29×2 mmol)、アリルブロミド(0.074 mL, 0.29×3 mmol)を加えて、室温で一晩攪拌した。反応後、溶媒を留去し、水を加えてクロロホルム抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 75 mg, 44.9%)を得た。
ESI-MS m/z: 576 [M+H]+ , 578 [M+2+H]+. Example 185
Synthesis of N-allyl-4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine 4-Bromo-N- (t-butyloxycarbonyl) deacetylcolchicine (158 mg, 0.29 mmol) was converted to N, N- Dissolved in dimethylformamide (3.2 mL). 50% sodium hydride (28 mg, 0.29 × 2 mmol) and allyl bromide (0.074 mL, 0.29 × 3 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off, and water was added to extract with chloroform. Washed with saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 75 mg, 44.9%).
ESI-MS m / z: 576 [M + H] + , 578 [M + 2 + H] + .
実施例１８６
4-ブロモ- N-(トリフルオロアセチル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(40 mg, 0.09 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへトリフルオロ無水酢酸(0.015 mL, 0.09×1.2 mmol)、トリエチルアミン(0.019mL, 0.09×1.5 mmol)を加えて室温で2時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 41 mg, 85.6%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 10.17 (1H, d, J = 7.1 Hz), 7.17 (1H, d, J = 10.7 Hz), 7.07 (1H, d, J = 11.0 Hz), 7.03 (1H, s), 4.31-4.25 (1H, m), 3.91 (3H, s), 3.90 (3H, s), 3.86 (3H, s), 3.54 (3H, s), 3.18-3.13 (1H, m), 2.27-2.19 (1H, m), 2.09-2.03 (2H, m).
ESI-MS m/z: 532 [M+H]+ , 534 [M+2+H]+. Example 186
Synthesis of 4-bromo-N- (trifluoroacetyl) deacetylcolchicine 4-Bromodeacetylcolchicine (40 mg, 0.09 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic anhydride (0.015 mL, 0.09 × 1.2 mmol) and triethylamine (0.019 mL, 0.09 × 1.5 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 41 mg, 85.6%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 10.17 (1H, d, J = 7.1 Hz), 7.17 (1H, d, J = 10.7 Hz), 7.07 (1H, d, J = 11.0 Hz), 7.03 (1H, s), 4.31-4.25 (1H, m), 3.91 (3H, s), 3.90 (3H, s), 3.86 (3H, s), 3.54 (3H, s), 3.18-3.13 (1H, m), 2.27-2.19 (1H, m), 2.09-2.03 (2H, m).
ESI-MS m / z: 532 [M + H] + , 534 [M + 2 + H] + .
実施例１８７
N-(アセトキシアセチル)-4-ブロモデアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(100 mg, 0.23 mmol)をジクロロメタン(2.5 mL)に溶解した。そこへアセトキシアセチルクロリド(0.030 mL, 0.23×1.2 mmol)、トリエチルアミン(0.048 mL, 0.23×1.5 mmol)を加えて室温で2時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 145 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.80 (1H, d, J = 7.3 Hz), 7.14-7.10 (2H, m), 7.03 (1H, d, J = 10.7 Hz), 4.50 (2H, s), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.12 (1H, dd, J = 13.7, 4.4 Hz), 2.24-2.16 (1H, m), 2.05 (3H, s), 1.99-1.83 (2H, m).
ESI-MS m/z: 536 [M+H]+ , 538 [M+2+H]+. Example 187
Synthesis of N- (acetoxyacetyl) -4-bromodeacetylcolchicine 4-Bromodeacetylcolchicine (100 mg, 0.23 mmol) was dissolved in dichloromethane (2.5 mL). Acetoxyacetyl chloride (0.030 mL, 0.23 × 1.2 mmol) and triethylamine (0.048 mL, 0.23 × 1.5 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 145 mg, quant.).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.80 (1H, d, J = 7.3 Hz), 7.14-7.10 (2H, m), 7.03 (1H, d, J = 10.7 Hz), 4.50 (2H, s), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.12 (1H, dd, J = 13.7, 4.4 Hz), 2.24-2.16 (1H, m), 2.05 (3H, s), 1.99-1.83 (2H, m).
ESI-MS m / z: 536 [M + H] + , 538 [M + 2 + H] + .
実施例１８８
4-ブロモ-N-(2-ピリジンカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(46 mg, 0.105 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへ2-ピリジンカルボニルクロリド塩酸塩(22 mg, 0.105×1.2 mmol)、トリエチルアミン(0.022 mL, 0.105×1.5 mmol)を加えて室温で3時間攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 42 mg, 73.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.56 (1H, d, J = 7.8 Hz), 8.74 (1H, dq, J = 4.8, 0.9 Hz), 7.99 (1H, td, J = 7.7, 1.4 Hz), 7.93 (1H, d, J = 7.7 Hz), 7.65 (1H, ddd, J = 7.7, 4.8, 1.4 Hz), 7.21 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.53-4.47 (1H, m), 3.93 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.16 (1H, dd, J = 13.5, 6.0 Hz), 2.37-2.21 (2H, m), 2.03-1.94 (1H, m).
ESI-MS m/z: 542 [M+H]+ , 544 [M+2+H]+. Example 188
Synthesis of 4-bromo-N- (2-pyridinecarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (46 mg, 0.105 mmol) was dissolved in dichloromethane (1.2 mL). Thereto were added 2-pyridinecarbonyl chloride hydrochloride (22 mg, 0.105 × 1.2 mmol) and triethylamine (0.022 mL, 0.105 × 1.5 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 42 mg, 73.9%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.56 (1H, d, J = 7.8 Hz), 8.74 (1H, dq, J = 4.8, 0.9 Hz), 7.99 (1H, td, J = 7.7, 1.4 Hz), 7.93 (1H, d, J = 7.7 Hz), 7.65 (1H, ddd, J = 7.7, 4.8, 1.4 Hz), 7.21 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.53-4.47 (1H, m), 3.93 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.16 (1H, dd, J = 13.5, 6.0 Hz), 2.37-2.21 (2H, m), 2.03-1.94 (1H, m).
ESI-MS m / z: 542 [M + H] + , 544 [M + 2 + H] + .
実施例１８９
N-アリル-4-ブロモデアセチルコルヒチンの合成
　N-アリル-4-ブロモ-N-(t-ブチルオキシカルボニル)デアセチルコルヒチン(90 mg, 0.156 mmol)にトリフルオロ酢酸(0.22 mL, 0.156×19 mmol)を加えて室温で1時間攪拌した。クロロホルムを加えて、1 mol/L水酸化ナトリウム水溶液を加えてpH=14にした。クロロホルム:メタノール=5:1で抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 39 mg, 52.5%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.56 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 5.71 (1H, ddd, J = 22.0, 10.6, 6.2 Hz), 4.98 (1H, dd, J = 17.3, 1.7 Hz), 4.92 (1H, dd, J = 10.6, 1.7 Hz), 3.89 (6H, s), 3.85 (3H, s), 3.48 (3H, s), 3.14-3.08 (1H, m), 3.06-3.00 (2H, m), 2.86-2.79 (1H, m), 2.61-2.56 (1H, m), 2.18-2.00 (2H, m), 1.56-1.49 (1H, m).
ESI-MS m/z: 477 [M+H]+ , 479 [M+2+H]+. Example 189
Synthesis of N-allyl-4-bromodeacetylcolchicine N-allyl-4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine (90 mg, 0.156 mmol) to trifluoroacetic acid (0.22 mL, 0.156 × 19 mmol) was added and stirred at room temperature for 1 hour. Chloroform was added, and 1 mol / L aqueous sodium hydroxide solution was added to adjust pH = 14. Extraction was performed with chloroform: methanol = 5: 1. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 39 mg, 52.5%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.56 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 5.71 ( 1H, ddd, J = 22.0, 10.6, 6.2 Hz), 4.98 (1H, dd, J = 17.3, 1.7 Hz), 4.92 (1H, dd, J = 10.6, 1.7 Hz), 3.89 (6H, s), 3.85 (3H, s), 3.48 (3H, s), 3.14-3.08 (1H, m), 3.06-3.00 (2H, m), 2.86-2.79 (1H, m), 2.61-2.56 (1H, m), 2.18 -2.00 (2H, m), 1.56-1.49 (1H, m).
ESI-MS m / z: 477 [M + H] + , 479 [M + 2 + H] + .
実施例１９０
N-(ベンジルオキシカルボニル)-4-ブロモデアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(63 mg, 0.144 mmol)をジクロロメタン(1.3 mL)に溶解した。ベンジルオキシカルボニルクロリド(0.025 mL, 0.144×1.2 mmol)、トリエチルアミン(0.030 mL, 0.144×1.5 mmol)を加えて室温で1晩攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 18 mg, 21.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.23 (1H, d, J = 7.3 Hz), 7.37-7.30 (5H, m), 7.21 (1H, s), 7.13 (1H, d, J = 11.0 Hz), 7.04 (1H, d, J = 11.0 Hz), 4.98 (2H, d, J = 5.9 Hz), 4.07-4.01 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.52 (3H, s), 3.10 (1H, dd, J = 13.3, 5.2 Hz), 2.21-2.12 (1H, m), 2.03-1.93 (1H, m), 1.84-1.77 (1H, m).
ESI-MS m/z: 571 [M+H]+ , 573 [M+2+H]+. Example 190
Synthesis of N- (benzyloxycarbonyl) -4-bromodeacetylcolchicine 4-Bromodeacetylcolchicine (63 mg, 0.144 mmol) was dissolved in dichloromethane (1.3 mL). Benzyloxycarbonyl chloride (0.025 mL, 0.144 × 1.2 mmol) and triethylamine (0.030 mL, 0.144 × 1.5 mmol) were added and stirred at room temperature overnight. After the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 18 mg, 21.9%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.23 (1H, d, J = 7.3 Hz), 7.37-7.30 (5H, m), 7.21 (1H, s), 7.13 (1H, d , J = 11.0 Hz), 7.04 (1H, d, J = 11.0 Hz), 4.98 (2H, d, J = 5.9 Hz), 4.07-4.01 (1H, m), 3.91 (3H, s), 3.89 (3H , s), 3.86 (3H, s), 3.52 (3H, s), 3.10 (1H, dd, J = 13.3, 5.2 Hz), 2.21-2.12 (1H, m), 2.03-1.93 (1H, m), 1.84-1.77 (1H, m).
ESI-MS m / z: 571 [M + H] + , 573 [M + 2 + H] + .
実施例１９１
4-ブロモ-N-[(メチルチオ)アセチル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(126 mg, 0.29 mmol)をN,N-ジメチルホルムアミド(2.5 mL)に溶解し、氷冷した。そこへメチルチオ酢酸(0.030 mL, 0.29×1.2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(67 mg, 0.29×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(47 mg, 0.29×1.2 mmol)を加えて室温で2時間攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1 mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 112 mg, 73.6%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.77 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.03 (1H, d, J = 11.0 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.15-3.13 (1H, m), 3.11 (2H, d, J = 6.8 Hz), 2.25-2.16 (1H, m), 2.06 (3H, s), 2.01-1.91 (1H, m), 1.88-1.80 (1H, m).
ESI-MS m/z: 525 [M+H]+ , 527 [M+2+H]+. Example 191
Synthesis of 4-bromo-N-[(methylthio) acetyl] deacetylcolchicine 4-Bromodeacetylcolchicine (126 mg, 0.29 mmol) was dissolved in N, N-dimethylformamide (2.5 mL) and cooled on ice. Methylthioacetic acid (0.030 mL, 0.29 × 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (67 mg, 0.29 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate (47 mg, 0.29 × 1.2 mmol) was added and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 112 mg, 73.6%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.77 (1H, d, J = 7.3 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.03 ( 1H, d, J = 11.0 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.15-3.13 (1H, m), 3.11 (2H, d, J = 6.8 Hz), 2.25-2.16 (1H, m), 2.06 (3H, s), 2.01-1.91 (1H, m), 1.88-1.80 (1H, m ).
ESI-MS m / z: 525 [M + H] + , 527 [M + 2 + H] + .
実施例１９２
4-ブロモ-N-[(N',N'-ジメチルアミノ)アセチル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(124 mg, 0.28 mmol)をN,N-ジメチルホルムアミド(2.5 mL)に溶解し、氷冷した。そこへN,N-ジメチルアミノ酢酸(35 mg, 0.28×1.2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(65 mg, 0.28×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(46 mg, 0.28×1.2 mmol)を加えて室温で2.5時間攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1 mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g,クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 109 mg, 74.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.58 (1H, d, J = 7.6 Hz), 7.15 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.02 (1H, d, J = 11.0 Hz), 4.30-4.24 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.54 (3H, s), 3.11 (1H, dd, J = 13.4, 5.1 Hz), 2.94-2.84 (2H, m), 2.21 (6H, s), 2.18-2.14 (1H, m), 2.06-1.98 (1H, m), 1.94-1.85 (1H, m).
ESI-MS m/z: 522 [M+H]+ , 524 [M+2+H]+. Example 192
Synthesis of 4-bromo-N-[(N ', N'-dimethylamino) acetyl] deacetylcolchicine 4-bromodeacetylcolchicine (124 mg, 0.28 mmol) dissolved in N, N-dimethylformamide (2.5 mL) And cooled on ice. There, N, N-dimethylaminoacetic acid (35 mg, 0.28 × 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (65 mg, 0.28 × 1.2 mmol), 1-hydroxybenzo Triazole monohydrate (46 mg, 0.28 × 1.2 mmol) was added and stirred at room temperature for 2.5 hours. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 109 mg, 74.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.58 (1H, d, J = 7.6 Hz), 7.15 (1H, s), 7.12 (1H, d, J = 11.0 Hz), 7.02 ( 1H, d, J = 11.0 Hz), 4.30-4.24 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.54 (3H, s), 3.11 (1H , dd, J = 13.4, 5.1 Hz), 2.94-2.84 (2H, m), 2.21 (6H, s), 2.18-2.14 (1H, m), 2.06-1.98 (1H, m), 1.94-1.85 (1H , m).
ESI-MS m / z: 522 [M + H] + , 524 [M + 2 + H] + .
実施例１９３
4-ブロモ-N-プロピルデアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(96 mg, 0.22 mmol)をメタノール(2.0 mL)に溶解し、プロピオンアルデヒド(0.017 mL, 0.22×1.1 mmol)、オルトギ酸トリメチル(0.041 mL, 0.22×1.5 mmol)を加えて室温で1時間攪拌した。氷冷し、水素化ホウ素ナトリウム(12 mg, 0.22×1.5 mmol)を加えて室温で1時間攪拌した。水を加えて、クロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 43 mg, 40.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.56 (1H, s), 7.10 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.50 (3H, s), 3.07-3.01 (2H, m), 2.34-2.20 (2H, m), 2.18-2.01 (3H, m), 1.54-1.47 (1H, m), 1.39-1.30 (2H, m), 0.81 (3H, t, J = 7.3 Hz).
ESI-MS m/z: 479 [M+H]+ , 481 [M+2+H]+. Example 193
Synthesis of 4-bromo-N-propyldeacetylcolchicine 4-bromodeacetylcolchicine (96 mg, 0.22 mmol) was dissolved in methanol (2.0 mL), propionaldehyde (0.017 mL, 0.22 × 1.1 mmol), trimethyl orthoformate (0.041 mL, 0.22 × 1.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was ice-cooled, sodium borohydride (12 mg, 0.22 × 1.5 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 43 mg, 40.9%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.56 (1H, s), 7.10 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 3.90 ( 3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.50 (3H, s), 3.07-3.01 (2H, m), 2.34-2.20 (2H, m), 2.18-2.01 (3H, m), 1.54-1.47 (1H, m), 1.39-1.30 (2H, m), 0.81 (3H, t, J = 7.3 Hz).
ESI-MS m / z: 479 [M + H] + , 481 [M + 2 + H] + .
実施例１９４
4-ブロモ-N-(ヘキシルカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(68 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解し、ヘキシルイソシアネート(0.047 mL, 0.16×2 mmol)を加えて室温で3時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 80 mg, 88.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.18 (1H, s), 7.10 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.5 Hz), 6.66 (1H, d, J = 7.6 Hz), 5.92 (1H, t, J = 5.7 Hz), 4.13-4.07 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.52 (3H, s), 3.09 (1H, dd, J = 13.5, 5.5 Hz), 2.97-2.83 (2H, m), 2.21-2.13 (1H, m), 2.00-1.91 (1H, m), 1.71-1.64 (1H, m), 1.31-1.17 (8H, m), 0.83 (3H, t, J = 6.7 Hz).
ESI-MS m/z: 564 [M+H]+ , 566 [M+2+H]+. Example 194
Synthesis of 4-bromo-N- (hexylcarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (68 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL), and hexyl isocyanate (0.047 mL, 0.16 × 2 mmol) was dissolved. In addition, the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 80 mg, 88.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.18 (1H, s), 7.10 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.5 Hz), 6.66 ( 1H, d, J = 7.6 Hz), 5.92 (1H, t, J = 5.7 Hz), 4.13-4.07 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s ), 3.52 (3H, s), 3.09 (1H, dd, J = 13.5, 5.5 Hz), 2.97-2.83 (2H, m), 2.21-2.13 (1H, m), 2.00-1.91 (1H, m), 1.71-1.64 (1H, m), 1.31-1.17 (8H, m), 0.83 (3H, t, J = 6.7 Hz).
ESI-MS m / z: 564 [M + H] + , 566 [M + 2 + H] + .
実施例１９５
4-ブロモ-N-(フェニルカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(71 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解し、フェニルイソシアネート(0.035 mL, 0.16×2 mmol)を加えて室温で4時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 74 mg, 83.3%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.55 (1H, s), 7.32-7.29 (2H, m), 7.25 (1H, s), 7.20-7.13 (3H, m), 7.04 (1H, d, J = 11.2 Hz), 7.00 (1H, d, J = 7.3 Hz), 6.88 (1H, t, J = 7.3 Hz), 4.21-4.15 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.56 (3H, s), 3.13 (1H, dd, J = 13.8, 5.2 Hz), 2.26-2.18 (1H, m), 2.11-2.01 (1H, m), 1.81-1.74 (1H, m).
ESI-MS m/z: 556 [M+H]+ , 558 [M+2+H]+. Example 195
Synthesis of 4-bromo-N- (phenylcarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (71 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL), and phenyl isocyanate (0.035 mL, 0.16 × 2 mmol) was dissolved. In addition, the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 74 mg, 83.3%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.55 (1H, s), 7.32-7.29 (2H, m), 7.25 (1H, s), 7.20-7.13 (3H, m), 7.04 (1H, d, J = 11.2 Hz), 7.00 (1H, d, J = 7.3 Hz), 6.88 (1H, t, J = 7.3 Hz), 4.21-4.15 (1H, m), 3.92 (3H, s) , 3.89 (3H, s), 3.87 (3H, s), 3.56 (3H, s), 3.13 (1H, dd, J = 13.8, 5.2 Hz), 2.26-2.18 (1H, m), 2.11-2.01 (1H , m), 1.81-1.74 (1H, m).
ESI-MS m / z: 556 [M + H] + , 558 [M + 2 + H] + .
実施例１９６
4-ブロモ-N-(ヒドロキシアセチル)デアセチルコルヒチンの合成
　N-(アセトキシアセチル)-4-ブロモデアセチルコルヒチン(58 mg, 0.11 mmol)をメタノール(1.2 mL)、ジクロロメタン(1.2 mL)に溶解した。そこへナトリウムメトキシド(12 mg, 0.11×2 mmol)を加えて室温で2時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 31 mg, 57.0%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.54 (1H, d, J = 7.8 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.03 (1H, d, J = 10.5 Hz), 5.54 (1H, t, J = 5.9 Hz), 4.33-4.26 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.85-3.82 (2H, m), 3.83-3.80 (2H, m), 3.53 (3H, s), 3.11 (1H, dd, J = 13.9, 5.6 Hz), 2.23-2.15 (1H, m), 2.11-2.04 (1H, m), 1.93-1.85 (1H, m).
ESI-MS m/z: 495 [M+H]+ , 497 [M+2+H]+. Example 196
Synthesis of 4-bromo-N- (hydroxyacetyl) deacetylcolchicine N- (acetoxyacetyl) -4-bromodeacetylcolchicine (58 mg, 0.11 mmol) was dissolved in methanol (1.2 mL) and dichloromethane (1.2 mL) . Sodium methoxide (12 mg, 0.11 × 2 mmol) was added thereto and stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 31 mg, 57.0%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.54 (1H, d, J = 7.8 Hz), 7.16 (1H, s), 7.12 (1H, d, J = 10.5 Hz), 7.03 ( 1H, d, J = 10.5 Hz), 5.54 (1H, t, J = 5.9 Hz), 4.33-4.26 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s ), 3.85-3.82 (2H, m), 3.83-3.80 (2H, m), 3.53 (3H, s), 3.11 (1H, dd, J = 13.9, 5.6 Hz), 2.23-2.15 (1H, m), 2.11-2.04 (1H, m), 1.93-1.85 (1H, m).
ESI-MS m / z: 495 [M + H] + , 497 [M + 2 + H] + .
実施例１９７
4-ブロモ-N-(イソブタンスルホニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(57 mg, 0.13 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへイソブタンスルホニルクロリド(0.02 mL, 0.13×1.2 mmol)、トリエチルアミン(0.027 mL, 0.13×1.5 mmol)を加えて室温で2時間攪拌した。反応後、1 mol/L塩酸を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 39 mg, 53.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.11 (1H, d, J = 8.1 Hz), 7.43 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.04 (1H, d, J = 10.7 Hz), 3.91 (3H, s), 3.91-3.90 (1H, m), 3.90 (3H, s), 3.87 (3H, s), 3.48 (3H, s), 3.10 (1H, dd, J = 13.9, 4.6 Hz), 2.73 (2H, dd, J = 6.3, 2.2 Hz), 2.19-2.11 (1H, m), 2.07-1.94 (2H, m), 1.85-1.78 (1H, m), 0.90 (6H, dd, J = 6.8, 2.2 Hz).
ESI-MS m/z: 557 [M+H]+ , 559 [M+2+H]+. Example 197
Synthesis of 4-bromo-N- (isobutanesulfonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (57 mg, 0.13 mmol) was dissolved in dichloromethane (1.0 mL). The isobutane sulfonyl chloride (0.02 mL, 0.13 * 1.2 mmol) and the triethylamine (0.027 mL, 0.13 * 1.5 mmol) were added there, and it stirred at room temperature for 2 hours. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 39 mg, 53.9%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.11 (1H, d, J = 8.1 Hz), 7.43 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.04 ( 1H, d, J = 10.7 Hz), 3.91 (3H, s), 3.91-3.90 (1H, m), 3.90 (3H, s), 3.87 (3H, s), 3.48 (3H, s), 3.10 (1H , dd, J = 13.9, 4.6 Hz), 2.73 (2H, dd, J = 6.3, 2.2 Hz), 2.19-2.11 (1H, m), 2.07-1.94 (2H, m), 1.85-1.78 (1H, m ), 0.90 (6H, dd, J = 6.8, 2.2 Hz).
ESI-MS m / z: 557 [M + H] + , 559 [M + 2 + H] + .
実施例１９８
4-ブロモ-N-トシルデアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(60 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへトシルクロリド(32 mg, 0.14×1.2 mmol)、トリエチルアミン(0.029 mL, 0.14×1.5 mmol)を加えて室温で一晩攪拌した。反応後、1 mol/L塩酸を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 75 mg, 90.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.50 (1H, d, J = 7.6 Hz), 7.39 (1H, s), 7.37 (1H, s), 7.23 (1H, s), 7.22 (1H, s), 7.21 (1H, s), 7.08 (1H, d, J = 10.5 Hz), 6.98 (1H, d, J = 10.5 Hz), 3.92 (3H, s), 3.88 (3H, s), 3.85 (3H, s), 3.53 (3H, s), 3.51-3.48 (1H, m), 2.93 (1H, dd, J = 13.9, 5.6 Hz), 2.31 (3H, s), 2.09-2.00 (1H, m), 1.71-1.63 (1H, m), 1.55-1.48 (1H, m).
ESI-MS m/z: 591 [M+H]+ , 593 [M+2+H]+. Example 198
Synthesis of 4-bromo-N-tosyldeacetylcolchicine 4-Bromodeacetylcolchicine (60 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Tosyl chloride (32 mg, 0.14 × 1.2 mmol) and triethylamine (0.029 mL, 0.14 × 1.5 mmol) were added thereto and stirred at room temperature overnight. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 75 mg, 90.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.50 (1H, d, J = 7.6 Hz), 7.39 (1H, s), 7.37 (1H, s), 7.23 (1H, s), 7.22 (1H, s), 7.21 (1H, s), 7.08 (1H, d, J = 10.5 Hz), 6.98 (1H, d, J = 10.5 Hz), 3.92 (3H, s), 3.88 (3H, s ), 3.85 (3H, s), 3.53 (3H, s), 3.51-3.48 (1H, m), 2.93 (1H, dd, J = 13.9, 5.6 Hz), 2.31 (3H, s), 2.09-2.00 ( 1H, m), 1.71-1.63 (1H, m), 1.55-1.48 (1H, m).
ESI-MS m / z: 591 [M + H] + , 593 [M + 2 + H] + .
実施例１９９
4-ブロモ-N-(2-チオフェンスルホニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(66 mg, 0.15 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへ2-チオフェンスルホニルクロリド(33 mg, 0.15×1.2 mmol)、トリエチルアミン(0.031 mL, 0.15×1.5 mmol)を加えて室温で一晩攪拌した。反応後、1 mol/L塩酸を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 76 mg, 87.0%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.83 (1H, d, J = 7.6 Hz), 7.84 (1H, dd, J = 4.9, 1.5 Hz), 7.30 (1H, dd, J = 3.8, 1.5 Hz), 7.27 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.05-7.00 (2H, m), 3.92 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.71-3.64 (1H, m), 3.52 (3H, s), 2.99 (1H, dd, J = 13.5, 5.5 Hz), 2.14-2.05 (1H, m), 1.78-1.58 (2H, m).
ESI-MS m/z: 583 [M+H]+ , 585 [M+2+H]+. Example 199
Synthesis of 4-bromo-N- (2-thiophensulfonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (66 mg, 0.15 mmol) was dissolved in dichloromethane (1.3 mL). 2-thiophenesulfonyl chloride (33 mg, 0.15 × 1.2 mmol) and triethylamine (0.031 mL, 0.15 × 1.5 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 76 mg, 87.0%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.83 (1H, d, J = 7.6 Hz), 7.84 (1H, dd, J = 4.9, 1.5 Hz), 7.30 (1H, dd, J = 3.8, 1.5 Hz), 7.27 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.05-7.00 (2H, m), 3.92 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.71-3.64 (1H, m), 3.52 (3H, s), 2.99 (1H, dd, J = 13.5, 5.5 Hz), 2.14-2.05 (1H, m), 1.78-1.58 (2H , m).
ESI-MS m / z: 583 [M + H] + , 585 [M + 2 + H] + .
実施例２００
4-ブロモ-N-(2,4-ジフルオロベンゾイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)をN,N-ジメチルホルムアミド(1.3 mL)に溶解し、氷冷した。そこへ2,4-ジフルオロ安息香酸(27 mg, 0.14×1.2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、水、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 41 mg, 50.8%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.12 (1H, d, J = 7.1 Hz), 7.62 (1H, dd, J = 15.1, 8.3 Hz), 7.39 (1H, td, J = 10.0, 2.1 Hz), 7.24 (1H, s), 7.20 (1H, dd, J = 8.3, 2.4 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.44-4.38 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.58 (3H, s), 3.15 (1H, dd, J = 13.3, 4.8 Hz), 2.28-2.20 (1H, m), 2.08-1.94 (2H, m).
ESI-MS m/z: 577 [M+H]+ , 578 [M+2+H]+. Example 200
Synthesis of 4-bromo-N- (2,4-difluorobenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (62 mg, 0.14 mmol) was dissolved in N, N-dimethylformamide (1.3 mL) and ice-cooled. . 2,4-difluorobenzoic acid (27 mg, 0.14 × 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol), 1-hydroxybenzo Triazole monohydrate (23 mg, 0.14 × 1.2 mmol) was added and stirred overnight at room temperature. After the reaction, the solvent was distilled off. It was dissolved in chloroform and washed with water, 1 mol / L aqueous sodium hydroxide solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 41 mg, 50.8%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.12 (1H, d, J = 7.1 Hz), 7.62 (1H, dd, J = 15.1, 8.3 Hz), 7.39 (1H, td, J = 10.0, 2.1 Hz), 7.24 (1H, s), 7.20 (1H, dd, J = 8.3, 2.4 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz) ), 4.44-4.38 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.58 (3H, s), 3.15 (1H, dd, J = 13.3, 4.8 Hz), 2.28-2.20 (1H, m), 2.08-1.94 (2H, m).
ESI-MS m / z: 577 [M + H] + , 578 [M + 2 + H] + .
実施例２０１
4-ブロモ-N-[3-(N',N'-ジメチルアミノ)ベンゾイル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(63 mg, 0.144 mmol)をN,N-ジメチルホルムアミド(1.3 mL)に溶解し、氷冷した。そこへ3-(N,N-ジメチルアミノ)安息香酸(29 mg, 0.144×1.2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.144×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.144×1.2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、水、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g,クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 75 mg, 89.3%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.94 (1H, d, J = 7.3 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.20-7.13 (4H, m), 7.05 (1H, d, J = 11.0 Hz), 6.89 (1H, dd, J = 7.9, 2.3 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.1, 4.8 Hz), 2.92 (6H, s), 2.29-2.21 (1H, m), 2.16-1.98 (2H, m).
ESI-MS m/z: 584 [M+H]+ , 586 [M+2+H]+. Example 201
Synthesis of 4-bromo-N- [3- (N ', N'-dimethylamino) benzoyl] deacetylcolchicine 4-bromodeacetylcolchicine (63 mg, 0.144 mmol) was converted to N, N-dimethylformamide (1.3 mL) And dissolved in ice. 3- (N, N-dimethylamino) benzoic acid (29 mg, 0.144 × 1.2 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.144 × 1.2 mmol) , 1-hydroxybenzotriazole monohydrate (23 mg, 0.144 × 1.2 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction, the solvent was distilled off. It was dissolved in chloroform and washed with water, 1 mol / L aqueous sodium hydroxide solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 75 mg, 89.3%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.94 (1H, d, J = 7.3 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.20-7.13 (4H, m), 7.05 (1H, d, J = 11.0 Hz), 6.89 (1H, dd, J = 7.9, 2.3 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.1, 4.8 Hz), 2.92 (6H, s), 2.29-2.21 (1H, m), 2.16-1.98 (2H, m ).
ESI-MS m / z: 584 [M + H] + , 586 [M + 2 + H] + .
実施例２０２
4-ブロモ-N-(2-フルオロベンゾイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(46 mg, 0.11 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへ2-フルオロベンゾイルクロリド(0.016 mL, 0.11×1.2 mmol)、トリエチルアミン(0.023 mL, 0.11×1.5 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 56 mg, 91.2%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.13 (1H, d, J = 7.1 Hz), 7.58-7.52 (2H, m), 7.34-7.29 (2H, m), 7.27 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 4.45-4.39 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.59 (3H, s), 3.17-3.13 (1H, m), 2.28-2.20 (1H, m), 2.07-1.95 (2H, m).
ESI-MS m/z: 559 [M+H]+ , 561 [M+2+H]+. Example 202
Synthesis of 4-bromo-N- (2-fluorobenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (46 mg, 0.11 mmol) was dissolved in dichloromethane (1.0 mL). 2-Fluorobenzoyl chloride (0.016 mL, 0.11 × 1.2 mmol) and triethylamine (0.023 mL, 0.11 × 1.5 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 56 mg, 91.2%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.13 (1H, d, J = 7.1 Hz), 7.58-7.52 (2H, m), 7.34-7.29 (2H, m), 7.27 (1H , s), 7.16 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 4.45-4.39 (1H, m), 3.93 (3H, s), 3.90 (3H, s) , 3.88 (3H, s), 3.59 (3H, s), 3.17-3.13 (1H, m), 2.28-2.20 (1H, m), 2.07-1.95 (2H, m).
ESI-MS m / z: 559 [M + H] + , 561 [M + 2 + H] + .
実施例２０３
4-ブロモ-N-(3-メトキシベンゾイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(48 mg, 0.11 mmol)をジクロロメタン(1.0 mL)に溶解した。そこへ3-メトキシベンゾイルクロリド(0.018 mL, 0.11×1.2 mmol)、トリエチルアミン(0.023 mL, 0.11×1.5 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 63 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.05 (1H, d, J = 7.3 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.43-7.39 (2H, m), 7.19 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.13 (1H, dd, J = 8.3, 2.4 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.80 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.9, 4.9 Hz), 2.30-2.21 (1H, m), 2.15-2.01 (2H, m).
ESI-MS m/z: 571 [M+H]+ , 573 [M+2+H]+. Example 203
Synthesis of 4-bromo-N- (3-methoxybenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (48 mg, 0.11 mmol) was dissolved in dichloromethane (1.0 mL). 3-methoxy benzoyl chloride (0.018 mL, 0.11 * 1.2 mmol) and triethylamine (0.023 mL, 0.11 * 1.5 mmol) were added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 63 mg, quant.).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.05 (1H, d, J = 7.3 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.43-7.39 (2H, m), 7.19 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.13 (1H, dd, J = 8.3, 2.4 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.49-4.43 (1H , m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.80 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.9, 4.9 Hz), 2.30-2.21 (1H, m), 2.15-2.01 (2H, m).
ESI-MS m / z: 571 [M + H] + , 573 [M + 2 + H] + .
実施例２０４
4-ブロモ-N-(エチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(68 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへエチルイソチオシアネート(0.028 mL, 0.16×2 mmol)を加えて室温で4時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(BiotageIsolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 33 mg, 39.4%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.97 (1H, br s), 7.52 (1H, br s), 7.14 (1H, d, J = 10.5 Hz), 7.06 (1H, s), 7.03 (1H, d, J = 10.5 Hz), 4.79-4.70 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.41-3.27 (2H, m), 3.12 (1H, dd, J = 13.3, 5.7 Hz), 2.25-2.17 (1H, m), 2.09-1.81 (2H, m), 1.05 (3H, t, J = 7.1 Hz).
ESI-MS m/z: 524 [M+H]+ , 526 [M+2+H]+. Example 204
Synthesis of 4-bromo-N- (ethylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (68 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Ethyl isothiocyanate (0.028 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (BiotageIsolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 33 mg, 39.4%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.97 (1H, br s), 7.52 (1H, br s), 7.14 (1H, d, J = 10.5 Hz), 7.06 (1H, s ), 7.03 (1H, d, J = 10.5 Hz), 4.79-4.70 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s) , 3.41-3.27 (2H, m), 3.12 (1H, dd, J = 13.3, 5.7 Hz), 2.25-2.17 (1H, m), 2.09-1.81 (2H, m), 1.05 (3H, t, J = 7.1 Hz).
ESI-MS m / z: 524 [M + H] + , 526 [M + 2 + H] + .
実施例２０５
4-ブロモ-N-(フェニルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(68 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへフェニルイソチオシアネート(0.038 mL, 0.16×2 mmol)を加えて室温で5時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 97 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.70 (1H, br s), 8.43 (1H, d, J = 7.1 Hz), 7.46 (1H, s), 7.44 (1H, s), 7.32-7.28 (2H, m), 7.17-7.03 (4H, m), 4.80-4.74 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.15 (1H, dd, J = 13.1, 4.8 Hz), 2.28-2.09 (2H, m), 2.02-1.95 (1H, m).
ESI-MS m/z: 572 [M+H]+ , 574 [M+2+H]+. Example 205
Synthesis of 4-bromo-N- (phenylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (68 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). The phenyl isothiocyanate (0.038 mL, 0.16 * 2 mmol) was added there, and it stirred at room temperature for 5 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 97 mg, quant.).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.70 (1H, br s), 8.43 (1H, d, J = 7.1 Hz), 7.46 (1H, s), 7.44 (1H, s) , 7.32-7.28 (2H, m), 7.17-7.03 (4H, m), 4.80-4.74 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.15 (1H, dd, J = 13.1, 4.8 Hz), 2.28-2.09 (2H, m), 2.02-1.95 (1H, m).
ESI-MS m / z: 572 [M + H] + , 574 [M + 2 + H] + .
実施例２０６
4-ブロモ-N-(N',N'-ジエチルカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(113 mg, 0.26 mmol)を1,2-ジクロロエタン(2.2 mL)に溶解した。そこへジエチルカルバモイルクロリド(0.049 mL, 0.26×1.5 mmol)、トリエチルアミン(0.072 mL, 0.26×2 mmol)を加えて3時間加熱還流した。反応後、1 mol/L塩酸を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 51 mg, 36.6%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.21 (1H, s), 7.10 (1H, d, J = 10.7 Hz), 7.01 (1H, d, J = 10.7 Hz), 6.76 (1H, d, J = 7.6 Hz), 4.25-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.29-3.15 (4H, m), 3.11 (1H, dd, J = 13.7, 5.1 Hz), 2.21-2.12 (1H, m), 2.04-1.96 (1H, m), 1.93-1.85 (1H, m), 1.00 (6H, t, J = 7.0 Hz).
ESI-MS m/z: 536 [M+H]+ , 538 [M+2+H]+. Example 206
Synthesis of 4-bromo-N- (N ′, N′-diethylcarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (113 mg, 0.26 mmol) was dissolved in 1,2-dichloroethane (2.2 mL). Diethylcarbamoyl chloride (0.049 mL, 0.26 × 1.5 mmol) and triethylamine (0.072 mL, 0.26 × 2 mmol) were added thereto, and the mixture was heated to reflux for 3 hours. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 51 mg, 36.6%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.21 (1H, s), 7.10 (1H, d, J = 10.7 Hz), 7.01 (1H, d, J = 10.7 Hz), 6.76 ( 1H, d, J = 7.6 Hz), 4.25-4.18 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.29-3.15 (4H, m), 3.11 (1H, dd, J = 13.7, 5.1 Hz), 2.21-2.12 (1H, m), 2.04-1.96 (1H, m), 1.93-1.85 (1H, m), 1.00 (6H , t, J = 7.0 Hz).
ESI-MS m / z: 536 [M + H] + , 538 [M + 2 + H] + .
実施例２０７
4-ブロモ-N-(ピペリジン-１-イルカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(107 mg, 0.25 mmol)を1,2-ジクロロエタン(2.1 mL)に溶解した。そこへ1-ピペリジンカルボニルクロリド(0.047 mL, 0.25×1.5 mmol)、トリエチルアミン(0.070 mL, 0.25×2 mmol)を加えて3時間加熱還流した。反応後、1 mol/L塩酸を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 105 mg, 76.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.18 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.03-6.98 (2H, m), 4.20-4.13 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.30-3.24 (4H, m), 3.10 (1H, dd, J = 13.9, 3.7 Hz), 2.21-2.12 (1H, m), 1.98-1.85 (2H, m), 1.55-1.50 (2H, m), 1.42-1.36 (4H, m).
ESI-MS m/z: 548 [M+H]+ , 550 [M+2+H]+. Example 207
Synthesis of 4-bromo-N- (piperidin-1-ylcarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (107 mg, 0.25 mmol) was dissolved in 1,2-dichloroethane (2.1 mL). 1-piperidinecarbonyl chloride (0.047 mL, 0.25 × 1.5 mmol) and triethylamine (0.070 mL, 0.25 × 2 mmol) were added thereto, and the mixture was heated to reflux for 3 hours. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 105 mg, 76.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.18 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.03-6.98 (2H, m), 4.20-4.13 (1H , m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.30-3.24 (4H, m), 3.10 (1H, dd, J = 13.9 , 3.7 Hz), 2.21-2.12 (1H, m), 1.98-1.85 (2H, m), 1.55-1.50 (2H, m), 1.42-1.36 (4H, m).
ESI-MS m / z: 548 [M + H] + , 550 [M + 2 + H] + .
実施例２０８
4-ブロモ-N-(3-ヒドロキシ-2,2-ジメチルプロピオニル)デアセチルコルヒチンの合成
　ヒドロキシピバル酸(20 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.4 mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 79 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.02 (1H, d, J = 7.3 Hz), 7.13-7.10 (2H, m), 7.02 (1H, d, J = 11.0 Hz), 4.80 (1H, t, J = 5.4 Hz), 4.25-4.19 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.55 (3H, s), 3.42-3.34 (2H, m), 3.11 (1H, dd, J = 13.5, 5.0 Hz), 1.07 (3H, s), 1.00 (3H, s).
ESI-MS m/z: 537 [M+H]+ , 539 [M+2+H]+. Example 208
Synthesis of 4-bromo-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine Hydroxypivalic acid (20 mg, 0.14 × 1.2 mmol) was dissolved in N, N-dimethylformamide (0.4 mL) . Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 79 mg, quant.).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.02 (1H, d, J = 7.3 Hz), 7.13-7.10 (2H, m), 7.02 (1H, d, J = 11.0 Hz), 4.80 (1H, t, J = 5.4 Hz), 4.25-4.19 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.55 (3H, s), 3.42 -3.34 (2H, m), 3.11 (1H, dd, J = 13.5, 5.0 Hz), 1.07 (3H, s), 1.00 (3H, s).
ESI-MS m / z: 537 [M + H] + , 539 [M + 2 + H] + .
実施例２０９
4-ブロモ-N-(2-ヒドロキシ-2-メチルプロピオニル)デアセチルコルヒチンの合成
　2-ヒドロキシイソ酪酸(18 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.4 mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 79 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.38 (1H, d, J = 7.6 Hz), 7.17 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.7 Hz), 5.49 (1H, s), 4.22-4.15 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.11 (1H, dd, J = 12.8, 5.7 Hz), 2.23-2.08 (2H, m), 1.94-1.83 (1H, m), 1.21 (3H, s), 1.20 (3H, s).
ESI-MS m/z: 523 [M+H]+ , 525 [M+2+H]+. Example 209
Synthesis of 4-bromo-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine 2-Hydroxyisobutyric acid (18 mg, 0.14 × 1.2 mmol) was dissolved in N, N-dimethylformamide (0.4 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 79 mg, quant.).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.38 (1H, d, J = 7.6 Hz), 7.17 (1H, s), 7.11 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 5.49 (1H, s), 4.22-4.15 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.54 (3H , s), 3.11 (1H, dd, J = 12.8, 5.7 Hz), 2.23-2.08 (2H, m), 1.94-1.83 (1H, m), 1.21 (3H, s), 1.20 (3H, s).
ESI-MS m / z: 523 [M + H] + , 525 [M + 2 + H] + .
実施例２１０
4-ブロモ-N-(2-エチル-2-ヒドロキシブチリル)デアセチルコルヒチンの合成
　2-エチル-2-ヒドロキシ酪酸(23 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.4mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage IsoleraOne, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 68 mg,88.2%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.32 (1H, d, J = 6.8 Hz), 7.22 (1H, s), 7.10 (1H, d, J = 10.7 Hz), 7.01 (1H, d, J = 10.7 Hz), 4.97 (1H, s), 4.32-4.25 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.55 (3H, s), 3.11 (1H, dd, J = 12.7, 5.6 Hz), 2.23-2.11 (2H, m), 1.89-1.79 (1H, m), 1.65-1.56 (2H, m), 1.47-1.38 (2H, m), 0.76-0.69 (6H, m).
ESI-MS m/z: 551 [M+H]+ , 553 [M+2+H]+. Example 210
Synthesis of 4-bromo-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine 2-ethyl-2-hydroxybutyric acid (23 mg, 0.14 × 1.2 mmol) in N, N-dimethylformamide (0.4 mL) Dissolved in. Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage IsoleraOne, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 68 mg, 88.2%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.32 (1H, d, J = 6.8 Hz), 7.22 (1H, s), 7.10 (1H, d, J = 10.7 Hz), 7.01 ( 1H, d, J = 10.7 Hz), 4.97 (1H, s), 4.32-4.25 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.55 (3H , s), 3.11 (1H, dd, J = 12.7, 5.6 Hz), 2.23-2.11 (2H, m), 1.89-1.79 (1H, m), 1.65-1.56 (2H, m), 1.47-1.38 (2H , m), 0.76-0.69 (6H, m).
ESI-MS m / z: 551 [M + H] + , 553 [M + 2 + H] + .
実施例２１１
4-ブロモ-N-(1-ヒドロキシシクロプロパンカルボニル)デアセチルコルヒチンの合成
　1-ヒドロキシ-1-シクロプロパンカルボン酸(17 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.4 mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で1時間攪拌した。そこへ4-ブロモデアセチルコルヒチン(62mg, 0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 67 mg, 92.0%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.66 (1H, d, J = 7.8 Hz), 7.25 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 10.5 Hz), 6.43 (1H, s), 4.32-4.26 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.51 (3H, s), 3.11 (1H, dd, J = 12.6, 6.0 Hz), 2.23-2.15 (2H, m), 1.94-1.84 (1H, m), 0.95-0.79 (4H, m).
ESI-MS m/z: 521 [M+H]+ , 523 [M+2+H]+. Example 211
Synthesis of 4-bromo-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine 1-hydroxy-1-cyclopropanecarboxylic acid (17 mg, 0.14 × 1.2 mmol) was added to N, N-dimethylformamide (0.4 mL). Dissolved. Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) at room temperature. Stir for 1 hour. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 67 mg, 92.0%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.66 (1H, d, J = 7.8 Hz), 7.25 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.02 ( 1H, d, J = 10.5 Hz), 6.43 (1H, s), 4.32-4.26 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.51 (3H , s), 3.11 (1H, dd, J = 12.6, 6.0 Hz), 2.23-2.15 (2H, m), 1.94-1.84 (1H, m), 0.95-0.79 (4H, m).
ESI-MS m / z: 521 [M + H] + , 523 [M + 2 + H] + .
実施例２１２
4-ブロモ-N-[2,2-ビス(ヒドロキシメチル)プロピオニル]デアセチルコルヒチンの合成
　2,2-ビス(ヒドロキシメチル)プロピオン酸 (23 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.4 mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で1時間攪拌した。そこへ4-ブロモデアセチルコルヒチン(62mg, 0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 74 mg, 95.6%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.02 (1H, d, J = 7.1 Hz), 7.15 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 4.73 (1H, t, J = 5.2 Hz), 4.62 (1H, t, J = 5.4 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.55 (3H, s), 3.48 (2H, d, J = 5.4 Hz), 3.43 (2H, dd, J = 5.2, 2.6 Hz), 3.14-3.08 (1H, m), 2.23-2.15 (1H, m), 1.98-1.90 (2H, m), 1.00 (3H, s).
ESI-MS m/z: 553 [M+H]+ , 555 [M+2+H]+. Example 212
Synthesis of 4-bromo-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine (0.4 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) at room temperature. Stir for 1 hour. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 74 mg, 95.6%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.02 (1H, d, J = 7.1 Hz), 7.15 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.01 ( 1H, d, J = 10.5 Hz), 4.73 (1H, t, J = 5.2 Hz), 4.62 (1H, t, J = 5.4 Hz), 4.26-4.20 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.55 (3H, s), 3.48 (2H, d, J = 5.4 Hz), 3.43 (2H, dd, J = 5.2, 2.6 Hz), 3.14-3.08 (1H, m), 2.23-2.15 (1H, m), 1.98-1.90 (2H, m), 1.00 (3H, s).
ESI-MS m / z: 553 [M + H] + , 555 [M + 2 + H] + .
実施例２１３
4-ブロモ-N-(3-ヒドロキシ-3-メチルブチリル)デアセチルコルヒチンの合成
　β-ヒドロキシイソ吉草酸(41 mg, 0.29×1.2 mmol)をN,N-ジメチルホルムアミド(0.8 mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(67 mg, 0.29×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(47 mg, 0.29×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(127 mg, 0.29 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage IsoleraOne, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 153 mg, 98.4%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.17 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.03 (1H, d, J = 10.7 Hz), 4.63 (1H, s), 4.27-4.21 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.55 (3H, s), 3.11 (1H, dd, J = 13.7, 4.9 Hz), 2.26 (2H, s), 2.24-2.15 (1H, m), 2.00-1.90 (1H, m), 1.87-1.79 (1H, m), 1.12 (6H, d, J = 3.7 Hz).
ESI-MS m/z: 537 [M+H]+ , 539 [M+2+H]+. Example 213
Synthesis of 4-bromo-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine β-hydroxyisovaleric acid (41 mg, 0.29 × 1.2 mmol) was dissolved in N, N-dimethylformamide (0.8 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (67 mg, 0.29 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (47 mg, 0.29 × 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (127 mg, 0.29 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage IsoleraOne, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 153 mg, 98.4%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.17 (1H, s), 7.12 (1H, d, J = 10.7 Hz), 7.03 ( 1H, d, J = 10.7 Hz), 4.63 (1H, s), 4.27-4.21 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.55 (3H , s), 3.11 (1H, dd, J = 13.7, 4.9 Hz), 2.26 (2H, s), 2.24-2.15 (1H, m), 2.00-1.90 (1H, m), 1.87-1.79 (1H, m ), 1.12 (6H, d, J = 3.7 Hz).
ESI-MS m / z: 537 [M + H] + , 539 [M + 2 + H] + .
実施例２１４
4-ブロモ-N-[4-(ベンジルオキシ)ブチリル]デアセチルコルヒチンの合成
　4-ベンジルオキシ酪酸(0.060 mL, 0.28×1.2 mmol)をN,N-ジメチルホルムアミド(1.2 mL)に溶解した。1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(65 mg, 0.28×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(46 mg, 0.28×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(124 mg, 0.28 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage IsoleraOne, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 155 mg, 90.4%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.34-7.25 (5H, m), 7.13-7.11 (2H, m), 7.03 (1H, d, J = 11.0 Hz), 4.44 (2H, dd, J = 17.4, 12.1 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.37 (2H, t, J = 6.3 Hz), 3.11 (1H, dd, J = 14.1, 4.9 Hz), 2.25-2.21 (2H, m), 2.19-2.14 (1H, m), 1.97-1.88 (1H, m), 1.84-1.78 (1H, m), 1.76-1.68 (2H, m).
ESI-MS m/z: 613 [M+H]+ , 615 [M+2+H]+. Example 214
Synthesis of 4-bromo-N- [4- (benzyloxy) butyryl] deacetylcolchicine 4-Benzyloxybutyric acid (0.060 mL, 0.28 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1.2 mL). Add 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (65 mg, 0.28 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (46 mg, 0.28 × 1.2 mmol) at room temperature. Stir for 30 minutes. 4-bromo deacetyl colchicine (124 mg, 0.28 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, and saturated saline. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage IsoleraOne, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 155 mg, 90.4%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.34-7.25 (5H, m), 7.13-7.11 (2H, m), 7.03 (1H , d, J = 11.0 Hz), 4.44 (2H, dd, J = 17.4, 12.1 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.37 (2H, t, J = 6.3 Hz), 3.11 (1H, dd, J = 14.1, 4.9 Hz), 2.25-2.21 (2H, m), 2.19-2.14 (1H , m), 1.97-1.88 (1H, m), 1.84-1.78 (1H, m), 1.76-1.68 (2H, m).
ESI-MS m / z: 613 [M + H] + , 615 [M + 2 + H] + .
実施例２１５
4-ブロモ-N-(3-ニトロベンゾイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(67 mg, 0.15 mmol)をジクロロメタン(0.7 mL)に溶解した。そこへ3-ニトロベンゾイルクロリド(34 mg, 0.15×1.2 mmol)、トリエチルアミン(0.031 mL, 0.15×1.5 mmol)を加えて室温で3時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 77 mg, 87.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.46 (1H, d, J = 7.1 Hz), 8.77 (1H, t, J = 2.0 Hz), 8.42 (1H, dq, J = 8.2, 1.0 Hz), 8.32 (1H, d, J = 7.9 Hz), 7.81 (1H, t, J = 7.9 Hz), 7.19-7.17 (2H, m), 7.06 (1H, d, J = 11.0 Hz), 4.53-4.46 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.61 (3H, s), 3.21-3.17 (1H, m), 2.33-2.24 (1H, m), 2.15-2.08 (2H, m).
ESI-MS m/z: 586 [M+H]+ , 588 [M+2+H]+ Example 215
Synthesis of 4-bromo-N- (3-nitrobenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (67 mg, 0.15 mmol) was dissolved in dichloromethane (0.7 mL). 3-Nitrobenzoyl chloride (34 mg, 0.15 × 1.2 mmol) and triethylamine (0.031 mL, 0.15 × 1.5 mmol) were added thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 77 mg, 87.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.46 (1H, d, J = 7.1 Hz), 8.77 (1H, t, J = 2.0 Hz), 8.42 (1H, dq, J = 8.2 , 1.0 Hz), 8.32 (1H, d, J = 7.9 Hz), 7.81 (1H, t, J = 7.9 Hz), 7.19-7.17 (2H, m), 7.06 (1H, d, J = 11.0 Hz), 4.53-4.46 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.61 (3H, s), 3.21-3.17 (1H, m), 2.33-2.24 ( 1H, m), 2.15-2.08 (2H, m).
ESI-MS m / z: 586 [M + H] + , 588 [M + 2 + H] +
実施例２１６
4-ブロモ-N-(4-シアノベンゾイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)をジクロロメタン(0.6 mL)に溶解した。そこへ4-シアノベンゾイルクロリド(28 mg, 0.14×1.2 mmol)、トリエチルアミン(0.029 mL, 0.14×1.5 mmol)を加えて室温で3時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 72 mg, 90.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.32 (1H, d, J = 7.1 Hz), 8.05-7.98 (4H, m), 7.19-7.16 (2H, m), 7.06 (1H, d, J = 11.0 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.20-3.15 (1H, m), 2.30-2.22 (1H, m), 2.12-2.05 (2H, m).
ESI-MS m/z: 566 [M+H]+ , 568 [M+2+H]+ Example 216
Synthesis of 4-bromo-N- (4-cyanobenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (62 mg, 0.14 mmol) was dissolved in dichloromethane (0.6 mL). 4-Cyanobenzoyl chloride (28 mg, 0.14 * 1.2 mmol) and triethylamine (0.029 mL, 0.14 * 1.5 mmol) were added there, and it stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 72 mg, 90.9%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.32 (1H, d, J = 7.1 Hz), 8.05-7.98 (4H, m), 7.19-7.16 (2H, m), 7.06 (1H , d, J = 11.0 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.20-3.15 ( 1H, m), 2.30-2.22 (1H, m), 2.12-2.05 (2H, m).
ESI-MS m / z: 566 [M + H] + , 568 [M + 2 + H] +
実施例２１７
4-ブロモ-N-(3,5-ジメチルベンゾイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(65 mg, 0.15 mmol)をジクロロメタン(0.7 mL)に溶解した。そこへ3,5-ジメチルベンゾイルクロリド(30 mg, 0.15×1.2 mmol)、トリエチルアミン(0.031 mL, 0.15×1.5 mmol)を加えて室温で3時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 56 mg, 65.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.99 (1H, d, J = 7.1 Hz), 7.50 (2H, s), 7.19-7.15 (3H, m), 7.05 (1H, d, J = 11.2 Hz), 4.48-4.42 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.5, 5.2 Hz), 2.32 (6H, s), 2.29-2.21 (1H, m), 2.16-1.97 (2H, m).
ESI-MS m/z: 569 [M+H]+ , 571 [M+2+H]+ Example 217
Synthesis of 4-bromo-N- (3,5-dimethylbenzoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (65 mg, 0.15 mmol) was dissolved in dichloromethane (0.7 mL). 3,5-dimethylbenzoyl chloride (30 mg, 0.15 × 1.2 mmol) and triethylamine (0.031 mL, 0.15 × 1.5 mmol) were added thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 56 mg, 65.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.99 (1H, d, J = 7.1 Hz), 7.50 (2H, s), 7.19-7.15 (3H, m), 7.05 (1H, d , J = 11.2 Hz), 4.48-4.42 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.5, 5.2 Hz), 2.32 (6H, s), 2.29-2.21 (1H, m), 2.16-1.97 (2H, m).
ESI-MS m / z: 569 [M + H] + , 571 [M + 2 + H] +
実施例２１８
4-ブロモ-N-(4-メチルベンゾイル)デアセチルコルヒチンの合成
　p-トルイル酸(23 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.4 mL)に溶解した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1 mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 61 mg, 78.6%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.99 (1H, d, J = 7.3 Hz), 7.80 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.19 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.4, 5.4 Hz), 2.36 (3H, s), 2.29-2.21 (1H, m), 2.15-1.97 (2H, m).
ESI-MS m/z: 555 [M+H]+ , 557 [M+2+H]+ Example 218
Synthesis of 4-bromo-N- (4-methylbenzoyl) deacetylcolchicine p-Toluic acid (23 mg, 0.14 × 1.2 mmol) was dissolved in N, N-dimethylformamide (0.4 mL). 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) were added thereto. Stir at room temperature for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 61 mg, 78.6%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.99 (1H, d, J = 7.3 Hz), 7.80 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.19 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 4.49-4.43 (1H, m), 3.93 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.17 (1H, dd, J = 13.4, 5.4 Hz), 2.36 (3H, s), 2.29-2.21 (1H, m) , 2.15-1.97 (2H, m).
ESI-MS m / z: 555 [M + H] + , 557 [M + 2 + H] +
実施例２１９
4-ブロモ-N-[3-（ピロリジン-1-イル）ベンゾイル]デアセチルコルヒチンの合成
　3-(ピロリジン-1-イル)安息香酸(33 mg, 0.14×1.2 mmol)をN,N-ジメチルホルムアミド(0.6 mL)に溶解した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(33 mg, 0.14×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(23 mg, 0.14×1.2 mmol)を加えて室温で30分攪拌した。そこへ4-ブロモデアセチルコルヒチン(62 mg,0.14 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1 mol/L塩酸、1 mol/L水酸化ナトリウム水溶液、飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 10 mg, 11.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.93 (1H, d, J = 7.3 Hz), 7.27-7.12 (4H, m), 7.05 (1H, d, J = 11.0 Hz), 6.95 (1H, s), 6.69 (1H, dd, J = 8.2, 2.1 Hz), 4.49-4.42 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.24 (4H, t, J = 6.6 Hz), 3.17 (1H, dd, J = 13.7, 5.1 Hz), 2.29-2.21 (1H, m), 2.16-2.08 (1H, m), 2.07-1.98 (1H, m), 1.97-1.94 (4H, m).
ESI-MS m/z: 610 [M+H]+ , 612 [M+2+H]+ Example 219
Synthesis of 4-bromo-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine 3- (pyrrolidin-1-yl) benzoic acid (33 mg, 0.14 × 1.2 mmol) was converted to N, N-dimethylformamide (0.6 mL). 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (33 mg, 0.14 × 1.2 mmol) and 1-hydroxybenzotriazole monohydrate (23 mg, 0.14 × 1.2 mmol) were added thereto. Stir at room temperature for 30 minutes. 4-bromo deacetyl colchicine (62 mg, 0.14 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The product was dissolved in chloroform and washed with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution and saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 10 mg, 11.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.93 (1H, d, J = 7.3 Hz), 7.27-7.12 (4H, m), 7.05 (1H, d, J = 11.0 Hz), 6.95 (1H, s), 6.69 (1H, dd, J = 8.2, 2.1 Hz), 4.49-4.42 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.87 (3H, s) , 3.60 (3H, s), 3.24 (4H, t, J = 6.6 Hz), 3.17 (1H, dd, J = 13.7, 5.1 Hz), 2.29-2.21 (1H, m), 2.16-2.08 (1H, m ), 2.07-1.98 (1H, m), 1.97-1.94 (4H, m).
ESI-MS m / z: 610 [M + H] + , 612 [M + 2 + H] +
実施例２２０
4-ブロモ-N-(イソブチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(62 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへイソブチルイソチオシアネート(32 mg, 0.14×2 mmol)を加えて室温で6時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(BiotageIsolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 33 mg, 42.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.01 (1H, br s), 7.58 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.77-4.66 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.25-3.10 (3H, m), 2.26-2.17 (1H, m), 2.12-2.01 (1H, m), 1.88-1.74 (2H, m), 0.84 (6H, d, J = 6.6 Hz).
ESI-MS m/z: 552 [M+H]+ , 554 [M+2+H]+ Example 220
Synthesis of 4-bromo-N- (isobutylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (62 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). The isobutyl isothiocyanate (32 mg, 0.14 * 2 mmol) was added there, and it stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (BiotageIsolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 33 mg, 42.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.01 (1H, br s), 7.58 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H , m), 4.77-4.66 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.25-3.10 (3H, m), 2.26-2.17 (1H, m), 2.12-2.01 (1H, m), 1.88-1.74 (2H, m), 0.84 (6H, d, J = 6.6 Hz).
ESI-MS m / z: 552 [M + H] + , 554 [M + 2 + H] +
実施例２２１
4-ブロモ-N-(ベンジルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(64 mg, 0.15 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへベンジルイソチオシアネート(45 mg, 0.15×2 mmol)を加えて室温で6時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 77 mg, 87.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.21 (1H, br s), 7.97 (1H, br s), 7.33-7.22 (5H, m), 7.15 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.77-4.71 (1H, m), 4.68-4.58 (2H, m), 3.91 (3H, s), 3.90 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.13 (1H, dd, J = 13.1, 5.0 Hz), 2.26-2.18 (1H, m), 2.13-2.02 (1H, m), 1.93-1.83 (1H, m).
ESI-MS m/z: 586 [M+H]+ , 588 [M+2+H]+ Example 221
Synthesis of 4-bromo-N- (benzylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (64 mg, 0.15 mmol) was dissolved in dichloromethane (1.2 mL). Benzyl isothiocyanate (45 mg, 0.15 × 2 mmol) was added thereto and stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 77 mg, 87.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.21 (1H, br s), 7.97 (1H, br s), 7.33-7.22 (5H, m), 7.15 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.77-4.71 (1H, m), 4.68-4.58 (2H, m), 3.91 (3H, s), 3.90 ( 3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.13 (1H, dd, J = 13.1, 5.0 Hz), 2.26-2.18 (1H, m), 2.13-2.02 (1H, m) , 1.93-1.83 (1H, m).
ESI-MS m / z: 586 [M + H] + , 588 [M + 2 + H] +
実施例２２２
4-ブロモ-N-[4-(N',N'-ジメチルアミノ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(65 mg, 0.15 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへ4-N',N'-ジメチルアミノフェニルイソチオシアネート(53 mg, 0.15×2 mmol)を加えて室温で7時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 86 mg, 93.3%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.41 (1H, s), 8.03 (1H, d, J = 7.3 Hz), 7.15-7.13 (3H, m), 7.09 (1H, s), 7.03 (1H, d, J = 11.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 4.82-4.76 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.61 (3H, s), 3.12 (1H, dd, J = 12.7, 4.9 Hz), 2.87 (6H, s), 2.24-2.16 (1H, m), 2.11-1.96 (2H, m).
ESI-MS m/z: 615 [M+H]+ , 617 [M+2+H]+ Example 222
Synthesis of 4-bromo-N- [4- (N ', N'-dimethylamino) phenylthiocarbamoyl] deacetylcolchicine 4-Bromodeacetylcolchicine (65 mg, 0.15 mmol) was dissolved in dichloromethane (1.3 mL) . 4-N ′, N′-dimethylaminophenyl isothiocyanate (53 mg, 0.15 × 2 mmol) was added thereto and stirred at room temperature for 7 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 86 mg, 93.3%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.41 (1H, s), 8.03 (1H, d, J = 7.3 Hz), 7.15-7.13 (3H, m), 7.09 (1H, s ), 7.03 (1H, d, J = 11.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 4.82-4.76 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.61 (3H, s), 3.12 (1H, dd, J = 12.7, 4.9 Hz), 2.87 (6H, s), 2.24-2.16 (1H, m), 2.11-1.96 (2H, m ).
ESI-MS m / z: 615 [M + H] + , 617 [M + 2 + H] +
実施例２２３
4-ブロモ-N-(ピリジン-3-イルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(61 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへピリジン-3-イルイソチオシアネート(0.053 mL, 0.14×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 82 mg, quant.)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.80 (1H, s), 8.67 (1H, d, J = 7.1 Hz), 8.56 (1H, d, J = 2.4 Hz), 8.28 (1H, dd, J = 4.8, 1.3 Hz), 7.94 (1H, d, J = 8.2 Hz), 7.32 (1H, dd, J = 8.2, 4.8 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.61 (3H, s), 3.15 (1H, dd, J = 12.6, 5.0 Hz), 2.28-2.10 (2H, m), 2.03-1.95 (1H, m).
ESI-MS m/z: 573 [M+H]+ , 575 [M+2+H]+ Example 223
Synthesis of 4-bromo-N- (pyridin-3-ylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (61 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Pyridin-3-yl isothiocyanate (0.053 mL, 0.14 × 2 mmol) was added thereto and stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 82 mg, quant.).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.80 (1H, s), 8.67 (1H, d, J = 7.1 Hz), 8.56 (1H, d, J = 2.4 Hz), 8.28 ( 1H, dd, J = 4.8, 1.3 Hz), 7.94 (1H, d, J = 8.2 Hz), 7.32 (1H, dd, J = 8.2, 4.8 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.61 (3H, s), 3.15 (1H, dd, J = 12.6, 5.0 Hz), 2.28-2.10 (2H, m), 2.03-1.95 (1H, m).
ESI-MS m / z: 573 [M + H] + , 575 [M + 2 + H] +
実施例２２４
4-ブロモ-N-(N',N'-ジエチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(59 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへチオホスゲン(0.011 mL, 0.14×1.05 mmol)、トリエチルアミン(0.047 mL, 0.14×2.4 mmol)を加えて室温で2時間攪拌した。そこへジエチルアミン(0.020 mL, 0.14×2mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 39 mg, 50.5%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.54 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.99-4.93 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.70-3.64 (4H, m), 3.62 (3H, s), 3.13 (1H, dd, J = 13.2, 5.4 Hz), 2.30-2.16 (2H, m), 2.01-1.94 (1H, m), 1.09 (6H, t, J = 7.0 Hz).
ESI-MS m/z: 552 [M+H]+ , 554 [M+2+H]+ Example 224
Synthesis of 4-bromo-N- (N ′, N′-diethylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (59 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.14 × 1.05 mmol) and triethylamine (0.047 mL, 0.14 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Diethylamine (0.020 mL, 0.14 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 39 mg, 50.5%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.54 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.99-4.93 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.70-3.64 (4H, m), 3.62 (3H, s), 3.13 (1H, dd, J = 13.2, 5.4 Hz), 2.30-2.16 (2H, m), 2.01-1.94 (1H, m), 1.09 (6H, t, J = 7.0 Hz).
ESI-MS m / z: 552 [M + H] + , 554 [M + 2 + H] +
実施例２２５
4-ブロモ-N-(ピロリジン-1-イルチオカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(58 mg, 0.13 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへチオホスゲン(0.011 mL, 0.13×1.05 mmol)、トリエチルアミン(0.043 mL, 0.13×2.4 mmol)を加えて室温で2時間攪拌した。そこへピロリジン(0.022 mL, 0.13×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 27 mg, 37.8%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.55 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.92-4.85 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.61 (3H, s), 3.58-3.44 (4H, m), 3.12 (1H, dd, J = 12.4, 5.9 Hz), 2.24-2.15 (2H, m), 2.01-1.96 (1H, m), 1.93-1.83 (4H, m).
ESI-MS m/z: 550 [M+H]+ , 552 [M+2+H]+ Example 225
Synthesis of 4-bromo-N- (pyrrolidin-1-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (58 mg, 0.13 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.13 × 1.05 mmol) and triethylamine (0.043 mL, 0.13 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Pyrrolidine (0.022 mL, 0.13 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 27 mg, 37.8%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.55 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.92-4.85 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.61 (3H, s), 3.58-3.44 (4H, m), 3.12 (1H, dd, J = 12.4, 5.9 Hz), 2.24-2.15 (2H, m), 2.01-1.96 (1H, m), 1.93-1.83 (4H, m).
ESI-MS m / z: 550 [M + H] + , 552 [M + 2 + H] +
実施例２２６
4-ブロモ-N-(ピペリジン-1-イルチオカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(60 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへチオホスゲン(0.011 mL, 0.14×1.05 mmol)、トリエチルアミン(0.047 mL, 0.14×2.4 mmol)を加えて室温で2時間攪拌した。そこへピペリジン(0.029 mL, 0.14×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 49 mg, 62.1%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.85 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.94-4.87 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.84-3.76 (4H, m), 3.63 (3H, s), 3.12 (1H, dd, J = 12.7, 5.9 Hz), 2.24-2.14 (2H, m), 2.03-1.93 (1H, m), 1.64-1.58 (2H, m), 1.51-1.44 (4H, m).
ESI-MS m/z: 564 [M+H]+ , 566 [M+2+H]+ Example 226
Synthesis of 4-bromo-N- (piperidin-1-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (60 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.14 × 1.05 mmol) and triethylamine (0.047 mL, 0.14 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Piperidine (0.029 mL, 0.14 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 49 mg, 62.1%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.85 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.94-4.87 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.84-3.76 (4H, m), 3.63 (3H, s), 3.12 (1H, dd, J = 12.7, 5.9 Hz), 2.24-2.14 (2H, m), 2.03-1.93 (1H, m), 1.64-1.58 (2H, m), 1.51-1.44 (4H, m).
ESI-MS m / z: 564 [M + H] + , 566 [M + 2 + H] +
実施例２２７
4-ブロモ-N-(4-ヒドロキシブチリル)デアセチルコルヒチンの合成
　4-ブロモ-N-(4-ベンジルオキシブチロイル)デアセチルコルヒチン(86 mg, 0.14 mmol)をジクロロメタン(1.7 mL)に溶解し-78℃で攪拌した。そこへ1 mol/L三臭化ホウ素ジクロロメタン溶液(0.14 mL, 0.14 mmol)を加えて-78℃で20分攪拌した。水、メタノールを加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 13 mg, 17.8%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.58 (1H, d, J = 7.3 Hz), 7.13-7.11 (2H, m), 7.03 (1H, d, J = 10.7 Hz), 4.45 (1H, t, J = 5.1 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.36-3.31 (2H, m), 3.11 (1H, dd, J = 13.4, 5.4 Hz), 2.23-2.15 (3H, m), 1.98-1.88 (1H, m), 1.85-1.77 (1H, m), 1.62-1.54 (2H, m).
ESI-MS m/z: 523 [M+H]+ , 525 [M+2+H]+ Example 227
Synthesis of 4-bromo-N- (4-hydroxybutyryl) deacetylcolchicine Dissolve 4-bromo-N- (4-benzyloxybutyroyl) deacetylcolchicine (86 mg, 0.14 mmol) in dichloromethane (1.7 mL) And stirred at -78 ° C. A 1 mol / L boron tribromide dichloromethane solution (0.14 mL, 0.14 mmol) was added thereto, and the mixture was stirred at -78 ° C for 20 minutes. Water and methanol were added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 13 mg, 17.8%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.58 (1H, d, J = 7.3 Hz), 7.13-7.11 (2H, m), 7.03 (1H, d, J = 10.7 Hz), 4.45 (1H, t, J = 5.1 Hz), 4.24-4.18 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.53 (3H, s), 3.36 -3.31 (2H, m), 3.11 (1H, dd, J = 13.4, 5.4 Hz), 2.23-2.15 (3H, m), 1.98-1.88 (1H, m), 1.85-1.77 (1H, m), 1.62 -1.54 (2H, m).
ESI-MS m / z: 523 [M + H] + , 525 [M + 2 + H] +
実施例２２８
4-ブロモ-N-(チオモルホリン-4-イルチオカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(60 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへチオホスゲン(0.011 mL, 0.14×1.05 mmol)、トリエチルアミン(0.047 mL, 0.14×2.4 mmol)を加えて室温で2時間攪拌した。そこへチオモルホリン(0.028 mL, 0.14×2mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 23 mg, 28.3%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 7.97 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.92-4.86 (1H, m), 4.21-4.09 (4H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J = 12.1, 5.2 Hz), 2.60 (4H, t, J = 4.9 Hz), 2.25-2.14 (2H, m), 2.07-1.98 (1H, m).
ESI-MS m/z: 582 [M+H]+ , 584 [M+2+H]+ Example 228
Synthesis of 4-bromo-N- (thiomorpholin-4-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (60 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.14 × 1.05 mmol) and triethylamine (0.047 mL, 0.14 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Thiomorpholine (0.028 mL, 0.14 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 23 mg, 28.3%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.97 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.92-4.86 (1H, m), 4.21-4.09 (4H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J = 12.1, 5.2 Hz), 2.60 (4H, t, J = 4.9 Hz), 2.25-2.14 (2H, m), 2.07-1.98 (1H, m).
ESI-MS m / z: 582 [M + H] + , 584 [M + 2 + H] +
実施例２２９
4-ブロモ-N-(1,1-ジオキソチオモルホリン-4-イルチオカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(59 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへチオホスゲン(0.011 mL, 0.14×1.05 mmol)、トリエチルアミン(0.047 mL, 0.14×2.4 mmol)を加えて室温で2時間攪拌した。そこへチオモルホリン-1,1-ジオキシド(38mg, 0.14×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 78 mg, 90.8%)を得た。
1H-NMR(400MHz, DMSO-d6) δ8.38 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.78 (1H, dd, J = 16.0, 8.4 Hz), 4.37-4.31 (2H, m), 4.23-4.18 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.63 (3H, s), 3.28-3.22 (2H, m), 3.16-3.08 (3H, m), 2.25-2.09 (3H, m).
ESI-MS m/z: 614 [M+H]+ , 616 [M+2+H]+ Example 229
Synthesis of 4-bromo-N- (1,1-dioxothiomorpholin-4-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (59 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.14 × 1.05 mmol) and triethylamine (0.047 mL, 0.14 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Thiomorpholine-1,1-dioxide (38 mg, 0.14 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 78 mg, 90.8%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.38 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.78 (1H , dd, J = 16.0, 8.4 Hz), 4.37-4.31 (2H, m), 4.23-4.18 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.63 (3H, s), 3.28-3.22 (2H, m), 3.16-3.08 (3H, m), 2.25-2.09 (3H, m).
ESI-MS m / z: 614 [M + H] + , 616 [M + 2 + H] +
実施例２３０
4-ブロモ-N-(4-メチルピペラジン-1-イルチオカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(60 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解した。そこへチオホスゲン(0.011 mL, 0.14×1.05 mmol)、トリエチルアミン(0.047 mL, 0.14×2.4 mmol)を加えて室温で2時間攪拌した。そこへ4-メチルピペラジン(0.031 mL, 0.14×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 37 mg, 45.7%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.01 (1H, d, J = 6.3 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.90-4.84 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.84-3.80 (2H, m), 3.62 (3H, s), 3.15-3.03 (4H, m), 2.39-2.30 (3H, m), 2.24-2.14 (5H, m), 2.04-1.94 (1H, m).
ESI-MS m/z: 579 [M+H]+ , 581 [M+2+H]+ Example 230
Synthesis of 4-bromo-N- (4-methylpiperazin-1-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (60 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL). Thiophosgene (0.011 mL, 0.14 × 1.05 mmol) and triethylamine (0.047 mL, 0.14 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. 4-methyl piperazine (0.031 mL, 0.14 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 37 mg, 45.7%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.01 (1H, d, J = 6.3 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.90-4.84 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.84-3.80 (2H, m), 3.62 (3H, s), 3.15-3.03 ( 4H, m), 2.39-2.30 (3H, m), 2.24-2.14 (5H, m), 2.04-1.94 (1H, m).
ESI-MS m / z: 579 [M + H] + , 581 [M + 2 + H] +
実施例２３１
4-ブロモ-N-(モルホリン-4-イルチオカルボニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(60 mg, 0.14 mmol)をジクロロメタン(1.2 mL)に溶解し、氷冷した。そこへチオホスゲン(0.011 mL, 0.14×1.05 mmol)、トリエチルアミン(0.047 mL, 0.14×2.4 mmol)を加えて氷冷下2時間攪拌した。そこへモルホリン(0.024 mL, 0.14×2 mmol)を加えて室温で一晩攪拌した。クロロホルムを加えて0.1 mol/L塩酸で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 69 mg, 87.2%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.04 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.90-4.83 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.84-3.78 (4H, m), 3.62 (3H, s), 3.59 (4H, t, J = 4.8 Hz), 3.13 (1H, dd, J = 12.9, 5.9 Hz), 2.25-2.11 (2H, m), 2.06-1.97 (1H, m).
ESI-MS m/z: 566 [M+H]+ , 568 [M+2+H]+ Example 231
Synthesis of 4-bromo-N- (morpholin-4-ylthiocarbonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (60 mg, 0.14 mmol) was dissolved in dichloromethane (1.2 mL) and cooled on ice. Thiophosgene (0.011 mL, 0.14 × 1.05 mmol) and triethylamine (0.047 mL, 0.14 × 2.4 mmol) were added thereto, and the mixture was stirred for 2 hours under ice cooling. Morpholine (0.024 mL, 0.14 × 2 mmol) was added thereto and stirred at room temperature overnight. Chloroform was added and washed with 0.1 mol / L hydrochloric acid. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 69 mg, 87.2%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.04 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.90-4.83 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.84-3.78 (4H, m), 3.62 (3H, s), 3.59 (4H, t, J = 4.8 Hz), 3.13 (1H, dd, J = 12.9, 5.9 Hz), 2.25-2.11 (2H, m), 2.06-1.97 (1H, m).
ESI-MS m / z: 566 [M + H] + , 568 [M + 2 + H] +
実施例２３２
4-ブロモ-N-(エタンスルホニル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(240 mg, 0.55 mmol)をジクロロメタン(5.0 mL)に溶解し、氷冷した。そこへエタンスルホニルクロリド(0.78 mL, 0.55×1.5 mmol)、トリエチルアミン(0.153 mL, 0.55×2 mmol)を加えて室温で3日間攪拌した。反応後、1 mol/L塩酸を加えてクロロホルム抽出した。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 267 mg, 91.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.09 (1H, d, J = 7.8 Hz), 7.45 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.04 (1H, d, J = 10.5 Hz), 3.91 (3H, s), 3.90 (3H, s), 3.89-3.88 (1H, m), 3.87 (3H, s), 3.48 (3H, s), 3.10 (1H, dd, J = 12.9, 4.6 Hz), 2.90-2.77 (2H, m), 2.18-1.98 (2H, m), 1.86-1.78 (1H, m), 1.10 (3H, t, J = 7.3 Hz).
ESI-MS m/z: 529 [M+H]+ , 531 [M+2+H]+. Example 232
Synthesis of 4-bromo-N- (ethanesulfonyl) deacetylcolchicine 4-Bromodeacetylcolchicine (240 mg, 0.55 mmol) was dissolved in dichloromethane (5.0 mL) and cooled on ice. Ethanesulfonyl chloride (0.78 mL, 0.55 × 1.5 mmol) and triethylamine (0.153 mL, 0.55 × 2 mmol) were added thereto, and the mixture was stirred at room temperature for 3 days. After the reaction, 1 mol / L hydrochloric acid was added and extracted with chloroform. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 267 mg, 91.9%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.09 (1H, d, J = 7.8 Hz), 7.45 (1H, s), 7.11 (1H, d, J = 10.5 Hz), 7.04 ( 1H, d, J = 10.5 Hz), 3.91 (3H, s), 3.90 (3H, s), 3.89-3.88 (1H, m), 3.87 (3H, s), 3.48 (3H, s), 3.10 (1H , dd, J = 12.9, 4.6 Hz), 2.90-2.77 (2H, m), 2.18-1.98 (2H, m), 1.86-1.78 (1H, m), 1.10 (3H, t, J = 7.3 Hz).
ESI-MS m / z: 529 [M + H] + , 531 [M + 2 + H] + .
実施例２３３
4-クロロ-2,3-ジデメチルコルヒチンの合成
　4-クロロコルヒチン(1.148 g, 2.65 mmol)を濃硫酸(3.8 mL)に溶解し、55℃で3時間攪拌し、さらに87℃で2時間攪拌した。反応液を氷水に注ぎ、1 mol/L水酸化ナトリウム水溶液(100 mL)を加えた。クロロホルム:メタノール=5:1で抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 162 mg, 15.1%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 9.49 (1H, s), 9.28 (1H, s), 8.60 (1H, d, J = 7.6 Hz), 7.13-7.10 (2H, m), 7.02 (1H, d, J = 11.0 Hz), 4.30-4.24 (1H, m), 3.88 (3H, s), 3.40 (3H, s), 3.03 (1H, dd, J = 13.3, 5.0 Hz), 2.07-1.98 (1H, m), 1.96-1.88 (1H, m), 1.85 (3H, s), 1.81-1.74 (1H, m).
ESI-MS m/z: 406 [M+H]+ . Example 233
Synthesis of 4-chloro-2,3-didemethylcolchicine 4-chlorocolchicine (1.148 g, 2.65 mmol) was dissolved in concentrated sulfuric acid (3.8 mL), stirred at 55 ° C for 3 hours, and further stirred at 87 ° C for 2 hours. did. The reaction solution was poured into ice water, and 1 mol / L aqueous sodium hydroxide solution (100 mL) was added. Extraction was performed with chloroform: methanol = 5: 1. Washed with saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 162 mg, 15.1%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.49 (1H, s), 9.28 (1H, s), 8.60 (1H, d, J = 7.6 Hz), 7.13-7.10 (2H, m ), 7.02 (1H, d, J = 11.0 Hz), 4.30-4.24 (1H, m), 3.88 (3H, s), 3.40 (3H, s), 3.03 (1H, dd, J = 13.3, 5.0 Hz) , 2.07-1.98 (1H, m), 1.96-1.88 (1H, m), 1.85 (3H, s), 1.81-1.74 (1H, m).
ESI-MS m / z: 406 [M + H] + .
実施例２３４
4-クロロ-2,3-(メチレンジオキシ)-2,3-ジデメトキシコルヒチンの合成
　4-クロロ-2,3-ジデメチルコルヒチン(51 mg, 0.126 mmol)をアセトニトリル(1.5 mL)に溶解した。そこへ炭酸カリウム(35 mg, 0.126×2 mmol)、ブロモクロロメタン(0.016 mL,0.126×2 mmol)を加えて7時間加熱還流した。さらに炭酸カリウム(35 mg, 0.126×2 mmol)、ブロモクロロメタン(0.016 mL, 0.126×2 mmol)、N,N-ジメチルホルムアミド(1.5 mL)を加えて90℃で一晩攪拌した。反応後、溶媒を留去した。水を加えてクロロホルム:メタノール=5:1で抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g,クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 36 mg, 68.4%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.57 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.10 (1H, d, J = 10.7 Hz), 7.01 (1H, d, J = 10.7 Hz), 6.20 (1H, d, J = 1.0 Hz), 6.19 (1H, d, J = 1.0 Hz), 4.30-4.24 (1H, m), 3.88 (3H, s), 3.74 (3H, s), 2.99 (1H, dd, J = 13.2, 4.9 Hz), 2.09-2.01 (1H, m), 1.97-1.89 (1H, m), 1.86 (3H, s), 1.82-1.75 (1H, m).
ESI-MS m/z: 418 [M+H]+ . Example 234
Synthesis of 4-chloro-2,3- (methylenedioxy) -2,3-didemethoxycolchicine 4-chloro-2,3-didemethylcolchicine (51 mg, 0.126 mmol) was dissolved in acetonitrile (1.5 mL) . Potassium carbonate (35 mg, 0.126 × 2 mmol) and bromochloromethane (0.016 mL, 0.126 × 2 mmol) were added thereto, and the mixture was heated to reflux for 7 hours. Furthermore, potassium carbonate (35 mg, 0.126 × 2 mmol), bromochloromethane (0.016 mL, 0.126 × 2 mmol), and N, N-dimethylformamide (1.5 mL) were added, and the mixture was stirred at 90 ° C. overnight. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform: methanol = 5: 1. Washed with saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 36 mg, 68.4%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.57 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.10 (1H, d, J = 10.7 Hz), 7.01 ( 1H, d, J = 10.7 Hz), 6.20 (1H, d, J = 1.0 Hz), 6.19 (1H, d, J = 1.0 Hz), 4.30-4.24 (1H, m), 3.88 (3H, s), 3.74 (3H, s), 2.99 (1H, dd, J = 13.2, 4.9 Hz), 2.09-2.01 (1H, m), 1.97-1.89 (1H, m), 1.86 (3H, s), 1.82-1.75 ( 1H, m).
ESI-MS m / z: 418 [M + H] + .
実施例２３５
4-クロロ-2,3-(エチレンジオキシ)-2,3-ジデメトキシコルヒチンの合成
　4-クロロ-2,3-ジデメチルコルヒチン(51 mg, 0.126 mmol)をアセトニトリル(1.5 mL)、N,N-ジメチルホルムアミド(1.5 mL)に溶解した。そこへ1,2-ジブロモエタン(0.012 mL, 0.126×1.1 mmol)、炭酸カリウム(44 mg, 0.126×2.5 mmol)、ヨウ化ナトリウム(1 mg, 0.126×0.05 mmol)を加えて90℃で一晩攪拌した。反応後、溶媒を留去した。水を加えてクロロホルム:メタノール=5:1で抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage IsoleraOne, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 9 mg, 16.5%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.11 (1H, s), 7.10 (1H, d, J = 11.0 Hz), 7.01 (1H, d, J = 11.0 Hz), 4.47-4.34 (4H, m), 4.28-4.22 (1H, m), 3.88 (3H, s), 3.51 (3H, s), 3.06 (1H, dd, J = 13.7, 5.6 Hz), 2.10-2.01 (1H, m), 1.96-1.88 (1H, m), 1.85 (3H, s), 1.83-1.75 (1H, m).
ESI-MS m/z: 432 [M+H]+ . Example 235
Synthesis of 4-chloro-2,3- (ethylenedioxy) -2,3-didemethoxycolchicine 4-chloro-2,3-didemethylcolchicine (51 mg, 0.126 mmol) in acetonitrile (1.5 mL), N, Dissolved in N-dimethylformamide (1.5 mL). 1,2-dibromoethane (0.012 mL, 0.126 × 1.1 mmol), potassium carbonate (44 mg, 0.126 × 2.5 mmol), sodium iodide (1 mg, 0.126 × 0.05 mmol) was added to it at 90 ° C. overnight. Stir. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform: methanol = 5: 1. Washed with saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage IsoleraOne, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 9 mg, 16.5%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.11 (1H, s), 7.10 (1H, d, J = 11.0 Hz), 7.01 ( 1H, d, J = 11.0 Hz), 4.47-4.34 (4H, m), 4.28-4.22 (1H, m), 3.88 (3H, s), 3.51 (3H, s), 3.06 (1H, dd, J = 13.7, 5.6 Hz), 2.10-2.01 (1H, m), 1.96-1.88 (1H, m), 1.85 (3H, s), 1.83-1.75 (1H, m).
ESI-MS m / z: 432 [M + H] + .
実施例２３６
1,2-ジデメチルコルヒチンの合成
　コルヒチン(1.214 g, 3.04 mmol)を濃硫酸(4.2 mL)に溶解し、55℃で3時間攪拌し、さらに87℃で2時間攪拌した。反応液を氷水に注ぎ、1 mol/L水酸化ナトリウム水溶液(100 mL)を加えた。クロロホルム:メタノール=5:1で抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 44 mg, 4.1%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.64 (1H, s), 8.55 (1H, s), 8.44 (1H, d, J = 7.8 Hz), 7.21 (1H, d, J = 10.7 Hz), 7.14 (1H, s), 7.00 (1H, d, J = 10.7 Hz), 6.42 (1H, s), 4.42-4.35 (1H, m), 3.86 (3H, s), 3.81 (3H, s), 2.48-2.43 (1H, m), 2.22-2.14 (1H, m), 2.04-1.95 (1H, m), 1.85 (3H, s), 1.80-1.72 (1H, m).
ESI-MS m/z: 372 [M+H]+ . Example 236
Synthesis of 1,2-didemethylcolchicine Colchicine (1.214 g, 3.04 mmol) was dissolved in concentrated sulfuric acid (4.2 mL), stirred at 55 ° C for 3 hours, and further stirred at 87 ° C for 2 hours. The reaction solution was poured into ice water, and 1 mol / L aqueous sodium hydroxide solution (100 mL) was added. Extraction was performed with chloroform: methanol = 5: 1. Washed with saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 44 mg, 4.1%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.64 (1H, s), 8.55 (1H, s), 8.44 (1H, d, J = 7.8 Hz), 7.21 (1H, d, J = 10.7 Hz), 7.14 (1H, s), 7.00 (1H, d, J = 10.7 Hz), 6.42 (1H, s), 4.42-4.35 (1H, m), 3.86 (3H, s), 3.81 (3H , s), 2.48-2.43 (1H, m), 2.22-2.14 (1H, m), 2.04-1.95 (1H, m), 1.85 (3H, s), 1.80-1.72 (1H, m).
ESI-MS m / z: 372 [M + H] + .
実施例２３７
1,2-(メチレンジオキシ)-1,2-ジデメトキシコルヒチンの合成
　1,2-デジメトキシコルヒチン(37 mg, 0.10 mmol)をN,N-ジメチルホルムアミド(1.1 mL)に溶解した。そこへ炭酸カリウム(28 mg, 0.10×2 mmol)、ブロモクロロメタン(0.013 mL, 0.10×2 mmol)を加えて90℃で一晩攪拌した。反応後、溶媒を留去した。水を加えてクロロホルム:メタノール=5:1で抽出した。飽和食塩水で洗った。無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage IsoleraOne, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 38 mg,99.1%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.52 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J = 10.5 Hz), 7.13 (1H, s), 7.00 (1H, d, J = 10.5 Hz), 6.62 (1H, s), 6.07 (2H, dd, J = 19.4, 0.9 Hz), 4.43-4.36 (1H, m), 3.86 (6H, s), 3.32 (3H, s), 2.60 (1H, dd, J = 13.3, 6.2 Hz), 2.30-2.22 (1H, m), 2.12-2.01 (1H, m), 1.90-1.87 (1H, m), 1.85 (3H, s).
ESI-MS m/z: 384 [M+H]+ . Example 237
Synthesis of 1,2- (methylenedioxy) -1,2-didemethoxycolchicine 1,2-dimethoxycolchicine (37 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (1.1 mL). Potassium carbonate (28 mg, 0.10 × 2 mmol) and bromochloromethane (0.013 mL, 0.10 × 2 mmol) were added thereto and stirred at 90 ° C. overnight. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform: methanol = 5: 1. Washed with saturated brine. It dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage IsoleraOne, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 38 mg, 99.1%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.52 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J = 10.5 Hz), 7.13 (1H, s), 7.00 ( 1H, d, J = 10.5 Hz), 6.62 (1H, s), 6.07 (2H, dd, J = 19.4, 0.9 Hz), 4.43-4.36 (1H, m), 3.86 (6H, s), 3.32 (3H , s), 2.60 (1H, dd, J = 13.3, 6.2 Hz), 2.30-2.22 (1H, m), 2.12-2.01 (1H, m), 1.90-1.87 (1H, m), 1.85 (3H, s ).
ESI-MS m / z: 384 [M + H] + .
実施例２３８
4-クロロ-1,2-(メチレンジオキシ)-1,2-ジデメトキシコルヒチンの合成
　1,2-(メチレンジオキシ)-1,2-ジデメトキシコルヒチン(23 mg, 0.0599 mmol)をアセトニトリル(0.5 mL)に溶解した。そこへN-クロロスクシンイミド(10 mg, 0.749 mmol)を加えて室温で2日間攪拌した。Waters社製MSトリガー付き分取LCシステムを用い、標記の化合物(黄色固体, 11 mg, 43.9%)を得た。
1H-NMR(400MHz, DMSO-d6) δ [ppm]: 8.57 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J = 10.7 Hz), 7.12 (1H, s), 7.01 (1H, d, J = 10.7 Hz), 6.16 (1H, d, J = 0.7 Hz), 6.13 (1H, d, J = 0.7 Hz), 4.35-4.28 (1H, m), 4.01 (3H, s), 3.88 (3H, s), 3.08 (1H, dd, J = 13.3, 5.2 Hz), 2.18-2.10 (1H, m), 2.04-1.95 (1H, m), 1.89-1.81 (4H, m).
ESI-MS m/z: 418 [M+H]+ .
MSトリガー付き分取システム
装置；Mass Detector 3100
Binary Gradient Module 2545
Sample Manager 2767
System Fludics Organizer
Photodiode Array Detector 2998
Mass Lynx
カラム；waters Sun Fire Prep C18 OBD(5μm 30×150 mm)
条件；水:アセトニトリル=9:1を2分間、その後20分間かけて水:アセトニトリル=9:1から水:アセトニトリル=1:9にグラジエントした。
流量；20 mL/分 Example 238
Synthesis of 4-chloro-1,2- (methylenedioxy) -1,2-didemethoxycolchicine 1,2- (methylenedioxy) -1,2-didemethoxycolchicine (23 mg, 0.0599 mmol) in acetonitrile ( 0.5 mL). N-chlorosuccinimide (10 mg, 0.749 mmol) was added thereto, and the mixture was stirred at room temperature for 2 days. The title compound (yellow solid, 11 mg, 43.9%) was obtained using a preparative LC system with an MS trigger manufactured by Waters.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.57 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J = 10.7 Hz), 7.12 (1H, s), 7.01 ( 1H, d, J = 10.7 Hz), 6.16 (1H, d, J = 0.7 Hz), 6.13 (1H, d, J = 0.7 Hz), 4.35-4.28 (1H, m), 4.01 (3H, s), 3.88 (3H, s), 3.08 (1H, dd, J = 13.3, 5.2 Hz), 2.18-2.10 (1H, m), 2.04-1.95 (1H, m), 1.89-1.81 (4H, m).
ESI-MS m / z: 418 [M + H] + .
MS trigger preparative system; Mass Detector 3100
Binary Gradient Module 2545
Sample Manager 2767
System Fludics Organizer
Photodiode Array Detector 2998
Mass Lynx
Column; waters Sun Fire Prep C18 OBD (5μm 30 × 150 mm)
Conditions: Water: acetonitrile = 9: 1 was gradient from water: acetonitrile = 9: 1 to water: acetonitrile = 1: 9 for 2 minutes and then for 20 minutes.
Flow rate: 20 mL / min
実施例２３９
4-クロロ-N-(エチルチオカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をメタノール-水 (2:1, 1.5 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸エチル (22 μl, 0.128 × 2 mmol) を加え、0℃で75分撹拌した。反応液をクロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 30 mg, 0.063 mmol, 49%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.44 (1H, br.s), 7.84 (1H, s), 7.50 (1H, dd, J = 10.7 Hz), 7.04 (1H, d, J = 11.0 Hz), 5.07-5.01 (1H, m), 4.07 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.74 (3H, s), 3.63-3.56 (1H, m), 3.38-3.33 (1H, m), 3.25 (1H, dd, J = 13.7, 5.4 Hz), 2.49-2.40 (1H, m), 2.13-2.10 (1H, m), 1.96-1.89 (1H, m), 1.11 (3H, t, J = 7.2 Hz).
ESI-MS m/z: 479 ([M+H]+) Example 239
Synthesis of 4-chloro-N- (ethylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in methanol-water (2: 1, 1.5 mL). Cooled to ° C. The ethyl isothiocyanate (22 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 30 mg, 0.063 mmol, 49%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.44 (1H, br.s), 7.84 (1H, s), 7.50 (1H, dd, J = 10.7 Hz), 7.04 (1H, d, J = 11.0 Hz), 5.07-5.01 (1H, m), 4.07 (3H, s), 4.00 (3H, s), 3.99 (3H, s), 3.74 (3H, s), 3.63-3.56 (1H, m) , 3.38-3.33 (1H, m), 3.25 (1H, dd, J = 13.7, 5.4 Hz), 2.49-2.40 (1H, m), 2.13-2.10 (1H, m), 1.96-1.89 (1H, m) , 1.11 (3H, t, J = 7.2 Hz).
ESI-MS m / z: 479 ([M + H] + )
実施例２４０
4-クロロ-N-(フェニルチオカルバモイル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-クロロデアセチルコルヒチン (50 mg, 0.128 mmol) をメタノール-水 (2:1, 1.5 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸フェニル (30μl, 0.128 × 2 mmol) を加え、0℃で75分撹拌した。反応液をクロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 50 mg, 0.095 mmol, 74%) を得た。
1H-NMR(400MHz, CDCl3) δ [ppm]: 8.85 (1H, br.s), 8.01 (1H, br.s), 7.86 (1H, d, J = 7.3 Hz), 7.50 (1H, d, J = 10.2 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.29-7.27 (2H, m), 7.15 (1H, t, J = 7.2Hz), 7.02 (1H, d, J = 11.2 Hz), 5.13-5.07 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.72 (3H, s), 3.20 (1H, dd, J = 13.8, 5.7 Hz), 2.45-2.35 (1H, m), 2.04-1.98 (1H, m), 1.94-1.86 (1H, m).
ESI-MS m/z: 527 ([M+H]+) Example 240
Synthesis of 4-chloro-N- (phenylthiocarbamoyl) deacetylcolchicine Under an argon atmosphere, 4-chlorodeacetylcolchicine (50 mg, 0.128 mmol) was dissolved in methanol-water (2: 1, 1.5 mL). Cooled to ° C. The phenyl isothiocyanate (30 microliters, 0.128 * 2 mmol) was added there, and it stirred at 0 degreeC for 75 minutes. The reaction solution was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 50 mg, 0.095 mmol, 74%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 8.85 (1H, br.s), 8.01 (1H, br.s), 7.86 (1H, d, J = 7.3 Hz), 7.50 (1H, d , J = 10.2 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.29-7.27 (2H, m), 7.15 (1H, t, J = 7.2 Hz), 7.02 (1H, d, J = 11.2 Hz ), 5.13-5.07 (1H, m), 4.04 (3H, s), 3.99 (3H, s), 3.99 (3H, s), 3.72 (3H, s), 3.20 (1H, dd, J = 13.8, 5.7 Hz), 2.45-2.35 (1H, m), 2.04-1.98 (1H, m), 1.94-1.86 (1H, m).
ESI-MS m / z: 527 ([M + H] + )
実施例２４１
4-クロロ-N-(4-ピペリジノピペリジン-1-カルボキシアセチル)デアセチルコルヒチンの合成
　4-クロロ-N-(ヒドロキシアセチル)デアセチルコルヒチン(0.107 g, 0.238 mmol)のジクロロメタン(有機合成用, 5 mL)溶液に、氷冷、アルゴンガス雰囲気下にて4-ジメチルアミノピリジン(12 mg, 0.238×0.4 mmol)、トリエチルアミン(82.9 μL, 0.238×2.5 mmol)及び、4-ピペリジノピペリジン-1-カルボニルクロリド(0.121 g, 0.238×2.2 mmol)を添加した。本溶液を徐々に室温に戻しながら一晩撹拌した後、クロロホルムと飽和重曹水を加えた。有機層を取り、水層は再びクロロホルムで抽出した。有機層は合わせてブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(乳白色固体, 0.112 g, 0.174 mmol, 73%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.74 (1H, d, J=7.6 Hz), 7.13 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.48 (2H, s), 4.27-4.21 (1H, m), 4.07-3.94 (2H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J=14.0, 4.5 Hz), 2.83-2.68 (2H, m), 2.56-2.33 (5H, m), 2.16-2.07 (1H, m), 2.00-1.83 (2H, m), 1.75-1.24 (10H, m).
ESI-MS m/z: 644 [M+H]+. Example 241
Synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine 4-chloro-N- (hydroxyacetyl) deacetylcolchicine (0.107 g, 0.238 mmol) in dichloromethane (for organic synthesis) , 5 mL) solution under ice-cooling and argon gas atmosphere, 4-dimethylaminopyridine (12 mg, 0.238 × 0.4 mmol), triethylamine (82.9 μL, 0.238 × 2.5 mmol) and 4-piperidinopiperidine- 1-Carbonyl chloride (0.121 g, 0.238 × 2.2 mmol) was added. The solution was stirred overnight while gradually returning to room temperature, and chloroform and saturated aqueous sodium hydrogen carbonate were added. The organic layer was taken and the aqueous layer was extracted again with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 0.112 g, 0.174 mmol, 73%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.74 (1H, d, J = 7.6 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.48 (2H, s), 4.27-4.21 (1H, m), 4.07-3.94 (2H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 14.0, 4.5 Hz), 2.83-2.68 (2H, m), 2.56-2.33 (5H, m), 2.16-2.07 (1H , m), 2.00-1.83 (2H, m), 1.75-1.24 (10H, m).
ESI-MS m / z: 644 [M + H] + .
実施例２４２
4-クロロ-N-(4-ピペリジノピペリジン-1-カルボキシアセチル)デアセチルコルヒチン塩酸塩の合成
　4-クロロ-N-(4-ピペリジノピペリジン-1-カルボキシアセチル)デアセチルコルヒチン(69 mg, 0.107 mmol)のアセトン(2 mL)溶液に、室温にて10%HCl-メタノール(65μL, 0.107×1.5 mmol)を添加した。本溶液を減圧下、濃縮乾固して標記化合物(乳白色固体, 72 mg,0.106 mmol, 99%, HPLC純度97.8%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.89 (1H, s), 8.78 (1H, d, J=7.3 Hz), 7.14 (1H, d, J=10.7 Hz), 7.12 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.50 (2H, s), 4.28-4.21 (1H, m), 4.12-3.99 (2H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.29-2.68 (6H, m), 3.12 (1H, dd, J=13.4, 5.4 Hz), 2.16-2.07 (1H, m), 2.01-1.34 (12H, m). Example 242
Synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine hydrochloride 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine (69 To a solution of mg, 0.107 mmol) in acetone (2 mL), 10% HCl-methanol (65 μL, 0.107 × 1.5 mmol) was added at room temperature. This solution was concentrated to dryness under reduced pressure to obtain the title compound (milky white solid, 72 mg, 0.106 mmol, 99%, HPLC purity 97.8%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.89 (1H, s), 8.78 (1H, d, J = 7.3 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.12 ( 1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.50 (2H, s), 4.28-4.21 (1H, m), 4.12-3.99 (2H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.54 (3H, s), 3.29-2.68 (6H, m), 3.12 (1H, dd, J = 13.4, 5.4 Hz), 2.16-2.07 (1H, m ), 2.01-1.34 (12H, m).
実施例２４３
4-クロロ-N-(1-メチルピペラジン-4-カルボキシアセチル)デアセチルコルヒチンの合成
　4-クロロ-N-(4-ピペリジノピペリジン-1-カルボキシアセチル)デアセチルコルヒチンの合成と同様の方法にて、標記化合物(乳白色固体, 25 mg, 0.043 mmol, 61%)を得た。4-ピペリジノピペリジン-1-カルボニルクロリドの代わりに1-メチルピペラジン-4-カルボニルクロリド塩酸塩(8.8 eq.)、さらにはトリエチルアミン(19 eq.)を用いた。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.33 (1H, s), 7.25 (1H, d, J=10.7 Hz), 7.09 (1H, s), 6.81 (1H, d, J=10.7Hz), 4.65 (1H, d, J=14.9 Hz), 4.61-4.54 (1H, m), 4.54 (1H, d, J=14.9 Hz), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.68-3.59 (4H, m), 3.62 (3H, s), 3.26 (1H, dd, J=13.1, 4.5 Hz), 2.62-2.40 (4H, m), 2.42 (3H, s), 2.28-2.14 (2H, m), 1.85-1.78 (1H, m).
ESI-MS m/z: 576 [M+H]+. Example 243
Synthesis of 4-chloro-N- (1-methylpiperazine-4-carboxyacetyl) deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine Gave the title compound (milky solid, 25 mg, 0.043 mmol, 61%). Instead of 4-piperidinopiperidine-1-carbonyl chloride, 1-methylpiperazine-4-carbonyl chloride hydrochloride (8.8 eq.) And triethylamine (19 eq.) Were used.
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.33 (1H, s), 7.25 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 6.81 (1H, d, J = 10.7 Hz), 4.65 (1H, d, J = 14.9 Hz), 4.61-4.54 (1H, m), 4.54 (1H, d, J = 14.9 Hz), 4.00 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.68-3.59 (4H, m), 3.62 (3H, s), 3.26 (1H, dd, J = 13.1, 4.5 Hz), 2.62-2.40 (4H, m), 2.42 (3H, s), 2.28-2.14 (2H, m), 1.85-1.78 (1H, m).
ESI-MS m / z: 576 [M + H] + .
実施例２４４
4-クロロ-N-(ジメチルアミノアセトキシアセチル)デアセチルコルヒチンの合成
　4-クロロ-N-(4-ピペリジノピペリジン-1-カルボキシアセチル)デアセチルコルヒチンの合成と同様の方法にて、標記化合物(乳白色固体, 35 mg)を得た。4-ピペリジノピペリジン-1-カルボニルクロリドの代わりにN,N-ジメチルグリシンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.86 (1H, d, J=6.3 Hz), 7.42 (1H, s), 7.27 (1H, d, J=10.7 Hz), 6.82 (1H, d, J=10.7 Hz), 4.67 (1H, d, J=15.4 Hz), 4.65-4.57 (1H, m), 4.60 (1H, d, J=15.4 Hz), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.41-3.24 (3H, m), 2.43 (3H, s), 2.42 (3H, s), 2.28-2.14 (2H, m), 1.97-1.90 (1H, m).
ESI-MS m/z : 535 [M+H]+. Example 244
Synthesis of 4-chloro-N- (dimethylaminoacetoxyacetyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine, the title compound (Oil white solid, 35 mg) was obtained. N, N-dimethylglycine was used instead of 4-piperidinopiperidine-1-carbonyl chloride.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.86 (1H, d, J = 6.3 Hz), 7.42 (1H, s), 7.27 (1H, d, J = 10.7 Hz), 6.82 ( 1H, d, J = 10.7 Hz), 4.67 (1H, d, J = 15.4 Hz), 4.65-4.57 (1H, m), 4.60 (1H, d, J = 15.4 Hz), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.41-3.24 (3H, m), 2.43 (3H, s), 2.42 (3H, s), 2.28-2.14 (2H, m), 1.97-1.90 (1H, m).
ESI-MS m / z: 535 [M + H] + .
実施例２４５
4-クロロ-N-[3-(ジメチルアミノ)プロピオニルオキシアセチル]デアセチルコルヒチンの合成
　4-クロロ-N-(4-ピペリジノピペリジン-1-カルボキシアセチル)デアセチルコルヒチンの合成と同様の方法にて、標記化合物(乳白色固体, 33 mg)を得た。4-ピペリジノピペリジン-1-カルボニルクロリドの代わりにN,N-ジメチルホモグリシンを用いた。
ESI-MS m/z : 549 [M+H]+. Example 245
Synthesis of 4-chloro-N- [3- (dimethylamino) propionyloxyacetyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine Gave the title compound (milky white solid, 33 mg). N, N-dimethylhomoglycine was used instead of 4-piperidinopiperidine-1-carbonyl chloride.
ESI-MS m / z: 549 [M + H] + .
実施例２４６
4-クロロ-N-[1-(ベンジルオキシカルボニル)ピペリジン-4-カルボキシアセチル]デアセチルコルヒチンの合成
　4-クロロ-N-(ヒドロキシアセチル)デアセチルコルヒチン(50 mg, 0.111 mmol)のジクロロメタン(有機合成用, 2.2 mL)溶液に、室温、アルゴンガス雰囲気下にて1-(ベンジルオキシカルボニル)ピペリジン-4-カルボン酸(58 mg, 0.111×2 mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(47 mg, 0.4111×2.2 mmol)、及び4-(ジメチルアミノ)ピリジン(5 mg, 0.111×0.4 mmol)を添加して一晩撹拌した。反応液をクロロホルム及びブラインで希釈して、有機層を取った。有機層は飽和重曹水、次いでブラインで洗浄後、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残留物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記化合物(乳白色固体, 72 mg, 0.104 mmol, 94%)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.41 (1H, s), 7.39-7.31 (5H, m), 7.30 (1H, d, J=10.7 Hz), 7.01 (1H, s), 6.85 (1H, d, J=10.7 Hz), 5.13 (2H, s), 4.65-4.55 (1H, m), 4.63 (1H, d, J=15.6 Hz), 4.56 (1H, d, J=15.6 Hz), 4.21-4.09 (2H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.61 (3H, s), 3.28 (1H, dd, J=13.1, 4.5 Hz), 2.97-2.86 (2H, m), 2.65-2.56 (1H, m), 2.32-2.14 (2H, m), 2.00-1.64 (5H, m).
ESI-MS m/z: 695 [M+H]+. Example 246
Synthesis of 4-chloro-N- [1- (benzyloxycarbonyl) piperidine-4-carboxyacetyl] deacetylcolchicine 4-chloro-N- (hydroxyacetyl) deacetylcolchicine (50 mg, 0.111 mmol) in dichloromethane (organic (For synthesis, 2.2 mL) solution, 1- (benzyloxycarbonyl) piperidine-4-carboxylic acid (58 mg, 0.111 × 2 mmol), 1-ethyl-3- (3-dimethyl) at room temperature under argon gas atmosphere Aminopropyl) carbodiimide hydrochloride (47 mg, 0.4111 × 2.2 mmol) and 4- (dimethylamino) pyridine (5 mg, 0.111 × 0.4 mmol) were added and stirred overnight. The reaction was diluted with chloroform and brine and the organic layer was taken. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 72 mg, 0.104 mmol, 94%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.41 (1H, s), 7.39-7.31 (5H, m), 7.30 (1H, d, J = 10.7 Hz), 7.01 (1H, s), 6.85 (1H, d, J = 10.7 Hz), 5.13 (2H, s), 4.65-4.55 (1H, m), 4.63 (1H, d, J = 15.6 Hz), 4.56 (1H, d, J = 15.6 Hz) ), 4.21-4.09 (2H, m), 4.02 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.61 (3H, s), 3.28 (1H, dd, J = 13.1, 4.5 Hz), 2.97-2.86 (2H, m), 2.65-2.56 (1H, m), 2.32-2.14 (2H, m), 2.00-1.64 (5H, m).
ESI-MS m / z: 695 [M + H] + .
実施例２４７
4-クロロ-N-(チオアセトキシアセチル)デアセチルコルヒチンの合成
　4-クロロ-N-(クロロアセチル)デアセチルコルヒチン(50 mg, 0.12 mmol)をアセトン(12mL)に溶解し、チオ酢酸カリウム(82 mg, 0.72 mmol, 6 eq)を加え65 ℃で3時間撹拌した。反応液を減圧留去し、残渣をクロロホルムに溶解し、水で洗浄した。有機層をブライン洗浄、無水硫酸マグネシウムにて乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルフラッシュカラムクロマトグラフィー (5%メタノール/酢酸エチル→ 10%メタノール/酢酸エチル)にて精製し、目的物の4-クロロ-N-(チオアセトキシアセチル)デアセチルコルヒチン(55.8 mg, 98 %)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.29 (1H, br-d), 7.28 (1H, s), 7.24 (1H, d, J=10.6 Hz), 6.80 (1H, d, J=10.8 Hz), 4.49 (1H, ddd, J=12.2, 6.1, 6.1 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.62 (1H, dd, J=14.5, 1.8 Hz), 3.60 (3H, s), 3.54 (1H, dd, J=14.4, 2.5 Hz), 3.25 (1H, m), 2.45 (3H, s), 2.25-2.12 (2H, overlapped), 1.78 (1H, ddd, J=11.0, 11.0, 4.9 Hz).
FAB-MS (NBA) m/z： 508 [M+H]+ Example 247
Synthesis of 4-chloro-N- (thioacetoxyacetyl) deacetylcolchicine 4-Chloro-N- (chloroacetyl) deacetylcolchicine (50 mg, 0.12 mmol) was dissolved in acetone (12 mL) and potassium thioacetate (82 mg, 0.72 mmol, 6 eq) was added, and the mixture was stirred at 65 ° C. for 3 hours. The reaction solution was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum. The obtained residue was purified by silica gel flash column chromatography (5% methanol / ethyl acetate → 10% methanol / ethyl acetate), and the desired 4-chloro-N- (thioacetoxyacetyl) deacetylcolchicine (55.8 mg , 98%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.29 (1H, br-d), 7.28 (1H, s), 7.24 (1H, d, J = 10.6 Hz), 6.80 (1H, d, J = 10.8 Hz), 4.49 (1H, ddd, J = 12.2, 6.1, 6.1 Hz), 4.00 (3H, s), 3.98 (3H, s), 3.97 (3H, s), 3.62 (1H, dd, J = 14.5, 1.8 Hz), 3.60 (3H, s), 3.54 (1H, dd, J = 14.4, 2.5 Hz), 3.25 (1H, m), 2.45 (3H, s), 2.25-2.12 (2H, overlapped), 1.78 (1H, ddd, J = 11.0, 11.0, 4.9 Hz).
FAB-MS (NBA) m / z: 508 [M + H] +
実施例２４８
4-クロロ-N-(メルカプトアセチル)デアセチルコルヒチンの合成
　4-クロロ-N-(チオアセトキシアセチル)デアセチルコルヒチン(10 mg, 0.020 mmolをメタノール(4.5 mL)に溶解し、1M ナトリウムメトキシド(30 μL, 0.030 mmol, 1.5 eq)を加え室温で40分間撹拌した。反応液に酢酸(3滴)を加え、弱酸性とした後、溶媒を減圧留去した。残渣をクロロホルムに溶解し、水で洗浄、有機層をブライン洗浄、無水硫酸マグネシウム乾燥、ろ過、減圧留去、真空乾燥した。得られた残渣をシリカゲルフラッシュカラムクロマトグラフィー (2%メタノール/クロロホルム→5%メタノール/クロロホルム)にて精製し、目的物の4-クロロ-N-(チオアセチル)デアセチルコルヒチン(9.5 mg, 定量的)を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.67 (1H, br-d, J=7.0 Hz), 7.40 (1H, s), 7.28 (1H, d, J=10.4 Hz), 6.83 (1H, d, J=10.8 Hz), 4.53 (1H, ddd, J=12.1, 6.2, 6.2 Hz), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H, s), 3.26 (3H, m), 2.33 (2H, m), 1.84 (1H, ddd, J=11.5, 11.5, 4.9 Hz).
FAB-MS (NBA) m/z： 466 [M+H]+ Example 248
Synthesis of 4-chloro-N- (mercaptoacetyl) deacetylcolchicine 4-chloro-N- (thioacetoxyacetyl) deacetylcolchicine (10 mg, 0.020 mmol was dissolved in methanol (4.5 mL), and 1M sodium methoxide ( 30 μL, 0.030 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 40 minutes.Acetic acid (3 drops) was added to the reaction solution to make it weakly acidic, and the solvent was distilled off under reduced pressure. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced pressure, and dried under vacuum, and the resulting residue was purified by silica gel flash column chromatography (2% methanol / chloroform → 5% methanol / chloroform). As a result, 4-chloro-N- (thioacetyl) deacetylcolchicine (9.5 mg, quantitative) was obtained.
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.67 (1H, br-d, J = 7.0 Hz), 7.40 (1H, s), 7.28 (1H, d, J = 10.4 Hz), 6.83 ( 1H, d, J = 10.8 Hz), 4.53 (1H, ddd, J = 12.1, 6.2, 6.2 Hz), 4.01 (3H, s), 3.99 (3H, s), 3.97 (3H, s), 3.62 (3H , s), 3.26 (3H, m), 2.33 (2H, m), 1.84 (1H, ddd, J = 11.5, 11.5, 4.9 Hz).
FAB-MS (NBA) m / z: 466 [M + H] +
実施例２４９
4-クロロ-N-[1-(エトキシカルボニル)ピペリジン-4-イルカルボニル]デアセチルコルヒチンの合成
　1-(エトキシカルボニル)ピペリジン-4-カルボン酸(17 mg, 0.0766×1.1 mmol)のジクロロメタン(2 mL)溶液に、氷冷、アルゴンガス雰囲気下にて1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(16 mg, 0.0766×1.1 mmol)及び1-ヒドロキシベンゾトリアゾール一水和物(13 mg, 0.0766×1.1 mmol)を添加して、30分間撹拌した。次いで、4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)を添加して、徐々に室温に戻しながら一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 41 mg, 0.0714 mmol, 93%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.59 (1H, d, J=7.3 Hz), 7.12 (1H, d, J=10.7 Hz), 7.09 (1H, s), 7.02 (1H, d, J=10.7 Hz), 4.24-4.17 (1H, m), 4.01-3.87 (2H, m), 4.01 (2H, q, J=7.1 Hz), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J=13.2, 5.4 Hz), 2.86-2.72 (2H, m), 2.45-2.37 (1H, m), 2.15-2.06 (1H, m), 2.00-1.81 (2H, m), 1.66 (2H, dd, J=28.8, 11.2 Hz), 1.40-1.27 (2H, m), 1.16 (3H, t, J=7.1 Hz).
ESI-MS m/z: 575 [M+H]+. Example 249
Synthesis of 4-chloro-N- [1- (ethoxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine 1- (ethoxycarbonyl) piperidine-4-carboxylic acid (17 mg, 0.0766 × 1.1 mmol) in dichloromethane (2 1) -ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (16 mg, 0.0766 × 1.1 mmol) and 1-hydroxybenzotriazole monohydrate under ice-cooling and argon gas atmosphere (13 mg, 0.0766 × 1.1 mmol) was added and stirred for 30 minutes. Next, 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) was added, and the mixture was stirred overnight while gradually returning to room temperature. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 41 mg, 0.0714 mmol, 93%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.12 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 4.24-4.17 (1H, m), 4.01-3.87 (2H, m), 4.01 (2H, q, J = 7.1 Hz), 3.91 (3H, s), 3.88 (3H , s), 3.88 (3H, s), 3.53 (3H, s), 3.11 (1H, dd, J = 13.2, 5.4 Hz), 2.86-2.72 (2H, m), 2.45-2.37 (1H, m), 2.15-2.06 (1H, m), 2.00-1.81 (2H, m), 1.66 (2H, dd, J = 28.8, 11.2 Hz), 1.40-1.27 (2H, m), 1.16 (3H, t, J = 7.1 Hz).
ESI-MS m / z: 575 [M + H] + .
参考例２３
4-([1,3]ジチオラン-2-イル)コルヒチンの合成
　4-ホルミルコルヒチン(50 mg, 0.117 mmol)のクロロホルム(1 mL)溶液に、室温、アルゴンガス雰囲気下にて1,2-エタンジチオール(14.6μL, 0.117×1.5 mmol)及びヨウ素(3 mg, 0.117×0.1 mmol)を加えて、一晩撹拌した。反応液に10%亜硫酸ナトリウムを加えて、10分間撹拌した後、クロロホルムを加えて有機層を取った。有機層はブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 32 mg, 0.0634 mmol, 54%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.56 (1H, d, J=7.1 Hz), 7.08 (1H, s), 7.05 (1H, d, J=10.7 Hz), 7.00 (1H, d, J=10.7 Hz), 6.38 (1H, s), 4.28-4.21 (1H, m), 3.88 (3H, s), 3.87 (3H, s), 3.84 (3H, s), 3.71 (1H, dd, J=13.5, 5.5 Hz), 3.58-3.51 (2H, m), 3.50 (3H, s), 3.42-3.35 (2H, m), 2.25-2.17 (1H, m), 2.03-1.95 (1H, m), 1.86 (3H, s), 1.80-1.72 (1H, m).
ESI-MS m/z: 504 [M+H]+. Reference Example 23
Synthesis of 4-([1,3] dithiolan-2-yl) colchicine To a solution of 4-formylcolchicine (50 mg, 0.117 mmol) in chloroform (1 mL) at room temperature under an argon gas atmosphere, 1,2-ethane Dithiol (14.6 μL, 0.117 × 1.5 mmol) and iodine (3 mg, 0.117 × 0.1 mmol) were added and stirred overnight. To the reaction solution was added 10% sodium sulfite, and the mixture was stirred for 10 minutes. Then, chloroform was added to remove the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 32 mg, 0.0634 mmol, 54%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.56 (1H, d, J = 7.1 Hz), 7.08 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 7.00 ( 1H, d, J = 10.7 Hz), 6.38 (1H, s), 4.28-4.21 (1H, m), 3.88 (3H, s), 3.87 (3H, s), 3.84 (3H, s), 3.71 (1H , dd, J = 13.5, 5.5 Hz), 3.58-3.51 (2H, m), 3.50 (3H, s), 3.42-3.35 (2H, m), 2.25-2.17 (1H, m), 2.03-1.95 (1H , m), 1.86 (3H, s), 1.80-1.72 (1H, m).
ESI-MS m / z: 504 [M + H] + .
参考例２４
4-([1,3]ジチアン-2-イル)コルヒチンの合成
　4-([1,3]ジチオラン-2-イル)コルヒチンの合成と同様の方法にて、標記化合物(淡褐色固体, 0.224 g, 0.432 mmol, 74%)を得た。1,2-エタンジチオールの代わりに、1,3-プロパンジチオールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.58 (1H, d, J=7.3 Hz), 7.08 (1H, s), 7.05 (1H, d, J=10.7 Hz), 6.99 (1H, d, J=10.7 Hz), 4.26-4.20 (1H, m), 3.94-3.89 (1H, m), 3.88 (3H, m), 3.88 (3H, s), 3.87 (3H, s), 3.50 (3H, s), 3.18-3.09 (2H, m), 2.94-2.85 (2H, m), 2.19-2.01 (3H, m), 1.88-1.80 (1H, m), 1.86 (3H, s), 1.73-1.63 (1H, m).
ESI-MS m/z: 518 [M+H]+. Reference Example 24
Synthesis of 4-([1,3] dithian-2-yl) colchicine In the same manner as the synthesis of 4-([1,3] dithiolan-2-yl) colchicine, the title compound (light brown solid, 0.224 g , 0.432 mmol, 74%). Instead of 1,2-ethanedithiol, 1,3-propanedithiol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.58 (1H, d, J = 7.3 Hz), 7.08 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 6.99 ( 1H, d, J = 10.7 Hz), 4.26-4.20 (1H, m), 3.94-3.89 (1H, m), 3.88 (3H, m), 3.88 (3H, s), 3.87 (3H, s), 3.50 (3H, s), 3.18-3.09 (2H, m), 2.94-2.85 (2H, m), 2.19-2.01 (3H, m), 1.88-1.80 (1H, m), 1.86 (3H, s), 1.73 -1.63 (1H, m).
ESI-MS m / z: 518 [M + H] + .
参考例２５
4-(ヒドロキシメチル)コルヒチンの合成
　4-ホルミルコルヒチン(100 mg, 0.234 mmol)のメタノール(2.5 mL)溶液に、室温、アルゴンガス雰囲気下にて水素化ホウ素ナトリウム(13 mg, 0.234×1.5 mmol)を添加して、室温で3時間撹拌した。反応液にアセトンを加えて30分間撹拌した後、クロロホルムと水を加えた。有機層を取り、水層はさらにクロロホルムにて抽出した。有機層は合わせてブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 74 mg, 0.173 mmol, 74%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.55 (1H, d, J=7.3 Hz), 7.11 (1H, s), 7.09 (1H, d, J=10.7 Hz), 7.02 (1H, d, J=10.7 Hz), 4.87 (1H, t, J=5.1 Hz), 4.54 (1H, dd, J=11.3, 4.4 Hz), 4.47 (1H, dd, J=11.3, 5.9 Hz), 4.31-4.24 (1H, m), 3.88 (3H, s), 3.87 (3H, s), 3.83 (3H, s), 3.50 (3H, s), 3.00 (1H, dd, J=12.6, 4.5 Hz), 2.10-1.95 (2H, m), 1.85 (3H, s), 1.81-1.73 (1H, m).
ESI-MS m/z: 430 [M+H]+. Reference Example 25
Synthesis of 4- (hydroxymethyl) colchicine 4-formylcolchicine (100 mg, 0.234 mmol) in methanol (2.5 mL) solution at room temperature under argon gas sodium borohydride (13 mg, 0.234 × 1.5 mmol) Was added and stirred at room temperature for 3 hours. Acetone was added to the reaction solution and stirred for 30 minutes, and then chloroform and water were added. The organic layer was taken and the aqueous layer was further extracted with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 74 mg, 0.173 mmol, 74%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.55 (1H, d, J = 7.3 Hz), 7.11 (1H, s), 7.09 (1H, d, J = 10.7 Hz), 7.02 ( 1H, d, J = 10.7 Hz), 4.87 (1H, t, J = 5.1 Hz), 4.54 (1H, dd, J = 11.3, 4.4 Hz), 4.47 (1H, dd, J = 11.3, 5.9 Hz), 4.31-4.24 (1H, m), 3.88 (3H, s), 3.87 (3H, s), 3.83 (3H, s), 3.50 (3H, s), 3.00 (1H, dd, J = 12.6, 4.5 Hz) , 2.10-1.95 (2H, m), 1.85 (3H, s), 1.81-1.73 (1H, m).
ESI-MS m / z: 430 [M + H] + .
実施例２５０
4-(フルオロメチル)コルヒチンの合成
　4-(ヒドロキシメチル)コルヒチン(30 mg, 0.0699 mmol)のジクロロメタン(1 mL)溶液に、氷冷、アルゴンガス雰囲気下にて(ジエチルアミノ)サルファートリフルオリド(11.0μL , 0.0699×1.2 mmol)を添加して、氷冷下2時間撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 19 mg, 0.0442 mmol, 63%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.60 (1H, d, J=7.3 Hz), 7.11 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J=10.7 Hz), 5.49 (2H, d, J=48.5 Hz), 4.28-4.21 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 2.93 (1H, dd, J=13.9, 4.6 Hz), 2.13-1.94 (2H, m), 1.86-1.77 (1H, m), 1.85 (3H, s).
ESI-MS m/z: 432 [M+H]+. Example 250
Synthesis of 4- (fluoromethyl) colchicine To a solution of 4- (hydroxymethyl) colchicine (30 mg, 0.0699 mmol) in dichloromethane (1 mL) under ice-cooling and argon gas atmosphere (diethylamino) sulfur trifluoride (11.0 μL) , 0.0699 × 1.2 mmol) was added, and the mixture was stirred for 2 hours under ice cooling. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 19 mg, 0.0442 mmol, 63%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.60 (1H, d, J = 7.3 Hz), 7.11 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 5.49 (2H, d, J = 48.5 Hz), 4.28-4.21 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.87 (3H, s ), 3.54 (3H, s), 2.93 (1H, dd, J = 13.9, 4.6 Hz), 2.13-1.94 (2H, m), 1.86-1.77 (1H, m), 1.85 (3H, s).
ESI-MS m / z: 432 [M + H] + .
実施例２５１
4-(ジフルオロメチル)コルヒチンの合成
　N-ヨードコハク酸イミド(87 mg, 0.0966×4 mmol)のジクロロメタン(5 mL)溶液に、-78℃付近、アルゴンガス雰囲気下にて、フッ化水素・ピリジン(HF:65%, 119 mg, 0.0966×40 mmol)のジクロロメタン(1 mL)溶液を添加した。-78℃付近で20分間撹拌した後、4-([1,3]ジチアン-2-イル)コルヒチン(50 mg, 0.0966 mmol)のジクロロメタン(1 mL)溶液を添加して、徐々に室温に戻しながら一晩撹拌した。反応液に10%亜硫酸ナトリウムを加えて10分間撹拌した後、クロロホルムと飽和重曹水を加えた。有機層を取り、飽和重曹水、0.1mol/L塩酸、飽和重曹水次いでブラインで洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物[41 mg, HPLC純度:60%(4-CHO体:23%)]をメタノール(2 mL)に溶解し、室温、アルゴンガス雰囲気下にて、水素化ホウ素ナトリウム(2 mg, 0.0966×0.5 mmol)を添加して、30分間撹拌した後、アセトンを加えて、さらに30分間撹拌した。反応液にクロロホルムと水を加えて有機層を取った。有機層はブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(白色固体, 30 mg, 0.0674 mmol, 70%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.62 (1H, d, J=7.3 Hz), 7.25 (1H, t, J=54.0 Hz), 7.11 (1H, d, J=10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.28-4.21 (1H, m), 3.90 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.56 (3H, s), 3.11 (1H, dd, J=13.7, 4.9 Hz), 2.17-2.08 (1H, m), 1.99-1.91 (1H, m), 1.87-1.80 (1H, m), 1.86 (3H, s).
ESI-MS m/z: 450 [M+H]+. Example 251
Synthesis of 4- (difluoromethyl) colchicine To a solution of N-iodosuccinimide (87 mg, 0.0966 × 4 mmol) in dichloromethane (5 mL) at −78 ° C. under an argon gas atmosphere, hydrogen fluoride / pyridine ( (HF: 65%, 119 mg, 0.0966 × 40 mmol) in dichloromethane (1 mL) was added. After stirring at around -78 ° C for 20 minutes, a solution of 4-([1,3] dithian-2-yl) colchicine (50 mg, 0.0966 mmol) in dichloromethane (1 mL) was added, and the temperature was gradually returned to room temperature. Stir overnight. After adding 10% sodium sulfite to the reaction solution and stirring for 10 minutes, chloroform and saturated aqueous sodium hydrogen carbonate were added. The organic layer was taken, washed with saturated aqueous sodium hydrogen carbonate, 0.1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue [41 mg, HPLC purity: 60% (4-CHO form: 23%)] was dissolved in methanol (2 mL), and sodium borohydride (2 mg, 0.0966 ×) at room temperature under an argon gas atmosphere. 0.5 mmol) was added and stirred for 30 minutes, then acetone was added and stirred for another 30 minutes. Chloroform and water were added to the reaction solution to obtain an organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (white solid, 30 mg, 0.0674 mmol, 70%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.62 (1H, d, J = 7.3 Hz), 7.25 (1H, t, J = 54.0 Hz), 7.11 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.28-4.21 (1H, m), 3.90 (3H, s), 3.90 (3H, s), 3.89 (3H, s ), 3.56 (3H, s), 3.11 (1H, dd, J = 13.7, 4.9 Hz), 2.17-2.08 (1H, m), 1.99-1.91 (1H, m), 1.87-1.80 (1H, m), 1.86 (3H, s).
ESI-MS m / z: 450 [M + H] + .
実施例２５２
4-クロロ-N-(N’,N’-ジメチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 37 mg, 0.0766 mmol, 定量的)を得た。ジエチルアミンの代わりに、ジメチルアミン塩酸塩及びトリエチルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.63 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=11.0 Hz), 7.09 (1H, s), 7.02 (1H, d, J=11.0 Hz), 4.91-4.85 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.20 (6H, s), 3.12 (1H, dd, J=13.2, 5.1 Hz), 2.26-2.18 (1H, m), 2.16-2.08 (1H, m), 2.04-1.95 (1H, m).
ESI-MS m/z: 479 [M+H]+. Example 252
Synthesis of 4-chloro-N- (N ', N'-dimethylthiocarbamoyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (pale yellow solid, 37 mg, 0.0766 mmol, quantitative) was obtained. Instead of diethylamine, dimethylamine hydrochloride and triethylamine were used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.63 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 11.0 Hz), 7.09 (1H, s), 7.02 ( 1H, d, J = 11.0 Hz), 4.91-4.85 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.20 (6H , s), 3.12 (1H, dd, J = 13.2, 5.1 Hz), 2.26-2.18 (1H, m), 2.16-2.08 (1H, m), 2.04-1.95 (1H, m).
ESI-MS m / z: 479 [M + H] + .
実施例２５３
4-クロロ-N-(N’,N’-ジプロピルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 41 mg, 0.0747 mmol, 98%)を得た。ジエチルアミンの代わりに、ジ-n-プロピルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.50 (1H, d, J=7.1 Hz), 7.14 (1H, d, J=10.7 Hz), 7.09 (1H, s), 7.02 (1H, d, J=10.7 Hz), 5.01-4.94 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.69-3.61 (2H, m), 3.62 (3H, s), 3.54-3.46 (2H, m), 3.13 (1H, dd, J=13.3, 5.2 Hz), 2.31-2.23 (1H, m), 2.16-2.07 (1H, m), 2.01-1.93 (1H, m), 1.60-1.50 (4H, m), 0.83 (6H, t, J=7.3 Hz).
ESI-MS m/z: 535 [M+H]+. Example 253
Synthesis of 4-chloro-N- (N ', N'-dipropylthiocarbamoyl) deacetylcolchicine In the same way as the synthesis of 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (milky white solid, 41 mg, 0.0747 mmol, 98%) was obtained. Di-n-propylamine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.50 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 5.01-4.94 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.69-3.61 (2H, m), 3.62 (3H, s), 3.54 -3.46 (2H, m), 3.13 (1H, dd, J = 13.3, 5.2 Hz), 2.31-2.23 (1H, m), 2.16-2.07 (1H, m), 2.01-1.93 (1H, m), 1.60 -1.50 (4H, m), 0.83 (6H, t, J = 7.3 Hz).
ESI-MS m / z: 535 [M + H] + .
実施例２５４
4-クロロ-N-[N’-エチル-N’-プロピルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 40 mg, 0.0766 mmol, 定量的)を得た。ジエチルアミンの代わりに、N-エチル-n-プロピルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.51 (1H, d, J=7.1 Hz), 7.14 (1H, d, J=10.7 Hz), 7.09 (1H, s), 7.02 (1H, d, J=10.7 Hz), 5.01-4.95 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.74-3.52 (4H, m), 3.62 (3H, s), 3.12 (1H, dd, J=14.1, 5.1 Hz), 2.33-2.23 (1H, m), 2.15-2.07 (1H, m), 2.02-1.92 (1H, m), 1.60-1.51 (2H, m), 1.09 (3H, t, J=7.0 Hz), 0.83 (3H, t, J=7.3 Hz).
ESI-MS m/z: 521 [M+H]+. Example 254
Synthesis of 4-chloro-N- [N'-ethyl-N'-propylthiocarbamoyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (milky white solid, 40 mg, 0.0766 mmol, quantitative). N-ethyl-n-propylamine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.51 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 5.01-4.95 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.74-3.52 (4H, m), 3.62 (3H, s), 3.12 (1H, dd, J = 14.1, 5.1 Hz), 2.33-2.23 (1H, m), 2.15-2.07 (1H, m), 2.02-1.92 (1H, m), 1.60-1.51 (2H, m), 1.09 (3H, t, J = 7.0 Hz), 0.83 (3H, t, J = 7.3 Hz).
ESI-MS m / z: 521 [M + H] + .
実施例２５５
4-クロロ-N-[(4-ヒドロキシピペリジン-1-イル)チオカルボニル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 41 mg, 0.0766 mmol, 定量的)を得た。ジエチルアミンの代わりに、4-ヒドロキシピペリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.90 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=11.0 Hz), 7.06 (1H, s), 7.02 (1H, d, J=11.0 Hz), 4.95-4.88 (1H, m), 4.74 (1H, d, J=4.1 Hz), 4.28-4.17 (2H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.76-3.70 (1H, m), 3.62 (3H, s), 3.49-3.38 (2H, m), 3.12 (1H, dd, J=12.9, 5.4 Hz), 2.22-1.96 (3H, m), 1.75-1.68 (2H, m), 1.35-1.26 (2H, m).
ESI-MS m/z: 535 [M+H]+. Example 255
Synthesis of 4-chloro-N-[(4-hydroxypiperidin-1-yl) thiocarbonyl] deacetylcolchicine Similar to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine By the method, the title compound (milky white solid, 41 mg, 0.0766 mmol, quantitative) was obtained. Instead of diethylamine, 4-hydroxypiperidine was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.90 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 11.0 Hz), 7.06 (1H, s), 7.02 ( 1H, d, J = 11.0 Hz), 4.95-4.88 (1H, m), 4.74 (1H, d, J = 4.1 Hz), 4.28-4.17 (2H, m), 3.91 (3H, s), 3.88 (3H , s), 3.88 (3H, s), 3.76-3.70 (1H, m), 3.62 (3H, s), 3.49-3.38 (2H, m), 3.12 (1H, dd, J = 12.9, 5.4 Hz), 2.22-1.96 (3H, m), 1.75-1.68 (2H, m), 1.35-1.26 (2H, m).
ESI-MS m / z: 535 [M + H] + .
実施例２５６
4-クロロ-N-[(4-メチルピペリジン-1-イル)チオカルボニル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 41 mg, 0.0766 mmol, 定量的)を得た。ジエチルアミンの代わりに、4-メチルピペリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.86 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=10.7 Hz), 7.06 (2H, s), 7.02 (2H, d, J=11.7 Hz), 4.95-4.89 (1H, m), 4.65 (2H, dd, J=28.4, 14.0 Hz), 3.91 (3H, s), 3.88 (6H, s), 3.62 (3H, s), 3.12 (1H, dd, J=12.9, 5.1 Hz), 2.98 (2H, q, J=12.8 Hz), 2.23-1.94 (3H, m), 1.62 (3H, t, J=10.5 Hz), 1.09-0.93 (2H, m), 0.89 (3H, d, J=6.1 Hz).
ESI-MS m/z: 533 [M+H]+. Example 256
Synthesis of 4-chloro-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine Similar to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine By the method, the title compound (pale yellow solid, 41 mg, 0.0766 mmol, quantitative) was obtained. 4-methylpiperidine was used instead of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.86 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.06 (2H, s), 7.02 ( 2H, d, J = 11.7 Hz), 4.95-4.89 (1H, m), 4.65 (2H, dd, J = 28.4, 14.0 Hz), 3.91 (3H, s), 3.88 (6H, s), 3.62 (3H , s), 3.12 (1H, dd, J = 12.9, 5.1 Hz), 2.98 (2H, q, J = 12.8 Hz), 2.23-1.94 (3H, m), 1.62 (3H, t, J = 10.5 Hz) , 1.09-0.93 (2H, m), 0.89 (3H, d, J = 6.1 Hz).
ESI-MS m / z: 533 [M + H] + .
実施例２５７
4-クロロ-N-{N’-[2-(ジメチルアミノ)エチル]-N’-メチルチオカルバモイル}デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 38 mg, 0.0710 mmol, 93%)を得た。ジエチルアミンの代わりに、N,N,N’-トリメチルエチレンジアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.15 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.02 (1H, d, J=10.7 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.86-3.66 (2H, m), 3.62 (3H, s), 3.17 (3H, s), 3.16-3.10 (1H, m), 2.27 (6H, s), 2.17-2.02 (3H, m).
ESI-MS m/z: 536 [M+H]+. Example 257
Synthesis of 4-chloro-N- {N '-[2- (dimethylamino) ethyl] -N'-methylthiocarbamoyl} deacetylcolchicine 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetyl The title compound (milky white solid, 38 mg, 0.0710 mmol, 93%) was obtained by a method similar to the synthesis of colchicine. Instead of diethylamine, N, N, N′-trimethylethylenediamine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.15 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 4.83- 4.77 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.86-3.66 (2H, m), 3.62 (3H, s), 3.17 (3H, s) , 3.16-3.10 (1H, m), 2.27 (6H, s), 2.17-2.02 (3H, m).
ESI-MS m / z: 536 [M + H] + .
実施例２５８
4-クロロ-N-{[4-(ジメチルアミノ)ピペリジン-1-イル]チオカルバモイル}デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 28 mg, 0.0499 mmol, 65%)を得た。ジエチルアミンの代わりに、4-(ジメチルアミノ)ピペリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.92 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.02 (1H, d, J=10.7 Hz), 4.93-4.87 (1H, m), 4.66 (2H, dd, J=25.5, 13.5 Hz), 3.91 (3H, s), 3.88 (6H, s), 3.62 (3H, s), 3.12 (1H, dd, J=12.7, 5.6 Hz), 3.01 (2H, q, J=11.8 Hz), 2.44-2.36 (1H, m), 2.22-1.97 (3H, m), 2.17 (6H, s), 1.74 (2H, t, J=11.8 Hz), 1.33-1.26 (2H, m).
ESI-MS m/z: 562 [M+H]+. Example 258
Synthesis of 4-chloro-N-{[4- (dimethylamino) piperidin-1-yl] thiocarbamoyl} deacetylcolchicine Synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine In the same manner, the title compound (milky white solid, 28 mg, 0.0499 mmol, 65%) was obtained. 4- (Dimethylamino) piperidine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.92 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 4.93-4.87 (1H, m), 4.66 (2H, dd, J = 25.5, 13.5 Hz), 3.91 (3H, s), 3.88 (6H, s), 3.62 (3H , s), 3.12 (1H, dd, J = 12.7, 5.6 Hz), 3.01 (2H, q, J = 11.8 Hz), 2.44-2.36 (1H, m), 2.22-1.97 (3H, m), 2.17 ( 6H, s), 1.74 (2H, t, J = 11.8 Hz), 1.33-1.26 (2H, m).
ESI-MS m / z: 562 [M + H] + .
実施例２５９
4-クロロ-N-(N’-エチル-N’-メチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 37 mg, 0.0746 mmol, 97%)を得た。ジエチルアミンの代わりに、N-エチルメチルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.58 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=10.7 Hz), 7.08 (1H, s), 7.02 (1H, d, J=10.7 Hz), 4.94-4.88 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.84-3.77 (1H, m), 3.69-3.62 (1H, m), 3.62 (3H, s), 3.15 (3H, s), 3.12 (1H, dd, J=13.3, 5.0 Hz), 2.28-2.20 (1H, m), 2.16-2.08 (1H, m), 2.04-1.95 (1H, m).
ESI-MS m/z: 493 [M+H]+. Example 259
Synthesis of 4-chloro-N- (N'-ethyl-N'-methylthiocarbamoyl) deacetylcolchicine The same method as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine To give the title compound (pale yellow solid, 37 mg, 0.0746 mmol, 97%). Instead of diethylamine, N-ethylmethylamine was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.58 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 4.94-4.88 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.84-3.77 (1H, m), 3.69 -3.62 (1H, m), 3.62 (3H, s), 3.15 (3H, s), 3.12 (1H, dd, J = 13.3, 5.0 Hz), 2.28-2.20 (1H, m), 2.16-2.08 (1H , m), 2.04-1.95 (1H, m).
ESI-MS m / z: 493 [M + H] + .
実施例２６０
4-クロロ-N-[1-アセチルピペラジン-4-イル)チオカルボニル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 32 mg, 0.0570 mmol, 74%)を得た。ジエチルアミンの代わりに、1-アセチルピペラジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.07 (1H, d, J=6.6 Hz), 7.16 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.04 (1H, d, J=11.7 Hz), 4.92-4.85 (1H, m), 3.96-3.75 (4H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.51-3.46 (4H, m), 3.13 (1H, dd, J=11.8, 4.0 Hz), 2.22-1.99 (3H, m), 2.02 (3H, s).
ESI-MS m/z: 562 [M+H]+. Example 260
Synthesis of 4-chloro-N- [1-acetylpiperazin-4-yl) thiocarbonyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (milky solid, 32 mg, 0.0570 mmol, 74%). 1-acetylpiperazine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.07 (1H, d, J = 6.6 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.04 ( 1H, d, J = 11.7 Hz), 4.92-4.85 (1H, m), 3.96-3.75 (4H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.51-3.46 (4H, m), 3.13 (1H, dd, J = 11.8, 4.0 Hz), 2.22-1.99 (3H, m), 2.02 (3H, s).
ESI-MS m / z: 562 [M + H] + .
実施例２６１
4-クロロ-N-[N’-(2-ヒドロキシエチル)-N’-メチルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 36 mg, 0.0707 mmol, 92%)を得た。ジエチルアミンの代わりに、2-(メチルアミノ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.75 (1H, d, J=6.3 Hz), 7.15 (1H, d, J=10.7 Hz), 7.08 (1H, s), 7.03 (1H, d, J=11.0 Hz), 4.98 (1H, br-s), 4.89-4.83 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.86-3.64 (2H, m), 3.62 (3H, s), 3.59-3.54 (2H, m), 3.21 (3H, s), 3.12 (1H, dd, J=12.6, 5.2 Hz), 2.21-1.97 (3H, m).
ESI-MS m/z: 509 [M+H]+. Example 261
Synthesis of 4-chloro-N- [N '-(2-hydroxyethyl) -N'-methylthiocarbamoyl] deacetylcolchicine Synthesis of 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetylcolchicine In the same manner, the title compound (pale yellow solid, 36 mg, 0.0707 mmol, 92%) was obtained. 2- (Methylamino) ethanol was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.75 (1H, d, J = 6.3 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.03 ( 1H, d, J = 11.0 Hz), 4.98 (1H, br-s), 4.89-4.83 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.86 -3.64 (2H, m), 3.62 (3H, s), 3.59-3.54 (2H, m), 3.21 (3H, s), 3.12 (1H, dd, J = 12.6, 5.2 Hz), 2.21-1.97 (3H , m).
ESI-MS m / z: 509 [M + H] + .
実施例２６２
4-クロロ-N-[N’-(3-ヒドロキシプロピル)-N’-メチルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 36 mg, 0.0689 mmol, 90%)を得た。ジエチルアミンの代わりに、3-(メチルアミノ)-1-プロパノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.68 (1H, d, J=6.6 Hz), 7.15 (1H, d, J=10.7 Hz), 7.07 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.89-4.83 (1H, m), 4.65 (1H, br-s), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.77-3.66 (2H, m), 3.62 (3H, s), 3.41-3.36 (2H, m), 3.15 (3H, s), 3.13 (1H, dd, J=14.6, 7.3 Hz), 2.22-1.99 (3H, m), 1.71-1.63 (2H, m).
ESI-MS m/z: 523 [M+H]+. Example 262
Synthesis of 4-chloro-N- [N '-(3-hydroxypropyl) -N'-methylthiocarbamoyl] deacetylcolchicine Synthesis of 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetylcolchicine In the same manner, the title compound (milky white solid, 36 mg, 0.0689 mmol, 90%) was obtained. Instead of diethylamine, 3- (methylamino) -1-propanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.68 (1H, d, J = 6.6 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.89-4.83 (1H, m), 4.65 (1H, br-s), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.77 -3.66 (2H, m), 3.62 (3H, s), 3.41-3.36 (2H, m), 3.15 (3H, s), 3.13 (1H, dd, J = 14.6, 7.3 Hz), 2.22-1.99 (3H , m), 1.71-1.63 (2H, m).
ESI-MS m / z: 523 [M + H] + .
実施例２６３
4-クロロ-N-[N’,N’-ビス(2-ヒドロキシエチル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 39 mg, 0.0729 mmol, 95%)を得た。ジエチルアミンの代わりに、ジエタノールアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.13 (1H, d, J=6.6 Hz), 7.15 (1H, d, J=10.7 Hz), 7.08 (1H, s), 7.02 (1H, d, J=10.7 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.80-3.69 (4H, m), 3.65-3.58 (4H, m), 3.62 (3H, s), 3.15-3.09 (1H, m), 2.17-2.00 (3H, m).
ESI-MS m/z: 523 [M+H]+. Example 263
Synthesis of 4-chloro-N- [N ', N'-bis (2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine Synthesis of 4-chloro-N- (N', N'-diethylthiocarbamoyl) deacetylcolchicine In the same manner as described above, the title compound (milky white solid, 39 mg, 0.0729 mmol, 95%) was obtained. Diethanolamine was used in place of diethylamine.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.13 (1H, d, J = 6.6 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.80-3.69 (4H, m), 3.65 -3.58 (4H, m), 3.62 (3H, s), 3.15-3.09 (1H, m), 2.17-2.00 (3H, m).
ESI-MS m / z: 523 [M + H] + .
実施例２６４
4-クロロ-N-[(3-ヒドロキシプロピル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 15 mg, 0.0295 mmol, 38%)を得た。ジエチルアミンの代わりに、3-アミノ-1-プロパノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.07 (1H, br-s), 7.52 (1H, br-s), 7.14 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.79-4.71 (1H, m), 4.53 (1H, br-s), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.45-3.35 (4H, m), 3.14-3.09 (1H, m), 2.16-1.82 (3H, m), 1.64-1.57 (2H, m).
ESI-MS m/z: 509 [M+H]+. Example 264
Synthesis of 4-chloro-N-[(3-hydroxypropyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine, The title compound (milky white solid, 15 mg, 0.0295 mmol, 38%) was obtained. Instead of diethylamine, 3-amino-1-propanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.07 (1H, br-s), 7.52 (1H, br-s), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H , s), 7.03 (1H, d, J = 10.7 Hz), 4.79-4.71 (1H, m), 4.53 (1H, br-s), 3.91 (3H, s), 3.88 (6H, s), 3.60 ( 3H, s), 3.45-3.35 (4H, m), 3.14-3.09 (1H, m), 2.16-1.82 (3H, m), 1.64-1.57 (2H, m).
ESI-MS m / z: 509 [M + H] + .
実施例２６５
4-クロロ-N-[(4,4-ジフルオロピペリジン-1-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 42 mg, 0.0748 mmol, 98%)を得た。ジエチルアミンの代わりに、4,4-ジフルオロピペリジン塩酸塩及びトリエチルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.24 (1H, d, J=6.8 Hz), 7.16 (1H, d, J=10.5 Hz), 7.05 (1H, s), 7.04 (1H, d, J=11.0 Hz), 4.87-4.81 (1H, m), 4.04-3.97 (2H, m), 3.95-3.87 (2H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J=11.3, 4.3 Hz), 2.20-1.91 (7H, m).
ESI-MS m/z: 555 [M+H]+. Example 265
Synthesis of 4-chloro-N-[(4,4-difluoropiperidin-1-yl) thiocarbamoyl] deacetylcolchicine Synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine In the same manner, the title compound (light brown solid, 42 mg, 0.0748 mmol, 98%) was obtained. Instead of diethylamine, 4,4-difluoropiperidine hydrochloride and triethylamine were used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.24 (1H, d, J = 6.8 Hz), 7.16 (1H, d, J = 10.5 Hz), 7.05 (1H, s), 7.04 ( 1H, d, J = 11.0 Hz), 4.87-4.81 (1H, m), 4.04-3.97 (2H, m), 3.95-3.87 (2H, m), 3.91 (3H, s), 3.89 (3H, s) , 3.88 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J = 11.3, 4.3 Hz), 2.20-1.91 (7H, m).
ESI-MS m / z: 555 [M + H] + .
実施例２６６
N-[(アゼチジン-1-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 7 mg, 0.0138 mmol, 18%)を得た。ジエチルアミンの代わりに、アゼチジンを用いた。精製は高速液体クロマトグラフ法にて行った。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.85 (1H, d, J=7.3 Hz), 7.14 (1H, d, J=11.0 Hz), 7.08 (1H, s), 7.03 (1H, d, J=11.0 Hz), 4.80-4.73 (1H, m), 4.08-3.90 (4H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J=12.6, 6.2 Hz), 2.22-2.06 (4H, m), 2.02-1.92 (1H, m).
ESI-MS m/z: 491 [M+H]+. Example 266
Synthesis of N-[(azetidin-1-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (milky white solid, 7 mg, 0.0138 mmol, 18%) was obtained. Instead of diethylamine, azetidine was used. Purification was performed by high performance liquid chromatography.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.85 (1H, d, J = 7.3 Hz), 7.14 (1H, d, J = 11.0 Hz), 7.08 (1H, s), 7.03 ( 1H, d, J = 11.0 Hz), 4.80-4.73 (1H, m), 4.08-3.90 (4H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J = 12.6, 6.2 Hz), 2.22-2.06 (4H, m), 2.02-1.92 (1H, m).
ESI-MS m / z: 491 [M + H] + .
実施例２６７
4-クロロ-N-[(インダゾール-5-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(微褐色固体, 44 mg, 0.0766 mmol, 定量的)を得た。ジエチルアミンの代わりに、5-アミノインダゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 13.04 (1H, s), 9.66 (1H, s), 8.26 (1H, d, J=7.1 Hz), 8.02 (1H, s), 7.75 (1H, s), 7.48 (1H, d, J=8.8 Hz), 7.26 (1H, d, J=9.0 Hz), 7.15 (1H, d, J=10.7 Hz), 7.13 (1H, s), 7.04 (1H, d, J=10.7 Hz), 4.87-4.80 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.17-3.08 (1H, m), 2.17-1.99 (3H, m).
ESI-MS m/z: 567 [M+H]+. Example 267
Synthesis of 4-chloro-N-[(indazol-5-yl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (light brown solid, 44 mg, 0.0766 mmol, quantitative) was obtained. Instead of diethylamine, 5-aminoindazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 13.04 (1H, s), 9.66 (1H, s), 8.26 (1H, d, J = 7.1 Hz), 8.02 (1H, s), 7.75 (1H, s), 7.48 (1H, d, J = 8.8 Hz), 7.26 (1H, d, J = 9.0 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.87-4.80 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.17-3.08 (1H, m) , 2.17-1.99 (3H, m).
ESI-MS m / z: 567 [M + H] + .
実施例２６８
4-クロロ-N-[(cis-2,6-ジメチルモルホリン-4-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 42 mg, 0.0766 mmol, 定量的)を得た。ジエチルアミンの代わりに、cis-2,6-ジメチルモルホリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.00 (1H, d, J=6.8 Hz), 7.16 (1H, d, J=10.7 Hz), 7.04 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.93-4.86 (1H, m), 4.61 (2H, dd, J=29.6, 13.1 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.52-3.43 (2H, m), 3.15-3.10 (1H, m), 2.65-2.57 (2H, m), 2.20-2.00 (3H, m), 1.10 (6H, t, J=6.7 Hz).
ESI-MS m/z: 549 [M+H]+. Example 268
Synthesis of 4-chloro-N-[(cis-2,6-dimethylmorpholin-4-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (pale yellow solid, 42 mg, 0.0766 mmol, quantitative) was obtained in the same manner as in the synthesis. Cis-2,6-dimethylmorpholine was used in place of diethylamine.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.00 (1H, d, J = 6.8 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.04 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.93-4.86 (1H, m), 4.61 (2H, dd, J = 29.6, 13.1 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H , s), 3.62 (3H, s), 3.52-3.43 (2H, m), 3.15-3.10 (1H, m), 2.65-2.57 (2H, m), 2.20-2.00 (3H, m), 1.10 (6H , t, J = 6.7 Hz).
ESI-MS m / z: 549 [M + H] + .
実施例２６９
4-クロロ-N-(2-トリルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 7 mg, 0.0130 mmol, 17%)を得た。ジエチルアミンの代わりに、o-トルイジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.20 (1H, s), 8.23 (1H, d, J=6.6 Hz), 7.24-7.12 (6H, m), 7.03 (1H, d, J=10.7 Hz), 4.86-4.79 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.59 (3H, s), 3.15-3.10 (1H, m), 2.17 (3H, s), 2.16-1.98 (3H, m).
ESI-MS m/z: 541 [M+H]+. Example 269
Synthesis of 4-chloro-N- (2-tolylthiocarbamoyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine, the title compound (Milky white solid, 7 mg, 0.0130 mmol, 17%) was obtained. Instead of diethylamine, o-toluidine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.20 (1H, s), 8.23 (1H, d, J = 6.6 Hz), 7.24-7.12 (6H, m), 7.03 (1H, d , J = 10.7 Hz), 4.86-4.79 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.59 (3H, s), 3.15-3.10 (1H, m), 2.17 (3H, s), 2.16-1.98 (3H, m).
ESI-MS m / z: 541 [M + H] + .
実施例２７０
4-クロロ-N-(3-トリルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 13 mg, 0.0245 mmol, 32%)を得た。ジエチルアミンの代わりに、m-トルイジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.62 (1H, s), 8.38 (1H, d, J=7.1 Hz), 7.28-7.12 (5H, m), 7.04 (1H, d, J=11.0 Hz), 6.91 (1H, d, J=7.1 Hz), 4.84-4.77 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.17-3.11 (1H, m), 2.26 (3H, s), 2.20-1.98 (3H, m).
ESI-MS m/z: 541 [M+H]+. Example 270
Synthesis of 4-chloro-N- (3-tolylthiocarbamoyl) deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine, the title compound (Milky white solid, 13 mg, 0.0245 mmol, 32%) was obtained. Instead of diethylamine, m-toluidine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.62 (1H, s), 8.38 (1H, d, J = 7.1 Hz), 7.28-7.12 (5H, m), 7.04 (1H, d , J = 11.0 Hz), 6.91 (1H, d, J = 7.1 Hz), 4.84-4.77 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.17 -3.11 (1H, m), 2.26 (3H, s), 2.20-1.98 (3H, m).
ESI-MS m / z: 541 [M + H] + .
実施例２７１
4-クロロ-N-[3-(ジメチルアミノ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 16 mg, 0.0276 mmol, 36%)を得た。ジエチルアミンの代わりに、N,N-ジメチル-m-フェニレンジアミン塩酸塩及びトリエチルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.60 (1H, s), 8.29 (1H, d, J=7.1 Hz), 7.16 (1H, d, J=10.9 Hz), 7.11 (1H, s), 7.10 (1H, t, J=8.1 Hz), 7.03 (1H, d, J=10.9 Hz), 6.91 (1H, t, J=2.0 Hz), 6.66 (1H, dd, J=8.1, 1.6 Hz), 6.48 (1H, dd, J=8.1, 2.4 Hz), 4.84-4.78 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.17-3.08 (1H, m), 2.86 (6H, s), 2.18-1.99 (3H, m).
ESI-MS m/z: 570 [M+H]+. Example 271
Synthesis of 4-chloro-N- [3- (dimethylamino) phenylthiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine The title compound (light brown solid, 16 mg, 0.0276 mmol, 36%) was obtained. Instead of diethylamine, N, N-dimethyl-m-phenylenediamine hydrochloride and triethylamine were used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.60 (1H, s), 8.29 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 10.9 Hz), 7.11 ( 1H, s), 7.10 (1H, t, J = 8.1 Hz), 7.03 (1H, d, J = 10.9 Hz), 6.91 (1H, t, J = 2.0 Hz), 6.66 (1H, dd, J = 8.1 , 1.6 Hz), 6.48 (1H, dd, J = 8.1, 2.4 Hz), 4.84-4.78 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.17 -3.08 (1H, m), 2.86 (6H, s), 2.18-1.99 (3H, m).
ESI-MS m / z: 570 [M + H] + .
実施例２７２
4-クロロ-N-[4-(2-ヒドロキシエチル)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 37 mg, 0.0644 mmol, 84%)を得た。ジエチルアミンの代わりに、2-(4-アミノフェニル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.62 (1H, s), 8.35 (1H, d, J=7.6 Hz), 7.32 (2H, d, J=8.5 Hz), 7.17-7.12 (4H, m), 7.04 (1H, d, J=11.0 Hz), 4.82-4.76 (1H, m), 4.62 (1H, t, J=5.3 Hz), 3.91 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.57 (2H, td, J=7.1, 5.3 Hz), 3.17-3.09 (1H, m), 2.67 (2H, t, J=7.1 Hz), 2.19-1.97 (3H, m).
ESI-MS m/z: 571 [M+H]+. Example 272
Synthesis of 4-chloro-N- [4- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (milky white solid, 37 mg, 0.0644 mmol, 84%). Instead of diethylamine, 2- (4-aminophenyl) ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.62 (1H, s), 8.35 (1H, d, J = 7.6 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.17- 7.12 (4H, m), 7.04 (1H, d, J = 11.0 Hz), 4.82-4.76 (1H, m), 4.62 (1H, t, J = 5.3 Hz), 3.91 (3H, s), 3.89 (6H , s), 3.62 (3H, s), 3.57 (2H, td, J = 7.1, 5.3 Hz), 3.17-3.09 (1H, m), 2.67 (2H, t, J = 7.1 Hz), 2.19-1.97 ( 3H, m).
ESI-MS m / z: 571 [M + H] + .
参考例２６
2-(3-アミノフェニル)エタノールの合成
　2-(3-ニトロフェニル)エタノール(200 mg, 1.20 mmol)のテトラヒドロフラン(2 mL)溶液に、氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(M)Dry(20 mg)を添加した。反応容器内を減圧下脱気した後、水素ガスで置換した。反応液は室温、水素ガス雰囲気下(風船)にて90分間激しく撹拌した。不溶物をろ去、THFで洗いこんだ後、ろ液と洗浄液は合わせて濃縮乾固し、標記の化合物(乳白色固体, 165 mg, 1.20 mmol, 定量的)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 6.89 (1H, t, J=7.7 Hz), 6.40-6.32 (3H, m), 4.92 (2H, s), 4.58 (1H, t, J=5.4 Hz), 3.53 (2H, td, J=7.4, 5.4 Hz), 2.55 (2H, t, J=7.4 Hz). Reference Example 26
Synthesis of 2- (3-aminophenyl) ethanol To a solution of 2- (3-nitrophenyl) ethanol (200 mg, 1.20 mmol) in tetrahydrofuran (2 mL), ice-cooled, 10% palladium-carbon under argon gas atmosphere (M) Dry (20 mg) was added. The reaction vessel was degassed under reduced pressure, and then replaced with hydrogen gas. The reaction solution was vigorously stirred for 90 minutes at room temperature under a hydrogen gas atmosphere (balloon). The insoluble material was removed by filtration and washed with THF, and the filtrate and the washing solution were combined and concentrated to dryness to obtain the title compound (milky white solid, 165 mg, 1.20 mmol, quantitative).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 6.89 (1H, t, J = 7.7 Hz), 6.40-6.32 (3H, m), 4.92 (2H, s), 4.58 (1H, t , J = 5.4 Hz), 3.53 (2H, td, J = 7.4, 5.4 Hz), 2.55 (2H, t, J = 7.4 Hz).
実施例２７３
4-クロロ-N-[3-(2-ヒドロキシエチル)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-(N’,N’-ジエチルチオカルバモイル)デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 40 mg, 0.0696 mmol, 91%)を得た。ジエチルアミンの代わりに、2-(3-アミノフェニル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.67 (1H, s), 8.37 (1H, d, J=7.1 Hz), 7.30-7.25 (2H, m), 7.20 (1H, t, J=7.6 Hz), 7.16 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J=10.7 Hz), 6.95 (1H, d, J=7.6 Hz), 4.83-4.75 (1H, m), 4.60 (1H,t, J=5.1 Hz), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.58 (2H, td, J=7.1, 5.1 Hz), 3.18-3.09 (1H, m), 2.68 (2H, t, J=7.1 Hz), 2.19-1.97 (3H, m). Example 273
Synthesis of 4-chloro-N- [3- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine Similar method to the synthesis of 4-chloro-N- (N ', N'-diethylthiocarbamoyl) deacetylcolchicine Gave the title compound (pale yellow solid, 40 mg, 0.0696 mmol, 91%). Instead of diethylamine, 2- (3-aminophenyl) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.67 (1H, s), 8.37 (1H, d, J = 7.1 Hz), 7.30-7.25 (2H, m), 7.20 (1H, t , J = 7.6 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 6.95 (1H, d, J = 7.6 Hz), 4.83-4.75 (1H, m), 4.60 (1H, t, J = 5.1 Hz), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.58 (2H, td, J = 7.1, 5.1 Hz), 3.18-3.09 (1H, m), 2.68 (2H, t, J = 7.1 Hz), 2.19-1.97 (3H, m).
実施例２７４
4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-シアノアニリン(14 mg, 0.0766×1.5 mmol)のジクロロメタン(1.5 mL)溶液に、氷冷、アルゴンガス雰囲気下にて、チオホスゲン(8.75 μL, 0.0766×1.5 mmol)およびトリエチルアミン(32.0 μL, 0.0766×3 mmol)を添加して、同温度で2時間撹拌した。4-クロロデアセチルコルヒチン(30 mg, 0.076 mmol)を添加した後、室温に徐々に戻しながら一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 42 mg, 0.0766 mmol, 定量的)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.12 (1H, s), 8.83 (1H, d, J=7.1 Hz), 7.76-7.71 (4H, m), 7.17 (1H, d, J=10.7 Hz), 7.12 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.77-4.71 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.20-3.11 (1H, m), 2.22-1.98 (3H, m).
ESI-MS m/z: 552 [M+H]+. Example 274
Synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine To a solution of 4-cyanoaniline (14 mg, 0.0766 × 1.5 mmol) in dichloromethane (1.5 mL) under ice-cooling and argon gas atmosphere Then, thiophosgene (8.75 μL, 0.0766 × 1.5 mmol) and triethylamine (32.0 μL, 0.0766 × 3 mmol) were added and stirred at the same temperature for 2 hours. 4-Chlorodeacetylcolchicine (30 mg, 0.076 mmol) was added, and the mixture was stirred overnight while gradually returning to room temperature. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 42 mg, 0.0766 mmol, quantitative).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.12 (1H, s), 8.83 (1H, d, J = 7.1 Hz), 7.76-7.71 (4H, m), 7.17 (1H, d , J = 10.7 Hz), 7.12 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.77-4.71 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.20-3.11 (1H, m), 2.22-1.98 (3H, m).
ESI-MS m / z: 552 [M + H] + .
実施例２７５
4-クロロ-N-[2,1,3-ベンゾチアジアゾール-4-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(黄色固体, 31 mg, 0.0528 mmol, 69%)を得た。4-シアノアニリンの代わりに、4-アミノ-2,1,3-ベンゾチアジアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.20 (1H, d, J=7.1 Hz), 8.56 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=8.8 Hz), 7.65 (1H, dd, J=8.8, 7.6 Hz), 7.19 (1H, d, J=10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.86-4.79 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.65 (3H, s), 3.16 (1H, dd, J=21.0, 13.4 Hz), 2.22-2.13 (2H, m), 1.98-1.92 (1H, m).
ESI-MS m/z: 585 [M+H]+. Example 275
Synthesis of 4-chloro-N- [2,1,3-benzothiadiazol-4-yl) thiocarbamoyl] deacetylcolchicine Synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine In the same manner, the title compound (yellow solid, 31 mg, 0.0528 mmol, 69%) was obtained. Instead of 4-cyanoaniline, 4-amino-2,1,3-benzothiadiazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.20 (1H, d, J = 7.1 Hz), 8.56 (1H, d, J = 7.6 Hz), 7.78 (1H, d, J = 8.8 Hz), 7.65 (1H, dd, J = 8.8, 7.6 Hz), 7.19 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.86- 4.79 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.65 (3H, s), 3.16 (1H, dd, J = 21.0, 13.4 Hz), 2.22 -2.13 (2H, m), 1.98-1.92 (1H, m).
ESI-MS m / z: 585 [M + H] + .
実施例２７６
4-クロロ-N-[(2-メトキシフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 14 mg, 0.0253 mmol, 33%)を得た。4-シアノアニリンの代わりに、o-アニシジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.17 (1H, s), 8.61 (1H, d, J=7.1 Hz), 7.92 (1H, dd, J=7.8 Hz, 1.4 Hz), 7.16 (1H, d, J=10.5 Hz), 7.13-7.09 (2H, m), 7.06-7.02 (2H, m), 6.86 (1H, td, J=7.8, 1.4 Hz), 4.84-4.78 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.86 (3H, s), 3.62 (3H, s), 3.18-3.10 (1H, m), 2.20-2.09 (2H, m), 1.99-1.91 (1H, m).
ESI-MS m/z: 557 [M+H]+. Example 276
Synthesis of 4-chloro-N-[(2-methoxyphenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine, the title (Milky white solid, 14 mg, 0.0253 mmol, 33%) was obtained. In place of 4-cyanoaniline, o-anisidine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.17 (1H, s), 8.61 (1H, d, J = 7.1 Hz), 7.92 (1H, dd, J = 7.8 Hz, 1.4 Hz) , 7.16 (1H, d, J = 10.5 Hz), 7.13-7.09 (2H, m), 7.06-7.02 (2H, m), 6.86 (1H, td, J = 7.8, 1.4 Hz), 4.84-4.78 (1H , m), 3.92 (3H, s), 3.89 (6H, s), 3.86 (3H, s), 3.62 (3H, s), 3.18-3.10 (1H, m), 2.20-2.09 (2H, m), 1.99-1.91 (1H, m).
ESI-MS m / z: 557 [M + H] + .
実施例２７７
4-クロロ-N-[(3-メトキシフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 39 mg, 0.0697 mmol, 91%)を得た。4-シアノアニリンの代わりに、m-アニシジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.72 (1H, s), 8.44 (1H, d, J=7.1 Hz), 7.22-7.11 (4H, m), 7.04 (1H, d, J=11.2 Hz), 6.95 (1H, dd, J=8.3, 1.5 Hz), 6.66 (1H, ddd, J=8.3, 2.4, 0.7 Hz), 4.83-4.76 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.71 (3H, s), 3.62 (3H, s), 3.16-3.10 (1H, m), 2.19-2.10 (2H, m), 2.04-1.98 (1H, m).
ESI-MS m/z: 557 [M+H]+. Example 277
Synthesis of 4-chloro-N-[(3-methoxyphenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine, the title (Milky white solid, 39 mg, 0.0697 mmol, 91%) was obtained. Instead of 4-cyanoaniline, m-anisidine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.72 (1H, s), 8.44 (1H, d, J = 7.1 Hz), 7.22-7.11 (4H, m), 7.04 (1H, d , J = 11.2 Hz), 6.95 (1H, dd, J = 8.3, 1.5 Hz), 6.66 (1H, ddd, J = 8.3, 2.4, 0.7 Hz), 4.83-4.76 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.71 (3H, s), 3.62 (3H, s), 3.16-3.10 (1H, m), 2.19-2.10 (2H, m), 2.04-1.98 (1H, m) .
ESI-MS m / z: 557 [M + H] + .
実施例２７８
4-クロロ-N-[(3-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 42 mg, 0.0766 mmol, 定量的)を得た。4-シアノアニリンの代わりに、3-シアノアニリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.95 (1H, s), 8.73 (1H, d, J=6.8 Hz), 8.03 (1H, s), 7.72 (1H, d, J=7.6 Hz), 7.54-7.47 (2H, m), 7.17 (1H, d, J=10.7 Hz), 7.12 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.80-4.74 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.20-3.11 (1H, m), 2.21-2.12 (2H, m), 2.04-1.98 (1H, m).
ESI-MS m/z: 552 [M+H]+. Example 278
Synthesis of 4-chloro-N-[(3-cyanophenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine, the title (Light brown solid, 42 mg, 0.0766 mmol, quantitative) was obtained. Instead of 4-cyanoaniline, 3-cyanoaniline was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.95 (1H, s), 8.73 (1H, d, J = 6.8 Hz), 8.03 (1H, s), 7.72 (1H, d, J = 7.6 Hz), 7.54-7.47 (2H, m), 7.17 (1H, d, J = 10.7 Hz), 7.12 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.80-4.74 (1H , m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.20-3.11 (1H, m), 2.21-2.12 (2H, m), 2.04-1.98 (1H, m ).
ESI-MS m / z: 552 [M + H] + .
実施例２７９
4-クロロ-N-[(3,4-ジメトキシフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 36 mg, 0.0613 mmol, 80%)を得た。4-シアノアニリンの代わりに、4-アミノベラトロールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.57 (1H, s), 8.20 (1H, d, J=7.1 Hz), 7.15 (1H, d, J=10.7 Hz), 7.10 (1H, s), 7.09 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=10.7 Hz), 6.90 (1H, d, J=8.5 Hz), 6.83 (1H, dd, J=8.5, 2.4 Hz), 4.87-4.81 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.73 (3H, s), 3.72 (3H, s), 3.62 (3H, s), 3.15-3.09 (1H, m), 2.16-2.01 (3H, m).
ESI-MS m/z: 587 [M+H]+. Example 279
Synthesis of 4-chloro-N-[(3,4-dimethoxyphenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine The title compound (light brown solid, 36 mg, 0.0613 mmol, 80%) was obtained. Instead of 4-cyanoaniline, 4-aminoveratrol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.57 (1H, s), 8.20 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.10 ( 1H, s), 7.09 (1H, d, J = 2.4 Hz), 7.03 (1H, d, J = 10.7 Hz), 6.90 (1H, d, J = 8.5 Hz), 6.83 (1H, dd, J = 8.5 , 2.4 Hz), 4.87-4.81 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.73 (3H, s), 3.72 (3H, s), 3.62 (3H, s), 3.15 -3.09 (1H, m), 2.16-2.01 (3H, m).
ESI-MS m / z: 587 [M + H] + .
実施例２８０
4-クロロ-N-[(2-クロロフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 36 mg, 0.0536 mmol, 70%)を得た。4-シアノアニリンの代わりに、2-クロロアニリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.34 (1H, s), 8.71 (1H, d, J=7.3 Hz), 7.62 (1H, dd, J=7.7, 1.5 Hz), 7.48 (1H, dd, J=7.7, 1.5 Hz), 7.29 (1H, td, J=7.7, 1.5 Hz), 7.21 (1H, td, J=7.7, 1.5 Hz), 7.16 (1H, d, J=11.0 Hz), 7.15 (1H, s), 7.04 (1H, d, J=11.0 Hz), 4.82-4.75 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.59 (3H, s), 3.18-3.10 (1H, m), 2.20-1.96 (3H, m).
ESI-MS m/z: 561 [M+H]+. Example 280
Synthesis of 4-chloro-N-[(2-chlorophenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine, the title The compound (milky white solid, 36 mg, 0.0536 mmol, 70%) was obtained. Instead of 4-cyanoaniline, 2-chloroaniline was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.34 (1H, s), 8.71 (1H, d, J = 7.3 Hz), 7.62 (1H, dd, J = 7.7, 1.5 Hz), 7.48 (1H, dd, J = 7.7, 1.5 Hz), 7.29 (1H, td, J = 7.7, 1.5 Hz), 7.21 (1H, td, J = 7.7, 1.5 Hz), 7.16 (1H, d, J = 11.0 Hz), 7.15 (1H, s), 7.04 (1H, d, J = 11.0 Hz), 4.82-4.75 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.59 (3H, s), 3.18-3.10 (1H, m), 2.20-1.96 (3H, m).
ESI-MS m / z: 561 [M + H] + .
実施例２８１
4-クロロ-N-[(3-クロロフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 40 mg, 0.0712 mmol, 93%)を得た。4-シアノアニリンの代わりに、3-クロロアニリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.86 (1H, s), 8.63 (1H, d, J=6.6 Hz), 7.74-7.73 (1H, m), 7.34-7.29 (2H, m), 7.17 (1H, d, J=10.7 Hz), 7.14-7.11 (2H, m), 7.05 (1H, d, J=10.7 Hz), 4.79-4.73 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.19-3.10 (1H, m), 2.20-1.97 (3H, m). 
ESI-MS m/z: 561 [M+H]+. Example 281
Synthesis of 4-chloro-N-[(3-chlorophenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine, the title The compound (milky white solid, 40 mg, 0.0712 mmol, 93%) was obtained. Instead of 4-cyanoaniline, 3-chloroaniline was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.86 (1H, s), 8.63 (1H, d, J = 6.6 Hz), 7.74-7.73 (1H, m), 7.34-7.29 (2H , m), 7.17 (1H, d, J = 10.7 Hz), 7.14-7.11 (2H, m), 7.05 (1H, d, J = 10.7 Hz), 4.79-4.73 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.19-3.10 (1H, m), 2.20-1.97 (3H, m).
ESI-MS m / z: 561 [M + H] + .
実施例２８２
4-クロロ-N-[(4-クロロフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 43 mg, 0.0766 mmol, 定量的)を得た。4-シアノアニリンの代わりに、4-クロロアニリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.79 (1H, s), 8.53 (1H, d, J=7.1 Hz), 7.48 (2H, d, J=8.8 Hz), 7.34 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J=10.7 Hz), 4.80-4.73 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.61 (3H, s), 3.18-3.10 (1H, m), 2.19-1.97 (3H, m).
ESI-MS m/z: 561 [M+H]+. Example 282
Synthesis of 4-chloro-N-[(4-chlorophenyl) thiocarbamoyl] deacetylcolchicine In the same manner as the synthesis of 4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine, the title The compound (milky white solid, 43 mg, 0.0766 mmol, quantitative) was obtained. Instead of 4-cyanoaniline, 4-chloroaniline was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.79 (1H, s), 8.53 (1H, d, J = 7.1 Hz), 7.48 (2H, d, J = 8.8 Hz), 7.34 ( 2H, d, J = 8.8 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.80-4.73 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.61 (3H, s), 3.18-3.10 (1H, m), 2.19-1.97 (3H, m).
ESI-MS m / z: 561 [M + H] + .
実施例２８３
4-クロロ-N-[(2-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　2-シアノアニリン(14 mg, 0.0766×1.5 mmol)のジクロロメタン-水(1:1, 3 mL)溶液に、室温でチオホスゲン(8.75 μL, 0.0766×1.5 mmol)を添加して3時間撹拌した。反応液に、4-クロロデアセチルコルヒチン(30 mg, 0.0766 mmol)のジクロロメタン(0.5 mL)溶液、および、炭酸ナトリウム(12 mg, 0.0766×1.5 mmol)の水(0.5 mL)溶液を加えて、室温で40分間撹拌した。反応液にクロロホルムとブラインを加えて、有機層を取った。有機層は無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 19 mg, 0.0345 mmol, 45%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.77 (1H, s), 8.87 (1H, d, J=7.1 Hz), 7.79 (1H, dd, J=7.7, 1.3 Hz), 7.66-7.57 (2H, m), 7.35 (1H, td, J=7.7, 1.3 Hz), 7.16 (1H, d, J=10.7 Hz), 7.14 (1H, s), 7.04 (1H, d, J=10.7 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.19-3.10 (1H, m), 2.17-1.98 (3H, m).
ESI-MS m/z: 552 [M+H]+. Example 283
Synthesis of 4-chloro-N-[(2-cyanophenyl) thiocarbamoyl] deacetylcolchicine To a solution of 2-cyanoaniline (14 mg, 0.0766 × 1.5 mmol) in dichloromethane-water (1: 1, 3 mL) at room temperature Was added with thiophosgene (8.75 μL, 0.0766 × 1.5 mmol) and stirred for 3 hours. To the reaction solution was added 4-chlorodeacetylcolchicine (30 mg, 0.0766 mmol) in dichloromethane (0.5 mL) and sodium carbonate (12 mg, 0.0766 × 1.5 mmol) in water (0.5 mL). For 40 minutes. Chloroform and brine were added to the reaction solution, and the organic layer was taken. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 19 mg, 0.0345 mmol, 45%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.77 (1H, s), 8.87 (1H, d, J = 7.1 Hz), 7.79 (1H, dd, J = 7.7, 1.3 Hz), 7.66-7.57 (2H, m), 7.35 (1H, td, J = 7.7, 1.3 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.14 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.60 (3H, s), 3.19-3.10 (1H, m), 2.17-1.98 (3H, m).
ESI-MS m / z: 552 [M + H] + .
参考例２７
イミダゾール-1-チオカルボン酸 チアゾール-2-イルアミドの合成
　2-アミノチアゾール(1.00 g, 9.99 mmol)のアセトニトリル(10 mL)溶液に、室温、アルゴンガス雰囲気下にて、1,1’-チオカルボニルジイミダゾール(1.78 g, 9.99 mmol)を添加し、40℃で2時間撹拌した(懸濁液となった)。反応液を5℃付近で数時間静置した後、析出物をろ取した。ろ取物を冷アセトニトリル、次いでヘキサンにて洗浄、減圧乾燥して、標記の化合物(淡黄色固体, 1.37 g, 6.49 mmol, 65%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.64 (1H, s), 7.95 (1H, t, J=1.2 Hz), 7.75 (1H, d, J=4.4 Hz), 7.31 (1H, dd, J=4.1 Hz), 7.07 (1H, s). Reference Example 27
Synthesis of imidazole-1-thiocarboxylic acid thiazol-2-ylamide To a solution of 2-aminothiazole (1.00 g, 9.99 mmol) in acetonitrile (10 mL) at room temperature under an argon gas atmosphere, 1,1′-thiocarbonyldithiol Imidazole (1.78 g, 9.99 mmol) was added, and the mixture was stirred at 40 ° C. for 2 hours (becomes a suspension). The reaction solution was allowed to stand at around 5 ° C. for several hours, and then the precipitate was collected by filtration. The filtered product was washed with cold acetonitrile and then hexane and dried under reduced pressure to obtain the title compound (pale yellow solid, 1.37 g, 6.49 mmol, 65%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.64 (1H, s), 7.95 (1H, t, J = 1.2 Hz), 7.75 (1H, d, J = 4.4 Hz), 7.31 ( 1H, dd, J = 4.1 Hz), 7.07 (1H, s).
実施例２８４
4-クロロ-N-[(チアゾール-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　7-アミノデアセチルコルヒチン(30 mg, 0.0766 mmol)のアセトニトリル(1.5 mL)溶液に、室温、アルゴンガス雰囲気下にてイミダゾール-1-チオカルボン酸 チアゾール-2-イルアミド(18 mg, 0.0766×1.1 mmol)を添加して、1時間煮沸還流した。反応液を室温まで冷却した後、酢酸エチルと10%硫酸水素ナトリウム水溶液を添加して、有機層を取った。有機層は、10%硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液、次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 38 mg, 0.0710 mmol, 93%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.44 (1H, br-s), 7.20-7.01 (4H, m), 4.76-4.69 (1H, m), 3.93 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.20-3.13 (1H, m), 2.23-1.98 (3H, m).
ESI-MS m/z: 534 [M+H]+. Example 284
Synthesis of 4-chloro-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine A solution of 7-aminodeacetylcolchicine (30 mg, 0.0766 mmol) in acetonitrile (1.5 mL) at room temperature under argon gas atmosphere Imidazole-1-thiocarboxylic acid thiazol-2-ylamide (18 mg, 0.0766 × 1.1 mmol) was added and boiled under reflux for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and 10% aqueous sodium hydrogensulfate solution were added, and the organic layer was taken. The organic layer was washed with 10% aqueous sodium sulfate solution, saturated aqueous sodium hydrogen carbonate solution, then brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 38 mg, 0.0710 mmol, 93%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.44 (1H, br-s), 7.20-7.01 (4H, m), 4.76-4.69 (1H, m), 3.93 (3H, s) , 3.89 (6H, s), 3.64 (3H, s), 3.20-3.13 (1H, m), 2.23-1.98 (3H, m).
ESI-MS m / z: 534 [M + H] + .
実施例２８５
4-クロロ-N-(チオカルバモイル)デアセチルコルヒチンの合成
　4-クロロ-7-イソチオシアネートデ(アセチルアミノ)コルヒチン(26 mg, 0.0599)の1,4-ジオキサン(1 mL)溶液に、室温、アルゴンガス雰囲気下にてアンモニア(0.5mol/L in 1,4-ジオキサン, 240 μL, 0.0599×2 mmol)を添加して、一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡褐色固体, 16 mg, 0.0345 mmol, 45%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.29 (1H, d, J=7.6 Hz), 7.14 (1H, d, J=11.0 Hz), 7.05 (1H, s), 7.03 (1H, d, J=11.0 Hz), 4.70-4.63 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J=12.4, 4.1 Hz), 2.17-2.01 (2H, m), 1.89-1.81 (1H, m). Example 285
Synthesis of 4-chloro-N- (thiocarbamoyl) deacetylcolchicine A solution of 4-chloro-7-isothiocyanate de (acetylamino) colchicine (26 mg, 0.0599) in 1,4-dioxane (1 mL) at room temperature Ammonia (0.5 mol / L in 1,4-dioxane, 240 μL, 0.0599 × 2 mmol) was added under an argon gas atmosphere, and the mixture was stirred overnight. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 16 mg, 0.0345 mmol, 45%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.29 (1H, d, J = 7.6 Hz), 7.14 (1H, d, J = 11.0 Hz), 7.05 (1H, s), 7.03 ( 1H, d, J = 11.0 Hz), 4.70-4.63 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.59 (3H, s), 3.11 (1H , dd, J = 12.4, 4.1 Hz), 2.17-2.01 (2H, m), 1.89-1.81 (1H, m).
実施例２８６
4-クロロ-N-(メチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(63 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへメチルアミン塩酸塩(22 mg, 0.16×2 mmol)、トリエチルアミン(0.045mL, 0.16×2 mmol)を加えて室温で2日間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 58 mg, 77.9%)を得た。
1H-NMR (DMSO-d6) δ: 8.09 (1H, br s), 7.46 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.82-4.73 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.14-3.09 (1H, m), 2.82 (3H, d, J = 4.4 Hz), 2.16-1.85 (3H, m).
ESI-MS m/z: 465 [M+H]+ . Example 286
Synthesis of 4-chloro-N- (methylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (63 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Methylamine hydrochloride (22 mg, 0.16 × 2 mmol) and triethylamine (0.045 mL, 0.16 × 2 mmol) were added thereto, and the mixture was stirred at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 58 mg, 77.9%).
1 H-NMR (DMSO-d 6 ) δ: 8.09 (1H, br s), 7.46 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.03 (1H , d, J = 10.7 Hz), 4.82-4.73 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.14-3.09 (1H, m), 2.82 ( 3H, d, J = 4.4 Hz), 2.16-1.85 (3H, m).
ESI-MS m / z: 465 [M + H] + .
実施例２８７
4-クロロ-N-(n-プロピルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(63 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへプロピルアミン(0.026 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 54 mg, 68.5%)を得た。
1H-NMR (DMSO-d6) δ: 7.97 (1H, br s), 7.54 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.81-4.71 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.30-3.21 (2H, m), 3.12 (1H, dd, J = 12.9, 5.1 Hz), 2.17-1.81 (3H, m), 1.51-1.42 (2H, m), 0.84 (3H, t, J = 7.4 Hz).
ESI-MS m/z: 493 [M+H]+ . Example 287
Synthesis of 4-chloro-N- (n-propylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (63 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Propylamine (0.026 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 54 mg, 68.5%).
1 H-NMR (DMSO-d 6 ) δ: 7.97 (1H, br s), 7.54 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.03 (1H , d, J = 10.7 Hz), 4.81-4.71 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.30-3.21 (2H, m), 3.12 ( 1H, dd, J = 12.9, 5.1 Hz), 2.17-1.81 (3H, m), 1.51-1.42 (2H, m), 0.84 (3H, t, J = 7.4 Hz).
ESI-MS m / z: 493 [M + H] + .
実施例２８８
4-クロロ-N-(n-ブチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(64 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへブチルアミン(0.032 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 55 mg, 67.8%)を得た。
1H-NMR (DMSO-d6) δ: 7.96 (1H, br s), 7.51 (1H, br s), 7.14 (1H, d, J = 10.5 Hz), 7.05 (1H, s), 7.03 (1H, d, J = 10.5 Hz), 4.80-4.70 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.42-3.35 (1H, m), 3.30-3.26 (1H, m), 3.12 (1H, dd, J = 12.6, 5.0 Hz), 2.17-1.81 (3H, m), 1.47-1.40 (2H, m), 1.30-1.24 (2H, m), 0.86 (3H, t, J = 7.3 Hz).
ESI-MS m/z: 507 [M+H]+ . Example 288
Synthesis of 4-chloro-N- (n-butylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (64 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Butylamine (0.032 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 55 mg, 67.8%).
1 H-NMR (DMSO-d 6 ) δ: 7.96 (1H, br s), 7.51 (1H, br s), 7.14 (1H, d, J = 10.5 Hz), 7.05 (1H, s), 7.03 (1H , d, J = 10.5 Hz), 4.80-4.70 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.42-3.35 (1H, m), 3.30- 3.26 (1H, m), 3.12 (1H, dd, J = 12.6, 5.0 Hz), 2.17-1.81 (3H, m), 1.47-1.40 (2H, m), 1.30-1.24 (2H, m), 0.86 ( (3H, t, J = 7.3 Hz).
ESI-MS m / z: 507 [M + H] + .
実施例２８９
4-クロロ-N-(tert-ブチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(59 mg, 0.15 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.15×1.05 mmol)、トリエチルアミン(0.054 mL, 0.15×2.4 mmol)を加えて、室温で2時間攪拌した。そこへtert-ブチルアミン(0.031 mL, 0.15×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 57 mg, 74.9%)を得た。
1H-NMR (DMSO-d6) δ: 7.89 (1H, d, J = 7.1 Hz), 7.35 (1H, s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.75-4.69 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.13-3.08 (2H, m), 2.16-2.01 (2H, m), 1.81-1.74 (1H, m), 1.37 (9H, s).
ESI-MS m/z: 507 [M+H]+ . Example 289
Synthesis of 4-chloro-N- (tert-butylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (59 mg, 0.15 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.15 × 1.05 mmol) and triethylamine (0.054 mL, 0.15 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Thereto was added tert-butylamine (0.031 mL, 0.15 × 2 mmol), and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 57 mg, 74.9%).
1 H-NMR (DMSO-d 6) δ: 7.89 (1H, d, J = 7.1 Hz), 7.35 (1H, s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m ), 4.75-4.69 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.13-3.08 (2H, m), 2.16-2.01 (2H, m), 1.81-1.74 (1H, m), 1.37 (9H, s).
ESI-MS m / z: 507 [M + H] + .
実施例２９０
4-クロロ-N-(シクロペンチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへシクロペンチルアミン(0.032 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 72 mg, 86.7%)を得た。
1H-NMR (DMSO-d6) δ: 7.80 (1H, d, J = 6.8 Hz), 7.62 (1H, br s), 7.14 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.79-4.70 (1H, m), 4.31-4.23 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.13-3.09 (1H, m), 2.15-2.03 (2H, m), 1.91-1.82 (3H, m), 1.66-1.47 (4H, m), 1.42-1.33 (2H, m).
ESI-MS m/z: 519 [M+H]+ . Example 290
Synthesis of 4-chloro-N- (cyclopentylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Cyclopentylamine (0.032 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 72 mg, 86.7%).
1 H-NMR (DMSO-d 6 ) δ: 7.80 (1H, d, J = 6.8 Hz), 7.62 (1H, br s), 7.14 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.79-4.70 (1H, m), 4.31-4.23 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.13 -3.09 (1H, m), 2.15-2.03 (2H, m), 1.91-1.82 (3H, m), 1.66-1.47 (4H, m), 1.42-1.33 (2H, m).
ESI-MS m / z: 519 [M + H] + .
実施例２９１
4-クロロ-N-(イソプロピルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(65 mg, 0.165 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.165×1.05 mmol)、トリエチルアミン(0.054 mL, 0.165×2.4 mmol)を加えて、室温で2時間攪拌した。そこへイソプロピルアミン塩酸塩(32 mg, 0.165×2 mmol)、トリエチルアミン(0.046 mL, 0.165×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 75 mg, 92.2%)を得た。
1H-NMR (DMSO-d6) δ: 7.85 (1H, d, J = 7.3 Hz), 7.44 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.01 (2H, m), 4.79-4.71 (1H, m), 4.18-4.10 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.13-3.08 (1H, m), 2.16-1.80 (3H, m), 1.09 (6H, t, J = 6.8 Hz).
ESI-MS m/z: 493 [M+H]+ . Example 291
Synthesis of 4-chloro-N- (isopropylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (65 mg, 0.165 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.165 × 1.05 mmol) and triethylamine (0.054 mL, 0.165 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Isopropylamine hydrochloride (32 mg, 0.165 × 2 mmol) and triethylamine (0.046 mL, 0.165 × 2 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 75 mg, 92.2%).
1 H-NMR (DMSO-d 6 ) δ: 7.85 (1H, d, J = 7.3 Hz), 7.44 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.01 (2H, m), 4.79-4.71 (1H, m), 4.18-4.10 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.13 -3.08 (1H, m), 2.16-1.80 (3H, m), 1.09 (6H, t, J = 6.8 Hz).
ESI-MS m / z: 493 [M + H] + .
実施例２９２
4-クロロ-N-(n-ヘキシルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへn-ヘキシルアミン(0.042 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 54 mg, 63.1%)を得た。
1H-NMR (DMSO-d6) δ: 7.98 (1H, br s), 7.51 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.01 (2H, m), 4.81-4.69 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.31-3.23 (2H, m), 3.14-3.09 (1H, m), 2.17-1.80 (3H, m), 1.30-1.21 (8H, m), 0.85 (3H, t, J = 6.8 Hz).
ESI-MS m/z: 535 [M+H]+ . Example 292
Synthesis of 4-chloro-N- (n-hexylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Thereto was added n-hexylamine (0.042 mL, 0.16 × 2 mmol), and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 54 mg, 63.1%).
1 H-NMR (DMSO-d 6 ) δ: 7.98 (1H, br s), 7.51 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.01 (2H, m), 4.81 -4.69 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.31-3.23 (2H, m), 3.14-3.09 (1H, m), 2.17-1.80 (3H, m), 1.30-1.21 (8H, m), 0.85 (3H, t, J = 6.8 Hz).
ESI-MS m / z: 535 [M + H] + .
実施例２９３
4-クロロ-N-[(trans-4-ヒドロキシシクロヘキシル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへtrans-4-アミノシクロヘキサノール(37 mg, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 64 mg, 72.8%)を得た。
1H-NMR (DMSO-d6) δ: 7.90 (1H, br s), 7.47 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.77-4.69 (1H, m), 4.53 (1H, d, J = 4.4 Hz), 3.91 (3H, s), 3.88 (6H, s), 3.82-3.74 (1H, m), 3.60 (3H, s), 3.41-3.36 (1H, m), 2.16-2.03 (2H, m), 1.89-1.74 (5H, m), 1.30-1.23 (3H, m), 1.14-1.07 (1H, m).
ESI-MS m/z: 549 [M+H]+ . Example 293
Synthesis of 4-chloro-N-[(trans-4-hydroxycyclohexyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Trans-4-aminocyclohexanol (37 mg, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 64 mg, 72.8%).
1 H-NMR (DMSO-d 6 ) δ: 7.90 (1H, br s), 7.47 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.77 -4.69 (1H, m), 4.53 (1H, d, J = 4.4 Hz), 3.91 (3H, s), 3.88 (6H, s), 3.82-3.74 (1H, m), 3.60 (3H, s), 3.41-3.36 (1H, m), 2.16-2.03 (2H, m), 1.89-1.74 (5H, m), 1.30-1.23 (3H, m), 1.14-1.07 (1H, m).
ESI-MS m / z: 549 [M + H] + .
実施例２９４
4-クロロ-N-[2-(ジメチルアミノ)エチルチオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへジメチルアミノエチルアミン(0.035 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 34 mg, 63.1%)を得た。
1H-NMR (DMSO-d6) δ: 8.33 (1H, br s), 7.47 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.76-4.69 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.50-3.36 (2H, m), 3.14-3.07 (1H, m), 2.44-2.32 (1H, m), 2.19 (6H, s), 2.14-2.02 (2H, m), 1.88-1.78 (1H, m).
ESI-MS m/z: 522 [M+H]+ . Example 294
Synthesis of 4-chloro-N- [2- (dimethylamino) ethylthiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Dimethylaminoethylamine (0.035 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 34 mg, 63.1%).
1 H-NMR (DMSO-d 6 ) δ: 8.33 (1H, br s), 7.47 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.76 -4.69 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.50-3.36 (2H, m), 3.14-3.07 (1H, m), 2.44-2.32 (1H, m), 2.19 (6H, s), 2.14-2.02 (2H, m), 1.88-1.78 (1H, m).
ESI-MS m / z: 522 [M + H] + .
実施例２９５
4-クロロ-N-[(2-ヒドロキシエチル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへヒドロキシエチルアミン(0.019 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 15 mg, 18.9%)を得た。
1H-NMR (DMSO-d6) δ: 8.19 (1H, br s), 7.60 (1H, br s), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.82 (1H, s), 4.75 (1H, s), 3.91 (3H, s), 3.89 (6H, s), 3.60 (3H, s), 3.49-3.42 (3H, m), 3.39-3.35 (1H, m), 3.14-3.09 (1H, m), 2.17-2.03 (2H, m), 1.89-1.77 (1H, m).
ESI-MS m/z: 495 [M+H]+ . Example 295
Synthesis of 4-chloro-N-[(2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Hydroxyethylamine (0.019 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 15 mg, 18.9%).
1 H-NMR (DMSO-d 6 ) δ: 8.19 (1H, br s), 7.60 (1H, br s), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.82 (1H, s), 4.75 (1H, s), 3.91 (3H, s), 3.89 (6H, s), 3.60 (3H, s), 3.49-3.42 (3H, m), 3.39-3.35 (1H, m ), 3.14-3.09 (1H, m), 2.17-2.03 (2H, m), 1.89-1.77 (1H, m).
ESI-MS m / z: 495 [M + H] + .
実施例２９６
4-クロロ-N-[(4-メトキシフェニル) チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへp-アニシジン(39 mg, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 64 mg, 71.8%)を得た。
1H-NMR (DMSO-d6) δ: 9.50 (1H, s), 8.20 (1H, d, J = 7.3 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.5 Hz), 6.88 (2H, d, J = 8.8 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.73 (3H, s), 3.61 (3H, s), 3.15-3.10 (1H, m), 2.16-1.96 (3H, m).
ESI-MS m/z: 557 [M+H]+ . Example 296
Synthesis of 4-chloro-N-[(4-methoxyphenyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. P-anisidine (39 mg, 0.16 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 64 mg, 71.8%).
1 H-NMR (DMSO-d 6 ) δ: 9.50 (1H, s), 8.20 (1H, d, J = 7.3 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.15 (1H, d, J = 10.5 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.5 Hz), 6.88 (2H, d, J = 8.8 Hz), 4.83-4.77 (1H, m), 3.91 (3H, s ), 3.89 (6H, s), 3.73 (3H, s), 3.61 (3H, s), 3.15-3.10 (1H, m), 2.16-1.96 (3H, m).
ESI-MS m / z: 557 [M + H] + .
実施例２９７
4-クロロ-N-[(p-トルイル) チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへp-トルイルイソチオシアネート(29 mg, 0.16×1.2 mmol)、トリエチルアミン(0.033 mL, 0.16×1.5 mmol)を加えて、室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 80 mg, 92.4%)を得た。
1H-NMR (DMSO-d6) δ: 9.60 (1H, s), 8.31 (1H, d, J = 7.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.17-7.09 (4H, m), 7.03 (1H, d, J = 10.7 Hz), 4.82-4.77 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.61 (3H, s), 3.15-3.08 (1H, m), 2.26 (3H, s), 2.15-1.97 (3H, m).
ESI-MS m/z: 541 [M+H]+ . Example 297
Synthesis of 4-chloro-N-[(p-toluyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thereto were added p-toluyl isothiocyanate (29 mg, 0.16 × 1.2 mmol) and triethylamine (0.033 mL, 0.16 × 1.5 mmol), and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 80 mg, 92.4%).
1 H-NMR (DMSO-d 6 ) δ: 9.60 (1H, s), 8.31 (1H, d, J = 7.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.17-7.09 (4H, m ), 7.03 (1H, d, J = 10.7 Hz), 4.82-4.77 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.61 (3H, s), 3.15-3.08 (1H, m), 2.26 (3H, s), 2.15-1.97 (3H, m).
ESI-MS m / z: 541 [M + H] + .
実施例２９８
4-クロロ-N-(シクロプロピルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへシクロヘキシルイソチオシアネート(19 mg, 0.16×1.2 mmol)、トリエチルアミン(0.033 mL, 0.16×1.5 mmol)を加えて、室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 75 mg, 95.5%)を得た。
1H-NMR (DMSO-d6) δ: 8.05 (1H, br s), 7.90 (1H, d, J = 7.3 Hz), 7.16-7.12 (2H, m), 7.03 (1H, d, J = 10.7 Hz), 4.88-4.79 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.16-3.10 (1H, m), 2.74-2.68 (1H, m), 2.17-2.02 (3H, m), 0.78-0.67 (2H, m), 0.57-0.45 (2H, m).
ESI-MS m/z: 491 [M+H]+ . Example 298
Synthesis of 4-chloro-N- (cyclopropylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). The cyclohexyl isothiocyanate (19 mg, 0.16 * 1.2 mmol) and the triethylamine (0.033 mL, 0.16 * 1.5 mmol) were added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 75 mg, 95.5%).
1 H-NMR (DMSO-d 6 ) δ: 8.05 (1H, br s), 7.90 (1H, d, J = 7.3 Hz), 7.16-7.12 (2H, m), 7.03 (1H, d, J = 10.7 Hz), 4.88-4.79 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.16-3.10 (1H, m), 2.74 -2.68 (1H, m), 2.17-2.02 (3H, m), 0.78-0.67 (2H, m), 0.57-0.45 (2H, m).
ESI-MS m / z: 491 [M + H] + .
実施例２９９
4-クロロ-N-(アリルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへアリルアミン(0.024 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 33 mg, 42.0%)を得た。
1H-NMR (DMSO-d6) δ: 8.12 (1H, br s), 7.67 (1H, br s), 7.15 (1H, d, J = 10.5 Hz), 7.07 (1H, s), 7.03 (1H, d, J = 10.5 Hz), 5.86-5.76 (1H, m), 5.13 (1H, d, J = 17.3 Hz), 5.07 (1H, d, J = 10.2 Hz), 4.79-4.72 (1H, m), 4.03-3.99 (2H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.14-3.09 (1H, m), 2.17-1.82 (3H, m).
ESI-MS m/z: 491 [M+H]+ . Example 299
Synthesis of 4-chloro-N- (allylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Allylamine (0.024 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 33 mg, 42.0%).
1 H-NMR (DMSO-d 6 ) δ: 8.12 (1H, br s), 7.67 (1H, br s), 7.15 (1H, d, J = 10.5 Hz), 7.07 (1H, s), 7.03 (1H , d, J = 10.5 Hz), 5.86-5.76 (1H, m), 5.13 (1H, d, J = 17.3 Hz), 5.07 (1H, d, J = 10.2 Hz), 4.79-4.72 (1H, m) , 4.03-3.99 (2H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.14-3.09 (1H, m), 2.17-1.82 (3H, m).
ESI-MS m / z: 491 [M + H] + .
実施例３００
4-クロロ-N-[(1-メチルピペリジン-4-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへ4-アミノ-1-メチルピペリジン(37 mg, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 59 mg, 67.3%)を得た。
1H-NMR (DMSO-D6) δ: 8.08 (1H, br s), 7.84 (1H, br s), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.76-4.66 (1H, m), 4.03-3.96 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.16-3.01 (3H, m), 2.55-2.48 (5H, m), 2.17-1.86 (5H, m), 1.65-1.49 (2H, m).
ESI-MS m/z: 548 [M+H]+ . Example 300
Synthesis of 4-chloro-N-[(1-methylpiperidin-4-yl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. 4-amino-1-methylpiperidine (37 mg, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 59 mg, 67.3%).
1 H-NMR (DMSO-D 6 ) δ: 8.08 (1H, br s), 7.84 (1H, br s), 7.15 (1H, d, J = 10.5 Hz), 7.05-7.02 (2H, m), 4.76 -4.66 (1H, m), 4.03-3.96 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.16-3.01 (3H , m), 2.55-2.48 (5H, m), 2.17-1.86 (5H, m), 1.65-1.49 (2H, m).
ESI-MS m / z: 548 [M + H] + .
実施例３０１
4-クロロ-N-(シクロへプチルチオカルバモイル)デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへシクロへプチルアミン(0.041 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 73 mg, 83.4%)を得た。
1H-NMR (DMSO-d6) δ: 7.84 (1H, br s), 7.53 (1H, br s), 7.15 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.76-4.67 (1H, m), 4.09-4.03 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.14-3.08 (1H, m), 2.16-2.04 (2H, m), 1.85-1.77 (3H, m), 1.58-1.35 (10H, m).
ESI-MS m/z: 547 [M+H]+ . Example 301
Synthesis of 4-chloro-N- (cycloheptylthiocarbamoyl) deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Cycloheptylamine (0.041 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 73 mg, 83.4%).
1 H-NMR (DMSO-d 6 ) δ: 7.84 (1H, br s), 7.53 (1H, br s), 7.15 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.76 -4.67 (1H, m), 4.09-4.03 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.60 (3H, s), 3.14-3.08 (1H , m), 2.16-2.04 (2H, m), 1.85-1.77 (3H, m), 1.58-1.35 (10H, m).
ESI-MS m / z: 547 [M + H] + .
実施例３０２
4-クロロ-N-[(2-メトキシエチル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で2時間攪拌した。そこへメトキシエチルアミン(0.028 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)、さらにPLC(Merck, Silicagel 60 F254, 2mm)で精製し、標記の化合物(黄色固体, 23 mg, 28.2%)を得た。
1H-NMR (DMSO-d6) δ: 8.26 (1H, br s), 7.70 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.79-4.70 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.49-3.37 (4H, m), 3.26 (3H, s), 3.14-3.09 (1H, m), 2.14-1.80 (3H, m).
ESI-MS m/z: 509 [M+H]+ . Example 302
Synthesis of 4-chloro-N-[(2-methoxyethyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Methoxyethylamine (0.028 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) and further by PLC (Merck, Silicagel 60 F 254 , 2 mm) to give the title compound (yellow solid, 23 mg, 28.2%). Obtained.
1 H-NMR (DMSO-d 6 ) δ: 8.26 (1H, br s), 7.70 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.79 -4.70 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.49-3.37 (4H, m), 3.26 (3H, s), 3.14-3.09 (1H, m), 2.14-1.80 (3H, m).
ESI-MS m / z: 509 [M + H] + .
実施例３０３
4-クロロ-N-[(2,2,2-トリフルオロエチル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへ2,2,2-トリフルオロエチルアミン(0.025 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 35 mg, 41.0%)を得た。
1H-NMR (DMSO-d6) δ: 8.51 (1H, d, J = 6.8 Hz), 8.00 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.76-4.70 (1H, m), 4.49-4.38 (1H, m), 4.34-4.25 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.15-3.10 (1H, m), 2.19-2.08 (2H, m), 1.96-1.86 (1H, m).
ESI-MS m/z: 533 [M+H]+ . Example 303
Synthesis of 4-chloro-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2,2,2-trifluoroethylamine (0.025 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 35 mg, 41.0%).
1 H-NMR (DMSO-d 6 ) δ: 8.51 (1H, d, J = 6.8 Hz), 8.00 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m ), 4.76-4.70 (1H, m), 4.49-4.38 (1H, m), 4.34-4.25 (1H, m), 3.91 (3H, s), 3.88 (6H, s), 3.60 (3H, s), 3.15-3.10 (1H, m), 2.19-2.08 (2H, m), 1.96-1.86 (1H, m).
ESI-MS m / z: 533 [M + H] + .
実施例３０４
4-クロロ-N-[(インダン-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへ2-アミノインダン(0.042 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 70 mg, 77.1%)を得た。
1H-NMR (DMSO-d6) δ: 7.91-7.85 (2H, br m), 7.26-7.21 (2H, m), 7.18-7.14 (3H, m), 7.05-7.02 (2H, m), 4.80-4.72 (2H, m), 3.92 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.62 (3H, s), 3.25-3.17 (2H, m), 3.13-3.09 (1H, m), 2.82-2.74 (2H, m), 2.16-1.76 (3H, m).
ESI-MS m/z: 567 [M+H]+ . Example 304
Synthesis of 4-chloro-N-[(indan-2-yl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2-Aminoindane (0.042 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 70 mg, 77.1%).
1 H-NMR (DMSO-d 6 ) δ: 7.91-7.85 (2H, br m), 7.26-7.21 (2H, m), 7.18-7.14 (3H, m), 7.05-7.02 (2H, m), 4.80 -4.72 (2H, m), 3.92 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.62 (3H, s), 3.25-3.17 (2H, m), 3.13-3.09 (1H , m), 2.82-2.74 (2H, m), 2.16-1.76 (3H, m).
ESI-MS m / z: 567 [M + H] + .
実施例３０５
4-クロロ-N-[(4-スルファモイルフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへ4-イソチオシアネートベンゼンスルホンアミド(41 mg, 0.16×1.2mmol)、トリエチルアミン(0.033L, 0.16×1.5 mmol)を加えて、室温で一晩攪拌した。反応後、クロロホルムを加えて1 mol/L塩酸で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 84 mg, 86.6%)を得た。
1H-NMR (DMSO-d6) δ: 10.00 (1H, s), 8.71 (1H, d, J = 6.8 Hz), 7.72-7.65 (4H, m), 7.26 (2H, s), 7.17 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.80-4.74 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.15 (1H, d, J = 7.1 Hz), 2.23-2.12 (2H, m), 2.06-1.97 (1H, m).
ESI-MS m/z: 606 [M+H]+ . Example 305
Synthesis of 4-chloro-N-[(4-sulfamoylphenyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). 4-isothiocyanate benzenesulfonamide (41 mg, 0.16 × 1.2 mmol) and triethylamine (0.033 L, 0.16 × 1.5 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, chloroform was added and washed with 1 mol / L hydrochloric acid. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 84 mg, 86.6%).
1 H-NMR (DMSO-d 6 ) δ: 10.00 (1H, s), 8.71 (1H, d, J = 6.8 Hz), 7.72-7.65 (4H, m), 7.26 (2H, s), 7.17 (1H , d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.80-4.74 (1H, m), 3.92 (3H, s), 3.89 (6H, s) , 3.63 (3H, s), 3.15 (1H, d, J = 7.1 Hz), 2.23-2.12 (2H, m), 2.06-1.97 (1H, m).
ESI-MS m / z: 606 [M + H] + .
実施例３０６
4-クロロ-N-[(3,5-ジメチルイソオキサゾール-4-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-アミノ-3,5-ジメチルオキサゾール(27 mg, 0.16×1.5 mmol)をジクロロメタン(1 mL)に溶解した。そこへチオホスゲン(0.018 mL, 0.16×1.5 mmol)、トリエチルアミン(0.067 mL, 0.16×3 mmol)を加えて、室温で2時間攪拌した。そこへ4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 97 mg, quant.)を得た。
1H-NMR (DMSO-d6) δ: 7.15 (1H, d, J = 10.7 Hz), 7.08-7.02 (2H, m), 4.85-4.75 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.59 (3H, s), 3.11-3.06 (1H, m), 2.33-2.24 (1H, m), 2.21 (3H, s), 2.14-2.08 (3H, m), 2.04 (3H, s).
ESI-MS m/z: 546 [M+H]+ . Example 306
Synthesis of 4-chloro-N-[(3,5-dimethylisoxazol-4-yl) thiocarbamoyl] deacetylcolchicine 4-amino-3,5-dimethyloxazole (27 mg, 0.16 × 1.5 mmol) was added to dichloromethane ( 1 mL). Thiophosgene (0.018 mL, 0.16 × 1.5 mmol) and triethylamine (0.067 mL, 0.16 × 3 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. 4-chloro deacetyl colchicine (62 mg, 0.16 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 97 mg, quant.).
1 H-NMR (DMSO-d 6 ) δ: 7.15 (1H, d, J = 10.7 Hz), 7.08-7.02 (2H, m), 4.85-4.75 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.59 (3H, s), 3.11-3.06 (1H, m), 2.33-2.24 (1H, m), 2.21 (3H, s), 2.14-2.08 (3H , m), 2.04 (3H, s).
ESI-MS m / z: 546 [M + H] + .
実施例３０７
4-クロロ-N-[(4-ヒドロキシフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)をジクロロメタン(1.3 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへp-ヒドロキシアニリン(35 mg, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 79 mg, 90.9%)を得た。
1H-NMR (DMSO-d6) δ: 9.42 (1H, br s), 9.37 (1H, s), 8.10 (1H, d, J = 6.1 Hz), 7.16-7.10 (4H, m), 7.03 (1H, d, J = 11.0 Hz), 6.71 (1H, s), 6.69 (1H, s), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.61 (3H, s), 3.13-3.09 (1H, m), 2.16-1.99 (3H, m).
ESI-MS m/z: 543 [M+H]+ . Example 307
Synthesis of 4-chloro-N-[(4-hydroxyphenyl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (62 mg, 0.16 mmol) was dissolved in dichloromethane (1.3 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. P-hydroxy aniline (35 mg, 0.16 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 79 mg, 90.9%).
1 H-NMR (DMSO-d 6 ) δ: 9.42 (1H, br s), 9.37 (1H, s), 8.10 (1H, d, J = 6.1 Hz), 7.16-7.10 (4H, m), 7.03 ( 1H, d, J = 11.0 Hz), 6.71 (1H, s), 6.69 (1H, s), 4.83-4.77 (1H, m), 3.91 (3H, s), 3.89 (6H, s), 3.61 (3H , s), 3.13-3.09 (1H, m), 2.16-1.99 (3H, m).
ESI-MS m / z: 543 [M + H] + .
実施例３０８
4-クロロ-N-[(5-メチルピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　3-アミノ-5-メチルピラゾール(23 mg, 0.16×1.5 mmol)をジクロロメタン(1 mL)に溶解した。そこへチオホスゲン(0.018 mL, 0.16×1.5 mmol)、トリエチルアミン(0.067 mL, 0.16×3 mmol)を加えて、室温で1時間攪拌した。そこへ4-クロロデアセチルコルヒチン(62 mg, 0.16 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 73 mg, 85.9%)を得た。
1H-NMR (DMSO-d6) δ: 12.36 (1H, s), 10.59 (1H, br s), 10.46 (1H, br s), 7.18 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.96 (1H, s), 5.73 (1H, s), 4.86-4.80 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.18-3.08 (1H, m), 2.27-2.16 (5H, m), 1.96-1.90 (1H, m).
ESI-MS m/z: 531 [M+H]+ . Example 308
Synthesis of 4-chloro-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine Dissolve 3-amino-5-methylpyrazole (23 mg, 0.16 × 1.5 mmol) in dichloromethane (1 mL) did. Thiophosgene (0.018 mL, 0.16 × 1.5 mmol) and triethylamine (0.067 mL, 0.16 × 3 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 4-chloro deacetyl colchicine (62 mg, 0.16 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 73 mg, 85.9%).
1 H-NMR (DMSO-d 6 ) δ: 12.36 (1H, s), 10.59 (1H, br s), 10.46 (1H, br s), 7.18 (1H, d, J = 10.7 Hz), 7.06 (1H , d, J = 10.7 Hz), 6.96 (1H, s), 5.73 (1H, s), 4.86-4.80 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.18-3.08 (1H, m), 2.27-2.16 (5H, m), 1.96-1.90 (1H, m).
ESI-MS m / z: 531 [M + H] + .
実施例３０９
4-ブロモ-N-(プロピルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへプロピルアミン(0.026 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 68 mg, 79.1%)を得た。
1H-NMR (DMSO-d6) δ: 8.00 (1H, br s), 7.55 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.79-4.68 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.32-3.21 (2H, m), 3.14-3.09 (1H, m), 2.25-2.17 (1H, m), 2.09-1.78 (2H, m), 1.48-1.44 (2H, m), 0.84 (3H, t, J = 7.3 Hz).
ESI-MS m/z: 537 [M+H]+ , 539[M+2+H]+. Example 309
Synthesis of 4-bromo-N- (propylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Propylamine (0.026 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 68 mg, 79.1%).
1 H-NMR (DMSO-d 6 ) δ: 8.00 (1H, br s), 7.55 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 (1H , d, J = 10.7 Hz), 4.79-4.68 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.32-3.21 ( 2H, m), 3.14-3.09 (1H, m), 2.25-2.17 (1H, m), 2.09-1.78 (2H, m), 1.48-1.44 (2H, m), 0.84 (3H, t, J = 7.3 Hz).
ESI-MS m / z: 537 [M + H] + , 539 [M + 2 + H] + .
実施例３１０
4-ブロモ-N-(ブチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへブチルアミン(0.032 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 55 mg, 62.3%)を得た。
1H-NMR (DMSO-d6) δ: 7.99 (1H, br s), 7.52 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.79-4.66 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.32-3.26 (2H, m), 3.14-3.10 (1H, m), 2.25-2.17 (1H, m), 2.09-2.01 (1H, m), 1.90-1.76 (1H, m), 1.47-1.40 (2H, m), 1.32-1.28 (2H, m), 0.86 (3H, t, J = 7.1 Hz).
ESI-MS m/z: 551 [M+H]+ , 553[M+2+H]+. Example 310
Synthesis of 4-bromo-N- (butylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Butylamine (0.032 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 55 mg, 62.3%).
1 H-NMR (DMSO-d 6 ) δ: 7.99 (1H, br s), 7.52 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.79 -4.66 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.32-3.26 (2H, m), 3.14-3.10 (1H , m), 2.25-2.17 (1H, m), 2.09-2.01 (1H, m), 1.90-1.76 (1H, m), 1.47-1.40 (2H, m), 1.32-1.28 (2H, m), 0.86 (3H, t, J = 7.1 Hz).
ESI-MS m / z: 551 [M + H] + , 553 [M + 2 + H] + .
実施例３１１
4-ブロモ-N-[(2,2,2-トリフルオロエチル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへ2,2,2-トリフルオロエチルアミン(0.025 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 17 mg, 18.4%)を得た。
1H-NMR (DMSO-d6) δ: 8.54 (1H, d, J = 7.1 Hz), 8.03 (1H, s), 7.15 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m), 4.74-4.68 (1H, m), 4.48-4.38 (1H, m), 4.34-4.25 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.12-3.11 (1H, m), 2.27-2.19 (1H, m), 2.14-2.06 (1H, m), 1.94-1.85 (1H, m).
ESI-MS m/z: 577 [M+H]+ , 579[M+2+H]+. Example 311
Synthesis of 4-bromo-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2,2,2-trifluoroethylamine (0.025 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 17 mg, 18.4%).
1 H-NMR (DMSO-d 6 ) δ: 8.54 (1H, d, J = 7.1 Hz), 8.03 (1H, s), 7.15 (1H, d, J = 10.7 Hz), 7.05-7.02 (2H, m ), 4.74-4.68 (1H, m), 4.48-4.38 (1H, m), 4.34-4.25 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.12-3.11 (1H, m), 2.27-2.19 (1H, m), 2.14-2.06 (1H, m), 1.94-1.85 (1H, m).
ESI-MS m / z: 577 [M + H] + , 579 [M + 2 + H] + .
実施例３１２
4-ブロモ-N-(シクロペンチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへシクロペンチルアミン(0.027 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 45 mg, 52.4%)を得た。
1H-NMR (DMSO-d6) δ: 7.82 (1H, d, J = 5.4 Hz), 7.63 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.78-4.68 (1H, m), 4.31-4.23 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.14-3.11 (1H, m), 2.25-2.17 (1H, m), 2.09-2.01 (1H, m), 1.91-1.83 (3H, m), 1.67-1.59 (2H, m), 1.54-1.47 (2H, m), 1.41-1.33 (2H, m).
ESI-MS m/z: 563 [M+H]+ , 565[M+2+H]+. Example 312
Synthesis of 4-bromo-N- (cyclopentylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Cyclopentylamine (0.027 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 45 mg, 52.4%).
1 H-NMR (DMSO-d 6 ) δ: 7.82 (1H, d, J = 5.4 Hz), 7.63 (1H, br s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.78-4.68 (1H, m), 4.31-4.23 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.14 -3.11 (1H, m), 2.25-2.17 (1H, m), 2.09-2.01 (1H, m), 1.91-1.83 (3H, m), 1.67-1.59 (2H, m), 1.54-1.47 (2H, m), 1.41-1.33 (2H, m).
ESI-MS m / z: 563 [M + H] + , 565 [M + 2 + H] + .
実施例３１３
4-ブロモ-N-(シクロヘキシルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへシクロヘキシルアミン(0.037 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 54 mg, 58.4%)を得た。
1H-NMR (DMSO-d6) δ: 7.86 (1H, d, J = 6.8 Hz), 7.48 (1H, s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m), 4.77-4.67 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J = 13.3, 5.5 Hz), 2.25-2.17 (1H, m), 2.10-2.01 (1H, m), 1.86-1.78 (3H, m), 1.67-1.60 (2H, m), 1.55-1.50 (1H, m), 1.28-1.18 (6H, m).
ESI-MS m/z: 577 [M+H]+ , 579[M+2+H]+. Example 313
Synthesis of 4-bromo-N- (cyclohexylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. The cyclohexylamine (0.037 mL, 0.16 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 54 mg, 58.4%).
1 H-NMR (DMSO-d 6 ) δ: 7.86 (1H, d, J = 6.8 Hz), 7.48 (1H, s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.01 (2H, m ), 4.77-4.67 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J = 13.3, 5.5 Hz), 2.25-2.17 (1H, m), 2.10-2.01 (1H, m), 1.86-1.78 (3H, m), 1.67-1.60 (2H, m), 1.55-1.50 (1H, m), 1.28- 1.18 (6H, m).
ESI-MS m / z: 577 [M + H] + , 579 [M + 2 + H] + .
実施例３１４
4-ブロモ-N-[(4-メトキシフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへp-アニシジン(39 mg, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 28 mg, 29.1%)を得た。
1H-NMR (DMSO-d6) δ: 9.51 (1H, s), 8.21 (1H, d, J = 7.1 Hz), 7.28 (2H, d, J = 8.8 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 6.88 (2H, d, J = 8.8 Hz), 4.82-4.75 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.73 (3H, s), 3.61 (3H, s), 3.13 (1H, dd, J = 13.1, 5.5 Hz), 2.26-2.17 (1H, m), 2.14-2.05 (1H, m), 2.02-1.95 (1H, m).
ESI-MS m/z: 601 [M+H]+ , 603[M+2+H]+. Example 314
Synthesis of 4-bromo-N-[(4-methoxyphenyl) thiocarbamoyl] deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. P-anisidine (39 mg, 0.16 * 2 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 28 mg, 29.1%).
1 H-NMR (DMSO-d 6 ) δ: 9.51 (1H, s), 8.21 (1H, d, J = 7.1 Hz), 7.28 (2H, d, J = 8.8 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 6.88 (2H, d, J = 8.8 Hz), 4.82-4.75 (1H, m), 3.91 (3H, s ), 3.89 (3H, s), 3.87 (3H, s), 3.73 (3H, s), 3.61 (3H, s), 3.13 (1H, dd, J = 13.1, 5.5 Hz), 2.26-2.17 (1H, m), 2.14-2.05 (1H, m), 2.02-1.95 (1H, m).
ESI-MS m / z: 601 [M + H] + , 603 [M + 2 + H] + .
実施例３１５
4-ブロモ-N-{[2-(4-モルホリノ)エチル]チオカルバモイル}デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへ2-(4-モルホリノ)エチルアミン(0.042 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 37 mg, 38.0%)を得た。
1H-NMR (DMSO-d6) δ: 7.49 (1H, s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.02 (2H, m), 4.77-4.67 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63-3.56 (7H, m), 3.50-3.42 (2H, m), 3.15-3.06 (3H, m), 2.44-2.35 (4H, m), 2.26-2.17 (1H, m), 2.11-2.01 (1H, m), 1.92-1.79 (1H, m).
ESI-MS m/z: 608 [M+H]+ , 610[M+2+H]+. Example 315
Synthesis of 4-bromo-N-{[2- (4-morpholino) ethyl] thiocarbamoyl} deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 2- (4-morpholino) ethylamine (0.042 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 37 mg, 38.0%).
1 H-NMR (DMSO-d 6 ) δ: 7.49 (1H, s), 7.14 (1H, d, J = 10.7 Hz), 7.04-7.02 (2H, m), 4.77-4.67 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63-3.56 (7H, m), 3.50-3.42 (2H, m), 3.15-3.06 (3H, m), 2.44-2.35 (4H, m), 2.26-2.17 (1H, m), 2.11-2.01 (1H, m), 1.92-1.79 (1H, m).
ESI-MS m / z: 608 [M + H] + , 610 [M + 2 + H] + .
実施例３１６
4-ブロモ-N-(N’,N’-ジメチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへジメチルアミン塩酸塩(26 mg, 0.16×2 mmol)、トリエチルアミン(0.045 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 76 mg, 90.7%)を得た。
1H-NMR (DMSO-d6) δ: 7.63 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 4.89-4.83 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.62 (3H, s), 3.20 (6H, s), 3.15-3.10 (1H, m), 2.24-2.16 (2H, m), 2.05-1.95 (1H, m).
ESI-MS m/z: 523 [M+H]+ , 525[M+2+H]+. Example 316
Synthesis of 4-bromo-N- (N ′, N′-dimethylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Dimethylamine hydrochloride (26 mg, 0.16 × 2 mmol) and triethylamine (0.045 mL, 0.16 × 2 mmol) were added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 76 mg, 90.7%).
1 H-NMR (DMSO-d 6 ) δ: 7.63 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.08 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 4.89-4.83 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.62 (3H, s), 3.20 (6H, s), 3.15 -3.10 (1H, m), 2.24-2.16 (2H, m), 2.05-1.95 (1H, m).
ESI-MS m / z: 523 [M + H] + , 525 [M + 2 + H] + .
実施例３１７
4-ブロモ-N-(N’-エチル-N’-メチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへエチルメチルアミン(0.027 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 78 mg, 90.7%)を得た。
1H-NMR (DMSO-d6) δ: 7.58 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 4.92-4.86 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.62 (3H, s), 3.29 (2H, s), 3.15 (3H, s), 2.26-2.16 (2H, m), 2.02-1.95 (1H, m), 1.04 (3H, t, J = 7.0 Hz).
ESI-MS m/z: 537 [M+H]+ , 539[M+2+H]+. Example 317
Synthesis of 4-bromo-N- (N′-ethyl-N′-methylthiocarbamoyl) deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. Ethylmethylamine (0.027 mL, 0.16 × 2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 78 mg, 90.7%).
1 H-NMR (DMSO-d 6 ) δ: 7.58 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 4.92-4.86 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.62 (3H, s), 3.29 (2H, s), 3.15 (3H, s), 2.26-2.16 (2H, m), 2.02-1.95 (1H, m), 1.04 (3H, t, J = 7.0 Hz).
ESI-MS m / z: 537 [M + H] + , 539 [M + 2 + H] + .
実施例３１８
4-ブロモ-N-[(4-メチルピペリジン-1-イル)チオカルボニル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへ4-メチルピペリジン(0.038 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 73 mg, 79.0%)を得た。
1H-NMR (DMSO-d6) δ: 7.88 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.92-4.86 (1H, m), 4.65 (2H, dd, J = 30.7, 13.0 Hz), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.62 (3H, s), 3.12 (1H, dd, J = 12.4, 5.9 Hz), 2.98 (2H, q, J = 13.0 Hz), 2.24-2.14 (2H, m), 2.03-1.93 (1H, m), 1.28-1.23 (2H, m), 1.09-0.94 (2H, m), 0.89 (3H, d, J = 6.3 Hz), 0.86-0.84 (1H, m).
ESI-MS m/z: 577 [M+H]+ , 579[M+2+H]+. Example 318
Synthesis of 4-bromo-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL). Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 4-methylpiperidine (0.038 mL, 0.16 × 2 mmol) was added thereto and stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 73 mg, 79.0%).
1 H-NMR (DMSO-d 6 ) δ: 7.88 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 4.92-4.86 (1H, m), 4.65 (2H, dd, J = 30.7, 13.0 Hz), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.62 (3H, s), 3.12 (1H, dd, J = 12.4, 5.9 Hz), 2.98 (2H, q, J = 13.0 Hz), 2.24-2.14 (2H, m), 2.03-1.93 (1H, m), 1.28-1.23 (2H, m), 1.09-0.94 (2H, m), 0.89 (3H, d, J = 6.3 Hz), 0.86-0.84 (1H, m).
ESI-MS m / z: 577 [M + H] + , 579 [M + 2 + H] + .
実施例３１９
4-ブロモ-N-[(4,4-ジフルオロ-ピペリジン-1-イル)チオカルボニル]デアセチルコルヒチンの合成
　4-ブロモデアセチルコルヒチン(70 mg, 0.16 mmol)をジクロロメタン(1.4 mL)に溶解した。そこへチオホスゲン(0.013 mL, 0.16×1.05 mmol)、トリエチルアミン(0.054 mL, 0.16×2.4 mmol)を加えて、室温で1時間攪拌した。そこへ4,4-ジフルオロピペリジン塩酸塩(50 mg, 0.16×2 mmol)、トリエチルアミン(0.045 mL, 0.16×2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 82 mg, 85.5%)を得た。
1H-NMR (DMSO-d6) δ: 8.23 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.7 Hz), 4.85-4.79 (1H, m), 4.04-3.98 (2H, m), 3.94-3.91 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J = 12.6, 5.2 Hz), 2.25-2.13 (2H, m), 2.08-1.92 (5H, m).
ESI-MS m/z: 599 [M+H]+ , 601[M+2+H]+. Example 319
Synthesis of 4-bromo-N-[(4,4-difluoro-piperidin-1-yl) thiocarbonyl] deacetylcolchicine 4-Bromodeacetylcolchicine (70 mg, 0.16 mmol) was dissolved in dichloromethane (1.4 mL) . Thiophosgene (0.013 mL, 0.16 × 1.05 mmol) and triethylamine (0.054 mL, 0.16 × 2.4 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. 4,4-difluoropiperidine hydrochloride (50 mg, 0.16 × 2 mmol) and triethylamine (0.045 mL, 0.16 × 2 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 82 mg, 85.5%).
1 H-NMR (DMSO-d 6 ) δ: 8.23 (1H, d, J = 6.8 Hz), 7.15 (1H, d, J = 10.7 Hz), 4.85-4.79 (1H, m), 4.04-3.98 (2H , m), 3.94-3.91 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.63 (3H, s), 3.13 (1H, dd, J = 12.6 , 5.2 Hz), 2.25-2.13 (2H, m), 2.08-1.92 (5H, m).
ESI-MS m / z: 599 [M + H] + , 601 [M + 2 + H] + .
参考例２８
3-イソチオシアネート-5メチルイソオキサゾールの合成
　3-アミノ-5-メチルイソオキサゾール(326 mg, 3.3 mmol)をジクロロメタン(6.5 mL)に溶解し、氷冷した。そこへチオホスゲン(0.278 mL, 3.3×1.1 mmol)、炭酸ナトリウム水溶液(769 mg, 3.3×2.2 mmol, 4 mL)を加えて室温で2.5時間攪拌した。反応後、クロロホルムを加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色オイル, 255 mg, 55.1%)を得た。
1H-NMR (CDCl3) δ: 5.97 (1H, t, J = 0.9 Hz), 2.43 (3H, t, J = 0.9 Hz).
ESI-MS m/z: 141 [M+H]+ . Reference Example 28
Synthesis of 3-isothiocyanate-5methylisoxazole 3-Amino-5-methylisoxazole (326 mg, 3.3 mmol) was dissolved in dichloromethane (6.5 mL) and cooled on ice. Thiophosgene (0.278 mL, 3.3 * 1.1 mmol) and sodium carbonate aqueous solution (769 mg, 3.3 * 2.2 mmol, 4 mL) were added there, and it stirred at room temperature for 2.5 hours. After the reaction, chloroform was added and washed with saturated saline. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow oil, 255 mg, 55.1%).
1 H-NMR (CDCl 3 ) δ: 5.97 (1H, t, J = 0.9 Hz), 2.43 (3H, t, J = 0.9 Hz).
ESI-MS m / z: 141 [M + H] + .
実施例３２０
4-クロロ-N-[(5-メチルイソオキサゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　3-イソチオシアネート-5メチルイソオキサゾール(32 mg, 0.19×1.2 mmol)をジクロロメタンに溶解した。そこへ4-クロロデアセチルコルヒチン(75 mg, 0.19 mmol)、トリエチルアミン(0.04 mL, 0.19×1.5 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 98 mg, 80.0%)を得た。
1H-NMR (DMSO-d6) δ: 9.20 (1H, s), 7.17 (1H, d, J = 10.5 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.5 Hz), 4.25-4.14 (1H, m), 3.93 (3H, s), 3.88 (6H, s), 3.54 (3H, s), 3.15 (1H, dd, J = 12.8, 4.8 Hz), 2.28-2.12 (2H, m), 1.93 (3H, s), 1.91-1.83 (1H, m).
ESI-MS m/z: 532 [M+H]+ . Example 320
Synthesis of 4-chloro-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine 3-isothiocyanate-5methylisoxazole (32 mg, 0.19 × 1.2 mmol) was dissolved in dichloromethane. 4-chloro deacetyl colchicine (75 mg, 0.19 mmol) and triethylamine (0.04 mL, 0.19 × 1.5 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 98 mg, 80.0%).
1 H-NMR (DMSO-d 6 ) δ: 9.20 (1H, s), 7.17 (1H, d, J = 10.5 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.5 Hz), 4.25-4.14 (1H, m), 3.93 (3H, s), 3.88 (6H, s), 3.54 (3H, s), 3.15 (1H, dd, J = 12.8, 4.8 Hz), 2.28-2.12 (2H, m), 1.93 (3H, s), 1.91-1.83 (1H, m).
ESI-MS m / z: 532 [M + H] + .
参考例２９
イミダゾール-1-カルボチオ酸 (5-メチル-１，２，４－トリアゾール-3-イル)-アミドの合成
　3-アミノ-5メチル－１，２，４－トリアゾール(265 mg, 2.7 mmol)をアセトニトリル(2.7 mL)に溶解した。そこへチオカルボニルジイミダゾール(481 mg, 2.7 mmol)を加えて室温で2時間攪拌した。反応後、沈殿物をろ過し、アセトニトリルで洗った。ろ過物を減圧乾燥することで標記の化合物(黄色固体, 377 mg, 67.1%)を得た。
1H-NMR (DMSO-d6) δ: 8.41 (1H, t, J = 1.1 Hz), 8.26 (2H, br s), 7.83 (1H, t, J = 1.5 Hz), 7.05 (1H, dd, J = 1.5, 1.1 Hz), 2.12 (3H, s).
ESI-MS m/z: 209 [M+H]+ . Reference Example 29
Synthesis of imidazole-1-carbothioic acid (5-methyl-1,2,4-triazol-3-yl) -amide 3-amino-5methyl-1,2,4-triazole (265 mg, 2.7 mmol) in acetonitrile Dissolved in (2.7 mL). The thiocarbonyl diimidazole (481 mg, 2.7 mmol) was added there, and it stirred at room temperature for 2 hours. After the reaction, the precipitate was filtered and washed with acetonitrile. The filtrate was dried under reduced pressure to give the title compound (yellow solid, 377 mg, 67.1%).
1 H-NMR (DMSO-d 6 ) δ: 8.41 (1H, t, J = 1.1 Hz), 8.26 (2H, br s), 7.83 (1H, t, J = 1.5 Hz), 7.05 (1H, dd, J = 1.5, 1.1 Hz), 2.12 (3H, s).
ESI-MS m / z: 209 [M + H] + .
実施例３２１
4-クロロ-N-[(5-メチル－１，２，４－トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(61 mg, 0.156 mmol)をDMF(2 mL)に溶解した。そこへイミダゾール-1-カルボチオ酸 (5-メチル-１，２，４－トリアゾール-3-イル)-アミド(36 mg, 0.156×1.1 mmol)を加えて60℃で2時間攪拌した。反応後、溶媒を留去した。酢酸エチルを加えて飽和重曹水、飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 46 mg, 55.4%)を得た。
1H-NMR (DMSO-d6) δ: 10.32 (1H, d, J = 7.3 Hz), 8.06 (2H, br s), 7.19 (1H, d, J = 10.7 Hz), 7.07-7.04 (2H, m), 4.82-4.76 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.15 (1H, dd, J = 12.9, 5.4 Hz), 2.60-2.53 (1H, m), 2.20 (3H, s), 2.18-1.99 (2H, m).ESI-MS m/z: 532 [M+H]+. Example 321
Synthesis of 4-chloro-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chlorodeacetylcolchicine (61 mg, 0.156 mmol) in DMF (2 mL ). Thereto was added imidazole-1-carbothioic acid (5-methyl-1,2,4-triazol-3-yl) -amide (36 mg, 0.156 × 1.1 mmol), and the mixture was stirred at 60 ° C. for 2 hours. After the reaction, the solvent was distilled off. Ethyl acetate was added and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 46 mg, 55.4%).
1 H-NMR (DMSO-d 6 ) δ: 10.32 (1H, d, J = 7.3 Hz), 8.06 (2H, br s), 7.19 (1H, d, J = 10.7 Hz), 7.07-7.04 (2H, m), 4.82-4.76 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.15 (1H, dd, J = 12.9, 5.4 Hz), 2.60-2.53 (1H, m), 2.20 (3H, s), 2.18-1.99 (2H, m) .ESI-MS m / z: 532 [M + H] + .
参考例３０
3-イソチオシアネートイソオキサゾールの合成
　3-アミノイソオキサゾール(247 mg, 2.94 mmol)をジクロロメタン(5 mL)に溶解し、氷冷した。チオホスゲン(0.248 mL, 2.94×1.1 mmol)、炭酸ナトリウム水溶液(686 mg, 2.94×2.2 mmol, 3.4 mL)を加えて氷冷下2時間攪拌した。反応後、クロロホルムを加えて飽和重曹水、飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色オイル, 110 mg, 29.7%)を得た。
1H-NMR (CDCl3) δ: 8.40 (1H, dd, J = 1.7, 0.7 Hz), 6.33 (1H, dd, J = 2.0, 0.7 Hz). Reference Example 30
Synthesis of 3-isothiocyanate isoxazole 3-Aminoisoxazole (247 mg, 2.94 mmol) was dissolved in dichloromethane (5 mL) and cooled on ice. Thiophosgene (0.248 mL, 2.94 × 1.1 mmol) and aqueous sodium carbonate solution (686 mg, 2.94 × 2.2 mmol, 3.4 mL) were added, and the mixture was stirred for 2 hours under ice cooling. After the reaction, chloroform was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow oil, 110 mg, 29.7%).
1 H-NMR (CDCl 3 ) δ: 8.40 (1H, dd, J = 1.7, 0.7 Hz), 6.33 (1H, dd, J = 2.0, 0.7 Hz).
実施例３２２
4-クロロ-N-[(イソオキサゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロデアセチルコルヒチン(188 mg, 0.48 mmol)をアセトニトリル(3 mL)に溶解した。そこへ3-イソチオシアネートイソオキサゾール(105 mg, 0.48×1.7 mmol)を加えて室温で一晩攪拌した。さらにDMF(3 mL)を加えて80℃で4時間攪拌した。反応後、溶媒を留去した。酢酸エチルを加えて、0.1 mol/L塩酸、飽和重曹水、飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 87 mg, 35.0%)を得た。
ESI-MS m/z: 518 [M+H]+ . Example 322
Synthesis of 4-chloro-N-[(isoxazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-Chlorodeacetylcolchicine (188 mg, 0.48 mmol) was dissolved in acetonitrile (3 mL). 3-isothiocyanate isoxazole (105 mg, 0.48 × 1.7 mmol) was added thereto and stirred at room temperature overnight. Further, DMF (3 mL) was added and stirred at 80 ° C. for 4 hours. After the reaction, the solvent was distilled off. Ethyl acetate was added, and the mixture was washed with 0.1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 87 mg, 35.0%).
ESI-MS m / z: 518 [M + H] + .
実施例３２３
4-クロロ-N-[(１，２，４－トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-7-(イソチオシアネートデアセチルアミド)コルヒチン(72 mg, 0.166 mmol)をDMF(1 mL)に溶解した。そこへ3-アミノ－１，２，４－トリアゾール(17 mg, 0.166×1.2 mmol)を加えて80℃で1時間攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 27 mg, 31.4%)を得た。
ESI-MS m/z: 518 [M+H]+ . Example 323
Synthesis of 4-chloro-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7- (isothiocyanate deacetylamido) colchicine (72 mg, 0.166 mmol) Dissolved in DMF (1 mL). 3-amino-1,2,4-triazole (17 mg, 0.166 × 1.2 mmol) was added thereto, and the mixture was stirred at 80 ° C. for 1 hour. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 27 mg, 31.4%).
ESI-MS m / z: 518 [M + H] + .
実施例３２４
4-クロロ-N-[(3,4-ジメチルイソオキサゾール-５-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-7-(イソチオシアネートデアセチルアミド)コルヒチン(69 mg, 0.159 mmol)をDMF(1 mL)に溶解した。そこへ5-アミノ-3,4-ジメチルイソオキサゾール(21 mg, 0.159×1.2 mmol)を加えて80℃で4時間攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 24 mg, 27.6%)を得た。
1H-NMR (DMSO-d6) δ: 9.87 (1H, s), 8.81 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.78-4.71 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.59 (3H, s), 3.17-3.10 (1H, m), 2.13 (3H, s), 2.11-2.04 (3H, m), 1.73 (3H, s).
ESI-MS m/z: 546 [M+H]+ . Example 324
Synthesis of 4-chloro-N-[(3,4-dimethylisoxazol-5-yl) thiocarbamoyl] deacetylcolchicine 4-Chloro-7- (isothiocyanate deacetylamido) colchicine (69 mg, 0.159 mmol) Dissolved in DMF (1 mL). 5-amino-3,4-dimethylisoxazole (21 mg, 0.159 × 1.2 mmol) was added thereto and stirred at 80 ° C. for 4 hours. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 10 g, chloroform / methanol) to obtain the title compound (yellow solid, 24 mg, 27.6%).
1 H-NMR (DMSO-d 6 ) δ: 9.87 (1H, s), 8.81 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.10 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.78-4.71 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.59 (3H, s), 3.17 -3.10 (1H, m), 2.13 (3H, s), 2.11-2.04 (3H, m), 1.73 (3H, s).
ESI-MS m / z: 546 [M + H] + .
実施例３２５
4-クロロ-N-[(4-シアノピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-7-(イソチオシアネートデアセチルアミド)コルヒチン(77 mg, 0.178 mmol)をDMF(1 mL)に溶解した。そこへ3-アミノ-4-シアノピラゾール(23 mg, 0.178×1.2 mmol)を加えて80℃で4時間攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 41 mg, 42.5%)を得た。
1H-NMR (DMSO-d6) δ: 13.60 (1H, s), 10.42 (1H, s), 9.31 (1H, d, J = 6.6 Hz), 8.57 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.06-7.04 (2H, m), 4.82-4.76 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.14 (1H, d, J = 8.3 Hz), 2.19-2.14 (2H, m), 2.04-1.97 (1H, m).
ESI-MS m/z: 593 [M+H]+ . Example 325
Synthesis of 4-chloro-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7- (isothiocyanate deacetylamido) colchicine (77 mg, 0.178 mmol) was converted to DMF (1 mL). 3-amino-4-cyanopyrazole (23 mg, 0.178 × 1.2 mmol) was added thereto, and the mixture was stirred at 80 ° C. for 4 hours. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 41 mg, 42.5%).
1 H-NMR (DMSO-d 6 ) δ: 13.60 (1H, s), 10.42 (1H, s), 9.31 (1H, d, J = 6.6 Hz), 8.57 (1H, s), 7.17 (1H, d , J = 10.7 Hz), 7.06-7.04 (2H, m), 4.82-4.76 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.62 (3H, s), 3.14 (1H, d, J = 8.3 Hz), 2.19-2.14 (2H, m), 2.04-1.97 (1H, m).
ESI-MS m / z: 593 [M + H] + .
実施例３２６
4-クロロ-N-[(5-フェニルピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-7-(イソチオシアネートデアセチルアミド)コルヒチン(82 mg, 0.189 mmol)をDMF(1 mL)に溶解した。そこへ3-アミノ-5-フェニルピラゾール(36 mg, 0.189×1.2 mmol)を加えて80℃で一晩攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 113 mg, quant.)を得た。
1H-NMR (DMSO-d6) δ: 13.17 (1H, s), 10.75 (1H, s), 10.33 (1H, s), 7.73 (2H, d, J = 7.6 Hz), 7.50-7.46 (2H, m), 7.40 (1H, t, J = 7.3 Hz), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 7.03 (1H, s), 6.33 (1H, s), 4.90-4.84 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.64 (3H, s), 3.19-3.17 (1H, m), 2.33-2.19 (2H, m), 1.99-1.93 (1H, m).
ESI-MS m/z: 546 [M+H]+ . Example 326
Synthesis of 4-chloro-N-[(5-phenylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7- (isothiocyanate deacetylamido) colchicine (82 mg, 0.189 mmol) was converted to DMF (1 mL). 3-amino-5-phenylpyrazole (36 mg, 0.189 × 1.2 mmol) was added thereto and stirred at 80 ° C. overnight. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 113 mg, quant.).
1 H-NMR (DMSO-d 6 ) δ: 13.17 (1H, s), 10.75 (1H, s), 10.33 (1H, s), 7.73 (2H, d, J = 7.6 Hz), 7.50-7.46 (2H , m), 7.40 (1H, t, J = 7.3 Hz), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 7.03 (1H, s), 6.33 (1H , s), 4.90-4.84 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.64 (3H, s), 3.19-3.17 (1H, m), 2.33-2.19 (2H, m ), 1.99-1.93 (1H, m).
ESI-MS m / z: 546 [M + H] + .
参考例３１
4-ヨードコルヒチンの合成
　アルゴン雰囲気下、コルヒチン(4.47 g, 11.2 mmol) を酢酸 (56 mL) に溶解した。そこへN-ヨードこはく酸イミド (8.81 g, 11.2 × 3.5 mmol) を加え、70℃で4時間撹拌した。反応液を冷却し、エバポレーターにて酢酸を留去した。得られた残渣に飽和チオ硫酸ナトリウム水溶液を溶液が黄色になるまで加え、飽和重曹水で中和し、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 100 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 4.10 g, 7.80 mmol, 70%,) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.64 (1H, s), 7.44 (1H, d, J = 5.9 Hz), 7.33 (1H, d, J = 10.7 Hz), 6.91 (1H, d, J = 10.7 Hz), 4.55-4.49 (1H, m), 4.04 (3H, s), 3.97 (3H, s), 3.95 (3H, s), 3.62 (3H, s), 3.18 (1H, dd, J = 13.3, 4.8 Hz), 2.45-2.37 (1H, m), 2.34-2.25 (1H, m), 2.01 (3H, s), 1.85-1.78 (1H, m).
ESI-MS m/z: 526 ([M+H]+) Reference Example 31
Synthesis of 4-iodocolchicine Colchicine (4.47 g, 11.2 mmol) was dissolved in acetic acid (56 mL) under an argon atmosphere. N-iodo succinimide (8.81 g, 11.2 * 3.5 mmol) was added there, and it stirred at 70 degreeC for 4 hours. The reaction solution was cooled, and acetic acid was distilled off with an evaporator. A saturated aqueous sodium thiosulfate solution was added to the resulting residue until the solution turned yellow, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 100 g, methanol / chloroform) to obtain the title compound (yellow solid, 4.10 g, 7.80 mmol, 70%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.64 (1H, s), 7.44 (1H, d, J = 5.9 Hz), 7.33 (1H, d, J = 10.7 Hz), 6.91 (1H, d, J = 10.7 Hz), 4.55-4.49 (1H, m), 4.04 (3H, s), 3.97 (3H, s), 3.95 (3H, s), 3.62 (3H, s), 3.18 (1H, dd , J = 13.3, 4.8 Hz), 2.45-2.37 (1H, m), 2.34-2.25 (1H, m), 2.01 (3H, s), 1.85-1.78 (1H, m).
ESI-MS m / z: 526 ([M + H] + )
実施例３２７
N-(t-ブチルオキシカルボニル)-4-ヨードコルヒチンの合成
　アルゴン雰囲気下、4-ヨードコルヒチン (4.10 g, 7.80 mmol) をアセトニトリル (78 mL) に溶解した。そこへ4-ジメチルアミノピリジン (953 mg, 7.80 × 1 mmol), トリエチルアミン (3.2 mL, 7.80 × 3 mmol)、二炭酸ジ-tert-ブチル (8.52 g, 7.80 × 5 mmol) を加え、終夜加熱還流した。反応液を冷却し、飽和クエン酸水溶液を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 100 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 3.42 g, 5.47 mmol, 70%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.62 (1H, s), 7.17 (1H, d, J = 11.0 Hz), 6.79 (1H, d, J = 10.5 Hz), 5.06-5.01 (1H, m), 3.99 (3H, s), 3.96 (3H ,s), 3.94 (3H, s), 3.61 (3H, s), 3.24 (1H, dd, J = 13.4, 5.6 Hz), 2.64-2.47 (2H, m), 2.32 (3H, s), 1.98-1.90 (1H, m), 1.57 (9H, s).
ESI-MS m/z: 626 ([M+H]+) Example 327
Synthesis of N- (t-butyloxycarbonyl) -4-iodocolchicine 4-Iodocolchicine (4.10 g, 7.80 mmol) was dissolved in acetonitrile (78 mL) under an argon atmosphere. 4-Dimethylaminopyridine (953 mg, 7.80 × 1 mmol), triethylamine (3.2 mL, 7.80 × 3 mmol) and di-tert-butyl dicarbonate (8.52 g, 7.80 × 5 mmol) were added, and the mixture was heated to reflux overnight. did. The reaction mixture was cooled, saturated aqueous citric acid solution was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 100 g, methanol / chloroform) to obtain the title compound (brown solid, 3.42 g, 5.47 mmol, 70%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.62 (1H, s), 7.17 (1H, d, J = 11.0 Hz), 6.79 (1H, d, J = 10.5 Hz), 5.06-5.01 ( 1H, m), 3.99 (3H, s), 3.96 (3H, s), 3.94 (3H, s), 3.61 (3H, s), 3.24 (1H, dd, J = 13.4, 5.6 Hz), 2.64-2.47 (2H, m), 2.32 (3H, s), 1.98-1.90 (1H, m), 1.57 (9H, s).
ESI-MS m / z: 626 ([M + H] + )
実施例３２８
N-(t-ブチルオキシカルボニル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、N-(t-ブチルオキシカルボニル)-4-ヨードコルヒチン (801 mg, 1.28 mmol) をメタノール (6 mL) に溶解した。そこへナトリウムメトキシド (138 mg, 1.28 × 2 mmol) を加え、室温で1時間撹拌した。反応液に飽和食塩水を加えクエンチし、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 50 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡褐色固体, 535 mg, 0.917 mmol, 72%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.55 (1H, s), 7.21 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.96 (1H, d, J = 7.3 Hz), 4.30-4.24 (1H, m), 4.01 (3H, s), 3.96 (3H, s), 3.95 (3H, s), 3.62 (3H, s), 3.15 (1H, dd, J = 13.8, 4.5 Hz), 2.45-2.37 (1H, m), 2.31-2.19 (1H, m), 1.61-1.54 (1H, m), 1.38 (9H, s).
ESI-MS m/z: 584 ([M+H]+) Example 328
Synthesis of N- (t-butyloxycarbonyl) -4-iododeacetylcolchicine N- (t-butyloxycarbonyl) -4-iodocolchicine (801 mg, 1.28 mmol) in methanol (6 mL) under argon atmosphere Dissolved. Sodium methoxide (138 mg, 1.28 * 2 mmol) was added there, and it stirred at room temperature for 1 hour. The reaction solution was quenched by adding saturated brine, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 50 g, methanol / chloroform) to obtain the title compound (light brown solid, 535 mg, 0.917 mmol, 72%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.55 (1H, s), 7.21 (1H, d, J = 10.7 Hz), 6.81 (1H, d, J = 10.7 Hz), 4.96 (1H, d, J = 7.3 Hz), 4.30-4.24 (1H, m), 4.01 (3H, s), 3.96 (3H, s), 3.95 (3H, s), 3.62 (3H, s), 3.15 (1H, dd , J = 13.8, 4.5 Hz), 2.45-2.37 (1H, m), 2.31-2.19 (1H, m), 1.61-1.54 (1H, m), 1.38 (9H, s).
ESI-MS m / z: 584 ([M + H] + )
実施例３２９
4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、N-(t-ブチルオキシカルボニル)-4-ヨードデアセチルコルヒチン (515 mg, 0.883 mmol) をトリフルオロ酢酸 (1.3 mL) に溶解し、室温で3時間撹拌した。反応液を0℃に冷却し、1N 水酸化ナトリウム水溶液で塩基性にして、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 25 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 355 mg, 0.735 mmol, 83%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.65 (1H, s), 7.05 (1H, d, J= 10.5 Hz), 6.99 (1H, d, J = 10.7 Hz), 3.88 (3H, s), 3.86 (3H, s), 3.82 (3H, s), 3.55 (3H, s), 3.33-3.29 (1H, m), 2.95 (1H, dd, J = 13.5, 5.2 Hz), 2.34-2.26 (1H, m), 2.07-1.98 (1H, m), 1.98 (2H, br.s), 1.45-1.38 (1H, m).
ESI-MS m/z: 484 ([M+H]+) Example 329
Synthesis of 4-iododeacetylcolchicine N- (t-butyloxycarbonyl) -4-iododeacetylcolchicine (515 mg, 0.883 mmol) was dissolved in trifluoroacetic acid (1.3 mL) under an argon atmosphere, and 3 Stir for hours. The reaction mixture was cooled to 0 ° C., basified with 1N aqueous sodium hydroxide solution, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 25 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 355 mg, 0.735 mmol, 83%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.65 (1H, s), 7.05 (1H, d, J = 10.5 Hz), 6.99 (1H, d, J = 10.7 Hz), 3.88 ( 3H, s), 3.86 (3H, s), 3.82 (3H, s), 3.55 (3H, s), 3.33-3.29 (1H, m), 2.95 (1H, dd, J = 13.5, 5.2 Hz), 2.34 -2.26 (1H, m), 2.07-1.98 (1H, m), 1.98 (2H, br.s), 1.45-1.38 (1H, m).
ESI-MS m / z: 484 ([M + H] + )
実施例３３０
4-ヨード-N-プロピオニルデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、プロピオニルクロリド (9 μl, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 41 mg, 0.076 mmol, 74%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.54 (1H, s), 7.30 (1H, d, J = 10.7 Hz), 6.87 (1H, d, J = 11.0 Hz), 6.68 (1H, br.s), 4.56-4.50 (1H, m), 4.02 (3H, s), 3.97 (3H, s), 3.94 (3H, s), 3.63 (3H, s), 3.18 (1H, dd, J = 13.7, 5.1 Hz), 2.46-2.37 (1H, m), 2.33-2.21 (1H, m), 2.29 (2H, q, J = 7.5 Hz), 1.78-1.71 (1H, m), 1.11 (3H, t, J = 7.6 Hz)．
ESI-MS m/z: 540 ([M+H]+) Example 330
Synthesis of 4-iodo-N-propionyl deacetyl colchicine Under an argon atmosphere, 4-iodo deacetyl colchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 μl, 0.103 × 1.1 mmol) and propionyl chloride (9 μl, 0.103 × 1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 41 mg, 0.076 mmol, 74%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.54 (1H, s), 7.30 (1H, d, J = 10.7 Hz), 6.87 (1H, d, J = 11.0 Hz), 6.68 (1H, br.s), 4.56-4.50 (1H, m), 4.02 (3H, s), 3.97 (3H, s), 3.94 (3H, s), 3.63 (3H, s), 3.18 (1H, dd, J = 13.7, 5.1 Hz), 2.46-2.37 (1H, m), 2.33-2.21 (1H, m), 2.29 (2H, q, J = 7.5 Hz), 1.78-1.71 (1H, m), 1.11 (3H, t , J = 7.6 Hz).
ESI-MS m / z: 540 ([M + H] + )
実施例３３１
N-シクロプロピルカルボニル-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、シクロプロパンカルボニルクロリド (9 μl, 0.103 × 1.1 mmol) を加え、0℃で10分、次いで室温で1時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡褐色固体, 34 mg, 0.062 mmol, 60%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.66 (1H, s), 7.30 (1H, d, J = 10.7 Hz), 6.87 (1H, d, J = 11.0 Hz), 6.83 (1H, br.s), 4.58-4.52 (1H, m), 4.03 (3H, s), 3.96 (3H, s), 3.94 (3H, s), 3.60 (3H, s), 3.18 (1H, dd, J = 13.7, 4.6 Hz), 2.45-2.37 (1H, m), 2.33-2.24 (1H, m), 1.81-1.73 (1H, m), 1.58-1.49 (1H, m), 0.88-0.86 (2H, m), 0.74 (2H, d, J = 8.1 Hz).
ESI-MS m/z: 552 ([M+H]+) Example 331
Synthesis of N-cyclopropylcarbonyl-4-iododeacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 μl, 0.103 × 1.1 mmol) and cyclopropanecarbonyl chloride (9 μl, 0.103 × 1.1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (light brown solid, 34 mg, 0.062 mmol, 60%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.66 (1H, s), 7.30 (1H, d, J = 10.7 Hz), 6.87 (1H, d, J = 11.0 Hz), 6.83 (1H, br.s), 4.58-4.52 (1H, m), 4.03 (3H, s), 3.96 (3H, s), 3.94 (3H, s), 3.60 (3H, s), 3.18 (1H, dd, J = 13.7, 4.6 Hz), 2.45-2.37 (1H, m), 2.33-2.24 (1H, m), 1.81-1.73 (1H, m), 1.58-1.49 (1H, m), 0.88-0.86 (2H, m) , 0.74 (2H, d, J = 8.1 Hz).
ESI-MS m / z: 552 ([M + H] + )
実施例３３２
4-ヨード-N-(トリフルオロアセチル)デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリフルオロ酢酸無水物 (29 μl, 0.103 × 2 mmol) を加え、0℃で2時間撹拌した。反応液に水を加えクエンチし、飽和重曹水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 52 mg, 0.090 mmol, 87%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 8.72 (1H, br.s), 7.49 (1H, d, J = 3.2 Hz), 7.34 (1H, d, J = 11.0 Hz), 6.91 (1H, d, J = 10.7 Hz), 4.60-4.54 (1H, m), 4.04 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.63 (3H, s), 3.24 (1H, dd, J = 13.1, 4.3 Hz), 2.48-2.34 (2H, m), 2.08-1.98 (1H, m)．
ESI-MS m/z: 580 ([M+H]+) Example 332
Synthesis of 4-iodo-N- (trifluoroacetyl) deacetylcolchicine In an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Trifluoroacetic anhydride (29 microliters, 0.103 * 2 mmol) was added there, and it stirred at 0 degreeC for 2 hours. Water was added to the reaction solution to quench, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 52 mg, 0.090 mmol, 87%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 8.72 (1H, br.s), 7.49 (1H, d, J = 3.2 Hz), 7.34 (1H, d, J = 11.0 Hz), 6.91 ( 1H, d, J = 10.7 Hz), 4.60-4.54 (1H, m), 4.04 (3H, s), 3.98 (3H, s), 3.96 (3H, s), 3.63 (3H, s), 3.24 (1H , dd, J = 13.1, 4.3 Hz), 2.48-2.34 (2H, m), 2.08-1.98 (1H, m).
ESI-MS m / z: 580 ([M + H] + )
実施例３３３
N-エチルスルホニル-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (21 μl, 0.103 × 1.5 mmol)、エタンスルホニルクロリド (12 μl, 0.103 × 1.2 mmol) を加え、0℃で10分、次いで室温で終夜撹拌した。反応液に水を加えクエンチし、0.1 N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄褐色固体, 51 mg, 0.089 mmol, 86%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.72 (1H, s), 7.24 (1H, d, J = 11.2 Hz), 6.84 (1H, d, J = 11.0 Hz), 5.20 (1H, br.s), 4.29-4.24 (1H, m), 4.02 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.58 (3H, s), 3.20 (1H, dd, J = 13.7, 4.4 Hz), 3.01-2.90 (2H, m), 2.45-2.29 (2H, m), 1.83-1.76 (1H, m), 1.32 (3H, t, J = 7.4 Hz)．
ESI-MS m/z: 576 ([M+H]+) Example 333
Synthesis of N-ethylsulfonyl-4-iododeacetylcolchicine In an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (21 μl, 0.103 × 1.5 mmol) and ethanesulfonyl chloride (12 μl, 0.103 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature overnight. Water was added to the reaction solution to quench, 0.1 N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow brown solid, 51 mg, 0.089 mmol, 86%).
1 H-NMR (400 MHz, CDCl 3 ) δ [ppm]: 7.72 (1H, s), 7.24 (1H, d, J = 11.2 Hz), 6.84 (1H, d, J = 11.0 Hz), 5.20 (1H, br.s), 4.29-4.24 (1H, m), 4.02 (3H, s), 3.97 (3H, s), 3.97 (3H, s), 3.58 (3H, s), 3.20 (1H, dd, J = 13.7, 4.4 Hz), 3.01-2.90 (2H, m), 2.45-2.29 (2H, m), 1.83-1.76 (1H, m), 1.32 (3H, t, J = 7.4 Hz).
ESI-MS m / z: 576 ([M + H] + )
実施例３３４
N-[3-(ジメチルアミノ)ベンゾイル]-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、3-ジメチルアミノ安息香酸 (21 mg, 0.103 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (24 mg, 0.103 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (17 mg, 0.103 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) を加え、0℃で10分、次いで室温で終夜撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、0.1N 塩酸、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 41 mg, 0.065 mmol, 63%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.96 (1H, d, J = 7.1 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.23 (1H, d, J = 6.6 Hz), 7.20 (1H, s), 7.17-7.13 (1H, m), 7.15 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 11.0 Hz), 6.93 (1H, d, J = 7.3 Hz), 4.45-4.39 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.59 (3H, s), 3.10 (1H, dd, J = 13.9, 4.9 Hz), 2.94 (6H, s), 2.44-2.33 (1H, m), 2.12-1.96 (2H, m)．
ESI-MS m/z: 631 ([M+H]+) Example 334
Synthesis of N- [3- (dimethylamino) benzoyl] -4-iododeacetylcolchicine Under argon atmosphere, 3-dimethylaminobenzoic acid (21 mg, 0.103 × 1.2 mmol) was replaced with N, N-dimethylformamide (1 mL) And cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (24 mg, 0.103 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate (17 mg, 0.103 × 1.2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-Iododeacetylcolchicine (50 mg, 0.103 mmol) was added there, and it stirred at 0 degreeC for 10 minutes, and then at room temperature all night. Water was added to the reaction solution for quenching, ethyl acetate was added, and the mixture was washed with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 41 mg, 0.065 mmol, 63%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.96 (1H, d, J = 7.1 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.23 (1H, d, J = 6.6 Hz), 7.20 (1H, s), 7.17-7.13 (1H, m), 7.15 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 11.0 Hz), 6.93 (1H, d, J = 7.3 Hz), 4.45-4.39 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.59 (3H, s), 3.10 (1H, dd, J = 13.9, 4.9 Hz), 2.94 (6H, s), 2.44-2.33 (1H, m), 2.12-1.96 (2H, m).
ESI-MS m / z: 631 ([M + H] + )
実施例３３５
4-ヨード-N-(4-メトキシベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、4-メトキシベンゾイルクロリド (18 mg, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で3時間撹拌した。反応液に水を加えクエンチし、0.1 N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 46 mg, 0.075 mmol, 72%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.90 (1H, d, J = 7.3 Hz), 7.88 (2H, d, J = 8.8 Hz), 7.18 (1H, s), 7.14 (1H, d, J = 10.5 Hz), 7.04 (1H, d, J = 10.7 Hz), 7.02 (2H, d, J = 8.8 Hz), 4.45-4.39 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.84 (3H, s), 3.81 (3H, s), 3.59 (3H, s), 3.10 (1H, dd, J = 13.8, 4.8 Hz), 2.44-2.33 (1H, m), 2.11-1.96 (2H, m)．
ESI-MS m/z: 618 ([M+H]+) Example 335
Synthesis of 4-iodo-N- (4-methoxybenzoyl) deacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 μl, 0.103 × 1.1 mmol) and 4-methoxybenzoyl chloride (18 mg, 0.103 × 1 mmol) were added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 3 hours. Water was added to the reaction solution to quench, 0.1 N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 46 mg, 0.075 mmol, 72%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.90 (1H, d, J = 7.3 Hz), 7.88 (2H, d, J = 8.8 Hz), 7.18 (1H, s), 7.14 ( 1H, d, J = 10.5 Hz), 7.04 (1H, d, J = 10.7 Hz), 7.02 (2H, d, J = 8.8 Hz), 4.45-4.39 (1H, m), 3.91 (3H, s), 3.88 (3H, s), 3.84 (3H, s), 3.81 (3H, s), 3.59 (3H, s), 3.10 (1H, dd, J = 13.8, 4.8 Hz), 2.44-2.33 (1H, m) , 2.11-1.96 (2H, m).
ESI-MS m / z: 618 ([M + H] + )
実施例３３６
4-ヨード-N-(4-ニトロベンゾイル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、4-ニトロベンゾイルクロリド (19 mg, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で3時間撹拌した。反応液に水を加えクエンチし、0.1 N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 54 mg, 0.085 mmol, 83%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.41 (1H, d, J = 7.1 Hz), 8.35 (1H, dd, J = 9.2, 2.2 Hz), 8.12 (1H, dd, J = 9.3, 2.3 Hz), 7.18 (1H, s), 7.16 (1H, d, J = 11.0 Hz), 7.06 (1H, d, J = 11.2 Hz), 4.47-4.41 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.60 (3H, s), 3.14-3.09 (1H, m), 2.46-2.33 (1H, m), 2.09-2.03 (2H, m)．
ESI-MS m/z: 633 ([M+H]+) Example 336
Synthesis of 4-iodo-N- (4-nitrobenzoyl) deacetylcolchicine Under argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 μl, 0.103 × 1.1 mmol) and 4-nitrobenzoyl chloride (19 mg, 0.103 × 1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 3 hours. Water was added to the reaction solution to quench, 0.1 N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 54 mg, 0.085 mmol, 83%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.41 (1H, d, J = 7.1 Hz), 8.35 (1H, dd, J = 9.2, 2.2 Hz), 8.12 (1H, dd, J = 9.3, 2.3 Hz), 7.18 (1H, s), 7.16 (1H, d, J = 11.0 Hz), 7.06 (1H, d, J = 11.2 Hz), 4.47-4.41 (1H, m), 3.91 (3H , s), 3.89 (3H, s), 3.85 (3H, s), 3.60 (3H, s), 3.14-3.09 (1H, m), 2.46-2.33 (1H, m), 2.09-2.03 (2H, m ).
ESI-MS m / z: 633 ([M + H] + )
実施例３３７
N-(3,5-ジフルオロベンゾイル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、3,5-ジフルオロベンゾイルクロリド (13 μl, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で1時間撹拌した。反応液に水を加えクエンチし、0.1N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (褐色固体, 36 mg, 0.058 mmol, 56%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.19 (1H, d, J = 7.1 Hz), 7.63-7.58 (2H, m), 7.53-7.47 (1H, m), 7.16 (1H, d, J = 10.7 Hz), 7.14 (1H, s), 7.05 (1H, d, J = 11.0 Hz), 4.43-4.37 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 3.59 (3H, s), 3.14-3.09 (1H, m), 2.45-2.33 (1H, m), 2.07-2.01 (2H, m)．
ESI-MS m/z: 624 ([M+H]+) Example 337
Synthesis of N- (3,5-difluorobenzoyl) -4-iododeacetylcolchicine Under argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. did. Triethylamine (16 μl, 0.103 × 1.1 mmol) and 3,5-difluorobenzoyl chloride (13 μl, 0.103 × 1 mmol) were added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction solution to quench, 0.1N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (brown solid, 36 mg, 0.058 mmol, 56%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.19 (1H, d, J = 7.1 Hz), 7.63-7.58 (2H, m), 7.53-7.47 (1H, m), 7.16 (1H , d, J = 10.7 Hz), 7.14 (1H, s), 7.05 (1H, d, J = 11.0 Hz), 4.43-4.37 (1H, m), 3.91 (3H, s), 3.89 (3H, s) 3.84 (3H, s), 3.59 (3H, s), 3.14-3.09 (1H, m), 2.45-2.33 (1H, m), 2.07-2.01 (2H, m).
ESI-MS m / z: 624 ([M + H] + )
実施例３３８
N-(3-シアノベンゾイル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、3-シアノベンゾイルクロリド (17 mg, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で1時間撹拌した。反応液に水を加えクエンチし、0.1N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 44 mg, 0.072 mmol, 70%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.24 (1H, d, J = 7.1 Hz), 8.35 (1H, s), 8.16 (1H, dt, J = 7.9, 1.4 Hz), 8.04 (1H, dt, J = 7.8, 1.2 Hz), 7.72 (1H, t, J = 7.8 Hz), 7.16 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 11.0 Hz), 4.45-4.39 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J = 11.8, 3.5 Hz), 2.46-2.33 (1H, m), 2.08-2.03 (2H, m)
ESI-MS m/z: 613 ([M+H]+) Example 338
Synthesis of N- (3-cyanobenzoyl) -4-iododeacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 μl, 0.103 × 1.1 mmol) and 3-cyanobenzoyl chloride (17 mg, 0.103 × 1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Water was added to the reaction solution to quench, 0.1N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 44 mg, 0.072 mmol, 70%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.24 (1H, d, J = 7.1 Hz), 8.35 (1H, s), 8.16 (1H, dt, J = 7.9, 1.4 Hz), 8.04 (1H, dt, J = 7.8, 1.2 Hz), 7.72 (1H, t, J = 7.8 Hz), 7.16 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d , J = 11.0 Hz), 4.45-4.39 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J = 11.8, 3.5 Hz), 2.46-2.33 (1H, m), 2.08-2.03 (2H, m)
ESI-MS m / z: 613 ([M + H] + )
実施例３３９
N-(アセトキシアセチル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (100 mg, 0.207 mmol) をジクロロメタン (4 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (32 μl, 0.103 × 1.1 mmol)、アセトキシアセチルクロリド (22 μl, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で2時間撹拌した。反応液に水を加えクエンチし、0.1N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (橙色固体, 73 mg, 0.125 mmol, 61%) を得た。
1H-NMR(400MHz, CDCl3)δ[ppm]: 7.55 (1H, s), 7.33 (1H, d, J = 11.0 Hz), 7.20 (1H, br.s), 6.90 (1H, d, J = 10.7 Hz), 4.61 (1H, d, J = 15.6 Hz), 4.59-4.53 (1H, m), 4.55 (1H, d, J = 15.6 Hz), 4.03 (3H, s), 3.97 (3H, s), 3.95 (3H, s), 3.62 (3H, s), 3.21 (1H, dd, J = 13.5, 5.0 Hz), 2.47-2.39 (1H, m), 2.32-2.20 (1H, m), 2.18 (3H, s), 1.88-1.81 (1H, m)．
ESI-MS m/z: 584 ([M+H]+) Example 339
Synthesis of N- (acetoxyacetyl) -4-iododeacetylcolchicine In an argon atmosphere, 4-iododeacetylcolchicine (100 mg, 0.207 mmol) was dissolved in dichloromethane (4 mL) and cooled to 0 ° C. Triethylamine (32 μl, 0.103 × 1.1 mmol) and acetoxyacetyl chloride (22 μl, 0.103 × 1 mmol) were added thereto, followed by stirring at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Water was added to the reaction solution to quench, 0.1N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (orange solid, 73 mg, 0.125 mmol, 61%).
1 H-NMR (400MHz, CDCl 3 ) δ [ppm]: 7.55 (1H, s), 7.33 (1H, d, J = 11.0 Hz), 7.20 (1H, br.s), 6.90 (1H, d, J = 10.7 Hz), 4.61 (1H, d, J = 15.6 Hz), 4.59-4.53 (1H, m), 4.55 (1H, d, J = 15.6 Hz), 4.03 (3H, s), 3.97 (3H, s ), 3.95 (3H, s), 3.62 (3H, s), 3.21 (1H, dd, J = 13.5, 5.0 Hz), 2.47-2.39 (1H, m), 2.32-2.20 (1H, m), 2.18 ( 3H, s), 1.88-1.81 (1H, m).
ESI-MS m / z: 584 ([M + H] + )
実施例３４０
4-ヨード-N-(フェニルアセチル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (16 μl, 0.103 × 1.1 mmol)、フェニルアセチルクロリド (14 μl, 0.103 × 1 mmol) を加え、0℃で10分、次いで室温で2時間撹拌した。反応液に水を加えクエンチし、0.1N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 20 mg, 0.033 mmol, 32%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.87 (1H, d, J = 7.3 Hz), 7.29-7.17 (5H, m), 7.16 (1H, s), 7.09 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 11.2 Hz), 4.19-4.11 (1H, m), 3.88 (3H, s), 3.87 (3H, s), 3.82 (3H, s), 3.55-.348 (2H, m), 3.48 (3H, s), 3.06 (1H, dd, J = 14.1, 5.4 Hz), 2.40-2.31 (1H, m), 1.96-1.88 (1H, m), 1.86-1.78 (1H, m)．
ESI-MS m/z: 602 ([M+H]+) Example 340
Synthesis of 4-iodo-N- (phenylacetyl) deacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (16 μl, 0.103 × 1.1 mmol) and phenylacetyl chloride (14 μl, 0.103 × 1 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Water was added to the reaction solution to quench, 0.1N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 20 mg, 0.033 mmol, 32%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.87 (1H, d, J = 7.3 Hz), 7.29-7.17 (5H, m), 7.16 (1H, s), 7.09 (1H, d , J = 10.5 Hz), 7.01 (1H, d, J = 11.2 Hz), 4.19-4.11 (1H, m), 3.88 (3H, s), 3.87 (3H, s), 3.82 (3H, s), 3.55 -.348 (2H, m), 3.48 (3H, s), 3.06 (1H, dd, J = 14.1, 5.4 Hz), 2.40-2.31 (1H, m), 1.96-1.88 (1H, m), 1.86- 1.78 (1H, m).
ESI-MS m / z: 602 ([M + H] + )
実施例３４１
4-ヨード-N-プロピルデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン-酢酸 (50/1, 2 mL) に溶解した。そこへプロピオンアルデヒド (7 μl, 0.103 × 0.95 mmol) を加え、室温で10分撹拌した。そこへ水素化トリアセトキシホウ素ナトリウム (48 mg, 0.103 × 2.2 mmol) を加え、室温で終夜撹拌した。反応液に飽和重曹水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 31 mg, 0.059 mmol, 57%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.56 (1H, s), 7.09 (1H, d, J = 10.7 Hz), 7.00 (1H, d, J = 11.0 Hz), 3.89 (3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.50 (3H, s), 3.03-2.98 (1H, m), 2.96 (1H, dd, J = 14.1, 5.1 Hz), 2.33-2.19 (3H, m), 2.17-2.11 (1H, m), 2.09-2.00 (1H, m), 1.50-1.43 (1H, m), 1.39-1.30 (2H, m), 0.81 (3H, t, J = 7.4 Hz)．
ESI-MS m/z: 526 ([M+H]+) Example 341
Synthesis of 4-iodo-N-propyl deacetyl colchicine Under an argon atmosphere, 4-iodo deacetyl colchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane-acetic acid (50/1, 2 mL). Propionaldehyde (7 μl, 0.103 × 0.95 mmol) was added thereto and stirred at room temperature for 10 minutes. Thereto was added sodium triacetoxyborohydride (48 mg, 0.103 × 2.2 mmol), and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 31 mg, 0.059 mmol, 57%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.56 (1H, s), 7.09 (1H, d, J = 10.7 Hz), 7.00 (1H, d, J = 11.0 Hz), 3.89 ( 3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.50 (3H, s), 3.03-2.98 (1H, m), 2.96 (1H, dd, J = 14.1, 5.1 Hz), 2.33 -2.19 (3H, m), 2.17-2.11 (1H, m), 2.09-2.00 (1H, m), 1.50-1.43 (1H, m), 1.39-1.30 (2H, m), 0.81 (3H, t, J = 7.4 Hz).
ESI-MS m / z: 526 ([M + H] + )
実施例３４２
N-(ヒドロキシアセチル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、N-アセトキシアセチル-4-ヨードデアセチルコルヒチン (50 mg, 0.090 mmol) をメタノール (0.45 mL) に溶解し、0℃に冷却した。そこへナトリウムメトキシド (2.4 mg, 0.103 × 0.5 mmol) を加え、0℃で10分、次いで室温で1時間撹拌した。反応液に飽和食塩水を加え、クロロホルムで抽出した。クロロホルム層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 26 mg, 0.048 mmol, 53%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.52 (1H, d, J = 7.8 Hz), 7.15 (1H, s), 7.10 (1H, d, J = 10.5 Hz), 7.02 (1H, d, J = 11.0 Hz), 5.52 (1H, t, J = 5.9 Hz), 4.29-4.22 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.85-3.82 (2H, m), 3.83 (3H, s), 3.53 (3H, s), 3.04 (1H, dd, J = 13.8, 5.5 Hz), 2.38-2.30 (1H, m), 2.07-1.99 (1H, m), 1.90-1.82 (1H, m)．
ESI-MS m/z: 542 ([M+H]+) Example 342
Synthesis of N- (hydroxyacetyl) -4-iododeacetylcolchicine N-acetoxyacetyl-4-iododeacetylcolchicine (50 mg, 0.090 mmol) was dissolved in methanol (0.45 mL) under an argon atmosphere, Cooled down. Sodium methoxide (2.4 mg, 0.103 × 0.5 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 26 mg, 0.048 mmol, 53%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.52 (1H, d, J = 7.8 Hz), 7.15 (1H, s), 7.10 (1H, d, J = 10.5 Hz), 7.02 ( 1H, d, J = 11.0 Hz), 5.52 (1H, t, J = 5.9 Hz), 4.29-4.22 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.85-3.82 (2H , m), 3.83 (3H, s), 3.53 (3H, s), 3.04 (1H, dd, J = 13.8, 5.5 Hz), 2.38-2.30 (1H, m), 2.07-1.99 (1H, m), 1.90-1.82 (1H, m).
ESI-MS m / z: 542 ([M + H] + )
実施例３４３
N-[1-(ベンジルオキシカルボニル)ピペリジン-4-イルカルボニル]-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、1- (ベンジルオキシカルボニル) ピペリジン-4-カルボン酸 (33 mg, 0.103 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (24 mg, 0.103 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(17 mg, 0.103 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) を加え、0℃で10分、次いで室温で終夜撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、1N 塩酸、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 61 mg, 0.084 mmol, 81%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.38-7.28 (5H, m), 7.10 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 5.06 (2H, s), 4.18-4.12 (1H, m), 4.02-3.97 (2H, m), 3.89 (3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.53 (3H, s), 3.04 (1H, dd, J = 13.5, 5.0 Hz), 2.91-2.77 (2H, m), 2.47-2.39 (1H, m), 2.37-2.30 (1H, m), 1.96-1.86 (1H, m), 1.83-1.77 (1H, m), 1.75-1.64 (2H, m), 1.42-1.31 (2H, m)．
ESI-MS m/z: 729 ([M+H]+) Example 343
Synthesis of N- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] -4-iododeacetylcolchicine Under argon atmosphere, 1- (benzyloxycarbonyl) piperidine-4-carboxylic acid (33 mg, 0.103 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL) and cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (24 mg, 0.103 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate (17 mg, 0.103 × 1.2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-Iododeacetylcolchicine (50 mg, 0.103 mmol) was added there, and it stirred at 0 degreeC for 10 minutes, and then at room temperature all night. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 61 mg, 0.084 mmol, 81%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.38-7.28 (5H, m), 7.10 (1H, d, J = 10.7 Hz), 7.09 (1H, s), 7.02 (1H, d, J = 10.7 Hz), 5.06 (2H, s), 4.18-4.12 (1H, m), 4.02-3.97 (2H, m), 3.89 (3H, s) , 3.88 (3H, s), 3.83 (3H, s), 3.53 (3H, s), 3.04 (1H, dd, J = 13.5, 5.0 Hz), 2.91-2.77 (2H, m), 2.47-2.39 (1H m), 2.37-2.30 (1H, m), 1.96-1.86 (1H, m), 1.83-1.77 (1H, m), 1.75-1.64 (2H, m), 1.42-1.31 (2H, m).
ESI-MS m / z: 729 ([M + H] + )
実施例３４４
4-ヨード-N-(ピリジン-4-イルカルボニル) デアセチルコルヒチンの合成
　アルゴン雰囲気下、イソニコチン酸 (15 mg, 0.103 × 1.2 mmol) をN,N-ジメチルホルムアミド (1 mL) に溶解し、0℃に冷却した。そこへ1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩 (24 mg, 0.103 × 1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物 (17 mg, 0.103 × 1.2 mmol) を加え、0℃で30分撹拌した。そこへ4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) を加え、0℃で10分、次いで室温で終夜撹拌した。反応液に水を加えクエンチし、酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 55 mg, 0.093 mmol, 91%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.34 (1H, d, J = 7.1 Hz), 8.75 (2H, dd, J = 4.4, 1.7 Hz), 7.78 (2H, dd, J = 4.4, 1.7 Hz), 7.16 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 11.0 Hz), 4.46-4.39 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.85 (3H, s), 3.59 (3H, s), 3.14-3.09 (1H, m), 2.46-2.37 (1H, m), 2.08-2.02 (2H, m)．
ESI-MS m/z: 589 ([M+H]+) Example 344
Synthesis of 4-iodo-N- (pyridin-4-ylcarbonyl) deacetylcolchicine Under argon atmosphere, isonicotinic acid (15 mg, 0.103 × 1.2 mmol) was dissolved in N, N-dimethylformamide (1 mL). Cooled to 0 ° C. 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (24 mg, 0.103 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate (17 mg, 0.103 × 1.2 mmol) was added thereto, Stir at 0 ° C. for 30 minutes. 4-Iododeacetylcolchicine (50 mg, 0.103 mmol) was added there, and it stirred at 0 degreeC for 10 minutes, and then at room temperature all night. Water was added to the reaction solution to quench, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 55 mg, 0.093 mmol, 91%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.34 (1H, d, J = 7.1 Hz), 8.75 (2H, dd, J = 4.4, 1.7 Hz), 7.78 (2H, dd, J = 4.4, 1.7 Hz), 7.16 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 11.0 Hz), 4.46-4.39 (1H, m), 3.91 (3H , s), 3.89 (3H, s), 3.85 (3H, s), 3.59 (3H, s), 3.14-3.09 (1H, m), 2.46-2.37 (1H, m), 2.08-2.02 (2H, m ).
ESI-MS m / z: 589 ([M + H] + )
実施例３４５
N-フェニルスルホニル-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (21 μl, 0.103 × 1.5 mmol)、ベンゼンスルホニルクロリド (16 μl, 0.103 × 1.2 mmol) を加え、0℃で10分、次いで室温で2時間撹拌した。反応液に水を加えクエンチし、0.1 N 塩酸を加え、クロロホルムで抽出した。クロロホルム層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 41 mg, 0.066 mmol, 64%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.57-7.50 (3H, m), 7.45-7.41 (2H, m), 7.24 (1H, s), 7.06 (1H, d, J = 10.5 Hz), 6.98 (1H, d, J = 10.7 Hz), 3.89 (3H, s), 3.87 (3H, s), 3.82 (3H, s), 3.54-3.47 (1H, m), 3.51 (3H, s), 2.86 (1H, dd, J = 14.0, 5.5 Hz), 2.24-2.16 (1H, m), 1.68-1.61 (1H, m), 1.57-1.49 (1H, m)．
ESI-MS m/z: 624 ([M+H]+) Example 345
Synthesis of N-phenylsulfonyl-4-iododeacetylcolchicine In an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Triethylamine (21 μl, 0.103 × 1.5 mmol) and benzenesulfonyl chloride (16 μl, 0.103 × 1.2 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Water was added to the reaction solution to quench, 0.1 N hydrochloric acid was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 41 mg, 0.066 mmol, 64%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.59 (1H, d, J = 7.3 Hz), 7.57-7.50 (3H, m), 7.45-7.41 (2H, m), 7.24 (1H , s), 7.06 (1H, d, J = 10.5 Hz), 6.98 (1H, d, J = 10.7 Hz), 3.89 (3H, s), 3.87 (3H, s), 3.82 (3H, s), 3.54 -3.47 (1H, m), 3.51 (3H, s), 2.86 (1H, dd, J = 14.0, 5.5 Hz), 2.24-2.16 (1H, m), 1.68-1.61 (1H, m), 1.57-1.49 (1H, m).
ESI-MS m / z: 624 ([M + H] + )
実施例３４６
N-(シクロヘキシルチオカルバモイル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (1.5 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸シクロヘキシル (20 μl, 0.103 × 2 mmol) を加え、0℃で10分、次いで室温で終夜撹拌した。反応液に酢酸エチルを加え、0.1 N 塩酸、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 26 mg, 0.042 mmol, 40%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.85 (1H, d, J = 6.8 Hz), 7.49 (1H, br.s), 7.12 (1H, d, J = 10.5 Hz), 7.04 (1H, s), 7.02 (1H, d, J = 11.0 Hz), 4.72-4.64 (1H, m), 3.89 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 3.59 (3H, s), 3.05 (1H, dd, J = 13.3, 6.0 Hz), 2.40-2.32 (1H, m), 2.07-1.98 (1H, m), 1.85-1.77 (3H, m), 1.67-1.59 (2H, m), 1.55-1.49 (1H, m), 1.29-1.10 (6H, m)．
ESI-MS m/z: 625 ([M+H]+) Example 346
Synthesis of N- (cyclohexylthiocarbamoyl) -4-iododeacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (1.5 mL) and cooled to 0 ° C. Thereto was added cyclohexyl isothiocyanate (20 μl, 0.103 × 2 mmol), and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 26 mg, 0.042 mmol, 40%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.85 (1H, d, J = 6.8 Hz), 7.49 (1H, br.s), 7.12 (1H, d, J = 10.5 Hz), 7.04 (1H, s), 7.02 (1H, d, J = 11.0 Hz), 4.72-4.64 (1H, m), 3.89 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 3.59 (3H, s), 3.05 (1H, dd, J = 13.3, 6.0 Hz), 2.40-2.32 (1H, m), 2.07-1.98 (1H, m), 1.85-1.77 (3H, m), 1.67-1.59 (2H, m), 1.55-1.49 (1H, m), 1.29-1.10 (6H, m).
ESI-MS m / z: 625 ([M + H] + )
実施例３４７
N-[4-(ジメチルアミノ)フェニルチオカルバモイル]-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (1.5 mL) に溶解し、0℃に冷却した。そこへイソチオシアン酸p- (ジメチルアミノ) フェニル(37 mg, 0.103 × 2 mmol) を加え、0℃で10分、次いで室温で終夜撹拌した。反応液に酢酸エチルを加え、0.1 N 塩酸、飽和重曹水、飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 32 mg, 0.048 mmol, 47%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.40 (1H, s), 8.00 (1H, d, J = 6.8 Hz), 7.15-7.09 (4H, m), 7.03 (1H, d, J = 11.2 Hz), 6.69 (1H, dd, J = 6.8, 2.2 Hz), 4.78-4.72 (1H, m), 3.89 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 3.60 (3H, s), 3.05 (1H, dd, J = 13.7, 4.9 Hz), 2.87 (6H, s), 2.39-2.31 (1H, m), 2.09-2.01 (1H, m), 1.99-1.92 (1H, m)．
ESI-MS m/z: 662 ([M+H]+) Example 347
Synthesis of N- [4- (dimethylamino) phenylthiocarbamoyl] -4-iododeacetylcolchicine Under argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (1.5 mL). Cooled to ° C. Thereto was added p- (dimethylamino) phenyl isothiocyanate (37 mg, 0.103 × 2 mmol), and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 0.1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 32 mg, 0.048 mmol, 47%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.40 (1H, s), 8.00 (1H, d, J = 6.8 Hz), 7.15-7.09 (4H, m), 7.03 (1H, d , J = 11.2 Hz), 6.69 (1H, dd, J = 6.8, 2.2 Hz), 4.78-4.72 (1H, m), 3.89 (3H, s), 3.89 (3H, s), 3.84 (3H, s) , 3.60 (3H, s), 3.05 (1H, dd, J = 13.7, 4.9 Hz), 2.87 (6H, s), 2.39-2.31 (1H, m), 2.09-2.01 (1H, m), 1.99-1.92 (1H, m).
ESI-MS m / z: 662 ([M + H] + )
実施例３４８
N-(ベンジルカルバモイル)-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (1.5 mL) に溶解し、0℃に冷却した。そこへイソシアン酸ベンジル (26 μl, 0.103 × 1.2 mmol) を加え、室温に戻して2時間撹拌した。反応液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (淡黄色固体, 53 mg, 0.086 mmol, 84%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.31-7.25 (3H, m), 7.21-7.17 (3H, m), 7.09 (1H, d, J = 10.7 Hz), 7.02 (1H, d, J = 10.7 Hz), 6.88 (1H, d, J = 7.6 Hz), 6.46 (1H, t, J = 6.0 Hz), 4.24-4.06 (3H, m), 3.89 (3H, s), 3.89 (3H, s), 3,83 (3H, s), 3.50 (3H, s), 3.03 (1H, dd, J = 13.8, 5.2 Hz), 2.38-2.29 (1H, m), 2.01-1.91 (1H, m), 1.71-1.64 (1H, m)．
ESI-MS m/z: 617 ([M+H]+) Example 348
Synthesis of N- (benzylcarbamoyl) -4-iododeacetylcolchicine Under an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (1.5 mL) and cooled to 0 ° C. The benzyl isocyanate (26 microliters, 0.103 * 1.2 mmol) was added there, and it returned to room temperature, and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (pale yellow solid, 53 mg, 0.086 mmol, 84%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.31-7.25 (3H, m), 7.21-7.17 (3H, m), 7.09 (1H, d, J = 10.7 Hz), 7.02 (1H , d, J = 10.7 Hz), 6.88 (1H, d, J = 7.6 Hz), 6.46 (1H, t, J = 6.0 Hz), 4.24-4.06 (3H, m), 3.89 (3H, s), 3.89 (3H, s), 3,83 (3H, s), 3.50 (3H, s), 3.03 (1H, dd, J = 13.8, 5.2 Hz), 2.38-2.29 (1H, m), 2.01-1.91 (1H , m), 1.71-1.64 (1H, m).
ESI-MS m / z: 617 ([M + H] + )
実施例３４９
4-ヨード-N-[(ピペリジン-1-イル)カルボニル] デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (5 mL) に溶解した。そこへトリエチルアミン (70 μl, 0.103 × 5 mmol)、ピペリジン-1-カルボニルクロリド (65 μl, 0.103 × 5 mmol) を加え、終夜加熱還流した。反応液に水を加えクエンチし、酢酸エチルを加え、10% クエン酸水溶液、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 21 mg, 0.035 mmol, 34%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.17 (1H, s), 7.09 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 6.99 (1H, d, J = 6.1 Hz), 4.15-4.09 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.31-3.25 (4H, m), 3.06-3.01 (1H, m), 2.36-2.27 (1H, m), 1.91-1.85 (2H, m), 1.55-1.49 (2H, m), 1.42-1.36 (4H, m)．
ESI-MS m/z: 595 ([M+H]+) Example 349
Synthesis of 4-iodo-N-[(piperidin-1-yl) carbonyl] deacetylcolchicine 4-Iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (5 mL) under an argon atmosphere. Triethylamine (70 μl, 0.103 × 5 mmol) and piperidine-1-carbonyl chloride (65 μl, 0.103 × 5 mmol) were added thereto, and the mixture was heated to reflux overnight. Water was added to the reaction solution for quenching, ethyl acetate was added, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 21 mg, 0.035 mmol, 34%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.17 (1H, s), 7.09 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 10.5 Hz), 6.99 ( 1H, d, J = 6.1 Hz), 4.15-4.09 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.31-3.25 (4H, m), 3.06 -3.01 (1H, m), 2.36-2.27 (1H, m), 1.91-1.85 (2H, m), 1.55-1.49 (2H, m), 1.42-1.36 (4H, m).
ESI-MS m / z: 595 ([M + H] + )
実施例３５０
N-エチル-4-ヨードデアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン-酢酸 (50/1, 2 mL) に溶解した。そこへアセトアルデヒド (6 μl, 0.103 × 0.95 mmol) を加え、室温で10分撹拌した。そこへ水素化トリアセトキシホウ素ナトリウム (48 mg, 0.103 × 2.2 mmol) を加え、室温で終夜撹拌した。反応液に飽和重曹水を加え、クロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (白色固体, 32 mg, 0.063 mmol, 61%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.55 (1H, s), 7.09 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 11.0 Hz), 3.89 (3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.49 (3H, s), 3.05-3.01 (1H, m), 2.96 (1H, dd, J = 13.7, 5.1 Hz), 2.36-2.25 (3H, m), 2.23-2.15 (1H, m), 2.08-1.98 (2H, m), 1.49-1.42 (1H, m), 0.94 (3H, t, J = 6.7 Hz)．
ESI-MS m/z: 512 ([M+H]+) Example 350
Synthesis of N-ethyl-4-iododeacetylcolchicine In an argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane-acetic acid (50/1, 2 mL). Acetaldehyde (6 μl, 0.103 × 0.95 mmol) was added thereto and stirred at room temperature for 10 minutes. Thereto was added sodium triacetoxyborohydride (48 mg, 0.103 × 2.2 mmol), and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (white solid, 32 mg, 0.063 mmol, 61%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.55 (1H, s), 7.09 (1H, d, J = 10.5 Hz), 7.01 (1H, d, J = 11.0 Hz), 3.89 ( 3H, s), 3.88 (3H, s), 3.83 (3H, s), 3.49 (3H, s), 3.05-3.01 (1H, m), 2.96 (1H, dd, J = 13.7, 5.1 Hz), 2.36 -2.25 (3H, m), 2.23-2.15 (1H, m), 2.08-1.98 (2H, m), 1.49-1.42 (1H, m), 0.94 (3H, t, J = 6.7 Hz).
ESI-MS m / z: 512 ([M + H] + )
実施例３５１
4-ヨード-N-[(ピペリジン-1-イル)チオカルボニル] デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (34 μl, 0.103 × 2.4 mmol)、チオホスゲン (8 μl, 0.103 × 1.05 mmol) を加え、0℃で2時間撹拌した。そこへピペリジン (20 μl, 0.103 × 2 mmol) を加え、0℃で10分、次いで室温で2時間撹拌した。反応液に酢酸エチルを加え、10% クエン酸水溶液、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 45 mg, 0.074 mmol, 72%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.83 (1H, d, J = 7.1 Hz), 7.12 (1H, d, J = 10.5 Hz), 7.05 (1H, s), 7.02 (1H, d, J = 11.0 Hz), 4.89-4.83 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86-3.75 (4H, m), 3.84 (3H, s), 3.62 (3H, s), 3.06 (1H, dd, J = 13.9, 5.1 Hz), 2.39-2.31 (1H, m), 2.17-2.10 (1H, m), 2.00-1.91 (1H, m), 1.64-1.58 (2H, m), 1.51-1.45 (4H, m)．
ESI-MS m/z: 611 ([M+H]+) Example 351
Synthesis of 4-iodo-N-[(piperidin-1-yl) thiocarbonyl] deacetylcolchicine Under argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL). Cooled to ° C. Triethylamine (34 μl, 0.103 × 2.4 mmol) and thiophosgene (8 μl, 0.103 × 1.05 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 2 hours. Piperidine (20 μl, 0.103 × 2 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 45 mg, 0.074 mmol, 72%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.83 (1H, d, J = 7.1 Hz), 7.12 (1H, d, J = 10.5 Hz), 7.05 (1H, s), 7.02 ( 1H, d, J = 11.0 Hz), 4.89-4.83 (1H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86-3.75 (4H, m), 3.84 (3H, s), 3.62 (3H, s), 3.06 (1H, dd, J = 13.9, 5.1 Hz), 2.39-2.31 (1H, m), 2.17-2.10 (1H, m), 2.00-1.91 (1H, m), 1.64-1.58 (2H, m), 1.51-1.45 (4H, m).
ESI-MS m / z: 611 ([M + H] + )
実施例３５２
4-ヨード-N-[(チオモルホリン-4-イル)チオカルボニル] デアセチルコルヒチンの合成
　アルゴン雰囲気下、4-ヨードデアセチルコルヒチン (50 mg, 0.103 mmol) をジクロロメタン (2 mL) に溶解し、0℃に冷却した。そこへトリエチルアミン (34 μl, 0.103 × 2.4 mmol)、チオホスゲン (8 μl, 0.103 × 1.05 mmol) を加え、0℃で2時間撹拌した。そこへチオモルホリン (20 μl, 0.103 × 2 mmol) を加え、0℃で10分、次いで室温で2時間撹拌した。反応液に酢酸エチルを加え、10% クエン酸水溶液、飽和重曹水、飽和食塩水で洗浄した。酢酸エチル層を無水硫酸マグネシウムで乾燥させ、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー (Biotage Isolera One, SNAP 10 g, メタノール/クロロホルム) で精製し、標記の化合物 (黄色固体, 48 mg, 0.076 mmol, 74%) を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.96 (1H, d, J = 7.1 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.03 (1H, s), 7.03 (1H, d, J = 11.2 Hz), 4.88-4.82 (1H, m), 4.21-4.09 (4H, m), 3.89 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 3.62 (3H, s), 3.07 (1H, dd, J = 13.9, 5.1 Hz), 2.61-2.59 (4H, m), 2.40-2.32 (1H, m), 2.17-2.10 (1H, m), 2.05-1.95 (1H, m)．
ESI-MS m/z: 629 ([M+H]+) Example 352
Synthesis of 4-iodo-N-[(thiomorpholin-4-yl) thiocarbonyl] deacetylcolchicine Under argon atmosphere, 4-iododeacetylcolchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL). Cooled to 0 ° C. Triethylamine (34 μl, 0.103 × 2.4 mmol) and thiophosgene (8 μl, 0.103 × 1.05 mmol) were added thereto, and the mixture was stirred at 0 ° C. for 2 hours. Thiomorpholine (20 μl, 0.103 × 2 mmol) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate, and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (Biotage Isolera One, SNAP 10 g, methanol / chloroform) to obtain the title compound (yellow solid, 48 mg, 0.076 mmol, 74%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.96 (1H, d, J = 7.1 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.03 (1H, s), 7.03 ( 1H, d, J = 11.2 Hz), 4.88-4.82 (1H, m), 4.21-4.09 (4H, m), 3.89 (3H, s), 3.89 (3H, s), 3.84 (3H, s), 3.62 (3H, s), 3.07 (1H, dd, J = 13.9, 5.1 Hz), 2.61-2.59 (4H, m), 2.40-2.32 (1H, m), 2.17-2.10 (1H, m), 2.05-1.95 (1H, m).
ESI-MS m / z: 629 ([M + H] + )
参考例３２
4-クロロ-７-イソチオシアネート7-デ(アセトアミド)コルヒチンの合成
　4-クロロデアセチルコルヒチン(0.400 g, 1.02 mmol)のジクロロメタン(10 mL)溶液に、氷冷、アルゴンガス雰囲気下にて、チオホスゲン(93.2 μL, 1.02×1.2 mmol)およびトリエチルアミン(355 μL, 1.02×2.5 mmol)を添加して、同温度で2時間撹拌した。反応液にクロロホルムと10%硫酸水素ナトリウムを注ぎ、有機層を取った。有機層は飽和炭酸水素ナトリウム水様液、次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡褐色固体, 0.443 g, 1.02 mmol, 定量的)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.24 (1H, s), 7.17 (1H, d, J=10.7 Hz), 7.10 (1H, d, J=10.7 Hz), 4.92-4.87 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J=12.8, 6.0 Hz), 2.46-2.39 (1H, m), 2.20-2.08 (2H, m).
ESI-MS m/z: 434 [M+H]+. Reference Example 32
Synthesis of 4-chloro-7-isothiocyanate 7-de (acetamido) colchicine To a solution of 4-chlorodeacetylcolchicine (0.400 g, 1.02 mmol) in dichloromethane (10 mL) under ice-cooling and argon gas atmosphere, thiophosgene (93.2 μL, 1.02 × 1.2 mmol) and triethylamine (355 μL, 1.02 × 2.5 mmol) were added and stirred at the same temperature for 2 hours. Chloroform and 10% sodium hydrogen sulfate were poured into the reaction solution, and the organic layer was taken. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 0.443 g, 1.02 mmol, quantitative).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.24 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.10 (1H, d, J = 10.7 Hz), 4.92- 4.87 (1H, m), 3.92 (3H, s), 3.88 (3H, s), 3.88 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J = 12.8, 6.0 Hz), 2.46 -2.39 (1H, m), 2.20-2.08 (2H, m).
ESI-MS m / z: 434 [M + H] + .
実施例３５３
N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成
　4-クロロ-７-イソチオシアネート7-デ(アセトアミド)コルヒチン(30 mg, 0.0691 mmol)のN,N-ジメチルホルムアミド(2 mL)溶液に、室温で2-アミノ-1H-ベンゾイミダゾール(11 mg, 0.0691×1.2 mmol)を加えて、80℃で一晩撹拌した。反応液を室温まで冷却した後、クロロホルムとブラインを加えて有機層を取った。有機層は10%硫酸水素ナトリウム、飽和炭酸水素ナトリウム水溶液、次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡褐色固体, 18 mg, 0.0319 mmol, 46%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.54-7.41 (2H, m), 7.22-7.03 (5H, m), 4.86-4.79 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.65 (3H, s), 3.22-3.16 (1H, m), 2.31-2.09.
ESI-MS m/z: 567 [M+H]+. Example 353
Synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine 4-chloro-7-isothiocyanate 7-de (acetamido) colchicine (30 mg, 0.0691 mmol) N, N- To a dimethylformamide (2 mL) solution, 2-amino-1H-benzimidazole (11 mg, 0.0691 × 1.2 mmol) was added at room temperature, and the mixture was stirred at 80 ° C. overnight. After the reaction solution was cooled to room temperature, chloroform and brine were added to obtain an organic layer. The organic layer was washed with 10% sodium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate solution, then brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 18 mg, 0.0319 mmol, 46%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.54-7.41 (2H, m), 7.22-7.03 (5H, m), 4.86-4.79 (1H, m), 3.93 (3H, s) , 3.90 (3H, s), 3.89 (3H, s), 3.65 (3H, s), 3.22-3.16 (1H, m), 2.31-2.09.
ESI-MS m / z: 567 [M + H] + .
実施例３５４
N-[(ベンゾチアゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 11 mg, 0.0190 mmol, 28%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに2-アミノベンゾチアゾールを用いた。また、精製は分取HPLCにて行った。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.96-7.67 (br-m), 7.44-7.39 (1H, br-m), 7.28-7.26 (1H, br-m), 7.20 (1H, d, J=10.5 Hz), 7.12-7.03 (2H, m), 4.81-4.74 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.66 (3H, s), 3.21-3.14 (1H, m), 2.27-1.98 (3H, m).
ESI-MS m/z: 584 [M+H]+. Example 354
Synthesis of N-[(benzothiazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine Similar method to the synthesis of N-[(benzoimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine Gave the title compound (milky white solid, 11 mg, 0.0190 mmol, 28%). Instead of 2-amino-1H-benzimidazole, 2-aminobenzothiazole was used. Purification was performed by preparative HPLC.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.96-7.67 (br-m), 7.44-7.39 (1H, br-m), 7.28-7.26 (1H, br-m), 7.20 ( 1H, d, J = 10.5 Hz), 7.12-7.03 (2H, m), 4.81-4.74 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.66 (3H, s), 3.21-3.14 (1H, m), 2.27-1.98 (3H, m).
ESI-MS m / z: 584 [M + H] + .
実施例３５５
4-クロロ-N-[(ピリミジン-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 5 mg, 0.00934 mmol, 14%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに2-アミノピリミジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 11.84 (1H, d, J=6.6 Hz), 11.04 (1H, s), 8.73 (2H, d, J=4.9 Hz), 7.24 (2H, t, J=4.9 Hz), 7.20 (2H, d, J=10.5 Hz), 7.07 (1H, d, J=11.2 Hz), 6.99 (1H, s), 4.87-4.79 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.64 (3H, s), 3.20-3.16 (1H, m), 2.30-2.09 (3H, m).
ESI-MS m/z: 529 [M+H]+.  Example 355
Synthesis of 4-chloro-N-[(pyrimidin-2-yl) thiocarbamoyl] deacetylcolchicine In the same way as the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine The title compound (light brown solid, 5 mg, 0.00934 mmol, 14%) was obtained. 2-Aminopyrimidine was used instead of 2-amino-1H-benzimidazole.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 11.84 (1H, d, J = 6.6 Hz), 11.04 (1H, s), 8.73 (2H, d, J = 4.9 Hz), 7.24 ( 2H, t, J = 4.9 Hz), 7.20 (2H, d, J = 10.5 Hz), 7.07 (1H, d, J = 11.2 Hz), 6.99 (1H, s), 4.87-4.79 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.64 (3H, s), 3.20-3.16 (1H, m), 2.30-2.09 (3H, m).
ESI-MS m / z: 529 [M + H] + .
実施例３５６
4-クロロ-N-[(ピリダジン-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 20 mg, 0.0373 mmol, 54%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに3-アミノピリダジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 12.15 (1H, d, J=6.8 Hz), 11.07 (1H, s), 8.97 (1H, d, J=4.6 Hz), 7.74 (1H, dd, J=9.0, 4.6 Hz), 7.54 (1H, d, J=9.0 Hz), 7.21 (1H, d, J=10.7 Hz), 7.08 (1H, d, J=10.7 Hz), 7.00 (1H, s), 4.87-4.81 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.64 (3H, s), 3.19 (1H, dd, J=12.4, 3.4 Hz), 2.35-2.19 (2H, m), 2.13-2.05 (1H, m).
ESI-MS m/z: 529 [M+H]+. Example 356
Synthesis of 4-chloro-N-[(pyridazin-3-yl) thiocarbamoyl] deacetylcolchicine In a manner similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine The title compound (milky white solid, 20 mg, 0.0373 mmol, 54%) was obtained. 3-aminopyridazine was used instead of 2-amino-1H-benzimidazole.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 12.15 (1H, d, J = 6.8 Hz), 11.07 (1H, s), 8.97 (1H, d, J = 4.6 Hz), 7.74 ( 1H, dd, J = 9.0, 4.6 Hz), 7.54 (1H, d, J = 9.0 Hz), 7.21 (1H, d, J = 10.7 Hz), 7.08 (1H, d, J = 10.7 Hz), 7.00 ( 1H, s), 4.87-4.81 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.64 (3H, s), 3.19 (1H, dd, J = 12.4, 3.4 Hz), 2.35 -2.19 (2H, m), 2.13-2.05 (1H, m).
ESI-MS m / z: 529 [M + H] + .
実施例３５７
4-クロロ-N-[(ピリジン-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 17 mg, 0.0326 mmol, 47%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに2-アミノピリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 12.37 (1H, d, J=6.8 Hz), 10.85 (1H, s), 8.34-8.32 (1H, m), 7.86-7.81 (1H, m), 7.22-7.18 (2H, m), 7.14-7.11 (1H, m), 7.07 (1H, d, J=10.7 Hz), 7.00 (1H, s), 4.87-4.80 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.63 (3H, s), 3.20-3.15 (1H, m), 2.31-2.09 (3H, m).
ESI-MS m/z: 528 [M+H]+. Example 357
Synthesis of 4-chloro-N-[(pyridin-2-yl) thiocarbamoyl] deacetylcolchicine In a manner similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine The title compound (milky white solid, 17 mg, 0.0326 mmol, 47%) was obtained. 2-Aminopyridine was used in place of 2-amino-1H-benzimidazole.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 12.37 (1H, d, J = 6.8 Hz), 10.85 (1H, s), 8.34-8.32 (1H, m), 7.86-7.81 (1H , m), 7.22-7.18 (2H, m), 7.14-7.11 (1H, m), 7.07 (1H, d, J = 10.7 Hz), 7.00 (1H, s), 4.87-4.80 (1H, m), 3.93 (3H, s), 3.90 (6H, s), 3.63 (3H, s), 3.20-3.15 (1H, m), 2.31-2.09 (3H, m).
ESI-MS m / z: 528 [M + H] + .
実施例３５８
4-クロロ-N-[(ピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(黄色固体, 26 mg, 0.0499 mmol, 72%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに3-アミノ-1H-ピラゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 12.64 (1H, s), 10.66 (1H, s), 10.39 (1H, br-s), 7.73 (1H, t, J=2.0 Hz), 7.18 (1H, d, J=10.7 Hz), 7.05 (1H, d, J=10.7 Hz), 6.98 (1H, s), 5.96 (1H, s), 4.88-4.81 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.30-2.16 (2H, m), 2.00-1.90 (1H, m).
ESI-MS m/z: 517 [M+H]+. Example 358
Synthesis of 4-chloro-N-[(pyrazol-3-yl) thiocarbamoyl] deacetylcolchicine In a similar manner to the synthesis of N-[(benzoimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine To give the title compound (yellow solid, 26 mg, 0.0499 mmol, 72%). Instead of 2-amino-1H-benzimidazole, 3-amino-1H-pyrazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 12.64 (1H, s), 10.66 (1H, s), 10.39 (1H, br-s), 7.73 (1H, t, J = 2.0 Hz ), 7.18 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 6.98 (1H, s), 5.96 (1H, s), 4.88-4.81 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.89 (3H, s), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.30-2.16 (2H, m), 2.00-1.90 (1H , m).
ESI-MS m / z: 517 [M + H] + .
実施例３５９
4-クロロ-N-[(1-メチルピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(黄色固体, 32 mg, 0.0598 mmol, 96%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに3-アミノ-1-メチル-1H-ピラゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.61 (1H, s), 10.20 (1H, br-s), 7.66 (1H, d, J=2.2 Hz), 7.18 (1H, d, J=10.7 Hz), 7.05 (1H, d, J=10.7 Hz), 6.98 (1H, s), 5.92 (1H, s), 4.83-4.76 (1H, m), 3.92 (3H, s), 3.90 (6H, s), 3.82 (3H, s), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.29-2.16 (2H, m), 2.05-1.98 (1H, m).
ESI-MS m/z: 531 [M+H]+. Example 359
Synthesis of 4-chloro-N-[(1-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine Similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine In this manner, the title compound (yellow solid, 32 mg, 0.0598 mmol, 96%) was obtained. Instead of 2-amino-1H-benzimidazole, 3-amino-1-methyl-1H-pyrazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.61 (1H, s), 10.20 (1H, br-s), 7.66 (1H, d, J = 2.2 Hz), 7.18 (1H, d , J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 6.98 (1H, s), 5.92 (1H, s), 4.83-4.76 (1H, m), 3.92 (3H, s), 3.90 (6H, s), 3.82 (3H, s), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.29-2.16 (2H, m), 2.05-1.98 (1H, m).
ESI-MS m / z: 531 [M + H] + .
実施例３６０
4-クロロ-N-[(4-メチルチアゾール-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(黄色固体, 25 mg, 0.0455 mmol, 66%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに2-アミノ-4-メチルチアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.18 (1H, d, J=10.5 Hz), 7.08-7.00 (2H, m), 6.69 (1H, br-s), 4.76-4.69 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.19-3.13 (1H, m), 2.27-2.00 (3H, m), 2.24 (3H, br-s).
ESI-MS m/z: 548 [M+H]+. Example 360
Synthesis of 4-chloro-N-[(4-methylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine Similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine By the method, the title compound (yellow solid, 25 mg, 0.0455 mmol, 66%) was obtained. 2-Amino-4-methylthiazole was used in place of 2-amino-1H-benzimidazole.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.18 (1H, d, J = 10.5 Hz), 7.08-7.00 (2H, m), 6.69 (1H, br-s), 4.76-4.69 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.19-3.13 (1H, m), 2.27-2.00 (3H, m), 2.24 (3H, br -s).
ESI-MS m / z: 548 [M + H] + .
実施例３６１
4-クロロ-N-[(4,5-ジメチルチアゾール-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(黄色固体, 6 mg, 0.0106 mmol, 15%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-アミノ-4,5-ジメチルチアゾール塩酸塩およびトリエチルアミンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.17 (1H, d, J=10.7 Hz), 7.08-6.99 (2H, m), 4.78-4.70 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.18-3.11 (1H, m), 2.25-1.96 (9H, m).
ESI-MS m/z: 562 [M+H]+. Example 361
Synthesis of 4-chloro-N-[(4,5-dimethylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine Synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine In the same manner, the title compound (yellow solid, 6 mg, 0.0106 mmol, 15%) was obtained. Instead of 2-amino-1H-benzimidazole, 2-amino-4,5-dimethylthiazole hydrochloride and triethylamine were used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.17 (1H, d, J = 10.7 Hz), 7.08-6.99 (2H, m), 4.78-4.70 (1H, m), 3.92 (3H , s), 3.89 (6H, s), 3.64 (3H, s), 3.18-3.11 (1H, m), 2.25-1.96 (9H, m).
ESI-MS m / z: 562 [M + H] + .
実施例３６２
4-クロロ-N-[(ピリジン-4-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 25 mg, 0.0479 mmol, 63%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、4-アミノピリジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.07 (1H, s), 8.89 (1H, d, J=6.8 Hz), 8.37 (2H, d, J=5.6 Hz), 7.59 (2H, d, J=5.6 Hz), 7.18 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.76-4.69 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.18-3.13 (1H, m), 2.22-2.12 (2H, m), 2.06-1.97 (1H, m).
ESI-MS m/z: 528 [M+H]+. Example 362
Synthesis of 4-chloro-N-[(pyridin-4-yl) thiocarbamoyl] deacetylcolchicine In the same way as the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine To give the title compound (light brown solid, 25 mg, 0.0479 mmol, 63%). Instead of 2-amino-1H-benzimidazole, 4-aminopyridine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.07 (1H, s), 8.89 (1H, d, J = 6.8 Hz), 8.37 (2H, d, J = 5.6 Hz), 7.59 ( 2H, d, J = 5.6 Hz), 7.18 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.76-4.69 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.18-3.13 (1H, m), 2.22-2.12 (2H, m), 2.06-1.97 (1H, m).
ESI-MS m / z: 528 [M + H] + .
実施例３６３
4-クロロ-N-[3-(2-ヒドロキシエトキシ)ベンゾイル]デアセチルコルヒチンの合成
　3-(2-ヒドロキシエトキシ)安息香酸(34 mg, 0.153×1.2 mmol)のジクロロメタン(4 mL)溶液に、室温、アルゴンガス雰囲気下にて1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(36 mg, 0153×1.2 mmol)、1-ヒドロキシベンゾトリアゾール一水和物(28 mg, 0.153×1.2mmol)を加えて30分間撹拌した。そこに、4-クロロデアセチルコルヒチン(60 mg, 0.153 mmol)を加えて室温で一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡黄色固体, 72 mg, 0.130 mmol, 85%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.05 (1H, d, J=7.3 Hz), 7.47-7.43 (2H, m), 7.39 (1H, t, J=7.8 Hz), 7.20 (1H, s), 7.17 (1H, d, J=10.7 Hz), 7.14-7.11 (1H, m), 7.05 (1H, d, J=10.7 Hz), 4.88 (1H, t, J=5.3 Hz), 4.51-4.45 (1H, m), 4.03 (2H, t, J=5.3 Hz), 3.93 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.73 (2H, q, J=5.3 Hz), 3.60 (3H, s), 3.19-3.13 (1H, m), 2.21-2.02 (3H, m).
ESI-MS m/z: 556 [M+H]+. Example 363
Synthesis of 4-chloro-N- [3- (2-hydroxyethoxy) benzoyl] deacetylcolchicine To a solution of 3- (2-hydroxyethoxy) benzoic acid (34 mg, 0.153 × 1.2 mmol) in dichloromethane (4 mL), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (36 mg, 0153 × 1.2 mmol), 1-hydroxybenzotriazole monohydrate (28 mg, 0.153 ×) at room temperature under argon gas atmosphere 1.2 mmol) was added and stirred for 30 minutes. 4-chloro deacetyl colchicine (60 mg, 0.153 mmol) was added there, and it stirred at room temperature overnight. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 72 mg, 0.130 mmol, 85%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.05 (1H, d, J = 7.3 Hz), 7.47-7.43 (2H, m), 7.39 (1H, t, J = 7.8 Hz), 7.20 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.14-7.11 (1H, m), 7.05 (1H, d, J = 10.7 Hz), 4.88 (1H, t, J = 5.3 Hz ), 4.51-4.45 (1H, m), 4.03 (2H, t, J = 5.3 Hz), 3.93 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.73 (2H, q, J = 5.3 Hz), 3.60 (3H, s), 3.19-3.13 (1H, m), 2.21-2.02 (3H, m).
ESI-MS m / z: 556 [M + H] + .
実施例３６４
4-クロロ-N-[3-(2-ヒドロキシエトキシ)-4-メトキシベンゾイル]デアセチルコルヒチンの合成
　4-クロロ-N-[3-(2-ヒドロキシエトキシ)ベンゾイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 64 mg, 0.109 mmol, 71%)を得た。3-(2-ヒドロキシエトキシ)安息香酸の代わりに、3-(2-ヒドロキシエトキシ)-4-メトキシ安息香酸を用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.90 (1H, d, J=7.1 Hz), 7.57 (1H, dd, J=8.3, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 7.20 (1H, s), 7.17 (1H, d, J=10.5 Hz), 7.05 (2H, d, J=10.5 Hz), 7.05 (2H, d, J=8.3 Hz), 4.87 (1H, t, J=5.3 Hz), 4.52-4.44 (1H, m), 4.01 (2H, t, J=5.3 Hz), 3.93 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.82 (2H, s), 3.72 (2H, q, J=5.3 Hz), 3.60 (3H, s), 3.17 (1H, dd, J=12.2, 5.4 Hz), 2.22-2.02 (3H, m).
ESI-MS m/z: 586 [M+H]+. Example 364
Synthesis of 4-chloro-N- [3- (2-hydroxyethoxy) -4-methoxybenzoyl] deacetylcolchicine Similar to the synthesis of 4-chloro-N- [3- (2-hydroxyethoxy) benzoyl] deacetylcolchicine In this manner, the title compound (pale yellow solid, 64 mg, 0.109 mmol, 71%) was obtained. Instead of 3- (2-hydroxyethoxy) benzoic acid, 3- (2-hydroxyethoxy) -4-methoxybenzoic acid was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.90 (1H, d, J = 7.1 Hz), 7.57 (1H, dd, J = 8.3, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.20 (1H, s), 7.17 (1H, d, J = 10.5 Hz), 7.05 (2H, d, J = 10.5 Hz), 7.05 (2H, d, J = 8.3 Hz), 4.87 ( 1H, t, J = 5.3 Hz), 4.52-4.44 (1H, m), 4.01 (2H, t, J = 5.3 Hz), 3.93 (3H, s), 3.89 (3H, s), 3.89 (3H, s ), 3.82 (2H, s), 3.72 (2H, q, J = 5.3 Hz), 3.60 (3H, s), 3.17 (1H, dd, J = 12.2, 5.4 Hz), 2.22-2.02 (3H, m) .
ESI-MS m / z: 586 [M + H] + .
実施例３６５
4-クロロ-N-[(ピラジン-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 14 mg, 0.0261 mmol, 38%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-アミノピラジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 11.51 (1H, d, J=6.8 Hz), 11.18 (1H, s), 8.59 (1H, d, J=1.2 Hz), 8.34 (1H, dd, J=2.7, 1.2 Hz), 8.32 (1H, d, J=2.7 Hz), 7.20 (1H, d, J=10.7 Hz), 7.07 (1H, d, J=10.7 Hz), 7.00 (1H, s), 4.84-4.78 (1H, m), 3.93 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.20-3.15 (1H, m), 2.30-2.12 (3H, m).
ESI-MS m/z: 529 [M+H]+. Example 365
Synthesis of 4-chloro-N-[(pyrazin-2-yl) thiocarbamoyl] deacetylcolchicine In a manner similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine The title compound (milky white solid, 14 mg, 0.0261 mmol, 38%) was obtained. Instead of 2-amino-1H-benzimidazole, 2-aminopyrazine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 11.51 (1H, d, J = 6.8 Hz), 11.18 (1H, s), 8.59 (1H, d, J = 1.2 Hz), 8.34 ( 1H, dd, J = 2.7, 1.2 Hz), 8.32 (1H, d, J = 2.7 Hz), 7.20 (1H, d, J = 10.7 Hz), 7.07 (1H, d, J = 10.7 Hz), 7.00 ( 1H, s), 4.84-4.78 (1H, m), 3.93 (3H, s), 3.89 (6H, s), 3.63 (3H, s), 3.20-3.15 (1H, m), 2.30-2.12 (3H, m).
ESI-MS m / z: 529 [M + H] + .
実施例３６６
4-クロロ-N-[(1,3,4-チアジアゾール-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 10 mg, 0.0187 mmol, 27%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-アミノ-1,3,4-チアジアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.20-7.02 (3H, m), 4.76-4.65 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.18-3.10 (2H, m), 2.25-1.98.
ESI-MS m/z: 535 [M+H]+. Example 366
Synthesis of 4-chloro-N-[(1,3,4-thiadiazol-2-yl) thiocarbamoyl] deacetylcolchicine N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine The title compound (light brown solid, 10 mg, 0.0187 mmol, 27%) was obtained in the same manner as in the synthesis. Instead of 2-amino-1H-benzimidazole, 2-amino-1,3,4-thiadiazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.20-7.02 (3H, m), 4.76-4.65 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.64 (3H, s), 3.18-3.10 (2H, m), 2.25-1.98.
ESI-MS m / z: 535 [M + H] + .
実施例３６７
4-クロロ-N-[(ピリミジン-5-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 18 mg, 0.0336 mmol, 49%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、5-アミノピリミジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.83 (1H, s), 8.89 (1H, d, J=7.1 Hz), 8.88 (1H, s), 8.87 (2H, s), 7.17 (1H, d, J=10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.81-4.74 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.61 (3H, s), 3.20-3.11 (1H, m), 2.23-2.11 (2H, m), 2.05-1.98 (1H, m).
ESI-MS m/z: 529 [M+H]+. Example 367
Synthesis of 4-chloro-N-[(pyrimidin-5-yl) thiocarbamoyl] deacetylcolchicine In a manner similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine To give the title compound (light brown solid, 18 mg, 0.0336 mmol, 49%). Instead of 2-amino-1H-benzimidazole, 5-aminopyrimidine was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.83 (1H, s), 8.89 (1H, d, J = 7.1 Hz), 8.88 (1H, s), 8.87 (2H, s), 7.17 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J = 10.7 Hz), 4.81-4.74 (1H, m), 3.91 (3H, s), 3.89 (3H , s), 3.89 (3H, s), 3.61 (3H, s), 3.20-3.11 (1H, m), 2.23-2.11 (2H, m), 2.05-1.98 (1H, m).
ESI-MS m / z: 529 [M + H] + .
参考例３３
2-(3-ニトロフェノキシ)エタノールの合成
　3-ニトロフェノール(0.500 g, 3.59 mmol)のアセトン(20 mL)溶液に、室温、アルゴンガス雰囲気下にて、炭酸カリウム(0.496 g, 3.59 mmol)および2-ブロモエタノール(509 μL, 3.59×2 mmol)を加えて6時間煮沸還流した。反応液を室温まで冷却した後、クロロホルムおよび水を加えた。有機層を取り、0.1 mol/L水酸化ナトリウム次いでブラインで洗浄後、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(0.213 g, 1.16 mmol, 32%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.83-7.80 (1H, m), 7.72 (1H, t, J=2.5 Hz), 7.58 (1H, t, J=8.3 Hz), 7.43 (1H, dd, J=8.3, 2.5 Hz), 4.94 (1H, t, J=5.0 Hz), 4.12 (2H, t, J=5.0 Hz), 3.74 (2H, q, J=5.0 Hz). Reference Example 33
Synthesis of 2- (3-nitrophenoxy) ethanol To a solution of 3-nitrophenol (0.500 g, 3.59 mmol) in acetone (20 mL) at room temperature under an argon gas atmosphere, potassium carbonate (0.496 g, 3.59 mmol) and 2-Bromoethanol (509 μL, 3.59 × 2 mmol) was added and the mixture was boiled and refluxed for 6 hours. After cooling the reaction solution to room temperature, chloroform and water were added. The organic layer was taken, washed with 0.1 mol / L sodium hydroxide and then brine, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (0.213 g, 1.16 mmol, 32%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.83-7.80 (1H, m), 7.72 (1H, t, J = 2.5 Hz), 7.58 (1H, t, J = 8.3 Hz), 7.43 (1H, dd, J = 8.3, 2.5 Hz), 4.94 (1H, t, J = 5.0 Hz), 4.12 (2H, t, J = 5.0 Hz), 3.74 (2H, q, J = 5.0 Hz).
参考例３４
2-(3-アミノフェノキシ)エタノールの合成
　2-(3-ニトロフェノキシ)エタノール(0.186 g, 1.02 mmol)の1,4-ジオキサン(10 mL)溶液に、氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(30 mg)を添加した後、反応容器内を水素ガスで置換した。反応液を室温、水素ガス雰囲気下(風船)にて7時間激しく撹拌した。不溶物をろ去、1,4-ジオキサンで洗いこんだ後、ろ液と洗浄液を合わせて濃縮乾固して、標記の化合物(褐色タール状物, 0.149 g, 0.970 mmol, 96%)の物は精製せずに次工程に使用した。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 6.87 (1H, t, J=8.3 Hz), 6.14-6.11 (2H, m), 6.08-6.05 (1H, m), 5.00 (2H, br-s), 4.78 (1H, t, J=5.3 Hz), 3.85 (2H, t, J=5.3 Hz), 3.66 (2H, q, J=5.3 Hz).
ESI-MS m/z: 154 [M+H]+. Reference Example 34
Synthesis of 2- (3-aminophenoxy) ethanol To a solution of 2- (3-nitrophenoxy) ethanol (0.186 g, 1.02 mmol) in 1,4-dioxane (10 mL) under ice-cooling and argon gas atmosphere, 10 After adding% palladium-carbon (30 mg), the inside of the reaction vessel was replaced with hydrogen gas. The reaction solution was vigorously stirred at room temperature under a hydrogen gas atmosphere (balloon) for 7 hours. The insoluble material was removed by filtration and washed with 1,4-dioxane. The filtrate and washings were combined and concentrated to dryness to give the title compound (brown tar, 0.149 g, 0.970 mmol, 96%). Was used in the next step without purification.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 6.87 (1H, t, J = 8.3 Hz), 6.14-6.11 (2H, m), 6.08-6.05 (1H, m), 5.00 (2H , br-s), 4.78 (1H, t, J = 5.3 Hz), 3.85 (2H, t, J = 5.3 Hz), 3.66 (2H, q, J = 5.3 Hz).
ESI-MS m / z: 154 [M + H] + .
参考例３５
2-(4-アミノフェノキシ)エタノールの合成
　2-(3-アミノフェノキシ)エタノールの合成の合成と同様の方法にて、標記の化合物(暗褐色固体, 0.250 g, 1.64 mmol, 定量的)を得た。2-(3-ニトロフェノキシ)エタノールの代わりに、2-(4-ニトロフェノキシ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 6.64 (2H, d, J=8.8 Hz), 6.49 (2H, d, J=8.8 Hz), 4.76 (1H, t, J=5.3 Hz), 4.58 (2H, br-s), 3.82 (2H, t, J=5.3 Hz), 3.64 (2H, q, J=5.3 Hz).
ESI-MS m/z: 154 [M+H]+. Reference Example 35
Synthesis of 2- (4-aminophenoxy) ethanol It was. Instead of 2- (3-nitrophenoxy) ethanol, 2- (4-nitrophenoxy) ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 6.64 (2H, d, J = 8.8 Hz), 6.49 (2H, d, J = 8.8 Hz), 4.76 (1H, t, J = 5.3 Hz), 4.58 (2H, br-s), 3.82 (2H, t, J = 5.3 Hz), 3.64 (2H, q, J = 5.3 Hz).
ESI-MS m / z: 154 [M + H] + .
実施例３６８
4-クロロ-N-[3-(2-ヒドロキシエトキシ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 35 mg, 0.0590 mmol, 85%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-(3-アミノフェノキシ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.72 (1H, s), 8.44 (1H, d, J=7.3 Hz), 7.24-7.15 (3H, m), 7.12 (1H, s), 7.04 (1H, d, J=11.0 Hz), 6.92 (1H, d, J=7.8 Hz), 6.66 (1H, dd, J=8.2, 2.1 Hz), 4.85 (1H, t, J=5.6 Hz), 4.82-4.75 (1H, m), 3.95-3.91 (2H, m), 3.92 (3H, s), 3.89 (6H, s), 3.71-3.67 (2H, m), 3.62 (3H, s), 3.19-3.09 (1H, m), 2.18-1.98 (3H, m).
ESI-MS m/z: 587 [M+H]+. Example 368
Synthesis of 4-chloro-N- [3- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine Similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine By the method, the title compound (light brown solid, 35 mg, 0.0590 mmol, 85%) was obtained. Instead of 2-amino-1H-benzimidazole, 2- (3-aminophenoxy) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.72 (1H, s), 8.44 (1H, d, J = 7.3 Hz), 7.24-7.15 (3H, m), 7.12 (1H, s ), 7.04 (1H, d, J = 11.0 Hz), 6.92 (1H, d, J = 7.8 Hz), 6.66 (1H, dd, J = 8.2, 2.1 Hz), 4.85 (1H, t, J = 5.6 Hz) ), 4.82-4.75 (1H, m), 3.95-3.91 (2H, m), 3.92 (3H, s), 3.89 (6H, s), 3.71-3.67 (2H, m), 3.62 (3H, s), 3.19-3.09 (1H, m), 2.18-1.98 (3H, m).
ESI-MS m / z: 587 [M + H] + .
実施例３６９
4-クロロ-N-[4-(2-ヒドロキシエトキシ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 24 mg, 0.0404 mmol, 59%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-(4-アミノフェノキシ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.51 (1H, s), 8.22 (1H, d, J=7.1 Hz), 7.27 (2H, d, J=8.0 Hz), 7.15 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J=10.7 Hz), 6.88 (2H, d, J=8.0 Hz), 4.86 (1H, t, J=5.0 Hz), 4.83-4.76 (1H, m), 3.95 (2H, t, J=5.0 Hz), 3.91 (3H, s), 3.89 (6H, s), 3.69 (2H, q, J=5.0 Hz), 3.61 (3H, s), 3.17-3.08 (1H, m), 2.16-1.97 (3H, m).
ESI-MS m/z: 587 [M+H]+. Example 369
Synthesis of 4-chloro-N- [4- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine Similar to the synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine By the method, the title compound (light brown solid, 24 mg, 0.0404 mmol, 59%) was obtained. Instead of 2-amino-1H-benzimidazole, 2- (4-aminophenoxy) ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.51 (1H, s), 8.22 (1H, d, J = 7.1 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.15 ( 1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 6.88 (2H, d, J = 8.0 Hz), 4.86 (1H, t, J = 5.0 Hz), 4.83-4.76 (1H, m), 3.95 (2H, t, J = 5.0 Hz), 3.91 (3H, s), 3.89 (6H, s), 3.69 (2H, q, J = 5.0 Hz), 3.61 (3H, s), 3.17-3.08 (1H, m), 2.16-1.97 (3H, m).
ESI-MS m / z: 587 [M + H] + .
参考例３６
5-アミノ-1,2-ジメチルイミダゾールの合成
　1,2-ジメチル-5-ニトロイミダゾール(0.300 g, 2.13 mmol)の1,4-ジオキサン(5 mL)溶液に、氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(60 mg)を添加した後、反応液を室温、水素ガス雰囲気下(風船)にて一晩撹拌した。不溶物をセライトパッドにてろ去、1,4-ジオキサンで洗いこんだ。ろ液と洗浄液は合わせて減圧下、3mL程度まで濃縮した。残渣物にn-ヘキサンを加えて析出物をろ取した。ろ取物はn-ヘキサンで洗浄、次いで減圧乾燥して、標記の化合物(黄土色固体, 0.180 g, 1.62 mmol, 76%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 5.89 (1H, s), 4.20 (2H, s), 3.24 (3H, s), 2.13 (3H, s). Reference Example 36
Synthesis of 5-amino-1,2-dimethylimidazole A solution of 1,2-dimethyl-5-nitroimidazole (0.300 g, 2.13 mmol) in 1,4-dioxane (5 mL) was cooled in an ice-cooled argon gas atmosphere. After adding 10% palladium-carbon (60 mg), the reaction solution was stirred overnight at room temperature under a hydrogen gas atmosphere (balloon). The insoluble material was filtered off through a celite pad and washed with 1,4-dioxane. The filtrate and the washing solution were combined and concentrated to about 3 mL under reduced pressure. N-Hexane was added to the residue, and the precipitate was collected by filtration. The filtered product was washed with n-hexane and then dried under reduced pressure to obtain the title compound (ocher solid, 0.180 g, 1.62 mmol, 76%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 5.89 (1H, s), 4.20 (2H, s), 3.24 (3H, s), 2.13 (3H, s).
参考例３７
5-アミノ-2-メチルイミダゾール-1-エタノールの合成
　2-メチル-5-ニトロイミダゾール-1-エタノール(0.300 g, 1.75 mmol)の1,4-ジオキサン(30 mL)溶液に、氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(200 mg)を添加した後、反応液を室温、水素ガス雰囲気下(風船)にて6時間撹拌した。不溶物をセライトパッドにてろ去、1,4-ジオキサンで洗いこんだ。ろ液と洗浄液は合わせて減圧下、10 mL程度まで濃縮した。残渣物にn-ヘキサンを加えて析出物をろ取した。ろ取物はn-ヘキサンで洗浄、次いで減圧乾燥して、標記の化合物(黄橙色固体, 0.156 g, 1.11 mmol, 63%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 5.91 (1H, s), 4.97 (1H,. br-s), 4.13 (2H, br-s), 3.75 (2H, t, J=5.7 Hz), 3.55 (2H, br-s), 2.16 (3H, s). Reference Example 37
Synthesis of 5-amino-2-methylimidazole-1-ethanol To a solution of 2-methyl-5-nitroimidazole-1-ethanol (0.300 g, 1.75 mmol) in 1,4-dioxane (30 mL), ice-cooled, argon After adding 10% palladium-carbon (200 mg) under a gas atmosphere, the reaction solution was stirred at room temperature under a hydrogen gas atmosphere (balloon) for 6 hours. The insoluble material was filtered off through a celite pad and washed with 1,4-dioxane. The filtrate and the washing solution were combined and concentrated to about 10 mL under reduced pressure. N-Hexane was added to the residue, and the precipitate was collected by filtration. The filtered product was washed with n-hexane and then dried under reduced pressure to obtain the title compound (yellow-orange solid, 0.156 g, 1.11 mmol, 63%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 5.91 (1H, s), 4.97 (1H ,. br-s), 4.13 (2H, br-s), 3.75 (2H, t, J = 5.7 Hz), 3.55 (2H, br-s), 2.16 (3H, s).
実施例３７０
4-クロロ-N-[(1,2-ジメチルイミダゾール-5-イル)チオカルバモイル]デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 12 mg, 0.0218 mmol, 32%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、5-アミノ-1,2-ジメチルイミダゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.11 (1H, d, J=7.6 Hz), 7.15 (1H, d, J=10.7 Hz), 7.05-7.00 (4H, m), 4.99-4.92 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.65 (3H, s), 3.32 (3H, s), 3.14 (1H, dd, J=13.3, 5.0 Hz), 2.45-2.37 (1H, m), 2.27 (3H, s), 2.21-2.10 (1H, m), 2.06-1.96 (1H, m).
ESI-MS m/z: 545 [M+H]+. Example 370
Synthesis of 4-chloro-N-[(1,2-dimethylimidazol-5-yl) thiocarbamoyl] deacetylcolchicine Synthesis of N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine In the same manner, the title compound (light brown solid, 12 mg, 0.0218 mmol, 32%) was obtained. Instead of 2-amino-1H-benzimidazole, 5-amino-1,2-dimethylimidazole was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.11 (1H, d, J = 7.6 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.05-7.00 (4H, m), 4.99-4.92 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.65 (3H, s), 3.32 (3H, s), 3.14 (1H, dd, J = 13.3, 5.0 Hz), 2.45-2.37 (1H, m), 2.27 (3H, s), 2.21-2.10 (1H, m), 2.06-1.96 (1H, m).
ESI-MS m / z: 545 [M + H] + .
実施例３７１
4-クロロ-N-{[1-(2-ヒドロキシエチル)-2-メチルイミダゾール-5-イル]チオカルバモイル}デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 11 mg, 0.0190 mmol, 28%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、5-アミノ-2-メチルイミダゾール-1-エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.11 (1H, d, J=7.6 Hz), 7.15 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.04-6.99 (3H, m), 5.06 (1H, t, J=5.1 Hz), 5.00-4.93 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.86-3.82 (2H, m), 3.65 (3H, s), 3.62-3.57 (2H, m), 3.14 (1H, dd, J=13.3, 5.5 Hz), 2.46-2.37 (1H, m), 2.30 (3H, s), 2.21-2.12 (1H, m), 2.05-1.96 (1H, m).
ESI-MS m/z: 575 [M+H]+. Example 371
Synthesis of 4-chloro-N-{[1- (2-hydroxyethyl) -2-methylimidazol-5-yl] thiocarbamoyl} deacetylcolchicine N-[(benzimidazol-2-yl) thiocarbamoyl] -4 The title compound (light brown solid, 11 mg, 0.0190 mmol, 28%) was obtained in the same manner as in the synthesis of -chlorodeacetylcolchicine. Instead of 2-amino-1H-benzimidazole, 5-amino-2-methylimidazole-1-ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.11 (1H, d, J = 7.6 Hz), 7.15 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.04- 6.99 (3H, m), 5.06 (1H, t, J = 5.1 Hz), 5.00-4.93 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.86 -3.82 (2H, m), 3.65 (3H, s), 3.62-3.57 (2H, m), 3.14 (1H, dd, J = 13.3, 5.5 Hz), 2.46-2.37 (1H, m), 2.30 (3H , s), 2.21-2.12 (1H, m), 2.05-1.96 (1H, m).
ESI-MS m / z: 575 [M + H] + .
参考例３８
2-(5-ニトロ-1H-ピラゾール-1-イル)エタノールおよび2-(3-ニトロ-1H-ピラゾール-1-イル)エタノールの合成
　3-ニトロ-1H-ピラゾール(0.300 g, 2.65 mmol)のアセトニトリル(15 mL)溶液に、炭酸カリウム(0.549 g, 2.65×1.5 mmol)、臭化テトラ-m-ブチルアンモニウム(43 mg, 2.65×0.5 mmol)および2-ブロモエタノール(376 μL, 2.65×2.0 mmol)を添加して、アルゴンガス雰囲気下にて、2時間煮沸還流した。反応液を室温まで放冷した後、クロロホルムとブラインを加えた。有機層を取り、水層はさらにクロロホルム(×2)にて抽出した。有機層は合わせて無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、2-(5-ニトロ-1H-ピラゾール-1-イル)エタノール(褐色タール状物, 69 mg, 0.439 mmol, 17%)および2-(3-ニトロ-1H-ピラゾール-1-イル)エタノール(褐色タール状物, 0.267 g, 1.70 mmol, 64%)を得た。
2-(5-ニトロ-1H-ピラゾール-1-イル)エタノール
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.70 (1H, d, J=2.2 Hz), 7.24 (1H, d, J=2.2 Hz), 4.94 (1H, t, J=5.7 Hz), 4.61 (2H, t, J=5.7 Hz), 3.71 (2H, q, J=5.7 Hz).
ESI-MS m/z: 158 [M+H]+.
2-(3-ニトロ-1H-ピラゾール-1-イル)エタノール
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.99 (1H, d, J=2.4 Hz), 7.03 (1H, d, J=2.4 Hz), 4.99 (1H, t, J=5.4 Hz), 4.27 (2H, t, J=5.4 Hz), 3.78 (2H, q, J=5.4 Hz).
ESI-MS m/z: 158 [M+H]+. Reference Example 38
Synthesis of 2- (5-nitro-1H-pyrazol-1-yl) ethanol and 2- (3-nitro-1H-pyrazol-1-yl) ethanol 3-nitro-1H-pyrazole (0.300 g, 2.65 mmol) To acetonitrile (15 mL) solution, potassium carbonate (0.549 g, 2.65 × 1.5 mmol), tetra-m-butylammonium bromide (43 mg, 2.65 × 0.5 mmol) and 2-bromoethanol (376 μL, 2.65 × 2.0 mmol) ) Was added and the mixture was boiled and refluxed for 2 hours under an argon gas atmosphere. The reaction solution was allowed to cool to room temperature, and chloroform and brine were added. The organic layer was taken, and the aqueous layer was further extracted with chloroform (× 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol), and 2- (5-nitro-1H-pyrazol-1-yl) ethanol (brown tar, 69 mg, 0.439) mmol, 17%) and 2- (3-nitro-1H-pyrazol-1-yl) ethanol (brown tar, 0.267 g, 1.70 mmol, 64%).
2- (5-Nitro-1H-pyrazol-1-yl) ethanol
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.70 (1H, d, J = 2.2 Hz), 7.24 (1H, d, J = 2.2 Hz), 4.94 (1H, t, J = 5.7 Hz), 4.61 (2H, t, J = 5.7 Hz), 3.71 (2H, q, J = 5.7 Hz).
ESI-MS m / z: 158 [M + H] + .
2- (3-Nitro-1H-pyrazol-1-yl) ethanol
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.99 (1H, d, J = 2.4 Hz), 7.03 (1H, d, J = 2.4 Hz), 4.99 (1H, t, J = 5.4 Hz), 4.27 (2H, t, J = 5.4 Hz), 3.78 (2H, q, J = 5.4 Hz).
ESI-MS m / z: 158 [M + H] + .
参考例３９
2-(5-アミノ-1H-ピラゾール-1-イル)エタノールの合成
　2-(5-ニトロ-1H-ピラゾール-1-イル)エタノール(69 mg, 0.439 mmol)のエタノール(2 mL)溶液に氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(10 mg)を添加した後、反応液を室温、水素ガス雰囲気下(風船)にて一晩撹拌した。不溶物をセライトパッドにてろ去、エタノールで洗いこんだ。ろ液と洗浄液は合わせて減圧下、濃縮乾固して、標記の化合物(白色固体, 52 mg, 0.408 mmol, 93%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.02 (1H, d, J=1.7 Hz), 5.26 (1H, d, J=1.7 Hz), 5.04 (2H, br-s), 4.90 (1H, t, J=5.7 Hz), 3.89 (2H, t, J=5.7 Hz), 3.64 (2H, q, J=5.7 Hz).
ESI-MS m/z: 128 [M+H]+. Reference Example 39
Synthesis of 2- (5-amino-1H-pyrazol-1-yl) ethanol Add 2- (5-nitro-1H-pyrazol-1-yl) ethanol (69 mg, 0.439 mmol) in ethanol (2 mL) with ice After adding 10% palladium-carbon (10 mg) under a cold, argon gas atmosphere, the reaction solution was stirred overnight at room temperature under a hydrogen gas atmosphere (balloon). The insoluble material was filtered off through a Celite pad and washed with ethanol. The filtrate and washings were combined and concentrated to dryness under reduced pressure to give the title compound (white solid, 52 mg, 0.408 mmol, 93%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.02 (1H, d, J = 1.7 Hz), 5.26 (1H, d, J = 1.7 Hz), 5.04 (2H, br-s), 4.90 (1H, t, J = 5.7 Hz), 3.89 (2H, t, J = 5.7 Hz), 3.64 (2H, q, J = 5.7 Hz).
ESI-MS m / z: 128 [M + H] + .
参考例４０
2-(3-アミノ-1H-ピラゾール-1-イル)エタノールの合成
　2-(3-ニトロ-1H-ピラゾール-1-イル)エタノール(0.187 g, 1.19 mmol)のエタノール(6 mL)溶液に氷冷、アルゴンガス雰囲気下にて10%パラジウム-炭素(20 mg)を添加した後、反応液を室温、水素ガス雰囲気下(風船)にて一晩撹拌した。不溶物をセライトパッドにてろ去、エタノールで洗いこんだ。ろ液と洗浄液は合わせて減圧下、濃縮乾固して、標記の化合物(淡褐色タール状物, 0.151 g, 1.18 mmol, 99%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.26 (1H, d, J=2.0 Hz), 5.34 (1H, d, J=2.0 Hz), 4.75 (1H, t, J=5.7 Hz), 4.48 (2H, br-s), 3.84 (2H, t, J=5.7 Hz), 3.63 (2H, q, J=5.7 Hz).
ESI-MS m/z: 128 [M+H]+. Reference Example 40
Synthesis of 2- (3-amino-1H-pyrazol-1-yl) ethanol 2- (3-nitro-1H-pyrazol-1-yl) ethanol (0.187 g, 1.19 mmol) in ethanol (6 mL) in ice After adding 10% palladium-carbon (20 mg) under a cold, argon gas atmosphere, the reaction solution was stirred overnight at room temperature under a hydrogen gas atmosphere (balloon). The insoluble material was filtered off through a Celite pad and washed with ethanol. The filtrate and washings were combined and concentrated to dryness under reduced pressure to give the title compound (light brown tar, 0.151 g, 1.18 mmol, 99%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.26 (1H, d, J = 2.0 Hz), 5.34 (1H, d, J = 2.0 Hz), 4.75 (1H, t, J = 5.7 Hz), 4.48 (2H, br-s), 3.84 (2H, t, J = 5.7 Hz), 3.63 (2H, q, J = 5.7 Hz).
ESI-MS m / z: 128 [M + H] + .
実施例３７２
4-クロロ-N-{[1-(2-ヒドロキシエチル)ピラゾール-5-イル]チオカルバモイル}デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡桃褐色固体, 25 mg, 0.0443 mmol, 64%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-(5-アミノ-1H-ピラゾール-1-イル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.28 (1H, s), 8.65 (1H, d, J=5.6 Hz), 7.39 (1H, d, J=1.7 Hz), 7.16 (1H, d, J=10.5 Hz), 7.09 (1H, s), 7.04 (1H, d, J=10.5 Hz), 6.15 (1H, d, J=1.7 Hz), 4.96 (1H, t, J=5.1 Hz), 4.80-4.73 (1H, m), 3.95 (2H, t, J=5.9 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.70 (2H, q, J=5.9 Hz), 3.59 (3H, s), 3.16-3.10 (1H, m), 2.15-1.98 (3H, m).
ESI-MS m/z: 561 [M+H]+. Example 372
Synthesis of 4-chloro-N-{[1- (2-hydroxyethyl) pyrazol-5-yl] thiocarbamoyl} deacetylcolchicine N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetyl The title compound (light peach brown solid, 25 mg, 0.0443 mmol, 64%) was obtained by a method similar to the synthesis of colchicine. Instead of 2-amino-1H-benzimidazole, 2- (5-amino-1H-pyrazol-1-yl) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.28 (1H, s), 8.65 (1H, d, J = 5.6 Hz), 7.39 (1H, d, J = 1.7 Hz), 7.16 ( 1H, d, J = 10.5 Hz), 7.09 (1H, s), 7.04 (1H, d, J = 10.5 Hz), 6.15 (1H, d, J = 1.7 Hz), 4.96 (1H, t, J = 5.1 Hz), 4.80-4.73 (1H, m), 3.95 (2H, t, J = 5.9 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.89 (3H, s), 3.70 (2H, q , J = 5.9 Hz), 3.59 (3H, s), 3.16-3.10 (1H, m), 2.15-1.98 (3H, m).
ESI-MS m / z: 561 [M + H] + .
実施例３７３
4-クロロ-N-{[1-(2-ヒドロキシエチル)ピラゾール-3-イル]チオカルバモイル}デアセチルコルヒチンの合成
　N-[(ベンゾイミダゾール-2-イル)チオカルバモイル]-4-クロロデアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡褐色固体, 33 mg, 0.0585 mmol, 85%)を得た。2-アミノ-1H-ベンゾイミダゾールの代わりに、2-(3-アミノ-1H-ピラゾール-1-イル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.65 (1H, s), 10.33 (1H, br-s), 7.68 (1H, d, J=2.4 Hz), 7.19 (1H, d, J=10.7 Hz), 7.06 (1H, d, J=10.7 Hz), 7.00 (1H, s), 5.91 (1H, s), 4.91 (1H, t, J=5.4 Hz), 4.83-4.76 (1H, m), 4.11 (2H, t, J=5.4 Hz), 3.93 (3H, s), 3.90 (6H, s), 3.75 (2H, q, J=5.4 Hz), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.26-2.18 (2H, m), 2.04-1.97 (1H, m).
ESI-MS m/z: 561 [M+H]+. Example 373
Synthesis of 4-chloro-N-{[1- (2-hydroxyethyl) pyrazol-3-yl] thiocarbamoyl} deacetylcolchicine N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetyl The title compound (light brown solid, 33 mg, 0.0585 mmol, 85%) was obtained by a method similar to the synthesis of colchicine. Instead of 2-amino-1H-benzimidazole, 2- (3-amino-1H-pyrazol-1-yl) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.65 (1H, s), 10.33 (1H, br-s), 7.68 (1H, d, J = 2.4 Hz), 7.19 (1H, d , J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 7.00 (1H, s), 5.91 (1H, s), 4.91 (1H, t, J = 5.4 Hz), 4.83-4.76 (1H , m), 4.11 (2H, t, J = 5.4 Hz), 3.93 (3H, s), 3.90 (6H, s), 3.75 (2H, q, J = 5.4 Hz), 3.63 (3H, s), 3.19 -3.14 (1H, m), 2.26-2.18 (2H, m), 2.04-1.97 (1H, m).
ESI-MS m / z: 561 [M + H] + .
参考例４１
4-ブロモ-７-イソチオシアネート7-デ(アセトアミド)コルヒチンの合成
　4-ブロモデアセチルコルヒチン(1.00 g, 2.29 mmol)のジクロロメタン(11 mL)溶液に、氷冷、アルゴンガス雰囲気下にて、チオホスゲン(192 μL, 2.29×1.1 mmol)およびトリエチルアミン(734 μL, 2.29×2.3 mmol)を添加して、徐々に室温に戻しながら一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡褐色固体, 1.04 g, 2.17 mmol, 95%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.24 (1H, s), 7.17 (1H, d, J=10.7 Hz), 7.10 (1H, d, J=10.7 Hz), 4.89 (1H, dd, J=10.9, 6.5 Hz), 3.92 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J=13.3, 5.7 Hz), 2.47-2.37 (1H, m), 2.29-2.20 (1H, m), 2.14-2.06 (1H, m).
ESI-MS m/z: 478 [M+H]+, 480 [M+2+H]+. Reference Example 41
Synthesis of 4-bromo-7-isothiocyanate 7-de (acetamido) colchicine To a solution of 4-bromodeacetylcolchicine (1.00 g, 2.29 mmol) in dichloromethane (11 mL) under ice-cooling and argon gas atmosphere, thiophosgene (192 μL, 2.29 × 1.1 mmol) and triethylamine (734 μL, 2.29 × 2.3 mmol) were added, and the mixture was stirred overnight while gradually returning to room temperature. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (light brown solid, 1.04 g, 2.17 mmol, 95%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.24 (1H, s), 7.17 (1H, d, J = 10.7 Hz), 7.10 (1H, d, J = 10.7 Hz), 4.89 ( 1H, dd, J = 10.9, 6.5 Hz), 3.92 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.59 (3H, s), 3.11 (1H, dd, J = 13.3, 5.7 Hz), 2.47-2.37 (1H, m), 2.29-2.20 (1H, m), 2.14-2.06 (1H, m).
ESI-MS m / z: 478 [M + H] + , 480 [M + 2 + H] + .
実施例３７４
4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-７-イソチオシアネート7-デ(アセトアミド)コルヒチン(30 mg, 0.0627 mmol)のN,N-ジメチルホルムアミド(1 mL)溶液に、室温で3-アミノ-5-メチル-1,2,4-トリアゾール (7 mg, 0.0627×1.2 mmol)を加えて、80℃で一晩撹拌した。反応液を室温まで冷却した後、クロロホルムとブラインを加えて有機層を取った。有機層は10%硫酸水素ナトリウム、飽和炭酸水素ナトリウム水溶液、次いでブラインにて洗浄、無水硫酸ナトリウムにて乾燥、ろ過、減圧下濃縮乾固した。残渣物をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 16 mg, 0.0279 mmol, 44%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 13.61 [1H, s], 11.03 (1H, s), 10.50 (1H, d, J=6.6 Hz), 7.18 (1H, d, J=10.7 Hz), 7.06 (1H, d, J=10.7 Hz), 6.94 (1H, s), 4.82-4.76 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.20-3.14 (1H, m), 2.38 (3H, s), 2.34-2.20 (2H, m), 2.01-1.93 (1H, m).
ESI-MS m/z: 576 [M+H]+, 578 ]M+2+H]+. Example 374
Synthesis of 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-7-isothiocyanate 7-de (acetamido) colchicine (30 mg , 0.0627 mmol) in N, N-dimethylformamide (1 mL) at room temperature, 3-amino-5-methyl-1,2,4-triazole (7 mg, 0.0627 × 1.2 mmol) was added at 80 ° C. Stir overnight. After the reaction solution was cooled to room temperature, chloroform and brine were added to obtain an organic layer. The organic layer was washed with 10% sodium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate solution, then brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 16 mg, 0.0279 mmol, 44%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 13.61 [1H, s], 11.03 (1H, s), 10.50 (1H, d, J = 6.6 Hz), 7.18 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.94 (1H, s), 4.82-4.76 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H , s), 3.62 (3H, s), 3.20-3.14 (1H, m), 2.38 (3H, s), 2.34-2.20 (2H, m), 2.01-1.93 (1H, m).
ESI-MS m / z: 576 [M + H] + , 578] M + 2 + H] + .
実施例３７５
4-ブロモ-N-[(1-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体,18 mg, 0.0314 mmol, 50%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノ-1-メチル-1H-1,2,4-トリアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 11.18 (1H, s), 10.42 (1H, d, J=6.8 Hz), 8.50 (1H, s), 7.18 (1H, d, J=10.7 Hz), 7.06 (1H, d, J=10.7 Hz), 6.95 (1H, s), 4.83-4.76 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.84 (3H, s), 3.62 (3H, s), 3.20-3.14 (1H, m), 2.34-2.17 (2H, m), 2.05-1.96 (1H, m).
ESI-MS m/z: 576 [M+H]+., 578 [M+2+H]+. Example 375
Synthesis of 4-bromo-N-[(1-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4- The title compound (milky white solid, 18 mg, 0.0314 mmol, 50%) was obtained by a method similar to the synthesis of triazol-3-yl) thiocarbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-amino-1-methyl-1H-1,2,4-triazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 11.18 (1H, s), 10.42 (1H, d, J = 6.8 Hz), 8.50 (1H, s), 7.18 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.95 (1H, s), 4.83-4.76 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H , s), 3.84 (3H, s), 3.62 (3H, s), 3.20-3.14 (1H, m), 2.34-2.17 (2H, m), 2.05-1.96 (1H, m).
ESI-MS m / z: 576 [M + H] + ., 578 [M + 2 + H] + .
実施例３７６
4-ブロモ-N-[(1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 18 mg, 0.0314 mmol, 50%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノ-1,2,4-トリアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.48 (1H, d, J=7.6 Hz), 8.11 (2H, s), 7.73 (1H, s), 7.19 (1H, d, J=10.7 Hz), 7.07 (1H, s), 7.06 (1H, d, J=10.7 Hz), 4.84-4.74 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.65 (3H, s), 3.20-3.14 (1H, m), 2.30-2.21 (1H, m), 2.10-2.01 (1H, m).
ESI-MS m/z: 562 [M+H]+, 564 [M+2+H]+. Example 376
Synthesis of 4-bromo-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazole-3- The title compound (milky white solid, 18 mg, 0.0314 mmol, 50%) was obtained in the same manner as in the synthesis of (yl) thiocarbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-amino-1,2,4-triazole was used.
1 H-NMR (400MHz, DMSO -d 6) δ [ppm]: 10.48 (1H, d, J = 7.6 Hz), 8.11 (2H, s), 7.73 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.06 (1H, d, J = 10.7 Hz), 4.84-4.74 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H , s), 3.65 (3H, s), 3.20-3.14 (1H, m), 2.30-2.21 (1H, m), 2.10-2.01 (1H, m).
ESI-MS m / z: 562 [M + H] + , 564 [M + 2 + H] + .
実施例３７７
4-ブロモ-N-[(4-シアノピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 22 mg, 0.0372 mmol, 59%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノ-4-ピラゾールカルボニトリルを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 13.59 (1H, s), 10.42 (1H, s), 9.30 (1H, d, J=5.9 Hz), 8.57 (1H, s), 7.16 (1H, d, J=10.7 Hz), 7.05 (1H, d, J=10.7 Hz), 7.05 (1H, s), 4.81-4.74 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.15 (1H, dd, J=12.8, 4.0 Hz), 2.29-2.10 (2H, m), 2.03-1.94 (1H, m).
ESI-MS m/z: 586 [M+H]+,588 [M+2+H]+. Example 377
Synthesis of 4-bromo-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thio The title compound (milky white solid, 22 mg, 0.0372 mmol, 59%) was obtained by a method similar to the synthesis of carbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-amino-4-pyrazolecarbonitrile was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 13.59 (1H, s), 10.42 (1H, s), 9.30 (1H, d, J = 5.9 Hz), 8.57 (1H, s), 7.16 (1H, d, J = 10.7 Hz), 7.05 (1H, d, J = 10.7 Hz), 7.05 (1H, s), 4.81-4.74 (1H, m), 3.91 (3H, s), 3.89 (3H , s), 3.88 (3H, s), 3.62 (3H, s), 3.15 (1H, dd, J = 12.8, 4.0 Hz), 2.29-2.10 (2H, m), 2.03-1.94 (1H, m).
ESI-MS m / z: 586 [M + H] + , 588 [M + 2 + H] + .
実施例３７８
4-ブロモ-N-[(5-メチルピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(黄色固体, 34 mg, 0.0592 mmol, 94%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノ-5-メチルピラゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 12.34 (1H, s), 10.57 (1H, s), 10.45 (1H, br-s), 7.17 (1H, d, J=10.7 Hz), 7.05 (1H, d, J=10.7 Hz), 6.97 (1H, s), 5.73 (1H, s), 4.86-4.79 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.62 (3H, s), 3.20-3.14 (1H, m), 2.34-2.17 (2H, m), 2.22 (3H, s), 1.95-1.87 (1H, m).
ESI-MS m/z: 575 [M+H]+, 577 [M+2+H]+. Example 378
Synthesis of 4-bromo-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thio The title compound (yellow solid, 34 mg, 0.0592 mmol, 94%) was obtained in the same manner as in the synthesis of carbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-amino-5-methylpyrazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 12.34 (1H, s), 10.57 (1H, s), 10.45 (1H, br-s), 7.17 (1H, d, J = 10.7 Hz ), 7.05 (1H, d, J = 10.7 Hz), 6.97 (1H, s), 5.73 (1H, s), 4.86-4.79 (1H, m), 3.92 (3H, s), 3.89 (3H, s) , 3.88 (3H, s), 3.62 (3H, s), 3.20-3.14 (1H, m), 2.34-2.17 (2H, m), 2.22 (3H, s), 1.95-1.87 (1H, m).
ESI-MS m / z: 575 [M + H] + , 577 [M + 2 + H] + .
実施例３７９
4-ブロモ-N-[(1-メチルピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 32 mg, 0.0557 mmol, 89%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノ-1-メチルピラゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.63 (1H, s), 10.22 (1H, br-s), 7.67 (1H, d, J=2.3 Hz), 7.18 (1H, d, J=10.9 Hz), 7.06 (1H, d, J=10.9 Hz), 6.98 (1H, s), 5.91 (1H, s), 4.79-4.74 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.82 (3H, s), 3.63 (3H, s), 3.20-3.16 (1H, m), 2.33-2.19 (2H, m), 2.04-1.97 (1H, m).
ESI-MS m/z: 575 [M+H]+, 577 [M+2+H]+. Example 379
Synthesis of 4-bromo-N-[(1-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thio The title compound (pale yellow solid, 32 mg, 0.0557 mmol, 89%) was obtained in the same manner as in the synthesis of carbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-amino-1-methylpyrazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.63 (1H, s), 10.22 (1H, br-s), 7.67 (1H, d, J = 2.3 Hz), 7.18 (1H, d , J = 10.9 Hz), 7.06 (1H, d, J = 10.9 Hz), 6.98 (1H, s), 5.91 (1H, s), 4.79-4.74 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.82 (3H, s), 3.63 (3H, s), 3.20-3.16 (1H, m), 2.33-2.19 (2H, m), 2.04-1.97 (1H , m).
ESI-MS m / z: 575 [M + H] + , 577 [M + 2 + H] + .
実施例３８０
4-ブロモ-N-[(ピラゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 25 mg, 0.0448 mmol, 71%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノピラゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.67 (1H, s), 10.40 (1H, br-s), 7.74 (1H, d, J=1.7 Hz), 7.18 (1H, d, J=10.7 Hz), 7.06 (1H, d, J=10.7 Hz), 6.98 (1H, s), 5.96 (1H, s), 4.86-4.80 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.20-3.15 (1H, m), 2.33-2.19 (2H, m), 1.96-1.89 (1H, m).
ESI-MS m/z: 561 [M+H]+, 563 [M+2+H]+. Example 380
Synthesis of 4-bromo-N-[(pyrazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] de The title compound (pale yellow solid, 25 mg, 0.0448 mmol, 71%) was obtained by a method similar to the synthesis of acetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-aminopyrazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.67 (1H, s), 10.40 (1H, br-s), 7.74 (1H, d, J = 1.7 Hz), 7.18 (1H, d , J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.98 (1H, s), 5.96 (1H, s), 4.86-4.80 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.63 (3H, s), 3.20-3.15 (1H, m), 2.33-2.19 (2H, m), 1.96-1.89 (1H, m).
ESI-MS m / z: 561 [M + H] + , 563 [M + 2 + H] + .
実施例３８１
4-ブロモ-N-[(3,4-ジメチルイソオキサゾール-5-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 22 mg, 0.0373 mmol, 59%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、5-アミノ-3,4-ジメチルイソキサゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.88 (1H, s), 8.81 (1H, d, J=7.4 Hz), 7.15 (1H, d, J=11.2 Hz), 7.10 (1H, s), 7.04 (1H, d, J=11.2 Hz), 4.75-4.70 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.59 (3H, s), 3.16-3.11 (1H, m), 2.26-2.18 (1H, m), 2.13 (3H, s), 2.09-2.03 (2H, m), 1.73 (3H, s).
ESI-MS m/z: 590 [M+H]+, 592 [M+2+H]+. Example 381
Synthesis of 4-bromo-N-[(3,4-dimethylisoxazol-5-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazole-3- The title compound (milky white solid, 22 mg, 0.0373 mmol, 59%) was obtained in a similar manner to the synthesis of (yl) thiocarbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 5-amino-3,4-dimethylisoxazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.88 (1H, s), 8.81 (1H, d, J = 7.4 Hz), 7.15 (1H, d, J = 11.2 Hz), 7.10 ( 1H, s), 7.04 (1H, d, J = 11.2 Hz), 4.75-4.70 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.59 (3H , s), 3.16-3.11 (1H, m), 2.26-2.18 (1H, m), 2.13 (3H, s), 2.09-2.03 (2H, m), 1.73 (3H, s).
ESI-MS m / z: 590 [M + H] + , 592 [M + 2 + H] + .
実施例３８２
4-ブロモ-N-[(5-メチルイソオキサゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 26 mg, 0.0453 mmol, 72%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノ-5-メチルイソキサゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.21 (1H, br-s), 7.17 (1H, d, J=10.7 Hz), 7.13 (1H, s), 7.05 (1H, d, J=10.7 Hz), 4.26-4.12 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.18-3.13 (1H, m), 2.29-2.17 (2H, m), 1.95-1.84 (1H, m), 1.93 (3H, s).
ESI-MS m/z: 576 [M+H]+, 578 [M+2+H]+. Example 382
Synthesis of 4-bromo-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) The title compound (milky white solid, 26 mg, 0.0453 mmol, 72%) was obtained in the same manner as in the synthesis of [thiocarbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-amino-5-methylisoxazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.21 (1H, br-s), 7.17 (1H, d, J = 10.7 Hz), 7.13 (1H, s), 7.05 (1H, d , J = 10.7 Hz), 4.26-4.12 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.54 (3H, s), 3.18-3.13 (1H, m), 2.29-2.17 (2H, m), 1.95-1.84 (1H, m), 1.93 (3H, s).
ESI-MS m / z: 576 [M + H] + , 578 [M + 2 + H] + .
実施例３８３
4-ブロモ-N-[(4-メチルチアゾール-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 29 mg, 0.0491 mmol, 78%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-アミノ-4-メチルチアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.18 (1H, d, J=11.0 Hz), 7.08-7.01 (2H, m), 4.73-4.66 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (3H, s), 3.19-3.13 (1H, m), 2.31-1.98 (3H, m), 2.24 (3H, s).
ESI-MS m/z: 592 [M+H]+, 594 [M+2+H]+. Example 383
Synthesis of 4-bromo-N-[(4-methylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thio The title compound (milky white solid, 29 mg, 0.0491 mmol, 78%) was obtained by a method similar to the synthesis of carbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2-amino-4-methylthiazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.18 (1H, d, J = 11.0 Hz), 7.08-7.01 (2H, m), 4.73-4.66 (1H, m), 3.92 (3H , s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (3H, s), 3.19-3.13 (1H, m), 2.31-1.98 (3H, m), 2.24 (3H, s).
ESI-MS m / z: 592 [M + H] + , 594 [M + 2 + H] + .
実施例３８４
4-ブロモ-N-[(チアゾール-2-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 32 mg, 0.0557 mmol, 89%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-アミノチアゾールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.44 (1H, br-s), 7.18 (1H, d, J=10.5 Hz), 7.10-7.00 (3H, m), 4.74-4.65 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.64 (3H, s), 3.19-3.13 (1H, m), 2.32-1.97 (3H, m).
ESI-MS m/z: 578 [M+H]+, 580 [M+2+H]+. Example 384
Synthesis of 4-bromo-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] de The title compound (milky white solid, 32 mg, 0.0557 mmol, 89%) was obtained by a method similar to the synthesis of acetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2-aminothiazole was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 7.44 (1H, br-s), 7.18 (1H, d, J = 10.5 Hz), 7.10-7.00 (3H, m), 4.74-4.65 (1H, m), 3.92 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.64 (3H, s), 3.19-3.13 (1H, m), 2.32-1.97 (3H, m ).
ESI-MS m / z: 578 [M + H] + , 580 [M + 2 + H] + .
実施例３８５
4-ブロモ-N-[3-(2-ヒドロキシエチル)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 34 mg, 0.0533 mmol, 85%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-(3-アミノフェニル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.69 (1H, s), 8.37 (1H, d, J=7.3 Hz), 7.31-7.25 (2H, m), 7.20 (1H, t, J=7.5 Hz), 7.16 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J=10.7 Hz), 6.95 (1H, d, J=7.5 Hz), 4.81-4.74 (1H, m), 4.61 (1H, br-s), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.62 (3H, s), 3.58 (2H, t, J=7.1 Hz), 3.18-3.12 (1H, m), 2.68 (2H, t, J=7.1 Hz), 2.29-2.08 (2H, m), 2.04-1.95 (1H, m).
ESI-MS m/z: 615 [M+H]+, 617 [M+2+H]+. Example 385
Synthesis of 4-bromo-N- [3- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl The title compound (milky white solid, 34 mg, 0.0533 mmol, 85%) was obtained by a method similar to the synthesis of deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2- (3-aminophenyl) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 9.69 (1H, s), 8.37 (1H, d, J = 7.3 Hz), 7.31-7.25 (2H, m), 7.20 (1H, t , J = 7.5 Hz), 7.16 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 6.95 (1H, d, J = 7.5 Hz), 4.81-4.74 (1H, m), 4.61 (1H, br-s), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.62 (3H, s), 3.58 (2H, t, J = 7.1 Hz), 3.18-3.12 (1H, m), 2.68 (2H, t, J = 7.1 Hz), 2.29-2.08 (2H, m), 2.04-1.95 (1H, m).
ESI-MS m / z: 615 [M + H] + , 617 [M + 2 + H] + .
実施例３８６
4-ブロモ-N-[(ピリダジン-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 20 mg, 0.0348 mmol, 56%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-アミノピリダジンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 12.15 (1H, d, J=6.8 Hz), 11.07 (1H, s), 8.97 (1H, dd, J=4.6, 0.8 Hz), 7.74 (1H, dd, J=8.9, 4.6 Hz), 7.54 (1H, dd, J=8.9, 0.8 Hz), 7.20 (1H, d, J=10.7 Hz), 7.08 (1H, d, J=10.7 Hz), 7.00 (1H, s), 4.85-4.79 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.64 (3H, s), 3.22-3.17 (1H, m), 2.37-2.24 (2H, m), 2.11-2.03 (1H, m).
ESI-MS m/z: 573 [M+H]+, 575 [M+2+H]+. Example 386
Synthesis of 4-bromo-N-[(pyridazin-3-yl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] de The title compound (milky white solid, 20 mg, 0.0348 mmol, 56%) was obtained by a method similar to the synthesis of acetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3-aminopyridazine was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 12.15 (1H, d, J = 6.8 Hz), 11.07 (1H, s), 8.97 (1H, dd, J = 4.6, 0.8 Hz), 7.74 (1H, dd, J = 8.9, 4.6 Hz), 7.54 (1H, dd, J = 8.9, 0.8 Hz), 7.20 (1H, d, J = 10.7 Hz), 7.08 (1H, d, J = 10.7 Hz) ), 7.00 (1H, s), 4.85-4.79 (1H, m), 3.93 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.64 (3H, s), 3.22-3.17 ( 1H, m), 2.37-2.24 (2H, m), 2.11-2.03 (1H, m).
ESI-MS m / z: 573 [M + H] + , 575 [M + 2 + H] + .
実施例３８７
N-[(アゼチジン-1-イル)チオカルボニル]-4-ブロモデアセチルコルヒチンの合成
　4-ブロモ-７-イソチオシアネート7-デ(アセトアミド)コルヒチン(30 mg, 0.0627 mmol)のジクロロメタン(2 mL)溶液に、室温でアゼチジン(5.1 μL, 0.0627×1.2 mmol)を加えて、室温で一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(乳白色固体, 30 mg, 0.0553 mmol, 88%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.85 (1H, d, J=7.6 Hz), 7.13 (1H, d, J=10.7 Hz), 7.07 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.78-4.71 (1H, m), 4.13-3.91 (4H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J=13.4, 5.4 Hz), 2.24-2.05 (4H, m), 2.00-1.90 (1H, m).
ESI-MS m/z: 535[M+H]+, 537 [M+2+H]+. Example 387
Synthesis of N-[(azetidin-1-yl) thiocarbonyl] -4-bromodeacetylcolchicine 4-Bromo-7-isothiocyanate 7-de (acetamido) colchicine (30 mg, 0.0627 mmol) in dichloromethane (2 mL) Azetidine (5.1 μL, 0.0627 × 1.2 mmol) was added to the solution at room temperature, and the mixture was stirred overnight at room temperature. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (milky white solid, 30 mg, 0.0553 mmol, 88%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.85 (1H, d, J = 7.6 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.07 (1H, s), 7.03 ( 1H, d, J = 10.7 Hz), 4.78-4.71 (1H, m), 4.13-3.91 (4H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.60 (3H, s), 3.12 (1H, dd, J = 13.4, 5.4 Hz), 2.24-2.05 (4H, m), 2.00-1.90 (1H, m).
ESI-MS m / z: 535 [M + H] + , 537 [M + 2 + H] + .
実施例３８８
4-ブロモ-N-(メチルチオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモ-７-イソチオシアネート7-デ(アセトアミド)コルヒチン(30 mg, 0.0627 mmol)のジクロロメタン(2 mL)溶液に、室温でメチルアミン塩酸塩(5 mg, 0.0627×1.2 mmol)およびトリエチルアミン(13.1 μL, 0.0627×1.5 mmol)を加えて、室温で一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(淡黄色固体, 28 mg, 0.0549 mmol, 88%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.10 (1H, br-s), 7.44 (1H, br-s), 7.14 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.03 (1H, d, J=10.7 Hz), 4.82-4.70 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.15-3.09 (1H, m), 2.82 (3H, d, J=4.6 Hz), 2.25-1.84 (3H, m).
ESI-MS m/z: 509[M+H]+, 511 [M+2+H]+. Example 388
Synthesis of 4-bromo-N- (methylthiocarbamoyl) deacetylcolchicine 4-bromo-7-isothiocyanate 7-de (acetamido) colchicine (30 mg, 0.0627 mmol) in dichloromethane (2 mL) at room temperature with methylamine Hydrochloride (5 mg, 0.0627 × 1.2 mmol) and triethylamine (13.1 μL, 0.0627 × 1.5 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (pale yellow solid, 28 mg, 0.0549 mmol, 88%).
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 8.10 (1H, br-s), 7.44 (1H, br-s), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H , s), 7.03 (1H, d, J = 10.7 Hz), 4.82-4.70 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.15-3.09 (1H, m), 2.82 (3H, d, J = 4.6 Hz), 2.25-1.84 (3H, m).
ESI-MS m / z: 509 [M + H] + , 511 [M + 2 + H] + .
実施例３８９
4-ブロモ-N-(チオカルバモイル)デアセチルコルヒチンの合成
　4-ブロモ-７-イソチオシアネート7-デ(アセトアミド)コルヒチン(30 mg, 0.0627 mmol)の1,4-ジオキサン(1 mL)溶液に、室温でアンモニア(0.5 mol/L in 1,4-ジオキサン, 301 μL, 0.0627×2.4 mmol)を加えて、室温で一晩撹拌した。反応液をフラッシュクロマトグラフ法(装置:Biotage社Isolera One, クロロホルム/メタノール)にて精製し、標記の化合物(白色固体, 23 mg, 0.0465 mmol, 74%)を得た。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.30 (1H, d, J=7.3 Hz), 7.13 (1H, d, J=10.7 Hz), 7.05 (2H, s), 7.03 (2H, d, J=10.7 Hz), 4.68-4.61 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.59 (3H, s), 3.12 (1H, dd, J=13.5, 5.0 Hz), 2.26-2.17 (1H, m), 2.09-2.00 (1H, m), 1.88-1.79 (1H, m).
ESI-MS m/z: 495 [M+H]+, 497 [M+2+H]+. Example 389
Synthesis of 4-bromo-N- (thiocarbamoyl) deacetylcolchicine 4-Bromo-7-isothiocyanate 7-de (acetamido) colchicine (30 mg, 0.0627 mmol) in 1,4-dioxane (1 mL) solution Ammonia (0.5 mol / L in 1,4-dioxane, 301 μL, 0.0627 × 2.4 mmol) was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was purified by flash chromatography (apparatus: Biotage Isolera One, chloroform / methanol) to obtain the title compound (white solid, 23 mg, 0.0465 mmol, 74%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.30 (1H, d, J = 7.3 Hz), 7.13 (1H, d, J = 10.7 Hz), 7.05 (2H, s), 7.03 ( 2H, d, J = 10.7 Hz), 4.68-4.61 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.59 (3H, s), 3.12 (1H , dd, J = 13.5, 5.0 Hz), 2.26-2.17 (1H, m), 2.09-2.00 (1H, m), 1.88-1.79 (1H, m).
ESI-MS m / z: 495 [M + H] + , 497 [M + 2 + H] + .
実施例３９０
4-ブロモ-N-{[1-(2-ヒドロキシエチル)-1,2,4-トリアゾール-3-イル]チオカルバモイル}デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(白色固体, 26 mg, 0.0429 mmol, 68%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-(3-アミノ-1H-1,2,4-トリアゾール-1-イル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 11.18 (1H, s), 10.48 (1H, d, J=6.8 Hz), 8.50 (1H, s), 7.18 (1H, d, J=10.7 Hz), 7.06 (1H, d, J=10.7 Hz), 6.97 (1H, s), 5.01 (1H, br-s), 4.84-4.77 (1H, m), 4.18 (2H, t, J=5.1 Hz), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.74 (2H, t, J=5.1 Hz), 3.63 (3H, s), 3.17 (1H, dd, J=12.3, 4.5 Hz), 2.33-2.17 (2H, m), 2.04-1.96 (1H, m).
ESI-MS m/z: 606 [M+H]+, 608 [M+2+H]+. Example 390
Synthesis of 4-bromo-N-{[1- (2-hydroxyethyl) -1,2,4-triazol-3-yl] thiocarbamoyl} deacetylcolchicine 4-bromo-N-[(5-methyl-1 , 2,4-Triazol-3-yl) thiocarbamoyl] deacetylcolchicine was used to give the title compound (white solid, 26 mg, 0.0429 mmol, 68%). Instead of 3-amino-5-methyl-1,2,4-triazole, 2- (3-amino-1H-1,2,4-triazol-1-yl) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 11.18 (1H, s), 10.48 (1H, d, J = 6.8 Hz), 8.50 (1H, s), 7.18 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.97 (1H, s), 5.01 (1H, br-s), 4.84-4.77 (1H, m), 4.18 (2H, t, J = 5.1 Hz), 3.92 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.74 (2H, t, J = 5.1 Hz), 3.63 (3H, s), 3.17 (1H, dd, J = 12.3, 4.5 Hz), 2.33-2.17 (2H, m), 2.04-1.96 (1H, m).
ESI-MS m / z: 606 [M + H] + , 608 [M + 2 + H] + .
実施例３９１
4-ブロモ-N-{[1-(2-ヒドロキシエチル)ピラゾール-3-イル]チオカルバモイル}デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(淡黄色固体, 32 mg, 0.0528 mmol, 84%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-(3-アミノ-1H-ピラゾール-1-イル)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.64 (1H, s), 10.32 (1H, s), 7.68 (1H, d, J=2.2 Hz), 7.18 (1H, d, J=10.7 Hz), 7.06 (1H, d, J=10.7 Hz), 7.00 (1H, s), 5.91 (1H, s), 4.91 (1H, t, J=5.2 Hz), 4.80-4.74 (1H, m), 4.11 (2H, t, J=5.5 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.75 (2H, dd, J=10.2, 5.1 Hz), 3.63 (3H, s), 3.17 (1H, dd, J=12.7, 4.1 Hz), 2.34-2.17 (2H, m), 2.03-1.95 (1H, m).
ESI-MS m/z: 605 [M+H]+, 607 [M+2+H]+. Example 391
Synthesis of 4-bromo-N-{[1- (2-hydroxyethyl) pyrazol-3-yl] thiocarbamoyl} deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazole- In the same manner as in the synthesis of 3-yl) thiocarbamoyl] deacetylcolchicine, the title compound (pale yellow solid, 32 mg, 0.0528 mmol, 84%) was obtained. Instead of 3-amino-5-methyl-1,2,4-triazole, 2- (3-amino-1H-pyrazol-1-yl) ethanol was used.
1 H-NMR (400MHz, DMSO-d 6 ) δ [ppm]: 10.64 (1H, s), 10.32 (1H, s), 7.68 (1H, d, J = 2.2 Hz), 7.18 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 7.00 (1H, s), 5.91 (1H, s), 4.91 (1H, t, J = 5.2 Hz), 4.80-4.74 (1H, m ), 4.11 (2H, t, J = 5.5 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.75 (2H, dd, J = 10.2, 5.1 Hz), 3.63 (3H, s), 3.17 (1H, dd, J = 12.7, 4.1 Hz), 2.34-2.17 (2H, m), 2.03-1.95 (1H, m).
ESI-MS m / z: 605 [M + H] + , 607 [M + 2 + H] + .
実施例３９２
4-ブロモ-N-[4-(2-ヒドロキシエトキシ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 30 mg, 0.0470 mmol, 75%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-(4-アミノフェノキシ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.50 (1H, s), 8.20 (1H, d, J=7.1 Hz), 7.27 (2H, d, J=9.0 Hz), 7.14 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J=10.7 Hz), 6.88 (2H, d, J=9.0 Hz), 4.84 (1H, t, J=5.0 Hz), 4.82-4.75 (1H, m), 3.95 (2H, t, J=5.0 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.69 (2H, q, J=5.0 Hz), 3.61 (3H, s), 3.13 (1H, dd, J=12.8, 5.2 Hz), 2.26-2.17 (1H, m), 2.14-2.04 (1H, m), 2.02-1.94 (1H, m).
ESI-MS m/z: 631 [M+H]+, 633 [M+2+H]+. Example 392
Synthesis of 4-bromo-N- [4- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl The title compound (milky white solid, 30 mg, 0.0470 mmol, 75%) was obtained by a method similar to the synthesis of deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2- (4-aminophenoxy) ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.50 (1H, s), 8.20 (1H, d, J = 7.1 Hz), 7.27 (2H, d, J = 9.0 Hz), 7.14 ( 1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.03 (1H, d, J = 10.7 Hz), 6.88 (2H, d, J = 9.0 Hz), 4.84 (1H, t, J = 5.0 Hz), 4.82-4.75 (1H, m), 3.95 (2H, t, J = 5.0 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.69 (2H, q , J = 5.0 Hz), 3.61 (3H, s), 3.13 (1H, dd, J = 12.8, 5.2 Hz), 2.26-2.17 (1H, m), 2.14-2.04 (1H, m), 2.02-1.94 ( 1H, m).
ESI-MS m / z: 631 [M + H] + , 633 [M + 2 + H] + .
実施例３９３
4-ブロモ-N-[3-(2-ヒドロキシエトキシ)フェニルチオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 31 mg, 0.0473 mmol, 76%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-(3-アミノフェノキシ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 9.71 (1H, s), 8.43 (1H, d, J=7.1 Hz), 7.24 (1H, t, J=2.0 Hz), 7.19 (2H, t, J=8.0 Hz), 7.16 (2H, d, J=10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J=10.7 Hz), 6.92 (1H, d, J=8.0 Hz), 6.66 (1H, dd, J=8.0, 2.0 Hz), 4.84 (1H, br-s), 4.80-4.74 (1H, m), 3.93 (2H, t, J=4.4 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.88 (3H, s), 3.69 (2H, t, J=4.4 Hz), 3.62 (3H, s), 3.14 (1H, dd, J=12.9, 5.1 Hz), 2.28-2.08 (2H, m), 2.04-1.95 (1H, m).
ESI-MS m/z: 631 [M+H]+, 633 [M+2+H]+. Example 393
Synthesis of 4-bromo-N- [3- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl The title compound (milky white solid, 31 mg, 0.0473 mmol, 76%) was obtained by a method similar to the synthesis of deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2- (3-aminophenoxy) ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 9.71 (1H, s), 8.43 (1H, d, J = 7.1 Hz), 7.24 (1H, t, J = 2.0 Hz), 7.19 ( 2H, t, J = 8.0 Hz), 7.16 (2H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 6.92 (1H, d, J = 8.0 Hz), 6.66 (1H, dd, J = 8.0, 2.0 Hz), 4.84 (1H, br-s), 4.80-4.74 (1H, m), 3.93 (2H, t, J = 4.4 Hz), 3.91 (3H , s), 3.89 (3H, s), 3.88 (3H, s), 3.69 (2H, t, J = 4.4 Hz), 3.62 (3H, s), 3.14 (1H, dd, J = 12.9, 5.1 Hz) , 2.28-2.08 (2H, m), 2.04-1.95 (1H, m).
ESI-MS m / z: 631 [M + H] + , 633 [M + 2 + H] + .
実施例３９４
4-ブロモ-N-[(4-シアノフェニル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(白色固体, 26 mg, 0.0441 mmol, 70%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、4-シアノアニリンを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 10.12 (1H, s), 8.81 (1H, d, J=6.8 Hz), 7.75 (2H, d, J=9.5 Hz), 7.72 (2H, d, J=9.5 Hz), 7.17 (1H, d, J=10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J=10.7 Hz), 4.76-4.69 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (3H, s), 3.19-3.13 (1H, m), 2.30-2.12 (2H, m), 2.03-1.94 (1H, m).
ESI-MS m/z: 596 [M+H]+, 598 [M+2+H]+. Example 394
Synthesis of 4-bromo-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetyl The title compound (white solid, 26 mg, 0.0441 mmol, 70%) was obtained by a method similar to the synthesis of colchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 4-cyanoaniline was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 10.12 (1H, s), 8.81 (1H, d, J = 6.8 Hz), 7.75 (2H, d, J = 9.5 Hz), 7.72 ( 2H, d, J = 9.5 Hz), 7.17 (1H, d, J = 10.7 Hz), 7.11 (1H, s), 7.04 (1H, d, J = 10.7 Hz), 4.76-4.69 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.63 (3H, s), 3.19-3.13 (1H, m), 2.30-2.12 (2H, m), 2.03-1.94 ( 1H, m).
ESI-MS m / z: 596 [M + H] + , 598 [M + 2 + H] + .
実施例３９５
4-ブロモ-N-[(2-ヒドロキシエチル)チオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 19 mg, 0.0350 mmol, 56%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-アミノエタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 8.18 (1H, d, J=5.4 Hz), 7.59 (1H, br-s), 7.14 (1H, d, J=10.5 Hz), 7.05 (2H, s), 7.03 (2H, d, J=10.5 Hz), 4.81 (1H, br-s), 4.77-4.70 (1H, m), 3.91 (3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.60 (3H, s), 3.50-3.35 (4H, m), 3.12 (1H, dd, J=13.5, 4.5 Hz), 2.26-2.16 (1H, m), 2.11-2.01 (1H, m), 1.88-1.77 (1H, m).
ESI-MS m/z: 539 [M+H]+, 541 [M+2+H]+. Example 395
Synthesis of 4-bromo-N-[(2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetyl The title compound (milky white solid, 19 mg, 0.0350 mmol, 56%) was obtained by a method similar to the synthesis of colchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2-aminoethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 8.18 (1H, d, J = 5.4 Hz), 7.59 (1H, br-s), 7.14 (1H, d, J = 10.5 Hz), 7.05 (2H, s), 7.03 (2H, d, J = 10.5 Hz), 4.81 (1H, br-s), 4.77-4.70 (1H, m), 3.91 (3H, s), 3.89 (3H, s) , 3.87 (3H, s), 3.60 (3H, s), 3.50-3.35 (4H, m), 3.12 (1H, dd, J = 13.5, 4.5 Hz), 2.26-2.16 (1H, m), 2.11-2.01 (1H, m), 1.88-1.77 (1H, m).
ESI-MS m / z: 539 [M + H] + , 541 [M + 2 + H] + .
実施例３９６
4-ブロモ-N-[N’-(2-ヒドロキシエチル)-N’-メチルチオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 35 mg, 0.0627 mmol, 定量的)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、2-(メチルアミノ)エタノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.74 (1H,. d, J=6.6 Hz), 7.14 (1H, d, J=10.8 Hz), 7.08 (1H, s), 7.02 (1H, d, J=10.8 Hz), 4.96 (1H, s), 4.87-4.81 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.84-3.76 (1H, m), 3.72-3.65 (1H, m), 3.62 (3H, s), 3.59-3.55 (2H, m), 3.21 (3H, s), 3.13 (1H, dd, J=12.8, 5.7 Hz), 2.25-2.10 (2H, m), 2.05-1.95 (1H, m).
ESI-MS m/z: 553 [M+H]+, 555 [M+2+H]+. Example 396
Synthesis of 4-bromo-N- [N '-(2-hydroxyethyl) -N'-methylthiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazole-3- The title compound (milky white solid, 35 mg, 0.0627 mmol, quantitative) was obtained in the same manner as in the synthesis of (yl) thiocarbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 2- (methylamino) ethanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.74 (1H ,. d, J = 6.6 Hz), 7.14 (1H, d, J = 10.8 Hz), 7.08 (1H, s), 7.02 (1H, d, J = 10.8 Hz), 4.96 (1H, s), 4.87-4.81 (1H, m), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.84- 3.76 (1H, m), 3.72-3.65 (1H, m), 3.62 (3H, s), 3.59-3.55 (2H, m), 3.21 (3H, s), 3.13 (1H, dd, J = 12.8, 5.7 Hz), 2.25-2.10 (2H, m), 2.05-1.95 (1H, m).
ESI-MS m / z: 553 [M + H] + , 555 [M + 2 + H] + .
実施例３９７
4-ブロモ-N-[N’-(3-ヒドロキシプロピル)-N’-メチルチオカルバモイル]デアセチルコルヒチンの合成
　4-ブロモ-N-[(5-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成と同様の方法にて、標記の化合物(乳白色固体, 33 mg, 0.0575 mmol, 92%)を得た。3-アミノ-5-メチル-1,2,4-トリアゾールの代わりに、3-(メチルアミノ)プロパノールを用いた。
1H-NMR(400MHz, DMSO-d6)δ[ppm]: 7.66 (1H, d, J=7.1 Hz), 7.14 (1H, d, J=10.7 Hz), 7.06 (1H, s), 7.02 (1H, d, J=10.7 Hz), 4.88-4.81 (1H, m), 4.63 (1H, br-s), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.77-3.68 (2H, m), 3.62 (3H, s), 3.41-3.36 (2H, m), 3.15 (3H, s), 3.13 (1H, dd, J=12.4, 5.4 Hz), 2.25-2.12 (2H, m), 2.06-1.96 (1H, m), 1.72-1.65 (2H, m).
ESI-MS m/z: 567 [M+H]+, 569 [M+2+H]+. Example 397
Synthesis of 4-bromo-N- [N '-(3-hydroxypropyl) -N'-methylthiocarbamoyl] deacetylcolchicine 4-bromo-N-[(5-methyl-1,2,4-triazole-3- The title compound (milky white solid, 33 mg, 0.0575 mmol, 92%) was obtained in the same manner as in the synthesis of (yl) thiocarbamoyl] deacetylcolchicine. Instead of 3-amino-5-methyl-1,2,4-triazole, 3- (methylamino) propanol was used.
1 H-NMR (400 MHz, DMSO-d 6 ) δ [ppm]: 7.66 (1H, d, J = 7.1 Hz), 7.14 (1H, d, J = 10.7 Hz), 7.06 (1H, s), 7.02 ( 1H, d, J = 10.7 Hz), 4.88-4.81 (1H, m), 4.63 (1H, br-s), 3.90 (3H, s), 3.89 (3H, s), 3.86 (3H, s), 3.77 -3.68 (2H, m), 3.62 (3H, s), 3.41-3.36 (2H, m), 3.15 (3H, s), 3.13 (1H, dd, J = 12.4, 5.4 Hz), 2.25-2.12 (2H , m), 2.06-1.96 (1H, m), 1.72-1.65 (2H, m).
ESI-MS m / z: 567 [M + H] + , 569 [M + 2 + H] + .
参考例４２
1-メチル-3-ニトロ-1H-1,2,4-トリアゾールの合成
　3-ニトロ-1,2,4-トリアゾール(1.018 g, 8.93 mmol)をメタノール(20 mL)に溶解し、そこへナトリウムメトキシド(1.446 g, 8.93×3 mmol)、ヨウ化メチル(1.67 mL, 8.93×3 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去し、クロロホルムに溶解した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 50 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(白色固体, 434 mg, 37.9%)を得た。
1H-NMR (CDCl3) δ: 8.17 (1H, s), 4.09 (3H, s).
ESI-MS m/z: 129 [M+H]+ . Reference Example 42
Synthesis of 1-methyl-3-nitro-1H-1,2,4-triazole 3-Nitro-1,2,4-triazole (1.018 g, 8.93 mmol) was dissolved in methanol (20 mL) and sodium Methoxide (1.446 g, 8.93 × 3 mmol) and methyl iodide (1.67 mL, 8.93 × 3 mmol) were added and stirred overnight at room temperature. After the reaction, the solvent was distilled off and dissolved in chloroform. Washed with saturated brine. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 50 g, chloroform / ethyl acetate) to obtain the title compound (white solid, 434 mg, 37.9%).
1 H-NMR (CDCl 3 ) δ: 8.17 (1H, s), 4.09 (3H, s).
ESI-MS m / z: 129 [M + H] + .
参考例４３
3-アミノ-1-メチル-1H-1,2,4-トリアゾールの合成
　1-メチル-3-ニトロ-1H-1,2,4-トリアゾール(97 mg, 0.76 mmol)をエタノール(5.0 mL)に溶解した。そこへ10%パラジウム-炭素(10 mg)を加えた。水素雰囲気下、室温で3時間攪拌した。反応後、セライトろ過した。溶媒を留去し、標記の化合物(黄色固体, 69 mg, 92.5%)を得た。
1H-NMR (CDCl3) δ: 7.63 (1H, s), 4.18 (2H, br s), 3.73 (3H, s).
ESI-MS m/z: 99 [M+H]+ . Reference Example 43
Synthesis of 3-amino-1-methyl-1H-1,2,4-triazole 1-methyl-3-nitro-1H-1,2,4-triazole (97 mg, 0.76 mmol) in ethanol (5.0 mL) Dissolved. 10% palladium-carbon (10 mg) was added thereto. The mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction, it was filtered through celite. The solvent was distilled off to obtain the title compound (yellow solid, 69 mg, 92.5%).
1 H-NMR (CDCl 3 ) δ: 7.63 (1H, s), 4.18 (2H, br s), 3.73 (3H, s).
ESI-MS m / z: 99 [M + H] + .
実施例３９８
4-クロロ-N-[(1-メチル-1,2,4-トリアゾール-3-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-7-イソチオシアネート7-デ(アセトアミド)コルヒチン(54 mg, 0.12 mmol)をDMF(1 mL)に溶解した。そこへ3-アミノ-1-メチル-1H-1,2,4-トリアゾール(15 mg, 0.12×1.2 mmol)を加えて80℃で一晩攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 42 mg, 65.8%)を得た。
1H-NMR (DMSO-d6) δ: 11.17 (1H, s), 10.42 (1H, d, J = 6.6 Hz), 8.50 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.95 (1H, s), 4.85-4.79 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.85 (3H, s), 3.63 (3H, s), 3.17-3.15 (1H, m), 2.26-2.19 (2H, m), 2.05-2.00 (1H, m).
ESI-MS m/z: 532 [M+H]+ . Example 398
Synthesis of 4-chloro-N-[(1-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7-isothiocyanate 7-de (acetamido) colchicine (54 mg , 0.12 mmol) was dissolved in DMF (1 mL). 3-amino-1-methyl-1H-1,2,4-triazole (15 mg, 0.12 × 1.2 mmol) was added thereto and stirred at 80 ° C. overnight. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 42 mg, 65.8%).
1 H-NMR (DMSO-d 6 ) δ: 11.17 (1H, s), 10.42 (1H, d, J = 6.6 Hz), 8.50 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.95 (1H, s), 4.85-4.79 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.85 (3H, s), 3.63 (3H, s), 3.17-3.15 (1H, m), 2.26-2.19 (2H, m), 2.05-2.00 (1H, m).
ESI-MS m / z: 532 [M + H] + .
参考例４４
1-メチル-5-ニトロ-1H-1,2,4-トリアゾールの合成
　3-ニトロ1,2,4-トリアゾール(573mg, 5.02mmol)をメタノール(11 mL)に溶解し、そこへナトリウムメトキシド(407 mg, 5.02×1.5 mmol)、ヨウ化メチル(0.375 mL, 5.02×1.2 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去し、クロロホルムに溶解した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(白色固体, 21 mg, 3.3%)を得た。
1H-NMR (CDCl3) δ: 7.94 (1H, s), 4.31 (3H, s).
ESI-MS m/z: 129 [M+H]+ . Reference Example 44
Synthesis of 1-methyl-5-nitro-1H-1,2,4-triazole 3-nitro 1,2,4-triazole (573 mg, 5.02 mmol) was dissolved in methanol (11 mL), and sodium methoxide was added thereto. (407 mg, 5.02 × 1.5 mmol) and methyl iodide (0.375 mL, 5.02 × 1.2 mmol) were added and stirred overnight at room temperature. After the reaction, the solvent was distilled off and dissolved in chloroform. Washed with saturated brine. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / ethyl acetate) to obtain the title compound (white solid, 21 mg, 3.3%).
1 H-NMR (CDCl 3 ) δ: 7.94 (1H, s), 4.31 (3H, s).
ESI-MS m / z: 129 [M + H] + .
参考例４５
5-アミノ-1-メチル-1H-1,2,4-トリアゾールの合成
　1-メチル-5-ニトロ-1H-1,2,4-トリアゾール(40 mg, 0.31 mmol)をエタノール(2.0 mL)に溶解した。そこへ10%パラジウム-炭素(4 mg)を加えた。水素雰囲気下、室温で3.5時間攪拌した。反応後、セライトろ過した。溶媒を留去し、標記の化合物(黄色固体, 26 mg, 85.5%)を得た。
1H-NMR (CDCl3) δ: 7.47 (1H, s), 4.39 (2H, br s), 3.64 (3H, s).
ESI-MS m/z: 99 [M+H]+ . Reference Example 45
Synthesis of 5-amino-1-methyl-1H-1,2,4-triazole 1-methyl-5-nitro-1H-1,2,4-triazole (40 mg, 0.31 mmol) in ethanol (2.0 mL) Dissolved. 10% palladium-carbon (4 mg) was added thereto. The mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. After the reaction, it was filtered through celite. The solvent was distilled off to obtain the title compound (yellow solid, 26 mg, 85.5%).
1 H-NMR (CDCl 3 ) δ: 7.47 (1H, s), 4.39 (2H, br s), 3.64 (3H, s).
ESI-MS m / z: 99 [M + H] + .
実施例３９９
4-クロロ-N-[(1-メチル-1,2,4-トリアゾール-5-イル)チオカルバモイル]デアセチルコルヒチンの合成
　4-クロロ-7-イソチオシアネート7-デ(アセトアミド)コルヒチン(81 mg, 0.18 mmol)をDMF(1 mL)に溶解した。そこへ5-アミノ-1-メチル-1H-1,2,4-トリアゾール(22 mg, 0.18×1.2 mmol)を加えて80℃で一晩攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 55 mg, 57.4%)を得た。
1H-NMR (DMSO-d6) δ: 10.96 (1H, s), 10.74 (1H, d, J = 6.8 Hz), 7.91 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.99 (1H, s), 4.82-4.75 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.77 (3H, s), 3.63 (3H, s), 3.20-3.17 (1H, m), 2.24-2.19 (2H, m), 2.08-2.01 (1H, m).
ESI-MS m/z: 532 [M+H]+ . Example 399
Synthesis of 4-chloro-N-[(1-methyl-1,2,4-triazol-5-yl) thiocarbamoyl] deacetylcolchicine 4-chloro-7-isothiocyanate 7-de (acetamido) colchicine (81 mg , 0.18 mmol) was dissolved in DMF (1 mL). 5-amino-1-methyl-1H-1,2,4-triazole (22 mg, 0.18 × 1.2 mmol) was added thereto and stirred at 80 ° C. overnight. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 55 mg, 57.4%).
1 H-NMR (DMSO-d 6 ) δ: 10.96 (1H, s), 10.74 (1H, d, J = 6.8 Hz), 7.91 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.99 (1H, s), 4.82-4.75 (1H, m), 3.92 (3H, s), 3.89 (6H, s), 3.77 (3H, s), 3.63 (3H, s), 3.20-3.17 (1H, m), 2.24-2.19 (2H, m), 2.08-2.01 (1H, m).
ESI-MS m / z: 532 [M + H] + .
参考例４６
2-(3-ニトロ-1H-1,2,4-トリアゾール-1-イル)エタノールの合成
　3-ニトロ-1,2,4-トリアゾール(1.045 g, 9.16 mmol)をDMF(5 mL)に溶解した。そこへ水酸化ナトリウム水溶液(439 mg, 9.16×1.2 mmol, 0.4 mL)、2-ブロモエタノール(1.30 mL, 9.16×2 mmol)を加えて80℃で一晩攪拌した。反応後、溶媒を留去した。水を加えて酢酸エチルで抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(黄色油状物, 969 mg, 66.9%)を得た。
1H-NMR (DMSO-d6) δ: 8.83 (1H, s), 5.08 (1H, t, J = 5.5 Hz), 4.37-4.35 (2H, m), 3.80-3.76 (2H, m).
ESI-MS m/z: 159 [M+H]+ . Reference Example 46
Synthesis of 2- (3-nitro-1H-1,2,4-triazol-1-yl) ethanol 3-Nitro-1,2,4-triazole (1.045 g, 9.16 mmol) dissolved in DMF (5 mL) did. Sodium hydroxide aqueous solution (439 mg, 9.16 * 1.2 mmol, 0.4 mL) and 2-bromoethanol (1.30 mL, 9.16 * 2 mmol) were added there, and it stirred at 80 degreeC overnight. After the reaction, the solvent was distilled off. Water was added and extracted with ethyl acetate. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / ethyl acetate) to obtain the title compound (yellow oil, 969 mg, 66.9%).
1 H-NMR (DMSO-d 6 ) δ: 8.83 (1H, s), 5.08 (1H, t, J = 5.5 Hz), 4.37-4.35 (2H, m), 3.80-3.76 (2H, m).
ESI-MS m / z: 159 [M + H] + .
参考例４７
2-(3-アミノ-1H-1,2,4-トリアゾール-1-イル)エタノールの合成
　2-(3-ニトロ-1H-1,2,4-トリアゾール-1-イル)エタノール(564 mg, 3.57 mmol)をエタノール(28 mL)に溶解した。そこへ10%パラジウム-炭素(56 mg)を加えた。水素雰囲気下、室温で4時間攪拌した。反応後、セライトろ過した。溶媒を留去し、標記の化合物(黄色油状物, 518 mg, quant.)を得た。
1H-NMR (DMSO-d6) δ: 7.87 (1H, s), 5.17 (2H, br s), 4.85 (1H, t, J = 5.4 Hz), 3.91 (2H, t, J = 5.4 Hz), 3.64 (2H, q, J = 5.4 Hz).
ESI-MS m/z: 129[M+H]+ . Reference Example 47
Synthesis of 2- (3-amino-1H-1,2,4-triazol-1-yl) ethanol 2- (3-nitro-1H-1,2,4-triazol-1-yl) ethanol (564 mg, 3.57 mmol) was dissolved in ethanol (28 mL). 10% palladium-carbon (56 mg) was added thereto. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After the reaction, it was filtered through celite. The solvent was distilled off to obtain the title compound (yellow oily substance, 518 mg, quant.).
1 H-NMR (DMSO-d 6 ) δ: 7.87 (1H, s), 5.17 (2H, br s), 4.85 (1H, t, J = 5.4 Hz), 3.91 (2H, t, J = 5.4 Hz) , 3.64 (2H, q, J = 5.4 Hz).
ESI-MS m / z: 129 [M + H] + .
実施例４００
4-クロロ-N-{[1-(2-ヒドロキシエチル)-1,2,4-トリアゾール-3-イル]チオカルバモイル}デアセチルコルヒチンの合成
　4-クロロ-7-イソチオシアネート7-デ(アセトアミド)コルヒチン(124 mg, 0.29 mmol)をDMF(3 mL)に溶解した。そこへ2-(3-アミノ-1H-1,2,4-トリアゾール-1-イル)エタノール(55 mg, 0.29×1.5 mmol)を加えて80℃で一晩攪拌した。反応後、溶媒を留去した。クロロホルムを加えて飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Biotage Isolera One, SANP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(黄色固体, 93 mg, 57.1%)を得た。
1H-NMR (DMSO-d6) δ: 11.20 (1H, s), 10.49 (1H, d, J = 6.8 Hz), 8.51 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.97 (1H, s), 5.02 (1H, t, J = 5.4 Hz), 4.85-4.79 (1H, m), 4.18 (2H, t, J = 5.1 Hz), 3.92 (3H, s), 3.89 (6H, s), 3.74 (2H, q, J = 5.4 Hz), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.29-2.19 (2H, m), 2.06-1.99 (1H, m).
ESI-MS m/z: 562 [M+H]+ . Example 400
Synthesis of 4-chloro-N-{[1- (2-hydroxyethyl) -1,2,4-triazol-3-yl] thiocarbamoyl} deacetylcolchicine 4-chloro-7-isothiocyanate 7-de (acetamide ) Colchicine (124 mg, 0.29 mmol) was dissolved in DMF (3 mL). 2- (3-amino-1H-1,2,4-triazol-1-yl) ethanol (55 mg, 0.29 × 1.5 mmol) was added thereto, and the mixture was stirred at 80 ° C. overnight. After the reaction, the solvent was distilled off. Chloroform was added and washed with saturated sodium bicarbonate water. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (Biotage Isolera One, SANP 25 g, chloroform / methanol) to obtain the title compound (yellow solid, 93 mg, 57.1%).
1 H-NMR (DMSO-d 6 ) δ: 11.20 (1H, s), 10.49 (1H, d, J = 6.8 Hz), 8.51 (1H, s), 7.19 (1H, d, J = 10.7 Hz), 7.06 (1H, d, J = 10.7 Hz), 6.97 (1H, s), 5.02 (1H, t, J = 5.4 Hz), 4.85-4.79 (1H, m), 4.18 (2H, t, J = 5.1 Hz ), 3.92 (3H, s), 3.89 (6H, s), 3.74 (2H, q, J = 5.4 Hz), 3.63 (3H, s), 3.19-3.14 (1H, m), 2.29-2.19 (2H, m), 2.06-1.99 (1H, m).
ESI-MS m / z: 562 [M + H] + .
試験例１
（in vitro細胞障害活性試験）
（方法）
　ヒト癌由来の腫瘍細胞2種類、すなわちA549（肺癌）、HT-29（大腸癌）をAmerican Type Culture Collection（ATCC）より購入して実験に使用した。10%牛胎仔血清（FBS）、10μg/mLゲンタマイシンを含むDMEM/F-12培地（以下培地と記述）で1 × 104 cells/1.9mLになるように調整した細胞浮遊液を、96ウェルプレートに1ウェルあたり190 μL（1000 cells）ずつ分注し、5％CO2、37℃の条件で一晩インキュベートした。翌日、所定の濃度の被検物質を含む培地を各ウェルに10 μLずつ添加した。96時間培養後、TetraColor One cell proliferation（生化学工業）を1ウェルあたり10 μLずつ加え、60分間インキュベートした後、マイクロプレートリーダーで波長450 nmにおける吸光度を測定した。 Test example 1
(In vitro cytotoxic activity test)
(Method)
Two types of human cancer-derived tumor cells, namely A549 (lung cancer) and HT-29 (colon cancer) were purchased from the American Type Culture Collection (ATCC) and used for experiments. A 96-well plate of cell suspension adjusted to 1 × 10 4 cells / 1.9 mL in DMEM / F-12 medium (hereinafter referred to as medium) containing 10% fetal bovine serum (FBS) and 10 μg / mL gentamicin 190 μL (1000 cells) was dispensed into each well and incubated overnight at 5% CO 2 and 37 ° C. On the next day, 10 μL of a medium containing a predetermined concentration of the test substance was added to each well. After 96 hours of culture, 10 μL of TetraColor One cell proliferation (Seikagaku Corporation) was added per well, incubated for 60 minutes, and the absorbance at a wavelength of 450 nm was measured with a microplate reader.
（結果）
　本試験にて検討した実施例３（４－フルオロコルヒチン）、実施例５（４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）コルヒチン）、実施例６（４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）デアセチルコルヒチン）、実施例１３（４－クロロ－Ｎ－プロピオニルデアセチルコルヒチン）、実施例１４（４－クロロ－Ｎ－ホルミルデアセチルコルヒチン）及び実施例１５（４－クロロ－Ｎ－（クロロアセチル）デアセチルコルヒチン）のA549肺癌細胞に対する細胞障害活性のIC50値（細胞増殖を50%抑制する薬剤の濃度）はそれぞれ16.0nM、7.6nM、8.8nM、7.9nM、10.2nM、3.5nMで、陽性対照薬であるコルヒチンの32.8nMと比較して明らかに低かった(表１)。同様に、本試験にて検討した実施例３（４－フルオロコルヒチン）、実施例５（４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）コルヒチン）、実施例６（４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）デアセチルコルヒチン）、実施例１３（４－クロロ－Ｎ－プロピオニルデアセチルコルヒチン）、実施例１４（４－クロロ－Ｎ－ホルミルデアセチルコルヒチン）及び実施例１５（４－クロロ－Ｎ－（クロロアセチル）デアセチルコルヒチン）のHT-29大腸癌細胞に対する細胞障害活性のIC50値はそれぞれ7.3nM、1.2nM、6.7nM、3.3nM、8.7nM、1.6nMで、陽性対照薬であるコルヒチンの16.2nMと比較して明らかに低かった(表２)。以上の結果から、本試験にて検討した本発明のコルヒチン誘導体の全てが陽性対照薬であるコルヒチンよりも優れた抗癌活性を有することが示された。 (result)
Example 3 (4-fluorocolchicine), Example 5 (4-chloro-N- (t-butoxycarbonyl) colchicine), Example 6 (4-chloro-N- (t-butoxycarbonyl) examined in this test ) Deacetyl colchicine), Example 13 (4-chloro-N-propionyl deacetyl colchicine), Example 14 (4-chloro-N-formyl deacetyl colchicine) and Example 15 (4-chloro-N- (chloro The IC 50 value (concentration of the drug that inhibits cell proliferation by 50%) of A549 lung cancer cells of acetyl) deacetylcolchicine) is 16.0nM, 7.6nM, 8.8nM, 7.9nM, 10.2nM, 3.5nM, respectively. It was clearly lower compared with 32.8 nM of colchicine which is a positive control drug (Table 1). Similarly, Example 3 (4-fluorocolchicine), Example 5 (4-chloro-N- (t-butoxycarbonyl) colchicine), and Example 6 (4-chloro-N- (t -Butoxycarbonyl) deacetylcolchicine), Example 13 (4-chloro-N-propionyl deacetylcolchicine), Example 14 (4-chloro-N-formyldeacetylcolchicine) and Example 15 (4-chloro-N - each the IC 50 values of cytotoxic activity against (chloroacetyl) de HT-29 colon cancer cells acetyl colchicine) 7.3nM, 1.2nM, 6.7nM, 3.3nM , 8.7nM, at 1.6 nM, are positive control drug It was clearly lower compared to 16.2 nM for colchicine (Table 2). From the above results, it was shown that all of the colchicine derivatives of the present invention examined in this test have an anticancer activity superior to colchicine, which is a positive control drug.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
試験例２
（最大投与量試験）
（方法）
　BALB/cヌードマウスの静脈内に被験物質を投与し、死亡例の認められない最大投与量（MD）を求めた。 Test example 2
(Maximum dose test)
(Method)
The test substance was administered intravenously to BALB / c nude mice, and the maximum dose (MD) at which no death occurred was determined.
（結果）
　本試験において検討した実施例３（４－フルオロコルヒチン）、実施例１３（４－クロロ－Ｎ－プロピオニルデアセチルコルヒチン）及び実施例１５（４－クロロ－Ｎ－（クロロアセチル）デアセチルコルヒチン）の最大投与量はそれぞれ5 mg/kg、60 mg/kg及び60 mg/kgで、コルヒチンの1.5 mg/kgと比較してそれぞれ3.3、40、40倍の用量が投与可能となった（表３）。以上の結果から、本試験にて検討した本発明のコルヒチン誘導体の全てが、陽性対照薬であるコルヒチンよりも動物に対する毒性が軽減されていることが示された。 (result)
Example 3 (4-fluorocolchicine), Example 13 (4-chloro-N-propionyl deacetylcolchicine) and Example 15 (4-chloro-N- (chloroacetyl) deacetylcolchicine) examined in this test The maximum doses were 5 mg / kg, 60 mg / kg, and 60 mg / kg, respectively, and 3.3, 40, and 40 times the dose of colchicine compared to 1.5 mg / kg became available (Table 3). . From the above results, it was shown that all of the colchicine derivatives of the present invention examined in this test had reduced toxicity to animals compared to colchicine, which is a positive control drug.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
試験例３
　試験例１及び２と同様にして、試験した結果を表４～表６に示す。 Test example 3
The test results are shown in Tables 4 to 6 in the same manner as in Test Examples 1 and 2.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
試験例４
（In vivo抗腫瘍効果の検定法）
（動物）
　動物は5週齢の雄ヌードマウス（BALB/c Slc-nu）を日本エスエルシー(株)より購入し、1群４～５匹として使用した。動物はポリカーボネート製ケージにて飼育し、水および飼料（放射線滅菌MF）は自由摂取とした。  Test example 4
(In vivo antitumor effect assay)
(animal)
As animals, 5-week-old male nude mice (BALB / c Slc-nu) were purchased from Japan SLC Co., Ltd. and used as 4-5 mice per group. Animals were raised in polycarbonate cages, and water and feed (radiation-sterilized MF) were allowed to ad libitum.
（検定法）
　2 × 106 cells/0.1mL/マウスのHCT116細胞をヌードマウスの左鼠径部皮下に注射筒および注射針を用いて移植した。1/2ab2(aは腫瘍の長径、bは短径)より求めた推定腫瘍体積が平均300mm3前後に達した時点に各群の推定腫瘍体積が均等になるよう群分け・割り付けを行った（Day 1）。その後、被験物質を静脈内（Days 1,5,9）に1日1回投与（1/4MD量または1/2MD量）した。対照群にはvehicle（Tween80/Propylene glycol/5% glucose (10/5/85)）を同様のスケジュールで投与した。Day 22に腫瘍を摘出し重量を測定した後、次式により腫瘍増殖阻止率IR(%)を求めた。
　腫瘍増殖阻止率IR(%) ＝（1－投与群の平均腫瘍重量／対照群の平均腫瘍重量）× 100 (Test method)
2 × 10 6 cells / 0.1 mL / mouse of HCT116 cells were transplanted subcutaneously into the left groin of nude mice using a syringe and a needle. When the estimated tumor volume calculated from 1 / 2ab 2 (a is the major axis of the tumor and b is the minor axis) reaches an average of around 300 mm 3 , grouping and allocation were performed so that the estimated tumor volume of each group became equal. (Day 1). Thereafter, the test substance was administered intravenously (Days 1, 5, 9) once a day (1/4 MD amount or 1/2 MD amount). A vehicle (Tween 80 / Propylene glycol / 5% glucose (10/5/85)) was administered to the control group according to the same schedule. After removing the tumor on Day 22 and measuring the weight, the tumor growth inhibition rate IR (%) was determined by the following formula.
Tumor growth inhibition rate IR (%) = (1−average tumor weight of administration group / average tumor weight of control group) × 100
Figure JPOXMLDOC01-appb-T000007
 （結果）
Figure JPOXMLDOC01-appb-T000007
 (result)
　本試験において検討した実施例１３、実施例１５、実施例１１８、実施例１２２及び実施例１５１の腫瘍増殖阻止率IR（％）は、コルヒチンを上回っていた。以上の結果から、本試験にて検討した本発明のコルヒチン誘導体が、陽性対照薬であるコルヒチンよりも動物に対する効果が優れていることが示された。 The tumor growth inhibition rate IR (%) of Example 13, Example 15, Example 118, Example 122, and Example 151 examined in this test was higher than that of colchicine. From the above results, it was shown that the colchicine derivative of the present invention examined in this test is more effective for animals than the positive control colchicine.

Claims (9)

  1. 　次の一般式（１）
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ1はハロゲン原子、ヒドロキシ基、ニトロ基、アミノ基又はモノ－、ジ－若しくはトリ－フルオロメチル基を示し；
    Ｒ2、Ｒ3及びＲ4はそれぞれメトキシ基、又はヒドロキシ基を示すか、Ｒ2とＲ3又はＲ3とＲ4が一緒になってメチレンジオキシ基、又はエチレンジオキシ基を示し；
    Ｒ5及びＲ6は同一又は異なって、水素原子、炭素数１～６のアルキル基、アリールアルキル基、炭素数２～６のアルケニル基、－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9、－ＣＯＮＲ10Ｒ11、又は－ＣＳＮＲ12Ｒ13を示すか、Ｒ5とＲ6が結合する窒素原子と一緒になって３～７員の環状アミノ基を示し；
    Ｒ7は水素原子、炭素数６～１４のアリール基、ヘテロアリール基、環状アミノ基、炭素数３～７の環状アルキル基又は炭素数１～６のアルキル基を示し、当該アルキル基には環状アルキル基、ハロゲン原子、アミノ基、アルキルアミノ基、アリールアルキルアミノ基、ジアルキルアミノ基、環状アミノ基、アルコキシカルボニルアミノ基、アリールアミノ基、ヘテロアリールアミノ基、カルボキシル基、アルコキシカルボニル基、ヒドロキシ基、アシルオキシ基、ジアルキルアミノアシルオキシ基、アルキルオキシ基、アリール基、アリールオキシ基、アリールアルキルオキシ基、ヘテロアリール基、ヘテロアリールオキシ基、チオール基、アシルチオ基、ジアルキルアミノアシルチオ基、アルキルチオ基、アルキルスルホニル基、アリールチオ基、ヘテロアリールチオ基、カルバモイルオキシ基及び環状アミノカルボニルオキシ基から選ばれる１～３個が置換していてもよく、当該アリール基にはハロゲン原子、アルコキシ基、ニトロ基、シアノ基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、アリール基、アルキルアミノアルキル基及びヒドロキシアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはアルキル基及びアルコキシカルボニル基から選ばれる１～２個が置換していてもよい；
    Ｒ8は炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は環状アミノ基を示し、当該アルキル基にはアミノ基、アルキルアミノ基、ジアルキルアミノ基、環状アミノ基、カルボキシル基、アルコキシカルボニル基、アリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはアルキル基及びアルコキシカルボニル基から選ばれる１～２個が置換していてもよく、当該環状アルキル基にはカルボキシル基及びアルコキシカルボニル基から選ばれる１～３個が置換していてもよい；
    Ｒ9は炭素数１～６のアルキル基、炭素数３～７の環状アルキル基、炭素数６～１４のアリール基又はヘテロアリール基を示し、当該アルキル基には１～３個のハロゲン原子が置換していてもよく、当該アリール基には１～３個の炭素数１～６のアルキル基が置換していてもよい；
    Ｒ10とＲ11は同一又は異なって、水素原子、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は炭素数１～７のアシル基を示すか、Ｒ10とＲ11が結合する窒素原子と一緒になって３～７員環の環状アミノ基を示し、当該アルキル基にはアリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、炭素数１～７のアシル基には１～３個のハロゲン原子が置換していてもよく、当該環状アミノ基にはさらに酸素原子、窒素原子又は硫黄原子が含まれていてもよい；
    Ｒ12とＲ13は同一又は異なって、水素原子、炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基又は炭素数３～７の環状アルキル基を示すか、Ｒ12とＲ13が結合する窒素原子と一緒になって３～７員環の環状アミノ基を示し、当該アルキル基にはアリール基、ヘテロアリール基、環状アミノ基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、ヒドロキシ基及びアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該環状アルキル基には１～３個のヒドロキシ基が置換していてもよく、当該アリール基にはジアルキルアミノアルキル基、アルキルオキシ基、アルキル基、シアノ基、ハロゲン原子、ヒドロキシアルキル基、ヒドロキシアルキルオキシ基、スルファモイル基及びヒドロキシ基から選ばれる１～３個が置換していてもよく、当該ヘテロアリール基にはアルキル基、シアノ基、アリール基及びヒドロキシアルキル基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはさらに酸素原子、窒素原子又は硫黄原子が含まれていてもよく、さらにアルキル基、ヒドロキシ基、ハロゲン原子、アミノ基、アシル基及びジアルキルアミノ基から選ばれる１～３個が置換していてもよい；
    　ただし、Ｒ1が塩素原子、臭素原子又はヨウ素原子であり、Ｒ2、Ｒ3及びＲ4がメトキシ基であり、Ｒ5が水素原子であり、かつＲ6がアセチル基である場合を除く。Ｒ1がヒドロキシ基のとき、Ｒ2、Ｒ3及びＲ4はメトキシ基である。）
    で表されるコルヒチン誘導体、その塩又はそれらの溶媒和物。     The following general formula (1)
    Figure JPOXMLDOC01-appb-C000003
     Wherein R 1 represents a halogen atom, a hydroxy group, a nitro group, an amino group or a mono-, di- or tri-fluoromethyl group;
    R 2 , R 3 and R 4 each represent a methoxy group or a hydroxy group, or R 2 and R 3 or R 3 and R 4 together represent a methylenedioxy group or an ethylenedioxy group;
    R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl group, an alkenyl group having 2 to 6 carbon atoms, —COR 7 , —COOR 8 , —SO 2 R 9 , -CONR 10 R 11 or -CSNR 12 R 13 or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 5 and R 6 are bonded;
    R 7 represents a hydrogen atom, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic amino group, a cyclic alkyl group having 3 to 7 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. Alkyl group, halogen atom, amino group, alkylamino group, arylalkylamino group, dialkylamino group, cyclic amino group, alkoxycarbonylamino group, arylamino group, heteroarylamino group, carboxyl group, alkoxycarbonyl group, hydroxy group, Acyloxy group, dialkylaminoacyloxy group, alkyloxy group, aryl group, aryloxy group, arylalkyloxy group, heteroaryl group, heteroaryloxy group, thiol group, acylthio group, dialkylaminoacylthio group, alkylthio group, alkylsulfonyl group , Ally One to three selected from a thio group, a heteroarylthio group, a carbamoyloxy group and a cyclic aminocarbonyloxy group may be substituted, and the aryl group includes a halogen atom, an alkoxy group, a nitro group, a cyano group, an amino group. 1 to 3 groups selected from a group, an alkylamino group, a dialkylamino group, an aryl group, an alkylaminoalkyl group and a hydroxyalkyloxy group may be substituted, and the cyclic amino group includes an alkyl group and an alkoxycarbonyl group. 1 to 2 selected may be substituted;
    R 8 represents an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms or a cyclic amino group. The alkyl group includes an amino group, an alkyl group One to three selected from an amino group, a dialkylamino group, a cyclic amino group, a carboxyl group, an alkoxycarbonyl group, an aryl group and a heteroaryl group may be substituted, and the cyclic amino group includes an alkyl group and an alkoxycarbonyl group. 1 to 2 selected from a group may be substituted, and the cyclic alkyl group may be substituted with 1 to 3 selected from a carboxyl group and an alkoxycarbonyl group;
    R 9 represents an alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, an aryl group or a heteroaryl group having 6 to 14 carbon atoms, and the alkyl group has 1 to 3 halogen atoms. The aryl group may be substituted with 1 to 3 alkyl groups having 1 to 6 carbon atoms;
    R 10 and R 11 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms, or 1 to 7 represents an acyl group, or a 3- to 7-membered cyclic amino group together with the nitrogen atom to which R 10 and R 11 are bonded. The alkyl group is selected from an aryl group and a heteroaryl group. 1 to 3 may be substituted, and the acyl group having 1 to 7 carbon atoms may be substituted with 1 to 3 halogen atoms. The cyclic amino group may be further substituted with an oxygen atom, a nitrogen atom, or a sulfur atom. Atoms may be included;
    R 12 and R 13 are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, or a cyclic alkyl group having 3 to 7 carbon atoms; Together with the nitrogen atom to which 12 and R 13 are bonded, a 3- to 7-membered cyclic amino group is shown, and the alkyl group includes an aryl group, heteroaryl group, cyclic amino group, amino group, alkylamino group, dialkyl 1 to 3 groups selected from an amino group, a hydroxy group and an alkyloxy group may be substituted, the cyclic alkyl group may be substituted with 1 to 3 hydroxy groups, and the aryl group has Selected from dialkylaminoalkyl group, alkyloxy group, alkyl group, cyano group, halogen atom, hydroxyalkyl group, hydroxyalkyloxy group, sulfamoyl group and hydroxy group 1 to 3 may be substituted, and the heteroaryl group may be substituted with 1 to 3 selected from an alkyl group, a cyano group, an aryl group and a hydroxyalkyl group, and the cyclic amino group May further contain an oxygen atom, a nitrogen atom or a sulfur atom, and 1 to 3 groups selected from an alkyl group, a hydroxy group, a halogen atom, an amino group, an acyl group and a dialkylamino group are substituted. May be;
    However, R 1 is a chlorine atom, bromine atom or iodine atom, R 2 , R 3 and R 4 are methoxy groups, R 5 is a hydrogen atom, and R 6 is an acetyl group. When R 1 is a hydroxy group, R 2 , R 3 and R 4 are methoxy groups. )
    Or a salt or solvate thereof.
  2. 　Ｒ5及びＲ6が次の組み合せである請求項１記載のコルヒチン誘導体、その塩又はそれらの溶媒和物。
    （１）Ｒ5及びＲ6が水素原子の場合、
    （２）Ｒ5が水素原子であり、Ｒ6が－ＣＯＲ7、－ＣＯＯＲ8、－ＳＯ2Ｒ9、又は－ＣＳＮＲ12Ｒ13である場合、
    （３）Ｒ5が－ＣＯＲ7で、Ｒ6が－ＣＯＯＲ8の場合、
    （ここで、Ｒ7は水素原子；炭素数２～６のアルキル基；炭素数３～７の環状アルキル基；Ｃ3-7環状アルキル基、ハロゲン原子、アミノ基、Ｃ1-6アルキルアミノ基、Ｃ6-14アリールアルキルアミノ基、ジＣ1-6アルキルアミノ基、環状アミノ基、Ｃ1-6アルコキシカルボニルアミノ基、Ｃ6-14アリールアミノ基、ヘテロアリールアミノ基、カルボキシル基、Ｃ1-6アルコキシカルボニル基、ヒドロキシ基、アシルオキシ基、ジＣ1-6アルキルアミノアシルオキシ基、Ｃ1-6アルキルオキシ基、Ｃ6-14アリール基、Ｃ6-14アリールオキシ基、Ｃ6-14アリールアルキルオキシ基、ヘテロアリール基、ヘテロアリールオキシ基、チオール基、アシルチオ基、ジＣ1-6アルキルアミノアシルチオ基、Ｃ1-6アルキルチオ基、Ｃ1-6アルキルスルホニル基、Ｃ6-14アリールチオ基及びヘテロアリールチオ基から選ばれる１～３個が置換した炭素数１～６のアルキル基；あるいはハロゲン原子、Ｃ1-6アルコキシ基、ニトロ基、シアノ基、アミノ基、Ｃ1-6アルキルアミノ基、ジＣ1-6アルキルアミノ基、Ｃ1-6アルキル基、Ｃ6-14アリール基及びＣ1-6アルキルアミノアルキル基から選ばれる１～３個が置換していてもよいＣ6-14アリール基又はヘテロアリール基である。
    　Ｒ8は炭素数１～６のアルキル基、炭素数６～１４のアリール基、ヘテロアリール基、炭素数３～７の環状アルキル基又は環状アミノ基が好ましく、当該アルキル基にはアミノ基、Ｃ1-6アルキルアミノ基、ジＣ1-6アルキルアミノ基、環状アミノ基、カルボキシル基、Ｃ1-6アルコキシカルボニル基、Ｃ6-14アリール基及びヘテロアリール基から選ばれる１～３個が置換していてもよく、当該環状アミノ基にはＣ1-6アルキル基又はＣ1-6アルコキシカルボニル基が置換していてもよく、当該環状アルキル基にはカルボキシル基、アルコキシカルボニル基が置換していてもよい。
    　Ｒ9はＣ6-14アリール基又はヘテロアリール基である。
    　Ｒ12とＲ13は同一又は異なって、水素原子、炭素数１～４のアルキル基、炭素数５～６の環状アルキル基、アリール基、ヘテロアリール基又はＲ12とＲ13が窒素原子と一緒になって形成する４～６員環の環状アミノ基が好ましく、当該アルキル基にはアルキルオキシ基、ヒドロキシ基が置換していてもよく、当該アリール基にはジアルキルアミノアルキル基、アルキルオキシ基、アルキル基、シアノ基、ハロゲン原子、ヒドロキシアルキル基及びヒドロキシアルキルオキシ基から選ばれる１～３個が置換していてもよく、当該ヘテロアリール基にはアルキル基、シアノ基、アリール基、ヒドロキシアルキル基から選ばれる１～３個が置換していてもよく、当該環状アミノ基には酸素原子、硫黄原子が含まれていてもよく、さらにはアルキル基、ハロゲン原子から選ばれる１～３個が置換していてもよい。）     The colchicine derivative, a salt thereof or a solvate thereof according to claim 1, wherein R 5 and R 6 are the following combinations.
    (1) When R 5 and R 6 are hydrogen atoms,
    (2) When R 5 is a hydrogen atom and R 6 is —COR 7 , —COOR 8 , —SO 2 R 9 , or —CSNR 12 R 13 ,
    (3) When R 5 is —COR 7 and R 6 is —COOR 8 ,
    (Where R 7 is a hydrogen atom; an alkyl group having 2 to 6 carbon atoms; a cyclic alkyl group having 3 to 7 carbon atoms; a C 3-7 cyclic alkyl group, a halogen atom, an amino group, or a C 1-6 alkylamino group. C 6-14 arylalkylamino group, di-C 1-6 alkylamino group, cyclic amino group, C 1-6 alkoxycarbonylamino group, C 6-14 arylamino group, heteroarylamino group, carboxyl group, C 1 -6 alkoxycarbonyl group, hydroxy group, acyloxy group, di C 1-6 alkylaminoacyloxy group, C 1-6 alkyloxy group, C 6-14 aryl group, C 6-14 aryloxy group, C 6-14 aryl alkyloxy group, a heteroaryl group, heteroaryloxy group, a thiol group, an acylthio group, di-C 1-6 alkylamino acylthioethyl group, C 1-6 alkylthio group, C 1-6 alkylsulfonyl group, C 6-14 ants Alkyl group of 1 to 3 is to 1 carbon atoms substituted 6 selected from thio group, and heteroarylthio group; or a halogen atom, C 1-6 alkoxy group, a nitro group, a cyano group, an amino group, C 1-6 1 to 3 selected from an alkylamino group, a di-C 1-6 alkylamino group, a C 1-6 alkyl group, a C 6-14 aryl group and a C 1-6 alkylaminoalkyl group may be substituted. 6-14 aryl group or heteroaryl group.
    R 8 is preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, a heteroaryl group, a cyclic alkyl group having 3 to 7 carbon atoms or a cyclic amino group. The alkyl group includes an amino group, C 1 to 3 selected from 1-6 alkylamino group, di-C 1-6 alkylamino group, cyclic amino group, carboxyl group, C 1-6 alkoxycarbonyl group, C 6-14 aryl group and heteroaryl group are substituted The cyclic amino group may be substituted with a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group, and the cyclic alkyl group is substituted with a carboxyl group or an alkoxycarbonyl group. May be.
    R 9 is a C 6-14 aryl group or a heteroaryl group.
    R 12 and R 13 are the same or different and are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 5 to 6 carbon atoms, an aryl group, a heteroaryl group, or R 12 and R 13 together with a nitrogen atom. And a 4- to 6-membered cyclic amino group formed as follows: the alkyl group may be substituted with an alkyloxy group or a hydroxy group, and the aryl group may be a dialkylaminoalkyl group, an alkyloxy group, One to three selected from an alkyl group, a cyano group, a halogen atom, a hydroxyalkyl group, and a hydroxyalkyloxy group may be substituted, and the heteroaryl group includes an alkyl group, a cyano group, an aryl group, and a hydroxyalkyl group. 1 to 3 selected from the above may be substituted, and the cyclic amino group may contain an oxygen atom or a sulfur atom, and further an alkyl group 1-3 selected from halogen atoms may be substituted. )
  3. 　Ｒ1がハロゲン原子、ニトロ基、アミノ基又はモノ－、ジ－若しくはトリ－フルオロメチル基である請求項１又は２記載のコルヒチン誘導体、その塩又はそれらの溶媒和物。 The colchicine derivative, a salt thereof or a solvate thereof according to claim 1 or 2, wherein R 1 is a halogen atom, a nitro group, an amino group, or a mono-, di- or tri-fluoromethyl group.
  4. 　下記から選ばれるコルヒチン誘導体、その塩又はそれらの溶媒和物。
    　４－ニトロコルヒチン、
    　４－ヒドロキシコルヒチン、
    　４－フルオロコルヒチン、
    　４－アミノコルヒチン、
    　４－クロロデアセチルコルヒチン、
    　４－フルオロデアセチルコルヒチン、
    　４－クロロ－Ｎ－プロピオニルデアセチルコルヒチン、
    　４－クロロ－Ｎ－ホルミルデアセチルコルヒチン、
    　４－クロロ－Ｎ－（クロロアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）コルヒチン、
    　４－クロロ－Ｎ－（ｔ－ブトキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ，Ｎ－ジメチルデアセチルコルヒチン、
    　４－クロロ－Ｎ，Ｎ－ジエチルデアセチルコルヒチン、
    　４－クロロ－７－（ピペラジン－１－イル）－７－デ（アセチルアミノ）コルヒチン、
    　Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロ－Ｎ－メチルデアセチルコルヒチン、
    　Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロ－Ｎ－エチルデアセチルコルヒチン、
    　Ｎ－アリル－４－クロロ－Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）デアセチルコルヒチン、
    　Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロ－Ｎ－（２－メチルアリル）デアセチルコルヒチン、
    　Ｎ－ベンジル－Ｎ－（ｔｅｒｔ－ブチルオキシカルボニル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－メチルデアセチルコルヒチン、
    　４－クロロ－Ｎ－エチルデアセチルコルヒチン、
    　Ｎ－アリル－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－メチルアリル）デアセチルコルヒチン、
    　Ｎ－ベンジル－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－プロピルデアセチルコルヒチン、
    　Ｎ－イソブチル－４－クロロデアセチルコルヒチン、
    　Ｎ－（アセトキシアセチル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（ヒドロキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－メチルピペラジン－４－イルオキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－イルオキシカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピペリジン－４－イルオキシカルボニル）デアセチルコルヒチン、
    　Ｎ－［ｔｒａｎｓ－１－（ベンジルオキシカルボニル）シクロヘキサン－４－イルオキシカルボニル］－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（チオモルホリン－４－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１，１－ジオキソチオモルホリン－４－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－メチルピペラジン－４－カルボニル）デアセチルコルヒチン、
    　Ｎ－ブチリル－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－イソブチリルデアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロプロパンカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－イソバレリルデアセチルコルヒチン、
    　４－クロロ－Ｎ－ヘプタノイルデアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロヘキサンカルボニル）デアセチルコルヒチン、
    　Ｎ－ベンゾイル－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（フェニルアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－３－イルカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－４－イルカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－２－イルカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（トリフルオロアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（メトキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（フェノキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（メチルチオ）アセチル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－ピリジルチオ）アセチル］デアセチルコルヒチン、
    　Ｎ－（４－ブロモブチリル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－フルオロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３，５－ジフルオロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３，４，５－トリフルオロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－メトキシベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３，４，５－トリメトキシベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－メトキシベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－メトキシベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（フェニルチオ）アセチル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－フルオロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－フルオロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２，４－ジフルオロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－３－イルオキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－２－イルアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－３－イルアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（メトキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（エトキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソプロピルオキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソブチルオキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（フェノキシカルボニル）デアセチルコルヒチン、
    　Ｎ－（ベンジルオキシカルボニル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（メタンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（エタンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソプロパンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロプロパンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソブタンスルホニル）デアセチルコルヒチン、
    　Ｎ－（ベンゼンスルホニル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（ｐ－トルエンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－チオフェンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（トリフルオロメタンスルホニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（エチルカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソプロピルカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ヘキシルカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（フェニルカルバモイル）デアセチルコルヒチン、
    　Ｎ－（ベンジルカルバモイル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（ジメチルカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ジエチルカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（モルフォリン－４－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピロリジン－１－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピペリジン－１－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（トリクロロアセチルカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ジメチルアミノアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ジエチルアミノアセチル）デアセチルコルヒチン、
    　Ｎ－（ｔ－ブチルオキシカルボニルアミノアセチル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（アミノアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピロリジン－１－イルアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピペリジン－１－イルアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－カルボキシプロピオニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（メトキシカルボニル）プロピオニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－カルボキシブチリル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（メトキシカルボニル）ブチリル］デアセチルコルヒチン、
    　Ｎ－（ｔｒａｎｓ－１－カルボキシシクロヘキサン－４－イルオキシカルボニル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピリジン－３－イルオキシカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－（ジメチルアミノ）プロピル－３－イルオキシカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ピロリジン－１－イル）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（４－モルホリニルメチル）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ジエチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピロリジン－１－チオカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピペリジン－１－チオカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（モルホリン－４－チオカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（チオモルホリン－４－チオカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１，１－ジオキソチオモルホリン－４－チオカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－メチルピペラジン－４－チオカルボニル）デアセチルコルヒチン、
    　（Ｓ）－４－クロロ－Ｎ－（２－アセトキシプロピオニル）デアセチルコルヒチン、
    　（Ｓ）－４－クロロ－Ｎ－（２－ヒドロキシプロピオニル）デアセチルコルヒチン、
    　（Ｒ）－４－クロロ－Ｎ－（２－アセトキシプロピオニル）デアセチルコルヒチン、
    　（Ｒ）－４－クロロ－Ｎ－（２－ヒドロキシプロピオニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－ヒドロキシ－２－メチルプロピオニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－ヒドロキシ－２，２－ジメチルプロピオニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［２，２－ビス（ヒドロキシメチル）プロピオニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－アセチルピペリジン－４－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－ベンゾイルピペリジン－４－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－（ｔｅｒｔ－ブチルオキシカルボニル）ピペリジン－４－カルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ピペリジン－４－カルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ジメチルアミノメチル）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（トリフェニルメチルオキシ）プロピオニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－ヒドロキシプロピオニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（メタンスルホニルアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ジメチルアミノ）プロピオニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ジエチルアミノ）プロピオニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－ピペリジノプロピオニル）デアセチルコルヒチン、
    　Ｎ－［Ｎ’－（ｔ－ブチルオキシカルボニル）－Ｎ’－メチルアミノアセチル］－４－クロロデアセチルコルヒチン、
    　Ｎ－［Ｎ’－ベンジル－Ｎ’－（ｔ－ブチルオキシカルボニル）アミノアセチル］－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－メチルピペリジン－４－イルカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－イルカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（Ｎ’－メチルアミノアセチル）デアセチルコルヒチン、
    　Ｎ－（Ｎ’－ベンジルアミノアセチル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（ジメチルアミノ）ブチリル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［２－（ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソブチルチオカルバモイル）デアセチルコルヒチン、
    　Ｎ－（ベンジルチオカルバモイル）－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロヘキシルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２－ピペリジノエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛［２－（４－モルフォリノ）エチル］チオカルバモイル｝デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－ピリジルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［ｐ－（ジメチルアミノ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－ニトロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－ナフトイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－ニトロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－メチルベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－フェニルベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３，５－ジニトロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３，５－ジメチルベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－ニトロベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３，５－ジメトキシベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２，４－ジメトキシベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２，４，６－トリメチルベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－シアノベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－ヒドロキシ－３－メチルブチリル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（ベンジルオキシ）ブチリル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－シアノベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－シアノベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－エチル－２－ヒドロキシブチリル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－ヒドロキシシクロプロパンカルボニル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－フェニルベンゾイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－ヒドロキシブチリル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ｔ－ブチルオキシカルボニル）コルヒチン、
    　４－ブロモ－Ｎ－（ｔ－ブチルオキシカルボニル）デアセチルコルヒチン、
    　４－ブロモデアセチルコルヒチン、
    　４－ブロモ－Ｎ－プロピオニルデアセチルコルヒチン、
    　４－ブロモ－Ｎ－（シクロヘキサンカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－ベンゾイルデアセチルコルヒチン、
    　４－ブロモ－Ｎ－（フェニルアセチル）デアセチルコルヒチン、
    　Ｎ－アリル－４－ブロモ－Ｎ－（ｔ－ブチルオキシカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（トリフルオロアセチル）デアセチルコルヒチン、
    　Ｎ－（アセトキシアセチル）－４－ブロモデアセチルコルヒチン、
    　４－ブロモ－Ｎ－（２－ピリジンカルボニル）デアセチルコルヒチン、
    　Ｎ－アリル－４－ブロモデアセチルコルヒチン、
    　Ｎ－（ベンジルオキシカルボニル）－４－ブロモデアセチルコルヒチン、
    　４－ブロモ－Ｎ－[（メチルチオ）アセチル]デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（Ｎ’，Ｎ’－ジメチルアミノ）アセチル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－プロピルデアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ヘキシルカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（フェニルカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ヒドロキシアセチル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（イソブタンスルホニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－トシルデアセチルコルヒチン、
    　４－ブロモ－Ｎ－（２－チオフェンスルホニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（２，４－ジフルオロベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［３－（Ｎ’，Ｎ’－ジメチルアミノ）ベンゾイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（２－フルオロベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（３－メトキシベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（エチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（フェニルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（Ｎ’，Ｎ’－ジエチルカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ピペリジン-１-イルカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（３－ヒドロキシ－２，２－ジメチルプロピオニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（２－ヒドロキシ－２－メチルプロピオニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（２－エチル－２－ヒドロキシブチリル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（１－ヒドロキシシクロプロパンカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［２，２－ビス（ヒドロキシメチル）プロピオニル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（３－ヒドロキシ－３－メチルブチリル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［４－（ベンジルオキシ）ブチリル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（３－ニトロベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（４－シアノベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（３，５－ジメチルベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（４－メチルベンゾイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－[３－（ピロリジン－１－イル）ベンゾイル]デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（イソブチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ベンジルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［４－（Ｎ’，Ｎ’－ジメチルアミノ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ピリジン－３－イルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（Ｎ’，Ｎ’－ジエチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ピロリジン－１－イルチオカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ピペリジン－１－イルチオカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（４－ヒドロキシブチリル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（チオモルホリン－４－イルチオカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（１，１－ジオキソチオモルホリン－４－イルチオカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（４－メチルピペラジン－１－イルチオカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（モルホリン－４－イルチオカルボニル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（エタンスルホニル）デアセチルコルヒチン、
    　４－クロロ－２，３－ジデメチルコルヒチン、
    　４－クロロ－２，３－（メチレンジオキシ）－２，３－ジデメトキシコルヒチン、
    　４－クロロ－２，３－（エチレンジオキシ）－２，３－ジデメトキシコルヒチン、
    　４－クロロ－１，２－（メチレンジオキシ）－１，２－ジデメトキシコルヒチン、
    　４－クロロ－Ｎ－（エチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（フェニルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（４－ピペリジノピペリジン－１－カルボキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（１－メチルピペラジン－４－カルボキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ジメチルアミノアセトキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ジメチルアミノ）プロピオニルオキシアセチル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－カルボキシアセチル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（チオアセトキシアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（メルカプトアセチル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－（エトキシカルボニル）ピペリジン－４－イルカルボニル］デアセチルコルヒチン、
    　４－（フルオロメチル）コルヒチン、
    　４－（ジフルオロメチル）コルヒチン、
    　４－クロロ－Ｎ－（Ｎ’，Ｎ’－ジメチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（Ｎ’，Ｎ’－ジプロピルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［Ｎ’－エチル－Ｎ’－プロピルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－ヒドロキシピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－メチルピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛Ｎ’－［２－（ジメチルアミノ）エチル］－Ｎ’－メチルチオカルバモイル｝デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛［４－（ジメチルアミノ）ピペリジン－１－イル］チオカルバモイル｝デアセチルコルヒチン、
    　４－クロロ－Ｎ－（Ｎ’－エチル－Ｎ’－メチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［１－アセチルピペラジン－４－イル）チオカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［Ｎ’－（２－ヒドロキシエチル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［Ｎ’－（３－ヒドロキシプロピル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［Ｎ’，Ｎ’－ビス（２－ヒドロキシエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３－ヒドロキシプロピル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４，４－ジフルオロピペリジン－１－イル）チオカルバモイル］デアセチルコルヒチン、
    　Ｎ－［（アゼチジン－１－イル）チオカルバモイル］－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－［（インダゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（２－トリルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（３－トリルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（ジメチルアミノ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（２－ヒドロキシエチル）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（２－ヒドロキシエチル）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［２，１，３－ベンゾチアジアゾール－４－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３，４－ジメトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２－クロロフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３－クロロフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－クロロフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（チアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（チオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（メチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ｎ－プロピルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ｎ－ブチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ｔｅｒｔ－ブチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロペンチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（イソプロピルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（ｎ－ヘキシルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ｔｒａｎｓ－４－ヒドロキシシクロヘキシル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［２－（ジメチルアミノ）エチルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２－ヒドロキシエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ｐ－トルイル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロプロピルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－（アリルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１－メチルピペリジン－４－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－（シクロへプチルチオカルバモイル）デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２－メトキシエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（２，２，２－トリフルオロエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（インダン－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－スルファモイルフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３，５－ジメチルイソオキサゾール－４－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－ヒドロキシフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（５－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（プロピルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（ブチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（２，２，２－トリフルオロエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（シクロペンチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（シクロヘキシルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（４－メトキシフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－｛［２－（４－モルホリノ）エチル］チオカルバモイル｝デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（Ｎ’，Ｎ’－ジメチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（Ｎ’－エチル－Ｎ’－メチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（４－メチルピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（４，４－ジフルオロ－ピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（５－メチルイソオキサゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（５－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（イソオキサゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（３，４－ジメチルイソオキサゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－シアノピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（５－フェニルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　Ｎ－（ｔ－ブチルオキシカルボニル）－４－ヨードコルヒチン、
    　Ｎ－（ｔ－ブチルオキシカルボニル）－４－ヨードデアセチルコルヒチン、
    　４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－プロピオニルデアセチルコルヒチン、
    　Ｎ－シクロプロピルカルボニル－４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－（トリフルオロアセチル）デアセチルコルヒチン、
    　Ｎ－エチルスルホニル－４－ヨードデアセチルコルヒチン、
    　Ｎ－［３－（ジメチルアミノ）ベンゾイル］－４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－（４－メトキシベンゾイル）デアセチルコルヒチン、
    　４－ヨード－Ｎ－（４－ニトロベンゾイル）デアセチルコルヒチン、
    　Ｎ－（３，５－ジフルオロベンゾイル）－４－ヨードデアセチルコルヒチン、
    　Ｎ－（３－シアノベンゾイル）－４－ヨードデアセチルコルヒチン、
    　Ｎ－（アセトキシアセチル）－４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－（フェニルアセチル）デアセチルコルヒチン、
    　４－ヨード－Ｎ－プロピルデアセチルコルヒチン、
    　Ｎ－（ヒドロキシアセチル）－４－ヨードデアセチルコルヒチン、
    　Ｎ－［１－（ベンジルオキシカルボニル）ピペリジン－４－イルカルボニル］－４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－（ピリジン－４－イルカルボニル）デアセチルコルヒチン、
    　Ｎ－フェニルスルホニル－４－ヨードデアセチルコルヒチン、
    　Ｎ－（シクロヘキシルチオカルバモイル）－４－ヨードデアセチルコルヒチン、
    　Ｎ－［４－（ジメチルアミノ）フェニルチオカルバモイル］－４－ヨードデアセチルコルヒチン、
    　Ｎ－（ベンジルカルバモイル）－４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－［（ピペリジン－１－イル）カルボニル］デアセチルコルヒチン、
    　Ｎ－エチル－４－ヨードデアセチルコルヒチン、
    　４－ヨード－Ｎ－［（ピペリジン－１－イル）チオカルボニル］デアセチルコルヒチン、
    　４－ヨード－Ｎ－［（チオモルホリン－４－イル）チオカルボニル］デアセチルコルヒチン、
    　Ｎ－［（ベンゾイミダゾール－２－イル）チオカルバモイル］－４－クロロデアセチルコルヒチン、
    　Ｎ－［（ベンゾチアゾール－２－イル）チオカルバモイル］－４－クロロデアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピリミジン－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピリダジン－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピリジン－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４－メチルチアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（４，５－ジメチルチアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピリジン－４－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（２－ヒドロキシエトキシ）ベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（２－ヒドロキシエトキシ）－４－メトキシベンゾイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピラジン－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１，３，４－チアジアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（ピリミジン－５－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［３－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［４－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１，２－ジメチルイミダゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）－２－メチルイミダゾール－５－イル］チオカルバモイル｝デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）ピラゾール－５－イル］チオカルバモイル｝デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）ピラゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（５－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（１－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（４－シアノピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（５－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（１－メチルピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（ピラゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（３，４－ジメチルイソオキサゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（５－メチルイソオキサゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（４－メチルチアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（チアゾール－２－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［３－（２－ヒドロキシエチル）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（ピリダジン－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　Ｎ－［（アゼチジン－１－イル）チオカルボニル］－４－ブロモデアセチルコルヒチン、
    　４－ブロモ－Ｎ－（メチルチオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－（チオカルバモイル）デアセチルコルヒチン、
    　４－ブロモ－Ｎ－｛［１－（２－ヒドロキシエチル）－１，２，４－トリアゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン、
    　４－ブロモ－Ｎ－｛［１－（２－ヒドロキシエチル）ピラゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［４－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［３－（２－ヒドロキシエトキシ）フェニルチオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（４－シアノフェニル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［（２－ヒドロキシエチル）チオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［Ｎ’－（２－ヒドロキシエチル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
    　４－ブロモ－Ｎ－［Ｎ’－（３－ヒドロキシプロピル）－Ｎ’－メチルチオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１－メチル－１，２，４－トリアゾール－３－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－［（１－メチル－１，２，４－トリアゾール－５－イル）チオカルバモイル］デアセチルコルヒチン、
    　４－クロロ－Ｎ－｛［１－（２－ヒドロキシエチル）－１，２，４－トリアゾール－３－イル］チオカルバモイル｝デアセチルコルヒチン。     A colchicine derivative selected from the following, a salt thereof, or a solvate thereof.
    4-nitrocolchicine,
    4-hydroxycolchicine,
    4-fluorocolchicine,
    4-aminocolchicine,
    4-chlorodeacetylcolchicine,
    4-fluorodeacetylcolchicine,
    4-chloro-N-propionyl deacetylcolchicine,
    4-chloro-N-formyl deacetyl colchicine,
    4-chloro-N- (chloroacetyl) deacetylcolchicine,
    4-chloro-N- (t-butoxycarbonyl) colchicine,
    4-chloro-N- (t-butoxycarbonyl) deacetylcolchicine,
    4-chloro-N, N-dimethyldeacetylcolchicine,
    4-chloro-N, N-diethyldeacetylcolchicine,
    4-chloro-7- (piperazin-1-yl) -7-de (acetylamino) colchicine,
    N- (tert-butyloxycarbonyl) -4-chloro-N-methyldeacetylcolchicine,
    N- (tert-butyloxycarbonyl) -4-chloro-N-ethyldeacetylcolchicine,
    N-allyl-4-chloro-N- (tert-butyloxycarbonyl) deacetylcolchicine,
    N- (tert-butyloxycarbonyl) -4-chloro-N- (2-methylallyl) deacetylcolchicine,
    N-benzyl-N- (tert-butyloxycarbonyl) -4-chlorodeacetylcolchicine,
    4-chloro-N-methyldeacetylcolchicine,
    4-chloro-N-ethyldeacetylcolchicine,
    N-allyl-4-chlorodeacetylcolchicine,
    4-chloro-N- (2-methylallyl) deacetylcolchicine,
    N-benzyl-4-chlorodeacetylcolchicine,
    4-chloro-N-propyl deacetylcolchicine,
    N-isobutyl-4-chlorodeacetylcolchicine,
    N- (acetoxyacetyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (hydroxyacetyl) deacetylcolchicine,
    4-chloro-N- (1-methylpiperazin-4-yloxycarbonyl) deacetylcolchicine,
    4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-yloxycarbonyl] deacetylcolchicine,
    4-chloro-N- (piperidin-4-yloxycarbonyl) deacetylcolchicine,
    N- [trans-1- (benzyloxycarbonyl) cyclohexane-4-yloxycarbonyl] -4-chlorodeacetylcolchicine,
    4-chloro-N- (thiomorpholine-4-carbonyl) deacetylcolchicine,
    4-chloro-N- (1,1-dioxothiomorpholine-4-carbonyl) deacetylcolchicine,
    4-chloro-N- (1-methylpiperazine-4-carbonyl) deacetylcolchicine,
    N-butyryl-4-chlorodeacetylcolchicine,
    4-chloro-N-isobutyryl deacetylcolchicine,
    4-chloro-N- (cyclopropanecarbonyl) deacetylcolchicine,
    4-chloro-N-isovaleryl deacetylcolchicine,
    4-chloro-N-heptanoyl deacetylcolchicine,
    4-chloro-N- (cyclohexanecarbonyl) deacetylcolchicine,
    N-benzoyl-4-chlorodeacetylcolchicine,
    4-chloro-N- (phenylacetyl) deacetylcolchicine,
    4-chloro-N- (pyridin-3-ylcarbonyl) deacetylcolchicine,
    4-chloro-N- (pyridin-4-ylcarbonyl) deacetylcolchicine,
    4-chloro-N- (pyridin-2-ylcarbonyl) deacetylcolchicine,
    4-chloro-N- (trifluoroacetyl) deacetylcolchicine,
    4-chloro-N- (methoxyacetyl) deacetylcolchicine,
    4-chloro-N- (phenoxyacetyl) deacetylcolchicine,
    4-chloro-N-[(methylthio) acetyl] deacetylcolchicine,
    4-chloro-N-[(4-pyridylthio) acetyl] deacetylcolchicine,
    N- (4-bromobutyryl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (4-fluorobenzoyl) deacetylcolchicine,
    4-chloro-N- (3,5-difluorobenzoyl) deacetylcolchicine,
    4-chloro-N- (3,4,5-trifluorobenzoyl) deacetylcolchicine,
    4-chloro-N- (4-methoxybenzoyl) deacetylcolchicine,
    4-chloro-N- (3,4,5-trimethoxybenzoyl) deacetylcolchicine,
    4-chloro-N- (2-methoxybenzoyl) deacetylcolchicine,
    4-chloro-N- (3-methoxybenzoyl) deacetylcolchicine,
    4-chloro-N-[(phenylthio) acetyl] deacetylcolchicine,
    4-chloro-N- [3- (dimethylamino) benzoyl] deacetylcolchicine,
    4-chloro-N- [4- (dimethylamino) benzoyl] deacetylcolchicine,
    4-chloro-N- (2-fluorobenzoyl) deacetylcolchicine,
    4-chloro-N- (3-fluorobenzoyl) deacetylcolchicine,
    4-chloro-N- (2,4-difluorobenzoyl) deacetylcolchicine,
    4-chloro-N- (pyridin-3-yloxyacetyl) deacetylcolchicine,
    4-chloro-N- (pyridin-2-ylacetyl) deacetylcolchicine,
    4-chloro-N- (pyridin-3-ylacetyl) deacetylcolchicine,
    4-chloro-N- (methoxycarbonyl) deacetylcolchicine,
    4-chloro-N- (ethoxycarbonyl) deacetylcolchicine,
    4-chloro-N- (isopropyloxycarbonyl) deacetylcolchicine,
    4-chloro-N- (isobutyloxycarbonyl) deacetylcolchicine,
    4-chloro-N- (phenoxycarbonyl) deacetylcolchicine,
    N- (benzyloxycarbonyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (methanesulfonyl) deacetylcolchicine,
    4-chloro-N- (ethanesulfonyl) deacetylcolchicine,
    4-chloro-N- (isopropanesulfonyl) deacetylcolchicine,
    4-chloro-N- (cyclopropanesulfonyl) deacetylcolchicine,
    4-chloro-N- (isobutanesulfonyl) deacetylcolchicine,
    N- (benzenesulfonyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (p-toluenesulfonyl) deacetylcolchicine,
    4-chloro-N- (2-thiophenesulfonyl) deacetylcolchicine,
    4-chloro-N- (trifluoromethanesulfonyl) deacetylcolchicine,
    4-chloro-N- (ethylcarbamoyl) deacetylcolchicine,
    4-chloro-N- (isopropylcarbamoyl) deacetylcolchicine,
    4-chloro-N- (hexylcarbamoyl) deacetylcolchicine,
    4-chloro-N- (phenylcarbamoyl) deacetylcolchicine,
    N- (benzylcarbamoyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (dimethylcarbamoyl) deacetylcolchicine,
    4-chloro-N- (diethylcarbamoyl) deacetylcolchicine,
    4-chloro-N- (morpholine-4-carbonyl) deacetylcolchicine,
    4-chloro-N- (pyrrolidine-1-carbonyl) deacetylcolchicine,
    4-chloro-N- (piperidine-1-carbonyl) deacetylcolchicine,
    4-chloro-N- (trichloroacetylcarbamoyl) deacetylcolchicine,
    4-chloro-N- (dimethylaminoacetyl) deacetylcolchicine,
    4-chloro-N- (diethylaminoacetyl) deacetylcolchicine,
    N- (t-butyloxycarbonylaminoacetyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (aminoacetyl) deacetylcolchicine,
    4-chloro-N- (pyrrolidin-1-ylacetyl) deacetylcolchicine,
    4-chloro-N- (piperidin-1-ylacetyl) deacetylcolchicine,
    4-chloro-N- (3-carboxypropionyl) deacetylcolchicine,
    4-chloro-N- [3- (methoxycarbonyl) propionyl] deacetylcolchicine,
    4-chloro-N- (4-carboxybutyryl) deacetylcolchicine,
    4-chloro-N- [4- (methoxycarbonyl) butyryl] deacetylcolchicine,
    N- (trans-1-carboxycyclohexane-4-yloxycarbonyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (pyridin-3-yloxycarbonyl) deacetylcolchicine,
    4-chloro-N- [1- (dimethylamino) propyl-3-yloxycarbonyl] deacetylcolchicine,
    4-chloro-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine,
    4-chloro-N- [4- (4-morpholinylmethyl) benzoyl] deacetylcolchicine,
    4-chloro-N- (diethylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (pyrrolidine-1-thiocarbonyl) deacetylcolchicine,
    4-chloro-N- (piperidine-1-thiocarbonyl) deacetylcolchicine,
    4-chloro-N- (morpholine-4-thiocarbonyl) deacetylcolchicine,
    4-chloro-N- (thiomorpholine-4-thiocarbonyl) deacetylcolchicine,
    4-chloro-N- (1,1-dioxothiomorpholine-4-thiocarbonyl) deacetylcolchicine,
    4-chloro-N- (1-methylpiperazine-4-thiocarbonyl) deacetylcolchicine,
    (S) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine,
    (S) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine,
    (R) -4-chloro-N- (2-acetoxypropionyl) deacetylcolchicine,
    (R) -4-chloro-N- (2-hydroxypropionyl) deacetylcolchicine,
    4-chloro-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine,
    4-chloro-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine,
    4-chloro-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine,
    4-chloro-N- (1-acetylpiperidine-4-carbonyl) deacetylcolchicine,
    4-chloro-N- (1-benzoylpiperidine-4-carbonyl) deacetylcolchicine,
    4-chloro-N- [1- (tert-butyloxycarbonyl) piperidine-4-carbonyl] deacetylcolchicine,
    4-chloro-N- (piperidine-4-carbonyl) deacetylcolchicine,
    4-chloro-N- [3- (dimethylaminomethyl) benzoyl] deacetylcolchicine,
    4-chloro-N- [3- (triphenylmethyloxy) propionyl] deacetylcolchicine,
    4-chloro-N- (3-hydroxypropionyl) deacetylcolchicine,
    4-chloro-N- (methanesulfonylacetyl) deacetylcolchicine,
    4-chloro-N- [3- (dimethylamino) propionyl] deacetylcolchicine,
    4-chloro-N- [3- (diethylamino) propionyl] deacetylcolchicine,
    4-chloro-N- (3-piperidinopropionyl) deacetylcolchicine,
    N- [N ′-(t-butyloxycarbonyl) -N′-methylaminoacetyl] -4-chlorodeacetylcolchicine,
    N- [N′-benzyl-N ′-(t-butyloxycarbonyl) aminoacetyl] -4-chlorodeacetylcolchicine,
    4-chloro-N- (1-methylpiperidin-4-ylcarbonyl) deacetylcolchicine,
    4-chloro-N- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine,
    4-chloro-N- (N′-methylaminoacetyl) deacetylcolchicine,
    N- (N′-benzylaminoacetyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- [4- (dimethylamino) butyryl] deacetylcolchicine,
    4-chloro-N- [2- (dimethylamino) benzoyl] deacetylcolchicine,
    4-chloro-N- (isobutylthiocarbamoyl) deacetylcolchicine,
    N- (benzylthiocarbamoyl) -4-chlorodeacetylcolchicine,
    4-chloro-N- (cyclohexylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N-[(2-piperidinoethyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-{[2- (4-morpholino) ethyl] thiocarbamoyl} deacetylcolchicine,
    4-chloro-N- (3-pyridylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- [p- (dimethylamino) phenylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N- (4-nitrobenzoyl) deacetylcolchicine,
    4-chloro-N- (2-naphthoyl) deacetylcolchicine,
    4-chloro-N- (2-nitrobenzoyl) deacetylcolchicine,
    4-chloro-N- (4-methylbenzoyl) deacetylcolchicine,
    4-chloro-N- (4-phenylbenzoyl) deacetylcolchicine,
    4-chloro-N- (3,5-dinitrobenzoyl) deacetylcolchicine,
    4-chloro-N- (3,5-dimethylbenzoyl) deacetylcolchicine,
    4-chloro-N- (3-nitrobenzoyl) deacetylcolchicine,
    4-chloro-N- (3,5-dimethoxybenzoyl) deacetylcolchicine,
    4-chloro-N- (2,4-dimethoxybenzoyl) deacetylcolchicine,
    4-chloro-N- (2,4,6-trimethylbenzoyl) deacetylcolchicine,
    4-chloro-N- (4-cyanobenzoyl) deacetylcolchicine,
    4-chloro-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine,
    4-chloro-N- [4- (benzyloxy) butyryl] deacetylcolchicine,
    4-chloro-N- (2-cyanobenzoyl) deacetylcolchicine,
    4-chloro-N- (3-cyanobenzoyl) deacetylcolchicine,
    4-chloro-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine,
    4-chloro-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine,
    4-chloro-N- (3-phenylbenzoyl) deacetylcolchicine,
    4-chloro-N- (4-hydroxybutyryl) deacetylcolchicine,
    4-bromo-N- (t-butyloxycarbonyl) colchicine,
    4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine,
    4-bromodeacetyl colchicine,
    4-bromo-N-propionyl deacetylcolchicine,
    4-bromo-N- (cyclohexanecarbonyl) deacetylcolchicine,
    4-bromo-N-benzoyl deacetyl colchicine,
    4-bromo-N- (phenylacetyl) deacetylcolchicine,
    N-allyl-4-bromo-N- (t-butyloxycarbonyl) deacetylcolchicine,
    4-bromo-N- (trifluoroacetyl) deacetylcolchicine,
    N- (acetoxyacetyl) -4-bromodeacetylcolchicine,
    4-bromo-N- (2-pyridinecarbonyl) deacetylcolchicine,
    N-allyl-4-bromodeacetylcolchicine,
    N- (benzyloxycarbonyl) -4-bromodeacetylcolchicine,
    4-bromo-N-[(methylthio) acetyl] deacetylcolchicine,
    4-bromo-N-[(N ′, N′-dimethylamino) acetyl] deacetylcolchicine,
    4-bromo-N-propyl deacetylcolchicine,
    4-bromo-N- (hexylcarbamoyl) deacetylcolchicine,
    4-bromo-N- (phenylcarbamoyl) deacetylcolchicine,
    4-bromo-N- (hydroxyacetyl) deacetylcolchicine,
    4-bromo-N- (isobutanesulfonyl) deacetylcolchicine,
    4-bromo-N-tosyldeacetylcolchicine,
    4-bromo-N- (2-thiophenesulfonyl) deacetylcolchicine,
    4-bromo-N- (2,4-difluorobenzoyl) deacetylcolchicine,
    4-bromo-N- [3- (N ′, N′-dimethylamino) benzoyl] deacetylcolchicine,
    4-bromo-N- (2-fluorobenzoyl) deacetylcolchicine,
    4-bromo-N- (3-methoxybenzoyl) deacetylcolchicine,
    4-bromo-N- (ethylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (phenylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (N ′, N′-diethylcarbamoyl) deacetylcolchicine,
    4-bromo-N- (piperidin-1-ylcarbonyl) deacetylcolchicine,
    4-bromo-N- (3-hydroxy-2,2-dimethylpropionyl) deacetylcolchicine,
    4-bromo-N- (2-hydroxy-2-methylpropionyl) deacetylcolchicine,
    4-bromo-N- (2-ethyl-2-hydroxybutyryl) deacetylcolchicine,
    4-bromo-N- (1-hydroxycyclopropanecarbonyl) deacetylcolchicine,
    4-bromo-N- [2,2-bis (hydroxymethyl) propionyl] deacetylcolchicine,
    4-bromo-N- (3-hydroxy-3-methylbutyryl) deacetylcolchicine,
    4-bromo-N- [4- (benzyloxy) butyryl] deacetylcolchicine,
    4-bromo-N- (3-nitrobenzoyl) deacetylcolchicine,
    4-bromo-N- (4-cyanobenzoyl) deacetylcolchicine,
    4-bromo-N- (3,5-dimethylbenzoyl) deacetylcolchicine,
    4-bromo-N- (4-methylbenzoyl) deacetylcolchicine,
    4-bromo-N- [3- (pyrrolidin-1-yl) benzoyl] deacetylcolchicine,
    4-bromo-N- (isobutylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (benzylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- [4- (N ′, N′-dimethylamino) phenylthiocarbamoyl] deacetylcolchicine,
    4-bromo-N- (pyridin-3-ylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (N ′, N′-diethylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (pyrrolidin-1-ylthiocarbonyl) deacetylcolchicine,
    4-bromo-N- (piperidin-1-ylthiocarbonyl) deacetylcolchicine,
    4-bromo-N- (4-hydroxybutyryl) deacetylcolchicine,
    4-bromo-N- (thiomorpholin-4-ylthiocarbonyl) deacetylcolchicine,
    4-bromo-N- (1,1-dioxothiomorpholin-4-ylthiocarbonyl) deacetylcolchicine,
    4-bromo-N- (4-methylpiperazin-1-ylthiocarbonyl) deacetylcolchicine,
    4-bromo-N- (morpholin-4-ylthiocarbonyl) deacetylcolchicine,
    4-bromo-N- (ethanesulfonyl) deacetylcolchicine,
    4-chloro-2,3-didemethylcolchicine,
    4-chloro-2,3- (methylenedioxy) -2,3-didemethoxycolchicine,
    4-chloro-2,3- (ethylenedioxy) -2,3-didemethoxycolchicine,
    4-chloro-1,2- (methylenedioxy) -1,2-didemethoxycolchicine,
    4-chloro-N- (ethylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (phenylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (4-piperidinopiperidine-1-carboxyacetyl) deacetylcolchicine,
    4-chloro-N- (1-methylpiperazine-4-carboxyacetyl) deacetylcolchicine,
    4-chloro-N- (dimethylaminoacetoxyacetyl) deacetylcolchicine,
    4-chloro-N- [3- (dimethylamino) propionyloxyacetyl] deacetylcolchicine,
    4-chloro-N- [1- (benzyloxycarbonyl) piperidine-4-carboxyacetyl] deacetylcolchicine,
    4-chloro-N- (thioacetoxyacetyl) deacetylcolchicine,
    4-chloro-N- (mercaptoacetyl) deacetylcolchicine,
    4-chloro-N- [1- (ethoxycarbonyl) piperidin-4-ylcarbonyl] deacetylcolchicine,
    4- (fluoromethyl) colchicine,
    4- (difluoromethyl) colchicine,
    4-chloro-N- (N ′, N′-dimethylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (N ′, N′-dipropylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- [N′-ethyl-N′-propylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-hydroxypiperidin-1-yl) thiocarbonyl] deacetylcolchicine,
    4-chloro-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine,
    4-chloro-N- {N ′-[2- (dimethylamino) ethyl] -N′-methylthiocarbamoyl} deacetylcolchicine,
    4-chloro-N-{[4- (dimethylamino) piperidin-1-yl] thiocarbamoyl} deacetylcolchicine,
    4-chloro-N- (N′-ethyl-N′-methylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- [1-acetylpiperazin-4-yl) thiocarbonyl] deacetylcolchicine,
    4-chloro-N- [N ′-(2-hydroxyethyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [N ′-(3-hydroxypropyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [N ′, N′-bis (2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3-hydroxypropyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4,4-difluoropiperidin-1-yl) thiocarbamoyl] deacetylcolchicine,
    N-[(azetidin-1-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine,
    4-chloro-N-[(indazol-5-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(cis-2,6-dimethylmorpholin-4-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- (2-tolylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (3-tolylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- [3- (dimethylamino) phenylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [4- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [3- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [2,1,3-benzothiadiazol-4-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(2-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3,4-dimethoxyphenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(2-chlorophenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3-chlorophenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-chlorophenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(2-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- (thiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (methylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (n-propylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (n-butylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (tert-butylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (cyclopentylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (isopropylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (n-hexylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N-[(trans-4-hydroxycyclohexyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [2- (dimethylamino) ethylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(p-toluyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- (cyclopropylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N- (allylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N-[(1-methylpiperidin-4-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- (cycloheptylthiocarbamoyl) deacetylcolchicine,
    4-chloro-N-[(2-methoxyethyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(indan-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-sulfamoylphenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3,5-dimethylisoxazol-4-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-hydroxyphenyl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N- (propylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (butylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N-[(2,2,2-trifluoroethyl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N- (cyclopentylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (cyclohexylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N-[(4-methoxyphenyl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-{[2- (4-morpholino) ethyl] thiocarbamoyl} deacetylcolchicine,
    4-bromo-N- (N ′, N′-dimethylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (N′-ethyl-N′-methylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N-[(4-methylpiperidin-1-yl) thiocarbonyl] deacetylcolchicine,
    4-bromo-N-[(4,4-difluoro-piperidin-1-yl) thiocarbonyl] deacetylcolchicine,
    4-chloro-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(isoxazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(3,4-dimethylisoxazol-5-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(5-phenylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    N- (t-butyloxycarbonyl) -4-iodocolchicine,
    N- (t-butyloxycarbonyl) -4-iododeacetylcolchicine,
    4-iodo deacetyl colchicine,
    4-iodo-N-propionyl deacetyl colchicine,
    N-cyclopropylcarbonyl-4-iododeacetylcolchicine,
    4-iodo-N- (trifluoroacetyl) deacetylcolchicine,
    N-ethylsulfonyl-4-iododeacetylcolchicine,
    N- [3- (dimethylamino) benzoyl] -4-iododeacetylcolchicine,
    4-iodo-N- (4-methoxybenzoyl) deacetylcolchicine,
    4-iodo-N- (4-nitrobenzoyl) deacetylcolchicine,
    N- (3,5-difluorobenzoyl) -4-iododeacetylcolchicine,
    N- (3-cyanobenzoyl) -4-iododeacetylcolchicine,
    N- (acetoxyacetyl) -4-iododeacetylcolchicine,
    4-iodo-N- (phenylacetyl) deacetylcolchicine,
    4-iodo-N-propyl deacetylcolchicine,
    N- (hydroxyacetyl) -4-iododeacetylcolchicine,
    N- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] -4-iododeacetylcolchicine,
    4-iodo-N- (pyridin-4-ylcarbonyl) deacetylcolchicine,
    N-phenylsulfonyl-4-iododeacetylcolchicine,
    N- (cyclohexylthiocarbamoyl) -4-iododeacetylcolchicine,
    N- [4- (dimethylamino) phenylthiocarbamoyl] -4-iododeacetylcolchicine,
    N- (benzylcarbamoyl) -4-iododeacetylcolchicine,
    4-iodo-N-[(piperidin-1-yl) carbonyl] deacetylcolchicine,
    N-ethyl-4-iododeacetylcolchicine,
    4-iodo-N-[(piperidin-1-yl) thiocarbonyl] deacetylcolchicine,
    4-iodo-N-[(thiomorpholin-4-yl) thiocarbonyl] deacetylcolchicine,
    N-[(benzimidazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine,
    N-[(benzothiazol-2-yl) thiocarbamoyl] -4-chlorodeacetylcolchicine,
    4-chloro-N-[(pyrimidin-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(pyridazin-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(pyridin-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(pyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(1-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4-methylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(4,5-dimethylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(pyridin-4-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [3- (2-hydroxyethoxy) benzoyl] deacetylcolchicine,
    4-chloro-N- [3- (2-hydroxyethoxy) -4-methoxybenzoyl] deacetylcolchicine,
    4-chloro-N-[(pyrazin-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(1,3,4-thiadiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(pyrimidin-5-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [3- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N- [4- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(1,2-dimethylimidazol-5-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-{[1- (2-hydroxyethyl) -2-methylimidazol-5-yl] thiocarbamoyl} deacetylcolchicine,
    4-chloro-N-{[1- (2-hydroxyethyl) pyrazol-5-yl] thiocarbamoyl} deacetylcolchicine,
    4-chloro-N-{[1- (2-hydroxyethyl) pyrazol-3-yl] thiocarbamoyl} deacetylcolchicine,
    4-bromo-N-[(5-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(1-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(4-cyanopyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(5-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(1-methylpyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(pyrazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(3,4-dimethylisoxazol-5-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(5-methylisoxazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(4-methylthiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(thiazol-2-yl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N- [3- (2-hydroxyethyl) phenylthiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(pyridazin-3-yl) thiocarbamoyl] deacetylcolchicine,
    N-[(azetidin-1-yl) thiocarbonyl] -4-bromodeacetylcolchicine,
    4-bromo-N- (methylthiocarbamoyl) deacetylcolchicine,
    4-bromo-N- (thiocarbamoyl) deacetylcolchicine,
    4-bromo-N-{[1- (2-hydroxyethyl) -1,2,4-triazol-3-yl] thiocarbamoyl} deacetylcolchicine,
    4-bromo-N-{[1- (2-hydroxyethyl) pyrazol-3-yl] thiocarbamoyl} deacetylcolchicine,
    4-bromo-N- [4- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
    4-bromo-N- [3- (2-hydroxyethoxy) phenylthiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(4-cyanophenyl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N-[(2-hydroxyethyl) thiocarbamoyl] deacetylcolchicine,
    4-bromo-N- [N ′-(2-hydroxyethyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
    4-bromo-N- [N ′-(3-hydroxypropyl) -N′-methylthiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(1-methyl-1,2,4-triazol-3-yl) thiocarbamoyl] deacetylcolchicine,
    4-chloro-N-[(1-methyl-1,2,4-triazol-5-yl) thiocarbamoyl] deacetylcolchicine,
    4-Chloro-N-{[1- (2-hydroxyethyl) -1,2,4-triazol-3-yl] thiocarbamoyl} deacetylcolchicine.
  5. 　請求項１～４のいずれか１項記載のコルヒチン誘導体、その塩又はそれらの溶媒和物を含有する医薬。 A pharmaceutical comprising the colchicine derivative according to any one of claims 1 to 4, a salt thereof, or a solvate thereof.
  6. 　請求項1～４のいずれか１項記載のコルヒチン誘導体、その塩又はそれらの溶媒和物、及び薬学的に許容される担体を含有する医薬組成物。 A pharmaceutical composition comprising the colchicine derivative according to any one of claims 1 to 4, a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
  7. 　請求項１～４のいずれか１項記載のコルヒチン誘導体、その塩又はそれらの溶媒和物を含有する抗癌剤。 An anticancer agent comprising the colchicine derivative according to any one of claims 1 to 4, a salt thereof, or a solvate thereof.
  8. 　癌治療用の請求項１～４のいずれか１項記載のコルヒチン誘導体、その塩又はそれらの溶媒和物。 The colchicine derivative, salt or solvate thereof according to any one of claims 1 to 4 for cancer treatment.
  9. 　請求項１～４のいずれか１項記載のコルヒチン誘導体、その塩又はそれらの溶媒和物の有効量を投与することを特徴とする癌の治療方法。 A method for treating cancer, comprising administering an effective amount of a colchicine derivative, a salt thereof or a solvate thereof according to any one of claims 1 to 4.
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