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WO1995004723A1 - Derive d'imidazolylalkylamine et composition pharmaceutique contenant ledit derive - Google Patents

Derive d'imidazolylalkylamine et composition pharmaceutique contenant ledit derive Download PDF

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Publication number
WO1995004723A1
WO1995004723A1 PCT/JP1994/001278 JP9401278W WO9504723A1 WO 1995004723 A1 WO1995004723 A1 WO 1995004723A1 JP 9401278 W JP9401278 W JP 9401278W WO 9504723 A1 WO9504723 A1 WO 9504723A1
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group
lower alkyl
alkyl group
substituted
methyl
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Japanese (ja)
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Minoru Okada
Toru Yoden
Eiji Kawaminami
Yoshiaki Shimada
Tsukasa Ishihara
Masafumi Kudou
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to imidazolylalkylamine derivatives and pharmaceutical compositions thereof.
  • the present invention relates to a novel imidazolylalkylamine derivative useful as a steroid 17-20 lyase inhibitor, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition.
  • the production of androgen from cholesterol in the living body involves the enzyme steroid 17-20 lyase at the final stage of its biosynthetic pathway.
  • the steroid 17-20 lyase is produced from cholesterol and has a carbon substituent at the 17 yS position, using 17-OH-pregnenolone and 17-OH-progesterone as substrates.
  • the bond between carbon and the carbon at position 20 of the carbon substituent is cleaved to produce an androgen. Therefore, by inhibiting the enzymatic activity of steroid 17-20 lyase, it is possible to suppress the production of androgen and the production of estrogen synthesized using androgen as a substrate, androgen and estrogen as hate factors.
  • steroid 17-20 lyase inhibitors can reduce estrogen, they are a more effective therapeutic agent for benign prostatic hyperplasia than those that block only androgens, and The drug is expected to have fewer side effects.
  • steroid 17-20-lyase inhibitors have been synthesized as steroid-type compounds and non-steroid-type compounds.
  • C As non-steroidal steroid 17-20-lyase inhibitors, For example, a (1H-imidazole-1-yl) methyl-substituted imidazole derivative in which a substituted benzimidazolyl group and an imidazolyl group described in JP-A-64-895975 are bonded by a methine carbon or a methylene carbon It has been known.
  • imidazolylalkylamine compounds having the structure of the compound of the present invention include, for example, Japanese Patent Publication No. 3-44072, imidazolylmethyl secondary amine derivatives having diuretic, antithrombotic, Shows antihypertensive action Proc. Int. Conf. 8th '1973 (Pub. 1974), 934-944 states that prillamines such as prillamine tertiary with imidazolylethyl and acetyl groups Are disclosed, respectively, as compounds exhibiting a cytokinin-induced germination inhibitory action, but there is no description of a steroid 17-20 lyase inhibitory action. Further, the present invention is a novel compound having a different structure from these compounds.
  • the present inventors have conducted intensive studies on compounds having a steroid 17-20 lyase inhibitory action under the state of the art, and as a result, have found that imidazolylalkylamine derivatives represented by the following general formula (I) or pharmaceuticals thereof.
  • the present inventors have found that the salts permitted in the present invention have an excellent steroid 17-20 lyase inhibitory action, and have completed the present invention.
  • R 1 is a hydrogen atom or a lower alkyl group
  • a lower alkylene group which may have one- minute technique which may have one- minute technique
  • R 3 alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, group represented by formula —A 3 —R 4 , halogeno lower alkyl group, cyano lower alkyl group, or substitution with a nitrogen atom as a hetero atom A young or unsubstituted heterocyclic group,
  • a 3 a lower alkylene group or a carbonyl group (—CO—) which may have a partial technique
  • R 4 a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic group having a nitrogen atom as a hetero atom.
  • the group —A 2 —R 2 and the group R 3 may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted tricyclic or tetracyclic fused heterocyclic ring, (2) When —A 2 —R 2 is a substituted or unsubstituted phenyl group or a benzyl group,
  • One A 1 -N is bonded to the 4- or 5-position of the imidazole ring.
  • the present invention also relates to a pharmaceutical composition, particularly a steroid 17-20 lyase inhibitor, comprising the above imidazolylalkylamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the present invention is an imidazolyl group which is tertiary-modified with a ring system or a ring alkyl group having at least one benzene ring at the amino nitrogen atom and various alkyl, ring alkyl or ketone substituents. It has the characteristic of a chemical structure in that it is a alkylamine
  • lower means a carbon chain having 1 to 6 carbon atoms.
  • a lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Accordingly, as the lower alkyl group, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl Group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl Group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbuty
  • the alkyl group represented by R 3 is preferably a linear or branched alkyl group having 1 to 8 carbon atoms.
  • a heptyl group, an isoheptyl group, And an octyl group and an isooctyl group is preferably a linear or branched alkyl group having 1 to 8 carbon atoms.
  • lower alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylaryl group, 1-methyl-1-propyl Nyl, 1-methylaryl, 1, 1-dimethylvinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3 —Methyl—3-butenyl group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group, 1—methyl-1-butenyl group, 1—methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethylaryl group, 1,2-
  • the “lower alkynyl group” is a straight- or branched-chain alkynyl group having 2 to 6 carbon atoms, and specifically includes an ethynyl group, a 1-propynyl group, a 2-propynyl group, and a 1-butynyl group.
  • a lower alkylene group which may have a partial technique is a straight-chain alkylene group having 1 to 6 carbon atoms and any methylene hydrogen of the straight-chain alkylene group is substituted with the above lower alkyl group.
  • Alkylene group having a special technique for example, methylene group, ethylene group, methylmethylene group, trimethylene group, propylene group, 1-methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2 —Methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2-ethylethylene group, 1,2-dimethylethylene group, pentamethylene group, hexamethylene group, propylmethylene group, isopropylmethylene group, butyrate Lmethylene group, isobutylmethylene group, 2-methylbutane 1-1,1-diyl group, 2,2-dimethylpropane 1-1,1 Jiiru groups, hexane - 1, 1 one Jiiru group
  • the “cycloalkyl group” preferably has 3 to 8 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • halogeno lower alkyl group means a group in which any hydrogen atom of the lower alkyl group is substituted with a halogen atom, specifically, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a halogen atom such as a fluorine atom include a trifluoromethyl group and a 2,2,2 trifluoroethyl group.
  • “Syano lower alkyl group” means a group in which any hydrogen atom of the lower alkyl group is substituted with a cyano group, specifically, a cyanomethyl group, a 2-cyanoethyl group, a 1-cyanoethyl group, a 3-cyanopropyl group. , 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl And the like can be exemplified as suitable groups.
  • a bicyclic or tricyclic hydrocarbon group having a fused benzene ring means a bicyclic or tricyclic carbocyclic group having at least one fused benzene ring, and specifically, a naphthyl group, a dihydro Naphthyl group
  • Examples include at least one tricyclic hydrocarbon ring group.
  • a bicyclic or tricyclic condensed heterocyclic group J having a heterocyclic ring having an oxygen atom and Z or a sulfur atom and / or a nitrogen atom as a heteroatom and a condensed benzene ring is preferably an oxygen atom, a sulfur atom and a nitrogen atom.
  • Nitrogen atom such as trahydrocinnolinyl group Atom as a bicyclic fused heterocyclic group, benzothiazolyl group, dihydrobenzene thiabril group sothiazolyl group, dihydrobene, diisothiazoly, benzoxazolyl group, dihi
  • Dihydrobenzisoxazolyl group (NH K benzothiadiazolyl group, benzoxaziazolyl group, benzothiazinyl group, dihydric benzothiazinyl group zoxazinyl group, dihid etc.
  • Hetero oxygen or sulfur atoms such as benzofurfuryl group, dihydroisobenzofuryl group, benzodithiolanyl group, benzodioxolyl group, benzothienyl group, chromenyl group, chromanyl group, and isochromanyl group
  • Tricyclic fused heterocyclic group having a nitrogen atom and a ⁇ or oxygen atom and / or a sulfur atom as a hetero atom.
  • heterocyclic group having a nitrogen atom as a hetero atom preferably, for example, a pyrrolyl group, a pyrrolinyl group, a pyrrolidinyl group, an imidazolyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolyl group, a virazolidinyl group, a virazolidinyl group , Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, virazinyl, indolyl, isoindolinyl, quinolyl, isoquinolyl, etc. And heterocyclic groups.
  • the “3-ring or 4-ring fused heterocyclic group” formed by the group — ⁇ 2 — R 2 and the group R 3 together with the adjacent nitrogen atom is represented by the following formula
  • ⁇ 2 has the above-mentioned meaning
  • ⁇ 4 is a lower alkylene group which may have a partial technique
  • ring ⁇ is a substituted or unsubstituted two or three ring having a fused benzene ring.
  • ring examples include a fluorenyl group, such as a dihydro-fluorenyl pyrrole ring group, a tetrahydro-monofluorene pyridine ring group, and a tetrahydro-fluorene group. And a diloazepine ring group.
  • Substituted fuunyl group '', ⁇ substituted bicyclic or tricyclic hydrocarbon ring group having a fused benzene ring '', ⁇ oxygen and / or sulfur and / or nitrogen Substituted two- or three-ring fused heterocyclic group having a heterocyclic ring and a fused benzene ring, a "substituted heterocyclic group having a nitrogen atom as a hetero atom", and a group A 2 — R 2
  • the group — a substituted 3- or 4-condensed heterocyclic ring formed by R 3 together with an adjacent nitrogen atom '' is a substituent used in the art as a substituent on a benzene ring or a heterocyclic ring
  • the group is not particularly limited as long as it is a group, and among these, the following groups are mentioned as examples.
  • Lower alkyl group lower alkenyl group, lower alkynyl group, halogeno lower alkyl group, cyano lower alkyl group, etc.
  • Cycloalkyl group (may be further substituted by one or more lower alkyl groups)
  • a phenyl group (which may be further substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a cyano lower alkyl group, a cyano group, and a nitro group) Good) etc.
  • Aralkyl substituent A phenyl lower alkyl group (further substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a cyano lower alkyl group, a cyano group and a nitro group; May be)
  • Hydroxyl group (sometimes in a tautomeric relationship with oxo group and keto-enol), lower alkoxy group, lower alkanoyloxy group, phenoxy group (further, halogen atom, lower alkyl group, halogeno lower alkyl group, cyano lower group) May be substituted with one or more substituents selected from the group consisting of an alkyl group, a cyano group and a nitro group; a phenyl lower alkoxy group (further, a halogen atom, a lower alkyl group, a halogeno lower alkyl) (7) oxo-type substituents, which may be substituted with one or more substituents selected from the group consisting of a group, a cyano lower alkyl group, a cyano group and a nitro group.
  • Oxo group (may have a keto-enol tautomerism with the hydroxyl group, and also includes oxoxide and dioxide bonded to the ring nitrogen and sulfur atoms.)
  • Heterocyclic group containing at least a nitrogen atom and optionally containing a sulfur atom and Z or an oxygen atom (further a group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a cyano lower alkyl group, a cyano group and a nitro group May be substituted with one or more substituents selected from). One or more of these substituents may be substituted.
  • halogen atom lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, halogeno lower alkyl group, and shiryono lower alkyl group
  • phenyl lower alkyl group "Means a group in which an arbitrary hydrogen atom of the lower alkyl group is substituted with a phenyl group, and specific examples include a benzyl group, a phenyl group, a benzylhydryl group and a trityl group.
  • lower alkoxy group specifically, for example, a methoxy group, an ethoxy group, a propoquine group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group And the like.
  • lower alkanoyloxy group examples include a formyloxy group, an acetoxy group, a propionyloxy group, a ptyryloxy group, an isoptyryloxy group, a valeryloxy group, an isovaleryloxy group, a vivaloyloxy group, and a hexanoyloxy group.
  • Phenyl lower alkoxy group means a group in which an arbitrary hydrogen atom of the lower alkoxy group is substituted with a phenyl group. Specifically, for example, a benzyloxy group, a phenyloquine group, a phenylpropoxy group, a phenylbutoxy group And the like.
  • the compounds of the present invention may form salts.
  • the present invention includes pharmaceutically acceptable salts.
  • Such salts include acid addition salts and quaternary ammonium salts.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, With organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, carbonic acid, aspartic acid, glutamic acid Acid addition salt, lower alkyl And quaternary ammonium salts obtained by reaction with benzyl halide, lower alkyl triflate, lower alkyl tosylate, and benzyl halide.
  • the compound of the general formula (I) may have an optical isomer based on an asymmetric carbon atom or a geometric isomer based on a double bond or a cyclohexane ring.
  • the present invention includes mixtures of these various isomers, such as geometric isomers and optical isomers, and separated isomers.
  • the present invention also includes hydrates, various solvates, tautomers and the like of the compound of the general formula (I). Further, some of the compounds of the present invention have a polymorphism, and all of these crystal forms are included.
  • a particularly preferred compound is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom or a lower alkyl group
  • a lower alkylene group which may have one- minute technique which may have one- minute technique
  • a 2 lower alkylene group which may have a bond or a division
  • R 2 ′ halogen atom, lower alkyl group, cycloalkyl group, phenyl group (further selected from the group consisting of halogen atom, lower alkyl group, halogeno lower alkyl group, cyano lower alkyl group, cyano group and nitro group May be substituted with one or more substituents), phenyl lower alkyl group (further from halogen atom, lower alkyl group, halogeno lower alkyl group, cyano lower alkyl group, cyano group and nitro group) May be substituted with one or more substituents selected from the group consisting of: a hydroxyl group, a lower alkoxy group, a phenoxy group (further a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a cyano lower alkyl group, May be substituted with one or more substituents selected from the group consisting of a cyano group and
  • R 3 ′ d-C 8 alkyl group, lower alkenyl group, lower alkynyl group, C 3 —C 8 cycloalkyl group, group represented by the formula A 3 —R 4 ′, halogeno lower alkyl group, cyano lower alkyl Or a heterocyclic group having a nitrogen atom as a hetero atom (in addition, one or more selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a cyano lower alkyl group, a cyano group and a nitro group) Is substituted with a substituent of )
  • a 3 a lower alkylene group or a carbonyl group (—CO—) which may have a partial technique
  • R 4 ′ a C 3 -C 8 cycloalkyl group (which may be further substituted by one or more lower alkyl groups), a phenyl group (further a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a cyano lower alkyl) Or a heterocyclic group having a nitrogen atom as a hetero atom (further, a halogen atom, a lower atom or a lower atom may be substituted with one or more substituents selected from the group consisting of It may be substituted with one or more substituents selected from the group consisting of an alkyl group, a halogeno lower alkyl group, a cyano lower alkyl group, a cyano group and a nitro group).
  • a 1 -NT binds to the 4- or 5-position of the imidabul ring ⁇ R 3 '
  • a more preferable compound is a 41-imidazolylmethylamine derivative represented by the following general formula (IE) or a pharmaceutically acceptable salt thereof.
  • R, A 2 , R 2 ′ and R 3 ′ have the meaning described above, and R 5 represents a hydrogen atom or a d—C 5 alkyl group
  • R 2 ′ and R 3 ′ represent the following R 2 ′′ and R 3 ′′ or a pharmaceutically acceptable salt thereof.
  • R 2 a halogen atom, a lower alkyl group, a phenyl group, a phenyl lower alkyl group (which may be further substituted with a cyano group), a hydroxyl group, a lower alkoxy group, a phenyl group (which is further substituted with a lower alkyl group; Oxo group, imidabryl group (may be further substituted with lower alkyl group), benzimidabril group (may be further substituted with lower alkyl group), thiazolyl group (lower alkyl group) Or a benzothiazolyl group (which may be further substituted with a lower alkyl group), which may be substituted with one or more substituents selected from the group consisting of Group,
  • R 3 " a C 1 -C 8 alkyl group, a lower alkenyl group, a C 3 -C 8 cycloalkyl group, a group represented by the formula A 3 -R 4 ", a trifluoromethyl group, or a cyano lower alkyl group,
  • a 3 ' a lower alkylene group which may have a partial technique
  • R 4 " a C 3 -C 8 cycloalkyl group, a phenyl group (in addition, 1 or 2 selected from the group consisting of a halogen atom, a cyano group and a nitro group) Or a 5- or 6-membered heterocyclic group having a nitrogen atom as a hetero atom.
  • the most preferred compound is a compound of the formula (I) wherein R 2 is substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group and an oxo group.
  • a pharmaceutically acceptable salt thereof which is a tricyclic hydrocarbon ring group having a condensed benzene ring which may be optionally selected from the group consisting of a lower alkyl group, a hydroxyl group and an oxo group.
  • Suitable compounds include fluorenyl groups which may be substituted with the above substituents, or pharmaceutically acceptable salts thereof.
  • protective groups include, for example, green
  • R 1 , A 1 , A 2 , R 2 and R 3 have the above-mentioned meanings, and other symbols have the above-mentioned meanings.
  • R 6 the same group as R 2 which may have a protecting group
  • R 7 hydrogen atom, lower alkyl group or protecting group
  • a 5 bond or a lower alkylene group which may have a divisional technique (however, the total number of carbon atoms with R 8 is an integer of 1 to 5)
  • R 8 a hydrogen atom or a lower alkyl group
  • X 1 a halogen atom or an organic sulfonic acid residue
  • R 9 hydrogen atom or the same group as R 4 which may have a protecting group, A 6 alkylene group which may have a bond or a partial technique (however, the total number of carbon atoms of R 1 (1 is Integer from 1 to 7.
  • R 10 hydrogen atom or lower alkyl group
  • R 11 the same group as R 3 which may have a protecting group
  • R 11 When R 11 is a good R 4 -CO- may have a protecting group is an activating group of the hydroxyl group or a carboxylic acid, when R 11 is a group other than said halogen atom or an organic sulfonic Acid residues,
  • a 7 a lower alkylene group which may have a bond or a partial technique (however, the total number of carbon atoms with R 12 is an integer of 1 to 5),
  • R 12 a hydrogen atom or a lower alkyl group.
  • one A 2 —R 6 and R 11 may be united with an adjacent nitrogen atom to form a substituted or unsubstituted tricyclic or tetracyclic heterocyclic group which may have a protecting group.
  • the compound (I) of the present invention has a tertiary amine as shown in the above reaction formula.
  • R 1- N And using one of the components of the primary Amin of any two components one R 3 as the starting compound, the other component of the aldehyde or ketone or pay de or sulphonate or carboxylic acid or other material that activation derivative conductor
  • the compound is used as a compound to undergo reductive amination (Method A) or N-alkylation or N-acylation (Method B) to synthesize a secondary amine or amide.
  • Reductive amination (method A) or N-alkylation or N-acylation (method B) to react with aldehyde or ketone or halide or sulfonate or carboxylic acid or activated derivative thereof and react with it. It can be produced by synthesizing a secondary amine or amide and, if necessary, removing the protecting group.
  • the halogen atoms represented by X 1 and Y include those described above.
  • the organic sulfonic acid residue include alkane sulfonyloxy groups such as methanesulfonyloxy (mesyl) group and ethanesulfonyloxy group.
  • aromatic sulfonyloxy groups such as a benzenesulfonyloxy group and a toluenesulfonyloxy (particularly, p-toluenesulfonyloxy (tosyl)) group.
  • Examples of the carboxylic acid activating group represented by Y include a halogen atom constituting an acid halide such as an acid chloride and an acid promide; an azide group constituting an acid azide; and benzotriazole which constitutes an active ester.
  • Active ester residue such as 1-yloxy group and succinimide 1-yloxy group; R 4 -COO 1 which may have a protecting group constituting an acid anhydride; alkyl carbonate, p-toluenesulfonic acid, etc.
  • Alkoxy carboxy groups constituting mixed acid anhydrides ⁇ Acid residues such as P-toluenesulfonyloxy groups; and other normal ester residues such as alkoxy groups forming normal esters such as methyl esters and ethyl esters What And so on.
  • the method A is a reductive amination in which the amine is reacted with an aldehyde or a ketone, and the resulting Schiff base is isolated or not, and then the Schiff base is reduced.
  • the ordinary law can be applied.
  • the reaction is carried out in an organic solvent inert to the reaction, for example, an aromatic hydrocarbon solvent such as benzene, toluene, xylene, an alcohol solvent such as methanol, ethanol, or isopropanol, dichloromethane, dichloroethane, or chloroform.
  • an aromatic hydrocarbon solvent such as benzene, toluene, xylene
  • an alcohol solvent such as methanol, ethanol, or isopropanol
  • a halogenated hydrocarbon solvent or an organic solvent such as acetic acid
  • the corresponding amounts of the amine and the aldehyde or ketone, or one of them are used as a slight molar excess, preferably p-toluenesulfonic acid, adipic acid, or oxalic acid.
  • reaction temperature is preferably set from room temperature to heating, and depending on the reaction conditions, azeotropic or reflux temperature.
  • the resulting Schiff base is reduced in the reaction solution at the previous stage or in a solvent inert to the reaction, for example, an alcoholic solvent such as methanol, ethanol, or isopropanol, an organic solvent such as acetic acid, water, or a mixed solvent thereof.
  • a metal hydride complex such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a reducing agent such as borane is advantageously added to react. . (B) Method B
  • the N-alkylation reaction in the method B is a reaction in which a primary or secondary amamine is reacted with a halide or a sulfonate to synthesize a secondary or tertiary amine, and in the present invention, a conventional method can be applied. .
  • a protecting group for suppressing the tertiary conversion such as a toluenesulfonyloxy group, an acetyl group, or a phenyl group.
  • a method of introducing a nasylsulfonyl group, a trifluoromethanesulfonyl group, a bisbenzenesulfonyl group, or the like to secondary amination and then removing the protecting group can be employed.
  • the N-alkylation reaction uses a reaction compound in an amount corresponding to or slightly in excess of one mole of the starting compound, and is a solvent inert to the reaction, for example, dimethylformamide; dimethylsulfoxide; ketones such as acetone and methylethylketone.
  • Solvents Halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform; Alcohol solvents such as methanol, ethanol, isopropanol, cellosolve (2-ethoxyethanol), and methylcellosolve (2-methoxyethanol); Ether-based solvents such as ether, tetrahydrofuran, dioxane, monoglyme (dimethoxyne), diglyme [bis (2-methoxethyl) ether]; organic solvents such as water; When cool down to room temperature, c When Lee de preferably carried out under a temperature condition of 0 ⁇ 1 5 0 ° C.
  • the ⁇ -acylation reaction in the method (1) is a reaction in which primary or secondary amine or a salt thereof is reacted with hepatic acid or an activated derivative thereof to form a ⁇ -acylated compound. Standard methods can be applied.
  • the reaction varies slightly depending on the type of activated derivative, etc., but halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform; ether solvents such as ether, tetrahydrofuran, and dioxane; aromatic solvents such as benzene, toluene, and xylene Type of activated derivative using a raw material compound in which the amount corresponding to the reaction or one of them is slightly excessive in a solvent inert to the reaction, such as an aromatic hydrocarbon solvent; dimethylformamide; ethyl acetate; acetonitrile; Depending on the case, the reaction is carried out under cooling, from cooling to room temperature, from room temperature to heating.
  • halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, and chloroform
  • ether solvents such as ether, tetrahydrofuran, and dioxane
  • aromatic solvents such as benzene, tol
  • an organic base such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, dimethylaniline, etc.
  • Potassium carbonate, sodium carbonate, hydrogen carbonate It may be advantageous to carry out the reaction in the presence of an inorganic base such as thorium, sodium hydroxide, hydroxylating lime.
  • the removal of the protecting group as required depends on the type of the protecting group, but for example, an imidazole ring imino group or an aralkyl group such as a benzyl group, a benzhydryl group or a trityl group in which the protecting group of the diamino group is substituted or unsubstituted.
  • Some urethane-type protecting groups such as system-protecting groups and substituted or unsubstituted benzyloxycarbonyl are hydrogenated under the catalyst of palladium black, palladium oxide, palladium hydroxide, platinum, platinum oxide, Raney nickel, etc.
  • Catalytic reduction, or acid treatment in a hydrobromic acid, hydrochloric acid, hydrofluoric acid, acetic acid, trifluoroacetic acid, a mixed acid thereof, or a mixed solvent of these and dioxane is used.
  • the protecting group is another perylene type protecting group such as a tert-butoxycarbonyl group
  • the protecting group for the amino group is a phthalimid group formed integrally with the amino amino group
  • the amino group is treated with a hydrazine such as hydrazine, methylhydrazine or ethylhydrazine, or a primary amine such as methylamine, ethylamine or propylamine.
  • a hydrazine such as hydrazine, methylhydrazine or ethylhydrazine
  • a primary amine such as methylamine, ethylamine or propylamine.
  • the compound (lb) of the present invention in which a lower alkyl group is substituted on the imidazole ring nitrogen can be produced by N-alkylating the corresponding imidazole compound (Ia) and, if necessary, subsequently removing the protecting group.
  • the reaction is carried out in the same manner as the N-alkylation in Method B (i) of the first production method and the removal of the protecting group in (C).
  • the compound of the present invention having a heterocyclic group having a nitrogen atom substituted with N-lower alkyl as a hetero atom, a mono- or di-lower alkylamiso group, or the like as R 2 and R 3 may also be N-alkylated, if necessary. Then, it can be produced by removing the protecting group. It can also be N-alkylated at the same time.
  • the compound (Ic) in which A 1 is a group represented by —A 5 —CH 2 — reduces the corresponding acid amide, and if necessary, the protecting group Can be produced.
  • Examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium borohydride, bis (2-methoxyethoxy) aluminum sodium hydride, sodium trithioborohydride, and metal hydrides such as diborane.
  • metal hydrides such as lithium aluminum hydride, sodium borohydride, bis (2-methoxyethoxy) aluminum sodium hydride, sodium trithioborohydride, and metal hydrides such as diborane.
  • An ordinary amide reducing agent that converts —CON to —CH 2 N ⁇ by the reduction of, for example, can be used. It can also be reduced by catalytic hydrogenation using Raney nickel or the like as a catalyst.
  • This production method is advantageously applied to compounds that do not contain a radical group such as 1 CO— or 1CON ⁇ in R 6 or R 11 of the starting compound, but the starting compound having 1 CO——CON ⁇ In such a case, these groups can also be reduced at the same time.
  • the starting compound (XV) is prepared by reacting a corresponding carboxylic acid or an activated derivative thereof with a corresponding amine or a salt thereof as shown in the following reaction formula, by the first production method B (ii) N-acylation It can be easily obtained by reacting in the same manner as described above.
  • R 13 is a lower alkyl group or a protecting group for imidazolyl nitrogen
  • ring C is a substituted or unsubstituted benzene ring, a substituted or unsubstituted bicyclic hydrocarbon ring, or an oxygen atom and / or a sulfur atom and a nitrogen atom
  • X 2 represents a halogen atom.
  • a compound obtained by condensing an imidazole ring, an oxazolyl ring and a thiazole ring is a cyclic It can be produced by reacting a haloketone (XVII) with an amidine, guanidine, amide,
  • the reaction is carried out by methanol.
  • methanol Such as ethanol, isopropanol, etc.
  • Alcohol solvents, ether solvents such as ether, tetrahydrofuran, dioxane, etc.
  • aromatic hydrocarbon solvents such as benzene, toluene, xylene, etc.
  • a salt of an inorganic base such as sodium hydroxide, hydroxide hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium carbonate, or a weak acid and a strong base, or pyridine or disopropyl It may be advantageous to add a base such as ethylamine to make the reaction proceed smoothly.
  • imidazoles can be given as a main product when the reaction is carried out under the reaction conditions of adding ammonium carbonate, ammonium acetate, and formamides in an ammonia stream.
  • the removal of the protecting group is performed in the same manner as in the first production method.
  • the starting compound (X can be produced according to a general synthesis method of amidine, guanidine, acid amide, urea, thiocarboxylic acid amide, and thiourea.
  • the compound (S) is obtained by reacting the compound ( ⁇ ⁇ ) produced by the first process as a raw material, and heating it to an isosolvent such as benzoyl isothiocyanate in an inert solvent such as acetone to reflux.
  • Production method 5 Trifluoromethylation to amino group
  • the compound (I e) having a trifluoromethyl group as R 3 in the compound of the present invention can be produced by fluorination of the corresponding dithiolamine rubinate.
  • ester-forming group represented by R 15 is not particularly limited as long as it is an ester-forming group that does not inhibit the fluorination reaction, and preferably includes a lower alkyl group such as a methyl group and an ethyl group.
  • the fluorinating agent used in the fluorination reaction is not particularly limited as long as it is a fluorinating agent that changes a carbon-oxygen or carbon-sulfur bond into a carbon-fluorine bond, but tetrabutylammonium dihydrogen trifluorofluoride Perfluorinated compounds of quaternary ammonium, such as lime, are preferably used.
  • the raw material compound (XI) and the fluorinating agent are combined with a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or an ether solvent such as ether, tetrahydrofuran, or dioxane.
  • a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, or an ether solvent such as ether, tetrahydrofuran, or dioxane.
  • an organic solvent such as an aromatic hydrocarbon solvent such as benzene
  • a solvent inert to a reaction such as water or a mixed solvent thereof, if necessary, usually under cooling in the presence of a catalyst such as N-bromosuccinic acid imide. It is advantageous to carry out at room temperature.
  • a 1 , A 2 , R 13 , R 14 and X 2 have the above-mentioned meanings, and R ′ 5 has a protecting group when it is a group having a reactive heterocycle —NH—. 2 means the same group
  • the compound (I g) having at least one hydroxyl group as a substituent of R 2 is a compound of the corresponding invention It can also be produced by reducing the oxo compound (If).
  • the reduction method used in this reduction reaction is not particularly limited as long as it is a reduction method of reducing a cyclic ketone to give a cyclic alcohol, but reduction with a metal hydride complex such as sodium borohydride is advantageously used. It is.
  • the reaction can be carried out according to a conventional method.
  • the reaction can be carried out using an organic solvent such as a halogenated hydrocarbon solvent such as dichloromethane, dichloroethane, and chloroform, an organic solvent such as methanol, ethanol, or isopropanol, or a mixed solvent thereof.
  • a reducing agent is added to the compound (If) in an inert organic solvent, and the reaction is usually carried out under cooling to room temperature.
  • the compound of the present invention thus produced is isolated and purified as a free compound, a salt thereof, a hydrate, various solvates and the like.
  • the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting the compound to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography.
  • Geometric isomers and tautomers can be separated using the difference in physicochemical properties between the isomers.
  • the optical isomer can be obtained by selecting an appropriate raw material compound or by a racemic resolution method of a racemic compound (for example, a method of leading to a diastereomer salt with a general optically active group and performing an optical fractionation). ) Can lead to stereochemically pure isomers.
  • the compound of the present invention has an action of inhibiting the activity of steroid 17-20 lyase, which is an enzyme involved in producing androgen from cholesterol in vivo. Therefore, the compound of the present invention can be used for various diseases in which androgen and estrogen synthesized using androgen as a substrate are aggravating factors, such as prostate cancer, benign prostatic hyperplasia, androgenesis, hirsutism, It is useful as a preventive and therapeutic agent for breast cancer, mastopathy, uterine fibroids, and endometriosis.
  • Testes were removed from 10-week-old male Wistar rats, and after homogenizing the testes, microsomes were obtained by centrifugation.
  • the test compound pH of 7.4 5 Dissolved in OmM phosphate buffer 1001, added NADPH solution, then incubated at 37 for 60 minutes.
  • 400 41 of a mixed solvent of methanol and tetrahydrofuran (2: 3) the mixture was centrifuged, and the radioactivity of substrates and products (androstenedione and testosterone) in the supernatant was determined.
  • the inhibitory activity of the test compound on steroid 17-20 lyase was determined by high performance liquid chromatography (HPLC) with a radioisotope detector.
  • Test drugs were orally administered to 10-week-old male Wistar rats under fasting conditions.
  • LH-RH (6 Ong / rat) was administered intramuscularly to increase testosterone synthesis.
  • decapitated blood was collected, and the testosterone concentration in the obtained serum was measured with a radioisotope Atsusei to determine the testosterone synthesis inhibitory activity.
  • control compound was disclosed as the compound of Example 187 of JP-A-64-85975.
  • the compound of the present invention showed an activity of 10 times or more.
  • control compound was disclosed as the compound of Example 1887 in JP-A-64-89597.
  • the compound of the present invention also exhibited the same or higher inhibitory activity on rat testosterone synthesis at a much lower dose than the control compound.
  • compositions containing, as an active ingredient, one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof may be a commonly used carrier for pharmaceutical preparations. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, etc., and orally or parenterally. You.
  • the dosage is appropriately determined depending on the individual case in consideration of the symptoms, age of the administration subject, gender, body weight, etc., and is usually 0.1 to 100 mg, preferably 0 to 100 mg / day for an adult. It is orally administered once to several times a day in the range of 1 to 100111, or in the range of 0.1 to 500 mg per adult, once to several times a day. Administered intravenously or 1 hour to 24 hours a day It is administered intravenously over a period of time. Of course, as described above, the dosage varies under various conditions, so that an amount smaller than the above dosage range may be sufficient.
  • one to three or more active substances may contain at least one inert diluent, such as lactose, mannitol, dextrose, hydroxypropylcellulose, microcrystalline.
  • the composition may be formulated according to the usual practice with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid or asparagine.
  • a solubilizing or solubilizing agent such as an acid may be contained.
  • Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified Contains water and ethanol.
  • the composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline.
  • diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and ethanol. Uno alcohols, polysorbate 80 (trade name) and the like.
  • Such compositions may further comprise additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injectable solvent before use.
  • the starting compounds of the present invention also include novel substances. Reference examples are listed and their production methods are shown.
  • the foam layer was dried over anhydrous magnesium sulfate.
  • the residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel gel chromatography, and the crystals obtained from the ethyl acetate eluted part were recrystallized with n-hexane-chloroform-form system to give 2-methyl- 6— [N-(1 -trityl-1H-imidazole-4-ylmethyl) ami Benzothiazole 1.68 g (3.45 mmo 1, 59 was obtained).
  • the reaction system was poured into 400 ml of a 1 M aqueous solution of potassium carbonate, and after liquid separation, the organic layer was subjected to 200 ml of a 1 M aqueous solution of carbonated lithium, 200 ml of purified water, 200 ml of purified water, and 150 ml of saturated saline. Washing was performed sequentially with m1.
  • the obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-chloroform to give 4-[[N- (9H-fluoren-1-yl) amino] methyl] -methyl. 16.5 g (73.8%) of trityl-1H-imidazole were obtained as white crystals.
  • Elemental analysis value (as C 18 H ie C 1 N 5 -C 2 H 2 04 ⁇ 0.7H 20 )
  • the same target product can be obtained by subjecting this mixture to the next step without separation.
  • Example 14 (1) 1 — [4— [N— (3-chloro benzyl) 1 N— (1—trityl 1 H—imidazo-1-ru 41-methyl) amino] phenyl] —1 1H—imidazole
  • Example 19 (1) 6— [N— (1-trityl—1H—imidazole-1--4-methyl) amino] quinoline in 1 Om 1 methylene chloride 1.0 1 g (2.
  • Nuclear magnetic resonance scan Bae spectrum (CDC 1 3, TMS internal standard): ⁇ : 4. 32 (2 H, s), 4. 34 (2 H, s), 6. 77 (1 H, s), 7. 1 4 (1H, s), 7.18-7.26 (3H, m) ', 7.40 (1H, s), 7.45 (1H, s), 7.5 0-7.56 (2H, m), 7.68-7.70 (3H, m), 8.5-5-8.61 (2H, m), 8.70-8.72 (1H, m).
  • Example 35 The following compounds were synthesized in the same manner as in Example 1 (1) and (2).
  • Example 35 The following compounds were synthesized in the same manner as in Example 1 (1) and (2).
  • Example 5 (1) 6- [N- (2-cyanobenzyl) -1-N- (1-trityl-1-H-imidazole-4-ylmethyl) amino] -2-methylbenzothiabour
  • Example 6 1 to 78 [However, except for Example 64 (1)]
  • Example 13 A solution of 1.13 g (2.13 mMol) of the ketone obtained in (1) in methylene chloride / methanol (1: 1 V01%, 20 ml) was added to ice temperature. Then, 322 mg (9.52 mmo 1) of sodium tetrahydroborate was added thereto, followed by stirring for 1 hour. After distilling off the solvent under reduced pressure, ethyl acetate and distilled water were added, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate.

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Abstract

Dérivé d'imidazolylalkylamine de formule générale (I) utile en tant que lyase stéroïde 17-20, sel pharmaceutiquement acceptable dudit dérivé et composition pharmaceutique contenant ledit dérivé en tant qu'ingrédient actif. Dans ladite formule (I), R1 représente hydrogène ou alkyle inférieur; A1 représente alkylène inférieur optionnellement ramifié; A2 représente alkylène inférieur optionnellement lié ou ramifié; R2 représente phényle (non) substitué, un cycle d'hydrocarbure bi ou tricyclique (non) substitué possédant des cycles benzène fusionnés; ou un cycle hétéro fusionné bi ou tricyclique (non) substitué possédant un (des) cycles(s) benzène fusionné(s) et un cycle hétéro contenant de l'oxygène et/ou du soufre et/ou de l'azote en tant qu'atome(s) hétéro; R3 représente alkyle, alcényle inférieur, alcynyle inférieur, cycloalkyle, -A3-R4, alkyle inférieur substitué par halogène, alkyle inférieur substitué par cyano ou par un cycle hétéro (non) substitué contenant de l'azote en tant qu'atome(s) hétéro; A3 représente alkylène inférieur ou carbonyle optionnellement ramifiés; et R4 représente cycloalkyle (non) substitué, phényle (non) substitué ou un cycle hétéro (non) substitué contenant de l'azote en tant qu'atome(s) hétéro; à condition (1) que -A?1-R2 et -R3¿ puissent être combinés avec l'atome d'azote adjacent pour former un cycle hétéro fusionné tri ou tétracyclique (non) substitué et (2) que lorsque A2-R2 représentent phényle ou benzyle (non) substitués, (a) soit lié au cycle imidazole en position 4 ou 5.
PCT/JP1994/001278 1993-08-04 1994-08-03 Derive d'imidazolylalkylamine et composition pharmaceutique contenant ledit derive Ceased WO1995004723A1 (fr)

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EP0721943A4 (fr) * 1993-09-30 1996-09-04 Yamanouchi Pharma Co Ltd Derive d'azole et composition pharmaceutique le contenant
EP0820989A4 (fr) * 1995-03-01 1998-05-06 Yamanouchi Pharma Co Ltd Derives d'imidazole et composition medicinale a base desdits derives
EP0841919A4 (fr) * 1995-05-24 1999-02-24 Merck & Co Inc Inhibiteurs de la farnesyle-proteine transferase
WO2001051479A3 (fr) * 2000-01-07 2002-02-14 Warner Lambert Co Composes tricycliques et procedes de traitement des herpesvirus
JP2002080458A (ja) * 1999-10-22 2002-03-19 Takeda Chem Ind Ltd １−置換−１−（１ｈ−イミダゾール−４−イル）メタノール類
EP1227086A4 (fr) * 1999-10-22 2002-10-28 Takeda Chemical Industries Ltd Alcools de phenyl-1-(1h-imidazol-4-yl) substitues en position 1, procede de preparation et utilisation de ces derniers
JP2004517848A (ja) * 2000-12-18 2004-06-17 バイオウタ サイエンティフィック マネジメント プロプライエタリー リミテッド 抗ウイルス剤
JP2006511460A (ja) * 2002-08-23 2006-04-06 ユニバーシティ オブ コネチカット 治療適応を持つケトカンナビノイド
EP1583530A4 (fr) * 2002-01-16 2008-07-23 Univ Virginia Activateurs allosteriques 2-aminothiazoles des recepteurs de l'adenosine a1
JP2013525334A (ja) * 2010-04-21 2013-06-20 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤としてのベンゾイミダゾール誘導体
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EP0820989A4 (fr) * 1995-03-01 1998-05-06 Yamanouchi Pharma Co Ltd Derives d'imidazole et composition medicinale a base desdits derives
EP0841919A4 (fr) * 1995-05-24 1999-02-24 Merck & Co Inc Inhibiteurs de la farnesyle-proteine transferase
US6518257B1 (en) 1999-10-22 2003-02-11 Takeda Chemical Industries, Ltd. 1-substituted phenyl-1-(1h-imidazol-4-yl) alcohols, process for producing the same and use thereof
JP2002080458A (ja) * 1999-10-22 2002-03-19 Takeda Chem Ind Ltd １−置換−１−（１ｈ−イミダゾール−４−イル）メタノール類
EP1227086A4 (fr) * 1999-10-22 2002-10-28 Takeda Chemical Industries Ltd Alcools de phenyl-1-(1h-imidazol-4-yl) substitues en position 1, procede de preparation et utilisation de ces derniers
WO2001051479A3 (fr) * 2000-01-07 2002-02-14 Warner Lambert Co Composes tricycliques et procedes de traitement des herpesvirus
US6800656B2 (en) 2000-01-07 2004-10-05 Warner Lambert Company Tricyclic compounds and method of treating herpes virus
JP2004517848A (ja) * 2000-12-18 2004-06-17 バイオウタ サイエンティフィック マネジメント プロプライエタリー リミテッド 抗ウイルス剤
US8624025B2 (en) 2000-12-18 2014-01-07 Biota Scientific Management Pty Ltd Antiviral agents
US8217171B2 (en) 2000-12-18 2012-07-10 Biota Scientific Management Pty. Ltd. Antiviral agents
JP2010189434A (ja) * 2000-12-18 2010-09-02 Biota Scientific Management Pty Ltd 抗ウイルス剤
US7829705B2 (en) 2000-12-18 2010-11-09 Biota Scientific Management Pty. Ltd. Antiviral agents
US7951955B2 (en) 2000-12-18 2011-05-31 Biota Scientific Management Pty Ltd Antiviral agents
EP1583530A4 (fr) * 2002-01-16 2008-07-23 Univ Virginia Activateurs allosteriques 2-aminothiazoles des recepteurs de l'adenosine a1
JP2006511460A (ja) * 2002-08-23 2006-04-06 ユニバーシティ オブ コネチカット 治療適応を持つケトカンナビノイド
JP2013525334A (ja) * 2010-04-21 2013-06-20 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤としてのベンゾイミダゾール誘導体
US20150023916A1 (en) * 2012-02-17 2015-01-22 Siga Technologies Inc. Antiviral drugs for treatment of arenavirus infection
US9498470B2 (en) * 2012-02-17 2016-11-22 Kineta Four, LLC Antiviral drugs for treatment of arenavirus infection
US10000486B2 (en) 2012-02-17 2018-06-19 Kineta Viral Hemorrhagic Fever, Llc Antiviral drugs for treatment of arenavirus infection

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