WO1998030539A1 - Derives acide thiocarbamique - Google Patents

Derives acide thiocarbamique Download PDF

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Publication number
WO1998030539A1
WO1998030539A1 PCT/JP1998/000034 JP9800034W WO9830539A1 WO 1998030539 A1 WO1998030539 A1 WO 1998030539A1 JP 9800034 W JP9800034 W JP 9800034W WO 9830539 A1 WO9830539 A1 WO 9830539A1
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WIPO (PCT)
Prior art keywords
group
methyl
phenyl
compound
ethyl
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PCT/JP1998/000034
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English (en)
Japanese (ja)
Inventor
Takumi Tokunaga
Kenji Tokuhisa
Hiroyuki Itoh
Takashi Yamamoto
Kimio Katsuura
Naomichi Ishida
Maki Goda
Sumio Matsuno
Yoshihisa Inoue
Kenji Yamauchi
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Tosoh Corporation
Yoshitomi Pharmaceutical Industries, Ltd.
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Publication of WO1998030539A1 publication Critical patent/WO1998030539A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel thiocarbamic acid derivative having squalene epoxidase inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and a method for producing them.
  • lovastatin In order to inhibit cholesterol biosynthesis in vivo, it is said that it is useful to inhibit the activity of enzymes involved in the biosynthesis.
  • cholesterol inhibitors As such cholesterol inhibitors, lovastatin, ebstatin, pravastatin and the like have already been clinically used. [Procedure 'National' Academy 'Science (Proc. Natl. Acad. Sci. USA), 77, 395 (1980), etc.].
  • HMG-CoA reductase 3-hydroxymethylglutarylucoenzyme A reductase
  • this enzyme is a relatively cholesterol biosynthetic system. It is located at an early stage.
  • enzyme inhibition by administration of the above-mentioned drug may also cause synthesis inhibition of other physiologically important metabolites such as dolichol-ubiquinone.
  • triparanol which is known as an inhibitor of an enzyme located late in the cholesterol biosynthesis system, can accumulate desmostol, which causes cataracts.
  • squalene / epoxidase inhibitors that target squalene / epoxidase which is located in the middle stage of the cholesterol biosynthesis system, have less risk of inhibiting the synthesis of other metabolites or accumulating harmful substances in the living body. It is expected to provide highly safe anticholesterol agents.
  • Examples of such squalene epoxidase inhibitors include (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -1-N-ethyl-3— [4- (3-cell) 1-2 —Chenylmethyloxy] benzylamine (NB—598) and other arylamine-based compounds (for example, JP-A-3-141275, WO 93/12069, WO 94 181 91 , WO 95/033 13), dibenzylamine-based compounds (eg, WO 94/18167, JP-A-7-233128), aryl alcohol-based compounds (eg, JP-A-6-49023) Gazettes) and benzylamine compounds (WO 95/18 121) are known.
  • thiocarbamate derivatives are known to be useful as antifungal agents or agricultural chemicals.
  • compounds having antifungal activity have been reported in Japanese Patent Publication No. 39-11213, US Pat. No. 3,395,230, and Japanese Patent Application Laid-Open No. 57-176952. It is known that thiocarbamate having antifungal activity expresses antibacterial activity by inhibiting bacterial steroid synthesis, especially squalene epoxidase. Also, a compound having herbicidal activity is reported in Japanese Patent Publication No. 62-54424. However, it has been reported that thiocarbamate derivatives with antifungal activity show only weak activity against mammalian squalene epoxidase [Drugs of the future), 18 (10), 9 11 (1 993)].
  • An object of the present invention is to provide an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent and an arteriosclerosis which are more safe and have an excellent anti-cholesterol effect than existing drugs. It is to provide a therapeutic and prophylactic agent. Disclosure of the invention
  • the present inventors have conducted intensive studies and as a result, have obtained a thiocarbamic acid having a certain substituent. o
  • the present inventors have found that an ester derivative has a high inhibitory activity on squalene epoxidase derived from mammals, and completed the present invention.
  • R is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, or one or more of oxygen, nitrogen or sulfur atoms, or a combination of each atom.
  • R 1 represents a hydrogen atom or a lower alkyl group. 1 represents an integer of 0 or 1.
  • X and Z are the same or different and each represents a carbonyl group or a group represented by the formula: CHR 9 — wherein R 9 represents a hydrogen atom or a lower alkyl group.
  • m represents an integer of 0 or 1.
  • n represents an integer of 1 or 2.
  • Y is an oxygen atom, a sulfur atom, or a formula: —NR 8 — (wherein R 8 represents a hydrogen atom, a lower acryl group, or a lower alkyl group optionally substituted with a halogen atom.) Represents a group.
  • Q is ethylene, trimethylene or the formula [2]
  • R 2 represents a hydrogen atom or a lower alkyl group.
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkenyl group, a lower alkoxy group, a lower alkylsilyl group, or a (cyano group, a lower alkyl group).
  • Optionally substituted ⁇ represents a lower alkyl group.
  • R 3 and R 4 may be taken together to form a 5- to 6-membered ring.
  • R 7 represents a hydrogen atom or a lower alkyl group.
  • R 6 represents a lower alkyl group which may be substituted with a lower alkoxy group or a cyano group.
  • R 5 represents a hydrogen atom or a lower alkyl group.
  • p represents an integer of 0 or 1.
  • R, R, X, Y, Z, Q, R 2 , 1, m, and n have the same meanings as described above. Represents a hydrogen atom, a lower acryl group or a lower alkoxycarbonyl group. ) Or a salt thereof.
  • Still another aspect of the present invention provides a compound represented by the following general formula
  • Another one of the production methods of the present invention has a general formula [9] as shown in the following reaction formula.
  • Still another one of the production methods of the present invention has a general formula [10] as shown in the following reaction formula.
  • Still another one of the production methods of the present invention has a general formula [12] as shown in the following reaction formula.
  • R, Rh X, Y, Z, Q, R 2 , 1, m , and n represent the same meaning as described above.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the above general formula [1] or a salt thereof, and a pharmaceutically acceptable simple substance.
  • the present invention also provides a squalene epoxidase inhibitor and a therapeutic and / or prophylactic agent for hypercholesterolemia, hyperlipidemia or arteriosclerosis containing the compound represented by the general formula [1] or a salt thereof. Things.
  • examples of the lower alkyl group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl Group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1, 2-trimethylpropyl group, 1, 2, 2-trimethylpropyl group, 1-ethyl-1
  • Examples of the lower alkenyl group include a vinyl group, an aryl group, a 1-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 2-pentenyl group, and a 3-pentenyl group.
  • 4-pentenyl group 1-methylvinyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-ethylvinyl group, 1-ethyl-1-propenyl group, 2-methyl- 1-propenyl group, 1,2-dimethyl-1-propenyl group, 1,1-dimethyl-2-propenyl group, 1,1-dimethyl-3-butenyl group, etc., and preferably 1 -Methylvinyl group, 1-methyl-1-propenyl group, 1,1-dimethyl-2-propenyl group, 1,1-dimethyl-3-butenyl group and the like.
  • Examples of the lower alkyl group which may be substituted with a halogen atom include, in addition to an unsubstituted lower alkyl group, for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1, 1 Difluoro mouth ethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 1,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 2 —Fluoropropyl, 3-fluoropropyl, 2, 2 —Difluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, 1, 1 Dichloro mouth ethyl, 1,2-dichloro mouth ethyl, 2,2-dichloroethyl,
  • Lower alkoxy groups include, for example, methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy, 3-methylbutyloxy, 1,2-dimethylpropyl Oxy, 1,1-dimethylpropyloxy, hexyloxy, 1-methylpentyloxy, 1-ethylpropyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4 -Methylpentyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, 1,1-dimethylbutyloxy, 2,2 —Dimethylbutyloxy group, 3,3-dimethylbutyloxy group, etc., preferably, methoxy group, ethoxy group, propoxy group, isopropoxy group, Examples include a toxic group,
  • Lower alkylsilyl groups include tert-butylsilyl group, sec-butylsilyl group, isobutylsilyl group, isopropylsilyl group, butylsilyl group, propylsilyl group, dimethylsilyl group, getylsilyl group, ethylmethylsilyl group, methylpropylsilyl group Group, isopropylmethylsilyl group, ethylpropylsilyl group, ethylisopropylsilyl group, butylmethylsilyl group, isobutylmethylsilyl group, sec-butylmethylsilyl group, tert-butylmethylsilyl group, ethyl Butylsilyl group, ethylisobutylsilyl group, sec-butylethylsilyl group, tert-butylethylsilyl group, butylprovylsilyl group
  • a trimethylsilyl group, a dimethylethylsilyl group, a dimethylmethylsilyl group, and a Examples include acetylsilyl, dimethylpropylsilyl, ethylmethylpropylsilyl, dimethylisopropylsilyl, butyldimethylsilyl, and tert-butyldimethylsilyl.
  • the lower acetyl group includes, for example, formyl group, acetyl group, propionyl group, butyryl group, isoptyryl group, phenolyl group, 1-methylpropylcarbonyl group, isovaleryl group, pentylcarbonyl group, 1-methylbutylcarbonyl group, Examples thereof include a 2-methylbutylcarbonyl group, a 3-methylbutylcarbonyl group, a 1-ethylpropylcarbonyl group, and a 2-ethylpropylcarbonyl group.
  • Preferred are a formyl group, an acetyl group, a propionyl group, a butyryl group and an isoptyryl group.
  • Examples of the lower alkylamino group include a methylamino group, an ethylamino group, a peptylamino group, a butylamino group, a pentylamino group, an isopropylamino group, an isobutylamino group, a sec-butylamino group, a dimethylamino group, Methylethylamino group, methylpropylamino group, methylbutylamino group, getylamino group, ethylpropylamino group, ethylethylamino group, ethylpentylamino group, dipropylamino group, propylbutylamino group And the like.
  • lower alkyl rubamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propyl carbamoyl, N-butylcarbamoyl, N, N-dimethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.
  • an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-propylcarbamoyl group, an N, N-dimethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, an N, N-getylcarbamoyl group, or the like is used. hole.
  • Examples of the lower alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. And the like. Preferred are a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group and the like.
  • Examples of the lower acyloxy group include a formyloxy group, an acetoxy group, a propionyloxy group, a ptyryloxy group, an isoptyryloxy group, and a valeryloxy group.
  • Preferred are a formyloxy group, an acetoxy group, a propionyloxy group and the like.
  • the lower acylamino groups include formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, amino'relylamino, formyl-1-N-methylamino, acetyl-N-methylamino-, propenyl-amino —Methylamino, formyl-N-ethylamino, acetyl-N-ethylamino, propionyl-N-ethylamino, formyl-N-propylamino, acetyl-N-propylamino, propionyl-N— And a propylamino group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • they are a fluorine atom, a chlorine atom and a bromine atom.
  • Examples of Y include an oxygen atom, a sulfur atom, and a group represented by the formula: —NR 8 —.
  • an oxygen atom or a group represented by the formula: 1 NR 8 — can be mentioned. More preferably, a group represented by the formula: —NR 8 — can be mentioned.
  • R 8 examples include a hydrogen atom, a lower acyl group, and a lower alkyl group which may be substituted with a halogen atom. Preferably, it is a hydrogen atom, a lower acyl group, or a lower alkyl group.
  • the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a pentyl group.
  • Alkyl fluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl, 2-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, Bromoethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 1-fluoro-1-methylethyl group, 2-fluoro-1,1-dimethylethyl group, 2,2-difluoro-1,1-dimethylethyl group, 1,1- Dimethyl-2,2,2-alkyl group substituted with halogen atom such as trifluoromethylethyl group, formyl Aminomethyl group, acetylaminomethyl group, propionylaminomethyl group, petyrylaminomethyl group, 1—formylaminoethyl group, 1
  • N-ethylformylamino ethyl group, 1- (acetyl-N-ethylamino) ethyl group, 1- (N-ethylpropionylamino) ethyl group, 1- (butylethyl N-ethylamino) ethyl Group, 2- (N-ethylformylamino) ethyl group, 2- (acetyl-N-ethylamino) ethyl group, 2- (propionyl-N-ethyl) Rumino) ethyl group, 2— (butylyl N-ethylamino) ethyl group, 1— (N—ethylformylamino) propyl group, 1— (acetyl-N-ethylamino) pill group, N-ethylpropionylamino) propyl group, 1- (butyryl-N-ethylamino) propy
  • a carbamoyl group such as (N, N-dimethylcarbamoyl) -1,1-dimethylpropyl group, 1,1-dimethyl-13- (N-ethyl-N-methylcarbamoyl) propyl group or a lower alkylcarbamoyl group; Examples thereof include a substituted lower alkyl group.
  • R is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, or one or more of oxygen, nitrogen, or sulfur, or two or more of each in combination.
  • the five- and six-membered heterocyclic rings included above can be mentioned. Any substituent may be substituted on the heterocycle.
  • R is an unsubstituted or optionally substituted phenyl group, or five or five or more containing one or more oxygen, nitrogen, or sulfur atoms or a combination of each atom.
  • a six-membered heterocyclic ring can be mentioned. Any substituent may be substituted on the heterocycle. More preferably, R can be a 5- or 6-membered heterocyclic ring containing at least one oxygen atom, nitrogen atom or sulfur atom or a combination of two or more atoms. . Any substituent may be substituted on the heterocycle.
  • X and Z may be the same or different and include a carbonyl group or a group represented by the formula: —CHR 9 —.
  • X and Z may be the same or different and include a group represented by the formula: —CHR 9 —.
  • Q is the formula [2] Is a group represented by
  • R 3 and R 4 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkenyl group, a lower alkoxy group, a lower alkylsilyl group or a (cyano group, a lower alkoxycarbonyl group, a carboxy group, a hydroxy group, Group, amino group, lower alkyl amino group, lower alkoxy group, carbamoyl group, lower alkyl rubamoyl group, lower acetyl group, lower acryloxy group, which may be substituted with a halogen atom or lower acrylamino group) Can be mentioned.
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a halogen atom, a lower Kenyl group, lower alkoxy group, lower alkylsilyl group or (cyano group, lower alkoxycarbonyl group, carboxy group, hydroxy group, amino group, lower alkylamino group, lower alkoxy group, alkamoyl group, lower alkyl A lower alkyl group, which may be substituted with a lower rubamoyl group, a lower acyl group, a lower acyloxy group, or a lower acylamino group.
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a halogen atom, a lower alkylsilyl group or a (cyano group, a lower alkoxycarbonyl group, a carboxy group, a hydroxy group, a hydroxy group, an amino group, (It may be substituted with a lower alkylamino group, a lower alkoxy group or a lower alkoxy group.)
  • a lower alkyl group can be exemplified.
  • Unsubstituted or optionally substituted phenyl groups include phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, and 4-methoxyphenyl.
  • Preferable examples include a phenyl group or a phenyl group in which one to three substituents of a methyl group, a methoxy group, a methylthio group, a mercapto group, a nitro group or a cyano group are substituted at any position.
  • 3-furyl group such as furyl group, 2-phenyl group, 3-phenyl group, 2-methyl-3-phenyl group, 4-methyl-3-phenyl group, 2-methoxycarbonyl-3-phenyl group, 2- Black mouth—3—Chenyl group, 2,5—Dichro mouth—3—Chenyl group, 2—Black mouth 4-Methyl-1—3-Chenyl group, 5—Chloro-1-methyl-3-Cenyl group, 2,5 —Dichloro mouth— 4 monomethyl—3—Chenyl group such as phenyl group, 1—pyraryl group, 2—pyrrolyl group, 3—pyraryl group such as pyrrolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4 Pyrazolyl group such as monopyrazolyl group, 5-pyrazolyl group, 2-oxazolyl group, 4-oxazolyl group, oxazolyl group such as 5-oxazolyl group, 3-isoxazolyl
  • Isoxazolyl group 2— Thiazolyl group such as azolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, isothiazolyl group such as 4-isothiazolyl group, 5-isothiazolyl group, 3- (1,2,5-thiadiazolyl) group, etc.
  • 1,2,4-thiadiazolyl groups such as 1,2,5-thiadiazolyl group, 3- (1,2,4-thiadiazolyl) group and 5- (1,2,4-thiadiazolyl) group
  • six-membered heterocyclic rings such as a pyridyl group such as a cyclic heterocyclic ring, a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group.
  • the substituent is not particularly limited, but specific examples include a lower alkyl group such as a methyl group and an ethyl group, a methoxycarbonyl group, and an ethoxycarbonyl group.
  • a lower alkoxycarbonyl group such as a chloro group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a hydroxy group, an amino group, a lower alkylamino group and a nitro group.
  • heterocyclic ring preferably 3-furyl, 2-phenyl, 3-phenyl, 3-pyrrolyl, 1-pyrazolyl, 4-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 3-isothiazolyl, (1,2,5-thiadiazolyl) group, 2-methyl-3-enyl group, 4-methyl-3-phenyl group, 2-methoxycarbonyl-3-phenyl group, 2-chloro-3-phenyl group, 5 —Dichloro-3 —Chenyl group, 4 —Fluoro-3 —Chenyl group, 2 —Chloro-4-monomethyl— 3 —Chenyl group, 5 —Chloro—4 Monomethyl-3 —Chenyl group, 2,5 It is a 5-membered heterocyclic ring such as 4-methyl-3-phenyl group.
  • Examples of the aromatic substituent represented by the formula [3] include an unsubstituted phenyl group, a 4-methoxyphenyl group, a 4-ethoxyphenyl group, a 4-propoxyphenyl group and a 4-isopropoxyphenyl group.
  • Some of the general formulas [1], [6] and [7] which are the compounds of the present invention include those containing an asymmetric carbon.
  • the compound of the present invention includes a mixture of various optical isomers such as an optically active form, a racemic form and a diastereomer, and an isolated form thereof.
  • Some of the compounds of the general formulas [1], [6] and [7] of the present invention have an amide residue.
  • These amine derivatives may form an acid adduct.
  • Such salts include, for example, mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, lingic acid, Examples thereof include acid adduct salts with organic acids such as tartaric acid, citric acid, methanesulfonic acid, and trifluoromethanesulfonic acid.
  • the compound represented by the formula [6] is R ,. When is a hydrogen atom, it is used as the compound [6a] in the synthesis of the compound [1].
  • the compound represented by the formula [6] is R ,. Is a lower acyl group or a lower alkoxycarbonyl group, and when R 2 is a hydrogen atom, the compound is obtained by deprotecting or reducing the lower acyl group or the lower alkoxycarbonyl group.
  • [6a] is synthesized and used for the synthesis of compound [1]. Further, the compound represented by the formula [6] is R,. When R is a lower acyl group or a lower alkoxycarbonyl group and R 2 is a lower alkyl group, the lower acyl group or the lower alkoxycarbonyl group is deprotected to synthesize compound [6a], and to synthesize compound [1] Used for
  • the compound represented by the formula [6] is a novel compound, and typical examples thereof are shown in Tables 72 to 86. The present invention is not limited thereto.
  • the compound represented by the formula [7] is used for the synthesis of the compound [1].
  • the compound represented by the formula [7] is a novel compound, and typical examples thereof are shown in Tables 87 to 92, but the present invention is not limited thereto.
  • the compounds of the present invention can be produced by various methods, c process exhibits the following typical production methods 1
  • the compound [1] of the present invention can be obtained by converting a halogenated thioformate represented by the general formula [8] and an amine represented by the general formula [6a], for example, in the presence or absence of a base, in the absence of a solvent or in a solvent.
  • the reaction can be carried out at a temperature of 80 ° C to 100 ° C for several minutes to 24 hours.
  • the base examples include inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, hydrogen carbonate carbonate, etc., sodium hydride, lithium hydride.
  • Alkali metal hydrides such as sodium hydroxide, alkaline earth metal hydrides such as lithium, organic lithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, or pyridinium
  • Organic bases such as gin, coridine, lutidine, triethylamine, trimethylenediamine, 1,8-diazabicyclo [5.4.0] -7-pandacene (DBU) can be mentioned.
  • the solvent examples include alcoholic solvents such as methanol, ethanol, propanol, and isopropanol; ketones such as acetone and methylethyl ketone; esters such as ethyl acetate; ethers such as getyl ether and tetrahydrofuran; Nitrites such as cetonitrile, non-protonic polar solvents such as dimethylformamide or dimethylsulfoxide, Solvents such as halogenated carbon such as chloromethane or chloroform, aliphatic hydrocarbons such as hexane, and aromatic hydrocarbons such as benzene and toluene can be used. It is preferable that the compound [8] and the compound [6a] are subjected to the reaction in substantially equimolar amounts or one in a slightly excess mole.
  • the compound represented by the general formula [6a] can be synthesized by various methods, some of which are described below.
  • Compound [6] is obtained by reacting halogen compound [11] with compound [13] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, and at room temperature to heating. It can be produced by reacting for from 24 minutes to 24 hours. This reaction may proceed without solvent, but usually a solvent is used.
  • Such solvents include water, methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylethyl acetate, geethylether, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, dimethylsulfoxide, Examples thereof include dichloromethane, hexane, benzene, and toluene. This reaction proceeds even in the absence of a phase transfer catalyst, but a phase transfer catalyst can be used if necessary.
  • phase transfer catalysts include quaternary ammonium salts such as tetrabutylammonium hydrogensulfate, tetra-n-butylammonium bromide, and benzylammonium chloride, and hexadecyltributylphosphonium bromide. 4 Phosphonium salts and the like can be mentioned.
  • Examples of the basic catalyst include inorganic bases such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydrogencarbonate, and sodium hydride.
  • Alkali metal hydrides such as lithium hydride, alkaline earth metals such as calcium hydride, organic lithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium and lithium diisopropylamide;
  • Organic bases such as gin, lutidine, triethylamine, trimethylenediamine, 1,8-diazabicyclo [5.4.0] —7-indene (DBU) and the like can be mentioned.
  • the amine compound [6a] is prepared by reacting the compound [6] (in the case where R, in the compound [6] is a lower acyl group or a lower alkoxycarbonyl group) with a solvent in the presence of a catalyst. It can be obtained by deprotecting the lower acyl group or lower alkoxycarbonyl group for several minutes to 24 hours under heating.
  • Solvents include water, methanol, ethanol, propanol, isopropanol, ethylene glycol, acetic acid, ethyl acetate, geethylether, tetrahydrofuran, diglyme, chloroform, dichloromethane, nitromethane, acetate nitrile, benzene, etc. Can be.
  • the catalyst examples include acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, aluminum chloride anhydride, and sulfuric acid; basic catalysts such as sodium hydroxide, hydroxylated water and barium hydroxide; trimethylsilyl iodide; trimethylsilyl chloride; Examples thereof include silicon derivatives such as trimethylsilinole triflate.
  • R, R, X, Y, Z, V, Q, 1, m, and n have the same meanings as described above.
  • R i 9 represents a lower acryl group or a lower alkoxycarbonyl group.
  • R 2 represents a lower alkyl group.
  • Compound [6e] can be produced from halogen compound [11] and compound [13a] under the same reaction conditions as in formula 11 above.
  • the amine [6aa] can be produced by reacting the compound [6e] with a reducing agent in the presence of a solvent at 0 ° C. to under heating for several minutes to 24 hours.
  • a solvent include water, methanol, ethanol, propanol, isopropanol, getyl ether, tetrahydrofuran, diglyme and the like.
  • the reducing agent include lithium aluminum hydride and sodium borohydride.
  • compound [6e] When X and Z of compound [6e] are carbonyl groups, compound [6e] may have an amide bond. These amide bonds can be simultaneously reduced to an amino group by the above reduction. Also, by selecting appropriate reaction conditions, selective reduction can be performed.
  • the compound [15] is obtained by converting the nitrous compound [14] and the halogen compound [11] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, at room temperature or under heating. It can be produced by reacting for several minutes to 24 hours. This reaction may proceed without solvent, but usually a solvent is used.
  • solvents include water, methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylethyl acetate, getylether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane.
  • phase transfer catalysts include quaternary ammonium salts such as tetrabutylammonium hydrogensulfate, tetra-n-butylammonium bromide, and benzyl diethylammonium chloride, and hexadecyl tributyl phosphonium bromide. And the like quaternary phosphonium salts.
  • Examples of the basic catalyst include inorganic bases such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydrogencarbonate, hydrogenation.
  • examples include alkali metal hydrides such as sodium and lithium hydride, alkaline earth metals such as calcium hydride, and organic bases such as pyridine, triethylamine, trimethylenediamine and the like.
  • the amine compound [6b] can be produced by reacting the compound [15] with a reducing agent in the presence of a solvent under heating at 0 ° C to a temperature of several minutes to 24 hours.
  • a solvent include getyl ether, tetrahydrofuran, diglyme and the like.
  • the reducing agent include lithium aluminum hydride, borane-tetrahydrofuran complex, and the like.
  • the amine [6b] can also be produced by reacting the compound [15] in the presence of a solvent, in the presence of a hydrogen reduction catalyst such as platinum oxide or palladium ion, and in a hydrogen atmosphere.
  • a solvent include ethanol, ethyl acetate, water and the like.
  • the amine compound [6b] can be protected with a lower acryl group or a lower alkoxycarbonyl group.
  • the amide [6c] (in the case where R and e in compound [6e] represent a lower acyl group.) Is the same as the amine [6b] and an organic acid such as formic acid or acetic acid or an organic acid. It can be produced by reacting an acid derivative or the like in a solvent at room temperature or under heating for several minutes to 24 hours. Examples of the solvent used include methylene chloride, dimethyl ether, dimethylformamide and the like. When dehydrating an amine [6b] with an organic acid such as formic acid or acetic acid, dicyclohexylcarposimide or 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimid is used.
  • a condensing agent such as On the other hand, in the reaction of the amine [6b] with an organic acid derivative such as acetyl chloride or an acetic anhydride, pyridine, triethylamine, sodium carbonate, carbonated lime, hydrogencarbonate are used as dehydrochlorinating agents. A nursery or the like can be used.
  • the olebamate [6d] (in the case of compound [6e], in which R 19 represents a lower alkoxycarbonyl group), the amide [6b] and ethyl ethyl chloroformate, di-tert-dicarbonate It can be produced by reacting -butyl or the like in a solvent in the presence of a basic catalyst at room temperature or under heating for several minutes to 24 hours.
  • Water, meta as solvent Solvents such as ethanol, propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, acetate nitrile, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, and toluene be able to.
  • the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogenated limestone, sodium hydride, and hydrogen.
  • alkali metal hydrides such as lithium chloride, alkaline earth metals such as calcium hydride, and organic bases such as pyridin, triethylamine, and trimethylenediamine.
  • the compound [6aa] can be obtained from the amide [6c] or the force-bombardment [6d] in the same manner as in the method shown in the above formula 1-1.
  • Compound [15] can be obtained by reacting compound [9] with halogen compound [16] in the absence or presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, at room temperature or under heating for several minutes. It can be produced by reacting for 24 hours. This reaction may proceed without solvent, but a solvent is usually used.
  • Such solvents include water, methanol, ethanol, propanol, isopropanol, acetone, methylethyl ketone, ethyl acetate, getyl ether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, dichlorometa And hexane, benzene, toluene and the like.
  • phase-transfer catalyst This reaction proceeds even in the absence of a phase-transfer catalyst.
  • a phase transfer catalyst examples include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide, and benzyltriethylammonium chloride, and hexadecyltributylphosphonium bromide. And other quaternary phosphonium salts.
  • Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogen carbonated lime, and the like, sodium hydride, hydrogen
  • examples include alkali metal hydrides such as lithium hydride, alkaline earth metals such as calcium hydride, and organic bases such as pyridine, triethylamine, and trimethylenediamin.
  • [6 a a] can be synthesized.
  • V represents Z, Q, R, R ,, X, Y, R 2, R 1 0, l, m, n are the same meanings as those described above.
  • Compound [6] can be prepared by reacting compound [9] with halogen compound [17] in the absence of a solvent or in the presence of a solvent, in the presence or absence of a phase transfer catalyst, in the presence of a basic catalyst, at room temperature or under heating for several minutes. It can be produced by reacting for 24 hours.
  • This reaction may proceed without solvent, but usually a solvent is used.
  • solvents include water, methanol, ethanol, propanol, isopropanol, acetone, methylethyl ketone, ethyl acetate, getyl ether, tetrahydrofuran, acetonitril, dimethylformamide, dimethyl sulfoxide.
  • solvents such as dichloromethane, hexane, benzene, and toluene. This reaction proceeds even in the absence of a phase-transfer catalyst. Can be.
  • phase transfer catalysts include quaternary ammonium salts such as tetrabutylammonium hydrogensulfate, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, and hexadecylammonium bromide.
  • quaternary phosphonium salts such as butylphosphonium.
  • Examples of the basic catalyst include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydride, and the like.
  • Metal hydrides such as lithium hydride and the like, alkaline earth metals such as calcium hydride and the like, and organic bases such as pyridine, triethylamine and trimethylenediamin can be mentioned.
  • Compound [6e] can be synthesized from compound [9] and halogen compound [17a] under the same reaction conditions as in the above reaction 115. From the compound [6e], an amine [6aa] can be obtained in the same manner as in the above Reaction formula 1-2.
  • the halogenated thioformate represented by the general formula [8] includes a novel compound. Representative examples of these synthesis methods are shown below.
  • the halogenated thioformate represented by the general formula [8] can be synthesized from the corresponding alcoholic or phenolic compound.
  • the halogenated thioformate represented by the general formula [8] is prepared by reacting the corresponding alcohol or phenolic compound with a halogenothiocarbinating agent such as thiophosgene in the presence of a base, in the absence of a solvent or in a solvent.
  • the reaction can be carried out at 110 ° C. to 100 ° C. for several minutes to 24 hours.
  • the base examples include inorganic bases such as sodium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogenated carbonate, and the like; Alkali metal hydride such as lithium hydride, alkaline earth metal hydride such as lithium hydride, or pyridine, coliidine, lutidine, triethylamine, trimethylenediamine, 1,8-diazabicyclo [5.4.0] 1-7—Organic bases such as pendene (DBU) can be mentioned.
  • inorganic bases such as sodium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogenated carbonate, and the like
  • Alkali metal hydride such as lithium hydride, alkaline earth metal hydride such as lithium hydride, or pyridine, coliidine, lutidine, triethylamine, trimethylenediamine, 1,8-diazabicyclo [5.4.0] 1-7
  • the solvent examples include water and organic solvents such as ⁇ -hexane, cyclohexane, dimethyl ether, tetrahydrofuran, dichloromethane, chloroform, benzene, toluene, and dimethylformamide. Further, several kinds of such solvents may be used as a mixture.
  • the alcohol or phenolic compound and the halogenothiocarbonylating agent such as thiophosgene are preferably used in the reaction in an equimolar amount or in a slight excess of one.
  • the halogenated thioformate represented by the general formula [8] can be isolated and used after its formation.However, an alcohol or a phenolic compound is reacted with a halogenothiolated reagent such as thiophosgene under the above reaction conditions. Then, the resulting halogenated thioformate can be used as it is.
  • the compound [1] of the present invention can be synthesized by directly reacting with the compound [6a] without isolating the halogenated thioformate formed from the alcohol or phenol derivative.
  • the compound of the present invention represented by the general formula [1a] is obtained by mixing a compound represented by the general formula [9] and a compound represented by the general formula [7] without a solvent or in the presence of a solvent in the presence of a phase transfer catalyst. It can be produced by reacting at ⁇ 50 ° C. to 100 ° C. for several minutes to 24 hours in the presence or absence of a basic catalyst.
  • This reaction may proceed without solvent, but usually a solvent is used.
  • solvents include water, methanol, ethanol, propanol, isopropanol, acetate, methylethyl ketone, ethyl acetate, dimethyl ether, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, dichloromethane, Examples of the solvent include hexane and toluene.
  • phase transfer catalysts include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, etc., and hexadecyltributylphosphonium bromide. And the like quaternary phosphonium salts.
  • the basic catalyst examples include inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, hydrogen carbonate carbonate, and the like; Alkali metal hydrides such as lithium and lithium hydride; alkaline earth metals such as calcium hydride; or pyridine, lutidine, triethylamine, trimethylenediamine, 1,8-diazabicyclo [5.4. 0] — 7 — Organic bases such as pendene (DBU).
  • DBU pendene
  • the compounds [9] and [7] are preferably subjected to the reaction in substantially equimolar amounts, or one in a slight excess.
  • Equation 2 The compound represented by the general formula [7] can be produced, for example, as follows. Equation 2—1
  • the compound represented by the general formula [7] is a compound represented by the general formula [10]
  • This reaction may proceed without solvent, but usually a solvent is used.
  • solvents include water, methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethethyl acetate, getyl ether, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, dimethyl sulfoxide.
  • Solvents such as dichloromethane, hexane, benzene, and toluene can be used. This reaction proceeds even in the absence of a phase-transfer catalyst, but a phase-transfer catalyst can be used if necessary.
  • phase transfer catalyst examples include quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium bromide, and benzyltriethylammonium chloride, and hexadecyltributyl bromide. And quaternary phosphonium salts such as phosphonium.
  • the basic catalyst examples include inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, sodium hydride, and hydrogen.
  • Alkali metal hydride such as lithium halide
  • alkaline earth metal hydrides such as calcium hydride
  • organic bases such as pyridine, triethylamine, and trimethylenediamine.
  • the compound [18] is preferably used in an equimolar amount or an excess molar amount with the compound [10].
  • the compound of the present invention [1] is usually reacted with a compound [10] and a halogen compound [11] in a solvent, in the presence of a base, in the presence or absence of a phase transfer catalyst, at room temperature or under heating for several minutes to 24 hours. It can be manufactured by doing.
  • Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylethyl citrate, dimethylether, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane,
  • solvent examples include hexane, toluene, pyridine, lutidine, and ⁇ , ⁇ -methylaniline.
  • inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, hydrogen carbonate carbonate, etc .; hydrogen such as sodium hydride, lithium hydride, etc.
  • Alkali metal hydrides, alkaline metal hydrides such as calcium hydride, or pyridine, triethylamine, trimethylenediamine, 1,8-diazabicyclo [5.4.0] — 7-dendene Organic bases such as DBU). This reaction proceeds even in the absence of a phase-transfer catalyst, but if necessary Transfer catalysts can be used.
  • phase transfer catalyst examples include quaternary ammonium salts such as tetrabutylammonium hydrogensulfate, tetra-n-butylammonium bromide, and benzyl triethylammonium chloride; and quaternary ammonium salts such as hexadecyltributylphosphonium bromide. Phosphonium salts and the like can be mentioned.
  • the compounds [10] and [11] are preferably used in the reaction in substantially equimolar amounts or one in a slight excess.
  • the compound of the present invention [1 c] is usually reacted with an alcohol compound A 2 OH [12] and a thiocarbamate compound [19] in a solvent in the presence of a base at ⁇ 78 ° C. to 100 ° C. for several minutes to 24 hours. It can be manufactured by the following.
  • Examples of the solvent used for the reaction include solvents such as geethylether, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, and toluene.
  • Examples of the base include inorganic bases such as sodium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogenated carbonated lime, and hydrogen such as sodium hydride and lithium hydride.
  • alkaline metal hydrides examples include alkaline metal hydrides, alkaline metal hydrides such as calcium hydride, and organic lithium compounds such as lithium diisopropylamide, n-butyllithium, sec-butyllithium, and tert-butyllithium.
  • a 2 OH [12] is preferably used in the reaction in a slight excess or a large excess over [19].
  • R represents a lower alkyl or lower acyl group.
  • the compound of the present invention [1 e] when RM represents a lower alkyl group, the compound of the present invention [1 d] (where X and Z have the same meanings as described above) usually in a solvent in the presence of a base. ) And an alkylating agent at ⁇ 78 ° C. to 100 ° C. for several minutes to 24 hours.
  • Solvents used for the reaction include solvents such as acetone, methylethyl ketone, ethyl acetate, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, toluene, pyridine and the like. be able to.
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal hydrides such as sodium hydride and lithium hydride, and hydrogen such as calcium hydride.
  • Alkaline earth metal or organic lithium compounds such as lithium diisopropylamide, n-butyllithium, sec-butyllithium and tert-butyllithium can be mentioned.
  • the alkylating agent examples include alkyl halides such as methyl iodide and butyl bromide, and sulfates such as dimethyl sulfate.
  • the alkylating agent and the compound [Id] are preferably subjected to the reaction in substantially equimolar amounts or one in a slight excess.
  • X and Z are the same or different, and the formula: one CHR 9 — (wherein R 9 represents a hydrogen atom or a lower alkyl group. ) Represents, and represents a lower acyl group. ] Is, for example, a compound of the present invention.
  • Compound [l h] of the present invention can be synthesized from compound [7] via compound [20].
  • Compound [20] can be produced by reacting compound [7] with YH 2 in a solvent usually in the presence of a base at ⁇ 78 ° C. to 100 ° C. for several minutes to 24 hours.
  • Solvents used in the reaction include methanol, ethanol, acetone, methylethyl ketone, ethyl acetate, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, toluene, pyridine, etc. Solvents can be mentioned.
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal hydrides such as sodium hydride and lithium hydride; and hydrogenation such as calcium hydride.
  • Al Examples thereof include organic bases such as potassium earth metal, pyridine, triethylamine, and methylamine; and organic lithium compounds such as lithium diisopropylamide, n-butyllithium, sec-butyllithium, and tert-butyllithium. It is preferable that YH 2 and the compound [7] are subjected to the reaction in almost equimolar amounts or one in a slight excess.
  • the compound [1h] of the present invention is usually produced by reacting the compound [20] and the organic acid [21] in a solvent in the presence of a dehydration condensing agent—from 10 ° C. to heating under heating for several minutes to 24 hours. can do.
  • a dehydration condensing agent from 10 ° C. to heating under heating for several minutes to 24 hours. can do.
  • the corresponding acid anhydride or acid halide may be used in place of the organic acid [21].
  • the solvent examples include methylene chloride, methyl ether, dimethylformamide and the like.
  • the dehydrating condensing agent examples include dicyclohexylcarbodiimide and 1-ethyl-13- (3′-dimethylaminopropyl) carbodiimide. It is preferable that the compound [20] and the organic acid [21] are used in the reaction in a substantially equimolar amount or one in a slight excess.
  • the compound of the present invention [1 j] (wherein R and 3 represent a lower alkoxy group, a lower alkylamino group, a lower acryloxy group or a lower alkyl group substituted with a lower acrylamino group, etc.) is usually contained in a solvent.
  • the compound of the present invention [1 (wherein R 12 represents a hydroxy group, an amino group or a lower alkyl group substituted with a lower acylamino group.)
  • an alkylating agent or an acylating agent It can be produced by reacting at a temperature of from 78 ° C to 100 ° C for several minutes to 24 hours in the presence of a base.
  • Used for reaction Solvents include acetone, methyl ethyl ketone, ethyl acetate, ethyl ether, tetrahydrofuran, acetonitril, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, pentane, benzene, toluene, pyridine, lutidine. , N, N-dimethylaniline and the like.
  • the base for example, inorganic bases such as sodium carbonate, sodium carbonate carbonate, sodium hydrogencarbonate, sodium carbonate hydrogen, aluminum hydride metals such as sodium hydride, lithium hydride, calcium hydride, etc.
  • Organic bases such as alkaline earth metal hydrides, pyridine, lutidine, ethyldiisopropylamine or organic lithium compounds such as lithium diisopropylamide, n-butyllithium, sec-butyllithium, tert-butyllithium Can be mentioned.
  • the acylating agent include organic acid chlorides such as acetyl chloride and organic acid anhydrides such as acetic anhydride.
  • Examples of the alkylating agent include an alkyl halide such as methyl iodide bromide or a sulfate such as dimethyl sulfate.
  • the alkylating agent or the acylating agent and the compound [1i] are used in the reaction in almost equimolar amounts or in a slightly excessive molar amount.
  • R 14 represents a lower alkyl group substituted by a lower acylamino group
  • a solvent and a catalyst at 0 ° C. to 120 ° C. for several minutes to 24 hours. It can be obtained by reacting for a time and hydrolyzing the lower acylamino group.
  • the solvent include water, methanol, ethanol, propanol, isopropanol, ethylene glycol, getyl ether, tetrahydrofuran, 1,4-dioxane, diglyme, chloroform, and dichloromethane.
  • the catalyst examples include acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, anhydrous aluminum chloride, and sulfuric acid, and basic catalysts such as sodium hydroxide, a hydroxide hydroxide, and a hydroxide hydroxide.
  • acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, anhydrous aluminum chloride, and sulfuric acid
  • basic catalysts such as sodium hydroxide, a hydroxide hydroxide, and a hydroxide hydroxide.
  • R 16 and R, 7 are the same or different and each represent a hydrogen atom or a lower alkyl group.
  • R 16 and R l7 represent. The same as defined above
  • Examples of the solvent include water, methanol, ethanol, propanol, isopropanol, ethylene glycol, getyl ether, tetrahydrofuran, 1,4-dioxane, diglyme, chloroform and dichloromethane.
  • Examples of the catalyst include acidic catalysts such as hydrochloric acid, acetic acid, trifluoroacetic acid, and sulfuric acid.
  • the compound of the formula [1] inhibits squalene epoxidase very selectively and strongly in vivo, it is used as an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and an anti-atherosclerotic agent Is a useful compound expected.
  • the compound [1] of the present invention can be administered orally or parenterally, and when formulated into a form suitable for such administration, it can be used to produce hypercholesterolemia, hyperlipidemia, It can be used for treatment and prevention of sclerosis and the like.
  • a pharmaceutically acceptable carrier in accordance with the administration form, and then administer the compound after preparing various formulations.
  • Various additives commonly used in the field of pharmaceutical preparations can be used in this case, such as gelatin, hydroxypropyl methylcellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, and white.
  • Celine magnesium metasilicate, magnesium aluminate, anhydrous calcium phosphate, citric acid, sodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid Esters, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light silica anhydride, talc, vegetable oil, benzene alcohol, gum arabic, propylene glycol, hydroxypropyl cyclodextrin, etc. Rukoto can.
  • Dosage forms formulated as a mixture with these excipients include, for example, solid preparations such as tablets, capsules, granules, powders or suppositories, or syrups, elixirs or injections.
  • liquid preparations which can be prepared according to usual methods in the field of preparations. In the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium before use. Also, especially for injection solutions In this case, they may be dissolved or suspended in a physiological saline or glucose solution as needed, and a buffer or a preservative may be added.
  • the preparation of the present invention can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 6% by weight, based on the whole drug. These formulations may also contain other therapeutically effective compounds.
  • the dosage and frequency of administration depend on the sex, age, weight, degree of symptoms and purpose of the patient. In general, for oral administration, 0.01 to 50 mg / kg per adult per day is divided into 1 to several doses, and for parenteral administration, It is preferable to administer 0.001 to 5 mg / kg in 1 to several divided doses.
  • a suspension of acetonitrile (50 ml) of 3.90 g of 3- (3-bromopropyloxy) nitrobenzene, 2.07 g of potassium carbonate and 1.50 g of 3-methylamino-thiothiophene was heated to reflux for 15 hours. After cooling at room temperature, insolubles were removed with a glass filter. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (developing solvent: benzene) to obtain 2.49 g of the target compound as a brown oil.
  • the collected organic layer was washed successively with 1N hydrochloric acid, water, and saturated saline, and dried over anhydrous magnesium sulfate. After the solution was concentrated under reduced pressure, it was purified by silica gel chromatography (developing solvent; hexane) to obtain 10.6 g of the target compound as a colorless oil.
  • Tin (II) chloride dihydrate 9.23 g in ethanol solution 5 Om 1 in N- (3-Cenyl) -1-N-methyl-13- (3-ditrophenoxy) propylamine 2.39 g An ethanol solution of 5 Om 1 was added. The mixture was heated to 60 ° C., and 154 mg of sodium borohydride was slowly added in a nitrogen atmosphere, and the mixture was further stirred at 60 ° C. for 1 hour and at room temperature for 1 hour. After completion of the reaction, the reaction mixture was put into cold water and neutralized with a 15% aqueous sodium hydroxide solution. After distilling off ethanol under reduced pressure, the pH was adjusted to 9 with a 15% aqueous sodium hydroxide solution.
  • a solution of 798 mg of carbodiimide in 2 Om 1 of methylene chloride was added dropwise, followed by stirring at room temperature for 3.5 hours. After the completion of the reaction, the mixture was washed twice with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 938 mg of the target compound as a brown oil.
  • 3-formylaminophenol 1.lg, N-methyl-N-[(3-Chenyl) methyl] —2-promoacetamide 2.0 g, anhydrous potassium carbonate 2.1 g and tetrabutylammonium hydrogen sulfate
  • 3 Om1 in dimethylformamide suspension was stirred at 50 ° C for 15 hours, 25 Om1 of water was added, and the mixture was extracted with ethyl acetate.
  • the collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 1.9 g of a pale yellow solid.
  • Lithium aluminum hydride 195 mg of tetrahydrofuran suspension in 5 ml of ice-cooled N- (3-Chenyl) -N-methyl-13- [3- (formylamino) phenoxy] propylamine 880 mg of tetrahydrofuran After 15 ml of the solution was added dropwise, the mixture was heated under reflux for 1.5 hours. After the reaction was completed, an aqueous solution of sodium hydroxide was added dropwise to produce The solid was filtered off. Water was added to the filtrate, and the mixture was extracted with ether. The collected organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 4: 1) to obtain 713 mg of the target compound as a yellow oil.
  • Chloropho The extract was extracted with aqueous solution, and the collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 33 Omg of a yellow oily substance as a target substance.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés acides thiocarbamiques plus sûrs et plus résistants au cholestérol que les médicaments conventionnels. Ces dérivés acides thiocarbamiques, ou certains de leurs sels tels que le O-(4-tert-butylphényl)N-méthyl-N-[3-[2-[N-méthyl-N-(3-thiénylméthyl)amino]éthoxy]phényl]thiocarbamate, sont caractérisés en ce qu'ils sont représentés par la formule générale (1). L'invention concerne également un hypocholestérolémiant, un hypolipidémiant, et un médicament préventif et curatif contre l'artériosclérose.
PCT/JP1998/000034 1997-01-09 1998-01-08 Derives acide thiocarbamique WO1998030539A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1330497 1997-01-09
JP9/13304 1997-01-09

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WO1998030539A1 true WO1998030539A1 (fr) 1998-07-16

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PCT/JP1998/000034 WO1998030539A1 (fr) 1997-01-09 1998-01-08 Derives acide thiocarbamique

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0971562A (ja) * 1995-06-27 1997-03-18 Green Cross Corp:The チオカルバミン酸誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0971562A (ja) * 1995-06-27 1997-03-18 Green Cross Corp:The チオカルバミン酸誘導体

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