WO1994008973A1 - Compose de type azole - Google Patents

Compose de type azole Download PDF

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Publication number
WO1994008973A1
WO1994008973A1 PCT/JP1993/001509 JP9301509W WO9408973A1 WO 1994008973 A1 WO1994008973 A1 WO 1994008973A1 JP 9301509 W JP9301509 W JP 9301509W WO 9408973 A1 WO9408973 A1 WO 9408973A1
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Prior art keywords
group
benzyl
cyano
carbon atoms
substituted
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PCT/JP1993/001509
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English (en)
Japanese (ja)
Inventor
Tomoyuki Shibata
Yukio Sugimura
Kazuhiko Tanzawa
Masaaki Takahashi
Tomowo Kobayashi
Yoshihiro Mitsuhashi
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Sankyo Company, Limited
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Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU52855/93A priority Critical patent/AU5285593A/en
Publication of WO1994008973A1 publication Critical patent/WO1994008973A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D233/64—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to a novel azole compound having excellent aromatase inhibitory activity, a method for producing the same, and a use thereof.
  • the present inventors have studied over many years to develop a novel compound which is superior to the above-mentioned compound having an aromatase inhibitory activity.
  • the azole compound of the present invention has a strong aromatase inhibitory activity.
  • the novel azole compounds having strong aromatase inhibitory activity of the present invention are represented by the general formula (1)
  • R 1 may be substituted with a methyl or ethyl group; 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, 1- (1,3,4) ) Triazolyl, 1- (1,2,3) triazolyl, 1-tetrazolyl or 2-tetrazolyl group, wherein R 2 is a substituent selected from the following group A Represents a naphthyl, phenanthryl or anthryl group which may be substituted with R 3 represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms ′) and a salt thereof.
  • Group A an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, an aromatic acyloxy group, a hydroxyl group, and a carbon atom having 1 to 4 carbon atoms Aliphatic acylamino group, alkoxy substituted alkoxy group, alkoxy substituted aliphatic acyloxy group, trialkylsilyloxy group
  • the compound (1) of the present invention has at least one asymmetric carbon and has stereoisomers in which the configuration is the R configuration or the S configuration. Included in the invention.
  • the relative position of the cyano group on the benzene ring is preferably the P-position or the m-position, and more preferably the P-position.
  • R 1 Preferable examples of the aforementioned R 1 include 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl, and 1-1 (1,2) which may be substituted by methyl. , 3) triazolyl or 2-tetrazolyl groups, most preferably 1-imidazolyl, 5-methyl-1-imidazolyl, 4-imidazolyl, 1-methyl-5-imidazolyl, 1- (1,2,4) ) Triazolyl, 1- (1,2,3) triazolyl or 2-tetrazolyl.
  • Examples of the above-mentioned alkyl group having 1 to 4 carbon atoms in Group A include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or 1-butyl group.
  • Examples of the above-mentioned alkoxy group having 1 to 4 carbon atoms in Group A include methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy and t-butoxy groups, and a methoxy group is preferred. .
  • Examples of the above-mentioned aliphatic asiloxy group having 1 to 6 carbon atoms in Group A include formyloxy, acetoxy, propionyloxy, butyryloxy, isoptyryloxy, valeryloxy, and bivaloyloxy groups. is there.
  • Examples of the aromatic acyloxy group of the above-mentioned group A include benzoyloxy, naphthylcarbonyloxy, phenanthrylcarbonyloxy, anthrylcarbonyloxy, and those having 1 to 3 substituents on these aromatic rings.
  • substituents examples include an alkyl group such as methyl and ethyl, a halogeno group such as fluorine and chlorine, and an alkoxy group such as methoxy and ethoxy, and preferably unsubstituted benzoyl and 3, 4, 5 — It is a trimethoxybenzoyl group.
  • Examples of the above-described aliphatic acetylamino group having 1 to 4 carbon atoms in Group A include formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, and bivaloylamino groups, and preferably acetylamino.
  • Examples of the alkoxy-substituted alkoxy group in Group A include methoxy methoxy, 2-methoxy ethoxy, ethoxy methoxy, 2-ethoxy ethoxy, and propoxy methoxy, and the like, preferably methoxy methoxy and 2-methoxy ethoxy. .
  • alkoxy-substituted aliphatic acyloxy group in Group A examples include methoxyacetoxy, ethoxyacetoxy, and methoxypropionyloxy groups, and are preferably methoxyacetoxy groups.
  • trialkylsilyloxy group in Group A examples include trimethylsilyloxy, triethylsilyloxy, diisopropylmethylsilyloxy, and 1: 1-butyldimethylsilyloxy, and preferably t-butyl. It is a dimethylsilyloxy group.
  • Examples of the above-mentioned phenanthryl group for R 2 include i-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-1 fenthryl group, and preferably 1-phenanthryl, 2-funanthryl or 9-1thryl group. It is a phenanthryl group, and more preferably, it is a 91-phenanthryl group.
  • the above-mentioned anthryl group for R 2 is a 1-1-anthryl, 2-anthryl or 91-anthryl group, preferably a 2-anthryl or 9-anthryl group, and more preferably a 91-anthryl group.
  • R 2 preferred are a naphthyl, an unsubstituted 91-anthryl or an unsubstituted 91-phenanthryl group which may be substituted with a substituent selected from the following A '' group,
  • naphthyl, unsubstituted phenanthryl and unsubstituted anthryl groups which may be substituted with a substituent selected from the following group A ′ ′′ ′′.
  • Examples of the above-mentioned alkyl group having 1 to 4 carbon atoms of R 3 include the same as the above-mentioned alkyl group having 1 to 4 carbon atoms in the group III , and preferably a methyl group.
  • R 3 as a whole is preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.
  • preferred compounds include the following compound groups. 2) General formula (1)
  • R 1 may be substituted with a methyl or ethyl group.
  • R 3 represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and a salt thereof.
  • R 1 may be substituted with a methyl or ethyl group, 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl,
  • R 2 is a substitution selected from the following group A'' A naphthyl, an unsubstituted phenanthryl or an unsubstituted anthryl group which may be substituted with a group
  • R 3 represents a hydrogen atom, an alkyl or cyano group having 1 to 4 carbon atoms) and Its salt.
  • R 1 may be substituted with a methyl or ethyl group; 1-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1- (1,2,4) triazolyl,
  • R 2 is a substituent selected from the following A '''' group
  • R 3 represents a hydrogen atom, a methyl or a cyano group, and a salt thereof.
  • R 1 is 1-imidazolyl, 5-methyl ⁇ 1-imidazolyl, 4-imidazolyl, 1-methyl-5-imidazolyl, 1-1 (1,2,4) triazolyl, 1-1 (1,2,3)
  • R 2 is naphthyl which may be substituted with a substituent selected from the following group A ′ ′′ ′, unsubstituted phena S represents a thrill or an unsubstituted anthryl group, and R 3 represents a hydrogen atom
  • the compound of the present invention can be converted into a salt when it has a basic group.
  • salts of mineral acids such as hydrochloride, hydrobromide, sulfate, organic sulfonates such as methanesulfonate, benzenesulfonate, acetate, propionate, butyrate And aliphatic carboxylate such as benzoate and the like.
  • mineral acids particularly hydrochloric acid
  • salts of aliphatic carboxylic acids particularly acetic acid
  • column CN shows the binding position of Shiano groups for bonding positions location of C a on the benzene ring of the following formula, in each group of columns of R 1, the number of the left end, C a and shows the bonding site to the imidazo Ichiru, triazole or tetrazole Ichiru, in each group of columns of R 2, numbers in the right end indicates C a and naphthyl, the binding position of the Fouesnant thrill or anthryl.
  • Im represents an imidazolyl group
  • Tri represents a triazolyl group
  • Tet represents a tetrazolyl group
  • Me represents a methyl group
  • Et represents an ethyl group
  • Pr represents a propyl group
  • Bu represents a butyl group
  • Nap h represents a naphthyl group
  • Phe represents a phenanthryl group
  • Ant represents an anthryl group
  • TBS represents a t-butyldimethylsilyl group
  • Ac represents an acetyl group
  • Pre represents a propionyl group
  • Ph represents a phenyl group.
  • 345TMeOPh represents a 3,4,5-trimethoxyphenyl group
  • diMe ⁇ represents dimethoxy
  • MeOEt represents a methoxyethoxy group.
  • the compound (1) of the present invention can be produced according to the reaction steps shown in Process Tables 1, 2 and 3.
  • R 1 , R 2, and R 3 have the same meanings as described above, R 3a represents an alkyl group having 1 to 4 carbon atoms or a cyano group, and R 2a represents water.
  • R 2 represents a naphthyl, phenanthryl or anthryl group substituted with an acid group; Represents a naphthyl, phenanthryl or anthryl group substituted with an aliphatic or aromatic acyloxy or alkoxysiloxy group, and R 4 represents a methyl or ethyl group.
  • Z 1 represents a hydrogen atom or a halogeno group
  • Z 2 represents a halogeno group
  • Z 3 is an alkylsulfonyloxy having 1 to 4 carbon atoms which may be substituted with a halogen atom
  • Z 4 and Z 5 represent a halogeno group.
  • the alkyl sulfates Honiruokishi group are carbon atoms and optionally 1 to four substituted with a halogen atom Z 3, methanesulfonyl O carboxymethyl, ethanesulfonyl O carboxymethyl, propanesulfonyl O alkoxy, or Bok Riffle O b methanesulfonyl O alkoxy group And a methanesulfonyloxy or trifluoromethanesulfonyl group.
  • Examples of the halogeno group for Z 1 , Z 2 , Z 3 , Z 4 and Z 5 include a chloro group, a bromo group and a chloride group, and preferably a bromo group for Z 1 , Z 2 and Z 5.
  • the Z 3 is black hole or bromo group
  • for Z 4 are bromo or Yodo group.
  • compound R 2 Z 1 (2) is reacted with a metal reagent in an inert solvent under an inert atmosphere. And converting it into an organometallic compound, and then reacting the compound (3) to obtain an alcohol compound (4).
  • the inert atmosphere a nitrogen atmosphere or an argon atmosphere is suitable.
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably selected from ethers such as tetrahydrofuran, dioxane and ether, and aliphatic solvents such as pentane and hexane. Hydrocarbons, aromatic hydrocarbons such as benzene, toluene and xylene, more preferably tetrahydrofuran, ether, hexane or benzene.
  • ethers such as tetrahydrofuran, dioxane and ether
  • aliphatic solvents such as pentane and hexane.
  • Hydrocarbons aromatic hydrocarbons such as benzene, toluene and xylene, more preferably tetrahydrofuran, ether, hexane or benzene.
  • metal reagent used examples include alkyllithiums such as n-butyllithium and tert-butyllithium, and alkaline earth metals such as metal magnesium, and preferably n-butyllithium. .
  • the reaction temperature when converting the compound (2) into an organometallic reagent varies depending on the metal reagent to be used, and is usually 1 to 78 ° C to 100 ° C, preferably -78 to 80 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 5 minutes to 15 hours, preferably 5 minutes to 5 hours.
  • the reaction temperature of the reaction between the formed organometallic compound and the compound (3) is -78 ° C to 100 ° C, preferably -78 ° C to 30 ° C, and the reaction time is as follows. Although it varies depending on the reaction temperature and the like, it is usually 5 minutes to 5 hours, preferably 30 minutes to 3 hours.
  • the target compound is obtained in a conventional manner, for example, by pouring the reaction mixture into water, extracting the mixture with a water-immiscible solvent such as ethyl acetate or methylene chloride, and distilling off the solvent from the extract.
  • a water-immiscible solvent such as ethyl acetate or methylene chloride
  • the obtained residue is obtained by recrystallization or purification by various types of chromatography.
  • a compound (5) is reacted with a metal reagent in an inert solvent in an inert atmosphere to convert the compound into an organometallic compound, and then the compound (6) is reacted to obtain an alcohol (4).
  • This can be performed in the same manner as in the first step.
  • This step is a step of reacting compound (4) with a sulfonylating agent or a halogenating agent in an inert solvent in the presence of a base to obtain compound (7).
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform, or an ester such as ethyl acetate or methyl acetate. And aliphatic hydrocarbons such as pentane and hexane, and nitriles such as acetonitrile, and more preferably, methylene chloride, chloroform and ethyl acetate.
  • a halogenated hydrocarbon such as methylene chloride or chloroform
  • an ester such as ethyl acetate or methyl acetate.
  • aliphatic hydrocarbons such as pentane and hexane, and nitriles such as acetonitrile, and more preferably, methylene chloride, chloroform and ethyl acetate.
  • organic amines such as triethylamine, N, N-dimethylaminopyridine, pyridine, and the like
  • alkali metal carbonates such as potassium carbonate and calcium carbonate or carbonates of alkaline earth metals are preferable. It is.
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus tribromide and the like, and preferably, thionyl chloride, thionyl bromide or phosphorus tribromide.
  • sulfonylating agent examples include sulfonyl halides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, and sulfonic anhydrides such as trifluoromethanesulfonic anhydride.
  • the reaction temperature is from 110 ° C to 100 ° C, preferably from 0 to 80 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is 5 minutes to 15 hours, preferably 30 minutes to 5 hours.
  • the target compound was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with a water-immiscible solution such as methylene chloride and ethyl acetate, and the extract was washed with water and saturated saline. Thereafter, it is obtained by distilling off the solvent from the extract.
  • the obtained target compound can be used in the next step without purification, or in some cases, can be purified by various types of chromatography.
  • the compound (7) is reacted with the azole compound R 1 H in an inert solvent to convert the sulfonyloxy group or the halogeno group of the compound (7) into an azolyl group (imidazolyl). , Triazolyl or tetrazolyl group) to obtain the compound (1) of the present invention.
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, and is preferably acetonitrile or ethyl acetate.
  • the reaction temperature is from 10 ° C. to 150 ° C., preferably from 60 ° C. to 100 ° C.
  • the reaction time varies depending on the compound, the reaction temperature, etc., but is usually from 10 minutes to 10 minutes. It is 30 hours, preferably 30 minutes to 15 hours.
  • the target compound is obtained by a conventional method, for example, by pouring the reaction mixture into water, extracting with a water-immiscible solvent such as methylene chloride or ethyl acetate, and distilling the solvent from the extract to obtain a mixture. It can be obtained by purification by various types of chromatography.
  • a water-immiscible solvent such as methylene chloride or ethyl acetate
  • This step is a step performed as desired when R 3 is a hydrogen atom.
  • the compound (1) is reacted with an alkyl halide or a cyanating agent in an inert atmosphere in an inert solvent in the presence of a base, and the hydrogen atom of R 3 is replaced with an alkyl group or a cyano group.
  • This is a step of obtaining a compound (la).
  • Examples of the inert atmosphere include a nitrogen atmosphere and an argon atmosphere.
  • the inert solvent is not particularly limited as long as it does not inhibit the reaction.
  • examples of the inert solvent include ethers such as tetrahydrofuran, dioxane and ether, and nitriles such as acetate nitrile. And tetrahydrofuran.
  • potassium t-butoxide and lithium diisopropylamide are preferable.
  • the reaction temperature is ⁇ 78 ° C. to 50 ° C., and the reaction temperature is preferably ⁇ 178 ° C. to 30 ° C.
  • alkyl halide examples include methyl iodide, methyl iodide, methyl bromide, and the like. Chill is preferred.
  • tosyl cyanide is preferred.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 minute to 30 hours, preferably 5 minutes to 15 hours.
  • the target compound is obtained by the same treatment as in the fourth step.
  • This step is an optional step performed in the case of the imidazolyl group of the R 1 of compound (7).
  • This step is a step of reacting compound (7) with 1-trimethylsilylimidazole in the presence of titanium tetrachloride in an inert atmosphere in a chloroform solution to obtain compound (1).
  • the reaction temperature is from 120 ° C. to 50 ° C., preferably from 110 ° C. to 30 ° C.
  • the reaction time varies depending on the compound and the reaction temperature, but is usually 1 minute to 30 hours, preferably 5 minutes to 15 hours.
  • the target compound is extracted by a conventional method, for example, by pouring the reaction mixture into a saturated aqueous solution of sodium hydrogen carbonate, extracting with a water-immiscible solvent such as chloroform, methylene chloride, ethyl acetate and the like, and distilling off the solvent.
  • a water-immiscible solvent such as chloroform, methylene chloride, ethyl acetate and the like
  • This step is a step of reacting the compound (7) with azolylurea in an inert solvent to obtain an aluminum salt (8).
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably acetonitrile or ethyl acetate.
  • 11- (N, N-dimethylaminocarbonyl) imidazole and 11- (N, N-dimethylaminocarbonyl) -14-methylimidazole are preferred.
  • the reaction temperature is from 0 ° C to 150 ° C, preferably from 60 ° C to 1 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 30 hours, preferably 1 hour to 15 hours.
  • the target compound of this step is used in the eighth step without purification. (8th process)
  • This step is a step of obtaining a compound (1) by reacting the compound (8) obtained in the seventh step with ammonia in an inert solvent.
  • the same inert solvent as that used in the seventh step is preferably used.
  • the reaction temperature is ⁇ 20 ° C. to 3 (TC, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 minute to 1 hour. Preferably, it is 1 minute to 15 minutes.
  • the target compound is obtained by the same treatment as in the fourth step.
  • the compound (1) is reacted with an acid in an inert solvent to remove the trialkylsilyloxy group to obtain the compound (lb).
  • inert solvent used examples include ethers (especially ethers) such as ether and tetrahydrofuran, alcohols such as methanol and ethanol, and water.
  • hydrogen chloride hydrogen chloride
  • hydrogen chloride hydrogen chloride
  • hydrogen sodide hydrogen sodide
  • the reaction temperature is from -10 ° C to 50 ° C, preferably from 0 ° C to 30 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 5 minutes to 15 hours, preferably 1 hour to 8 hours.
  • the target compound is obtained by the same treatment as in the sixth step.
  • a hydroxyl group on the compound (lb) is reacted with an acylating agent in an inert solvent in the presence of a base to convert the hydroxyl group into an acyloxy group, thereby obtaining a compound (lc).
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction. However, halogenated hydrocarbons such as chloroform and methylene chloride are preferred.
  • the base to be used triethylamine, N, N-dimethylaminopyridinine is preferred.
  • acylating agent to be used examples include a desired sulfonic acid anhydride such as acetic anhydride, and a desired alkoxyacyl halide such as methoxyacetyl chloride.
  • the reaction temperature is ⁇ 78 to 50 ° C., preferably ⁇ 10 to 30 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 5 minutes to 50 hours, preferably 30 minutes to 15 hours.
  • the target compound is obtained by the same treatment as in the sixth step.
  • This step is an optional step performed when the power of compound (1) is an imidazolyl group.
  • This step is a step of reacting compound (1) with N, N-dimethylpotassium chloride in an inert solvent in the presence of a base to obtain compound (9).
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, and is preferably acetonitrile.
  • the reaction temperature is from 120 to 100 ° C, preferably from 20 to 80 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 to 3 days.
  • the target compound is obtained by the same treatment as in the sixth step.
  • This step is a step of reacting the compound R 4 Z 5 (9) with an alkyl halide in an inert solvent to obtain an onium salt (10).
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably acetonitrile.
  • the alkyl halide used is preferably methyl iodide.
  • the reaction temperature is usually from 0 to 150 ° C., preferably from 60 to 100.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually from 30 minutes to 30 hours, preferably from 30 to 30 hours. 1 to 15 hours.
  • the target compound is used in the thirteenth step without any particular purification.
  • the compound (10) obtained in the twelfth step is reacted with ammonia in an inert solvent to obtain a compound (Id).
  • the same inert solvent as used in the twelfth step can be used as the inert solvent.
  • the reaction temperature is from 20 to 30 ° C, preferably from 0 to 30 ° C.
  • the reaction time varies depending on the compound, the reaction temperature and the like, but is usually 1 minute to 1 hour, preferably 1 to 15 minutes.
  • the target compound is subjected to the same treatment as in the fourth step.
  • Examples of the dosage form of the compound (1) of the present invention include oral administration by tablets, capsules, granules, powders, syrups and the like, and parenteral administration by injections and suppositories. These preparations are produced by known methods using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.
  • the dosage varies depending on symptoms, age, etc., but is 0.1 to 1000 mg / kg body weight per day, preferably 1 to 500 mg / kg body weight per day for normal adults once or several times a day. It can be administered in divided doses.
  • the compounds of the present invention have excellent pharmacological properties. That is, it is useful as an inhibitor of aromatase activity and an inhibitor of estrogen biosynthesis in mammals, and is also useful as a therapeutic agent for pathological symptoms caused by these.
  • the compounds of the present invention inhibit the metabolic conversion of androgens to estrogens in mammals, and are therefore useful, for example, in treating male breast hypertrophy. Also, the compounds of the present invention are useful in the treatment of estrogens-dependent diseases in women, such as estrogen-dependent breast cancer in women, especially in postmenopausal women, by inhibiting estrogen biosynthesis. is there.
  • the dog fraction is prepared from the human placenta substantially by the method of Thompson and Siiteri ( ⁇ Biol. Chem. 249, 5364 (1974)).
  • the resulting microsomal preparation is lyophilized and stored at 140 ° C.
  • the test can be proved by a modification of the method of Douglas F. Covey et al. ( ⁇ Biol. Chem. 256, 1076 (1981)).
  • the Iso value can be determined graphically as the concentration of the test compound at which the aromatization of androstenedione to the estrone is reduced to 50% of the comparative value.
  • In vivo inhibition of aromatic enzyme activity of a compound of the invention for example, inhibition of estrogen synthesis in rats, is calculated from the ovarian estrogen content in the treated animals as compared to control animals.
  • the in vivo inhibition of the aromatic enzyme activity of the compound of the present invention can also be evaluated, for example, by the following method. That is, androstenedione (30 mg Zkg administered subcutaneously), alone and with the aromatase inhibitor to be tested (oral or subcutaneous administration), is administered to immature female rats once a day for 4 days. After the fourth dose, the rats are sacrificed, the uterus is removed and weighed. Aromatase inhibition is evaluated by measuring the extent to which uterine hypertrophy induced by androstenedione alone is suppressed by co-administration of an aromatase inhibitor.
  • the antitumor activity has been demonstrated in vivo, for example, in human nude mice (Balb / cA-nu) in human ovarian cancer BG-1 strain (Geisinger, KR). et al., Cancer 63: 280-288 (1989)).
  • the compounds of the present invention by daily administration of 15 to SO mgZkg or more orally, degrade existing tumors and suppress the development of new tumors.
  • the compounds of the present invention have excellent estrogen biosynthesis inhibitory effects in mammals, such as, for example, breast cancer (breast carcinoma) in women, endometriosis, premature birth and uterine cancer, as well as breast enlargement in men. Useful for the treatment of estrogen-dependent diseases.
  • Example 3b 4- (p-cyanol c- (naphthalene-111-yl) benzyl) imidazole titanium tetrachloride (0.2 niL), N-trimethylsilyl midazol (0.27 mL) and p-cyananol obtained in Example 3b
  • the same treatment as in Example 2 was carried out using 1a- (naphthalene-1-yl) benzyl chloride (101 mg).
  • purification by silica gel column chromatography ethyl hexane monoacetate (1: 4)
  • 4- (p-cyano ⁇ - (naphthalene-11-yl) benzyl) imidazole 55 mg). .
  • Example 5b 4- (p-cyano ⁇ - (phenanthrene-91-yl) benzyl) imidazo-titanium tetrachloride (170 L), N-trimethylsilylimidazole (230 uL) and P- obtained in Example 5b
  • the same treatment as in Example 2 was carried out using cyano- ⁇ - (phenanthrene-1-yl) benzyl chloride (1 OO mg).
  • column chromatography of silica gel methylene chloride triethylamine
  • Example 10 1- ( ⁇ -cyano- ⁇ - (6-hydroxynaphthalene-1-yl) benzyl) imidazole (31 mg) obtained in Example 10 was dissolved in methylene chloride (2 ml), and triethylamine was dissolved. (151) and acetic anhydride (10w1) were added, and after stirring at room temperature for 1 hour, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 2 4- ( ⁇ -cyano- ⁇ - (naphthalene-2-yl) benzyl) imidazole (275 mg) obtained in Example 2 was dissolved in acetonitrile (3 ml), and triethylamine (1401) and dimethylcarbamoyl were dissolved. Chloride (90) Li1) was added, and the mixture was stirred at room temperature for 60 hours. Ether was added to the reaction solution, and the resulting precipitate was removed by filtration.
  • Example 17 1- (p-cyano a- (3,7-dimethoxynaphthalene-1-yl) benzyl) 1,1,2,4-triazolyl hydrochloride
  • P-Cyanophenyl (1,4-dimethoxyxanaphthalene-1-2-le) -ketone (207mg) is dissolved in isopropanol (2ml) -tetrahydrofuran (3ml) and sodium borohydride (248mg) was added and stirred at room temperature for 40 minutes.
  • the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain P-cyano-a- (1,4-dimethoxynaphthalene-12-yl) benzyl alcohol (208 mg).
  • Example 8 11- (P-cyano-a- (6-methoxynaphthalene-12-yl) benzyl) imidazole (100 mg), botacidium-tert-butoxide (33 mg) and tosyl cyanide (54 mg) obtained in Example 8 were added. And used in the same manner as in Example 32. However, silica gel column chromatography (ethyl acetate: ⁇ 68 / -0 OAV
  • P-cyano a- (isoquinoline-41-yl) benzyl alcohol 13 Omg was suspended in methylene chloride (2 mL), and thionyl chloride (75 uL) was added, followed by stirring at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with hexane to obtain p-cyano a- (isoquinoline-4-yl) benzyl chloride hydrochloride (146 mg).
  • P-Cyanore a (1,4-Benzodioxane-16-yl) Benzyl alcohol (1.115 g) and thionyl chloride (Q.54 mL) were used in the same manner as in Reference Example lb. — (1,4-Benzodioxane-1-6-yl) benzyl chloride (1.144 g) was obtained.
  • Reference Example 7c was prepared using P-cyano-a- (1,2-methylenedioxy-1-phen-141-yl) benzyl chloride (114 mg) and imidazole (286 mg). The same treatment was performed. However, it can be purified by silica gel column chromatography (ethyl hexane monoacetate (1: 3)) and purified by elution with 1- (P-cyano ⁇ - (1,2-methylenedioxyphen-14-1yl) benzyl) imidazole ( 107 mg), which was dissolved in methanol. An ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes. The solvent was distilled off under reduced pressure to remove 1- (p-cyano ⁇ - (1,2-methylenedioxyphene). -4-yl) benzyl) imidazole 'hydrochloride was obtained.
  • the organic layer was extracted with 1 N hydrochloric acid, the hydrochloric acid layer was neutralized with a 1 N aqueous sodium hydroxide solution, and then extracted with ethyl acetate.
  • the extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and 41- (P-cyano ⁇ - (1,4-benzodioxane-1-6-yl) benzyl) imidazole was purified. Obtained. This was dissolved in methanol, an ether solution of hydrogen chloride was added, and the mixture was stirred for 5 minutes.
  • P-Cyanore a— (1,2,3,4-tetrahydronaphthylene-1-yl) Dissolve benzyl alcohol (102 mg) in ethyl acetate (3 ml) and add thionyl chloride (140 u 1). The mixture was refluxed for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to remove P-cyano a- (1,2,3,4-tetrahydronaphthalene-1-yl) benzyl chloride ( 11 mg).
  • the aromatase inhibitory activity of the compounds of the present invention can be determined by an improved method of Douglas F. Covey et al. (Journal of Biological Chemistry, 256, 1076-1079, 1981). Proven by. That, 1 uM [19 - 14 C ] - androstenone - 3.17- dione, O.lm NADPH, and a small amount of dimethyl sulphoxide mediation Si buffer one containing the test I arsenide compound dissolved in de (1 Omm potassium phosphate buffer (HP7.5), 10 Om potassium chloride, ImMethylenediaminetetraacetic acid, 4% propylene glycol) and add 12.5 / 1 g of protein as a microsomal protein prepared from human placenta.
  • the final volume of the solution was adjusted to 0.5 mL, and the mixture was reacted at 37 ° C for 30 minutes.
  • the reaction was stopped by adding 2.5 mL of black-mouthed form, stirred with a vortex mixer for 40 seconds, and centrifuged at 2000 rpm for 5 minutes.
  • the aqueous layer 100 L was added to the scintillation one coater of 3 mL, the results obtained by measuring the count of free H 14 CO_ ⁇ _H by comparing inhibitor and results pair irradiation test tested without adding , conversion percent inhibition to estrone from androstenone dione seek ⁇ %) was determined 50% inhibitory concentration (1 5. value) graphically. I s of the compounds of the present invention. The values are shown in Table 2.
  • the skin was applied as required.

Abstract

L'invention concerne un composé répondant à la formule générale (I) dans laquelle R1 représente imidazolyle, triazolyle ou tétrazolyle, chacun de ces groupes pouvant être substitué par méthyle et/ou éthyle; R2 représente naphthyle, phénanthryle ou anthryle, chacun de ces groupes pouvant être substitué par un ou des substituants choisis dans le groupe A: alkyle C¿1?-C4, alcoxy C1-C4, acyloxy C1-C6, acyloxy aromatique, OH, trialkyle, acylamino C1-C4, alcoxyalcoxy, alcoxyacyloxy et trialkylsilyloxy; et R?3¿ représente hydrogène, méthyle ou cyano. Ce composé présente une excellente activité inhibitrice de l'aromatase et est particulièrement utile en tant que remède contre le cancer du sein.
PCT/JP1993/001509 1992-10-21 1993-10-20 Compose de type azole WO1994008973A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036876A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
US6063930A (en) * 1996-04-03 2000-05-16 Merck & Co., Inc. Substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
US6080870A (en) * 1996-04-03 2000-06-27 Merck & Co., Inc. Biaryl substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
WO2005007631A1 (fr) * 2003-07-10 2005-01-27 Osi Pharmaceuticals, Inc. Derives de naphtylene constituant des inhibiteurs du cytochrome p450
US7662844B2 (en) 2004-07-12 2010-02-16 Osi Pharmaceuticals, Inc. Naphthylene derivatives as cytochrome P450 inhibitors
JP2013516418A (ja) * 2009-12-31 2013-05-13 ヴィアメット ファーマスーティカルズ，インコーポレイテッド 金属酵素阻害化合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62212369A (ja) * 1986-03-07 1987-09-18 チバ・ガイギ−・アクチエンゲゼルシヤフト トルニトリル化合物、その製造方法及びそれを含むアロマターゼ阻害剤
EP0490816A2 (fr) * 1990-12-12 1992-06-17 Ciba-Geigy Ag Dérivés fluorés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62212369A (ja) * 1986-03-07 1987-09-18 チバ・ガイギ−・アクチエンゲゼルシヤフト トルニトリル化合物、その製造方法及びそれを含むアロマターゼ阻害剤
EP0490816A2 (fr) * 1990-12-12 1992-06-17 Ciba-Geigy Ag Dérivés fluorés

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036876A1 (fr) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
US6063930A (en) * 1996-04-03 2000-05-16 Merck & Co., Inc. Substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
US6080870A (en) * 1996-04-03 2000-06-27 Merck & Co., Inc. Biaryl substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
WO2005007631A1 (fr) * 2003-07-10 2005-01-27 Osi Pharmaceuticals, Inc. Derives de naphtylene constituant des inhibiteurs du cytochrome p450
US7662844B2 (en) 2004-07-12 2010-02-16 Osi Pharmaceuticals, Inc. Naphthylene derivatives as cytochrome P450 inhibitors
JP2013516418A (ja) * 2009-12-31 2013-05-13 ヴィアメット ファーマスーティカルズ，インコーポレイテッド 金属酵素阻害化合物

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