WO2011021397A1 - Dérivés de colchicine - Google Patents

Dérivés de colchicine 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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English (en)
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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Priority to JP2011527589A priority Critical patent/JP5829520B2/ja
Publication of WO2011021397A1 publication Critical patent/WO2011021397A1/fr

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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

L'invention concerne des composés de colchicine modifiés en 4 et des médicaments y faisant appel, et spécifiquement des dérivés de colchicine de formule générale (1), des sels et des solvates correspondants. Dans ladite formule (1), R1 est un atome d'halogène, un groupe hydroxyle, un groupe nitro, un groupe amino, ou un groupe mono-, di- ou tri-fluorométhyle; R2, R3 et R4 sont chacun un groupe méthoxy ou hydroxyle, ou sinon R2 et R3, ou R3 et R4 sont ensemble un groupe méthylènedioxy; R5 et R6 peuvent être identiques ou différents et sont chacun un atome d'hydrogène, un groupe alkyle C1-6, un groupe arylalkyle, un groupe alcényle C2-6, -COR7, -COOR8, -SO2R9, -CONR10R11, ou -CSNR12R13, ou sinon R5 et R6 avec l'atome d'azote auquel R5 et R6 sont liés peuvent former un groupe amino cyclique ayant entre trois et sept éléments; R7 est un groupe alkyle C1-6 ou autre; R8 est un groupe alkyle C1-6 ou autre; R9 est un groupe alkyle C1-6 ou autre; R10 et R11 peuvent être identiques ou différents et sont chacun un atome d'hydrogène, un groupe alkyle C1-6 ou autre; et R12 et R13 peuvent être identiques ou différents et sont chacun un atome d'hydrogène, un groupe alkyle ou autre.
PCT/JP2010/005136 2009-08-20 2010-08-20 Dérivés de colchicine WO2011021397A1 (fr)

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US11273155B2 (en) 2016-12-12 2022-03-15 Daiichi Sankyo Company, Limited Combination of antibody-drug conjugate and immune checkpoint inhibitor
US11318212B2 (en) 2017-08-31 2022-05-03 Daiichi Sankyo Company, Limited Method for producing antibody-drug conjugate
WO2023077977A1 (fr) * 2021-11-08 2023-05-11 天津市昕晨投资发展有限公司 Procédé de préparation d'un dérivé de colchicine et son utilisation
US11872289B2 (en) 2018-05-18 2024-01-16 Daiichi Sankyo Co., Ltd. Anti-MUC1 antibody-drug conjugate
US11945882B2 (en) 2017-08-31 2024-04-02 Daiichi Sankyo Company, Limited Method for producing antibody-drug conjugate

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