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WO1994018168A1 - Derives d'indole utilises comme inhibiteurs de 5-alpha-reductase - Google Patents

Derives d'indole utilises comme inhibiteurs de 5-alpha-reductase Download PDF

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Publication number
WO1994018168A1
WO1994018168A1 PCT/JP1994/000093 JP9400093W WO9418168A1 WO 1994018168 A1 WO1994018168 A1 WO 1994018168A1 JP 9400093 W JP9400093 W JP 9400093W WO 9418168 A1 WO9418168 A1 WO 9418168A1
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Prior art keywords
compound
salt
ester
mixture
formula
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PCT/JP1994/000093
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English (en)
Inventor
Satoshi Okada
Kozo Sawada
Akio Kuroda
Shinya Watanabe
Hirokazu Tanaka
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to JP6517863A priority Critical patent/JPH08506338A/ja
Publication of WO1994018168A1 publication Critical patent/WO1994018168A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel indole derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to novel indole derivatives and pharmaceutically acceptable salts thereof, which have pharmacological activities such as inhibitory activity on testosterone 5 ⁇ .-reductase, to a process for the preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.
  • indole derivatives are effective for testosterone 5 ⁇ .-reductase mediated diseases.
  • a testosterone 5 ⁇ -reductase inhibitor with stronger effect has been demanded.
  • one object of the present invention is to provide novel indole derivatives and pharmaceutically acceptable salts thereof, which are useful as a testosterone 5a- reductase inhibitor.
  • Another object of the present invention is to provide a process for the preparation of said indole derivatives or salts thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said indole derivative or a pharmaceutically acceptable salt thereof.
  • a still fur t her object of the present invention is to provide use of said indole derivatives or pharmaceutically acceptable salts thereof as a medicament such as a testosterone ⁇ a-reductase inhibitor useful for treating or preventing testosterone 5a-reductase mediated diseases such as alopecia, acnes and prostatism in human being or animals.
  • a medicament such as a testosterone ⁇ a-reductase inhibitor useful for treating or preventing testosterone 5a-reductase mediated diseases such as alopecia, acnes and prostatism in human being or animals.
  • Indole derivatives of the present invention are novel and can be represented by the formula (I):
  • R 1 is a carboxy or protected carboxy
  • R 2 is a lower alkyl, halo( lower)alkyl or phenyl
  • R 3 is a lower alkyl
  • R 4 is a hydrogen or halogen
  • A is a lower alkylene, with the proviso that when R 2 is a lower alkyl, R 4 is a halogen.
  • the object compound (I) and a salt thereof can be prepared by the, fol lowing processes.
  • R is a protected carboxy, 1 is a leaving group, and
  • W 2 and 3 are each an acid residue.
  • Suitable salts of the compound (I) are conventional, non- ' toxic, pharmaceutically acceptable salts and include salts with base or acid addition salts.
  • salts with inorganic base such as alkali metal salts (e.g. sodium salt, potassium salt, cesium salt), alkaline earth metal salts (e.g. calcium salt, magnesium salt) and ammonium salts; salts with organic base such as organic amine salts (e.g. triethylamine salt, pyridine salt, picoline salt, ethanola ine salt, triethanolamine salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt); inorganic acid addition salts (e.g.
  • hydrochloride, hydrobromide, sulfate, phosphate organic carboxylic or sulfonic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate) ; and salts with basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid).
  • the preferable examples thereof are acid addition salts.
  • lower means that the number of carbon atom is from 1 to 6, preferably 1 to 4, unless otherwise indicated.
  • Suitable "lower alkyl” includes straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl, preferable ones having 1 to 4 carbon atoms.
  • Halo( lower)a1ky1 has one, two or three halogen atoms.
  • Suitable “mono- or di- or tri-halo( lower)alkyl” includes chloro ethyl, fluoromethyl , chloroethyl, dichloromethyl, difluoromethyl, trifluoromethyl, trifluoropropyl and trifluoromethylpropyl.
  • halogen means fluoro, chloro, bromo and iodo.
  • Suitable "lower alkylene” includes straight or branched bivalent lower alkanes such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and propylene.
  • Suitable "leaving group” includes hydroxy, and reactive groups derived from hydroxy.
  • Suitable "reactive group derived from hydroxy” includes acid residues.
  • Suitable "acid residue” includes halogen (e.g. fluoro, chloro, bromo, iodo) and acyloxy (e.g. acetoxy, tosyloxy, mesyloxy).
  • halogen e.g. fluoro, chloro, bromo, iodo
  • acyloxy e.g. acetoxy, tosyloxy, mesyloxy
  • Suitable "protected carboxy” includes esterified carboxyl groups.
  • ester moiety of "esterified carboxy” are, for instance, lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester) which may have one or more suitable substituents such as lower alkanoyloxy( lower)alkyl ester [e.g.
  • acetoxymethyl ester propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyl oxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)- acetoxypropyl ester, l(or 2 or 3 or 4)-acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or 3)-propionyloxypropyl ester, l(or 2)-butyryloxyethyl ester, l(or 2)-isobutyryloxyethyl ester, l(or 2)-pivaloyloxyethyl ester, l(or 2)-hexanoyloxyethyl 3, 3-dimethylbutyryloxymethyl ester, l(or 2)-pentanoyloxyethyl ester],
  • 2-mesylethyl ester mono(or di or tri )-halo( lower)alkyl ester [e.g. 2-iodo- ethyl ester, 2, 2, 2-trichloroethyl ester], lower alkoxycarbonyl- oxy( lower)alkyl ester [e.g.
  • methoxycarbonyloxymethyl ester methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester], phthal idyl idene( lower)alkyl ester, or (5-lower alkyl-2- oxo-1, 3-dioxol-4-yl ) (lower)alkyl ester [e.g.
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxy- phenyl )methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5- di-tert-butylbenzyl ester]; aryl ester which may have one or more suitable substituents [e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester]; and phthal idyl ester.
  • suitable substituents e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl este
  • esterified carboxy examples include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxy- urbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxy- carbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl , 1-cyclo- propylethoxycarbonyl ) .
  • lower alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl , propoxycarbonyl, isopropoxycarbonyl, butoxy- urbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , pentyloxy- carbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl , 1-cyclo- propylethoxycarbonyl
  • R 1 , R 2 , R 3 , A, X and Y are as follows:
  • R 1 is carboxy and lower alkoxycarbonyl, more preferably, C1-C4 alkoxycarbonyl (e.g. ethoxycarbonyl),
  • R 2 is C1-C4 alkyl (e.g. propyl, butyl), mono- or tri-halo- (Ci-C alkyl (e.g. chloroethyl, trifluoropropyl ), and phenyl,
  • R 3 is C1-C4 alkyl (e.g. isobutyl), R 4 is hydrogen and halogen (e.g. fluoro), and A is C1-C4 alkylene (e.g. trimethylene).
  • the object compound (I) and a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
  • Suitable salts of the compounds (II) and (III) can be referred to ones as exemplified for the compound (I).
  • This reaction is usually carried out in a solvent such as an alcohol [e.g. methanol, ethanol], dichloromethane, benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent which does not adversely affect the reaction.
  • a solvent such as an alcohol [e.g. methanol, ethanol], dichloromethane, benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent which does not adversely affect the reaction.
  • solvents may be used alone o ⁇ * upon mixing with one another.
  • the reaction when W 1 in the compound (III) is an acid residue, the reaction may be carried out in the presence of an inorganic or organic base.
  • the base are, for instance, alkali metal hydroxides [e.g. sodium hydroxide, potassium hydroxide], alkali metal carbonates [e.g. sodium carbonate, potassium carbonate], alkali metal bicarbonates [e.g. sodium bicarbonate, potassium bicarbonate], alkali metal hydrides [e.g. sodium hydride, potassium hydride], tri(lower)- alkylamines [e.g. trimethylamine, triethylamine, diisopropyl- ethylamine], and pyridine and its derivatives [e.g. picoline, lutidine, 4-dimethylaminopyridine] .
  • the base to be used is a liquid, it can also be used as a solvent.
  • this reaction is usually carried out in the presence of a conventional condensing agent.
  • the condensing agent are, for instance, N,N' -dicyclohexylcarbodi imide; N-cyclohexyl-N' -morphol inoethyl- carbodi imide; N-cyclohexyl-N' -(4-diethylaminocyclohexyl )carbo- di imide; N,N' -diethylcarbodi imide; N,N'-di isopropylcarbodi imide; N-ethyl-N' -(3-dimethylaminopropyl )carbodi imide; N, N' -carbony1- bis(2-methyl imidazole) ; pentamethyleneketene-N-cyclohexyl imine; diphenylketene-N-cyclohexyl imine;
  • ethyl chloroformate isopropyl chloroformate
  • a combination of triarylphosphine e.g. triphenylphosphine
  • tri ( lower)alkylphosphine e.g. triethylphosphine
  • di ( lower)alkyl azodicarboxylate e.g.
  • reaction temperature is not critical, and the reaction can be carried out under cooling, at room temperature or under warming or heating.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
  • Process 3 The object compound (I-b) and a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to ax) elimination reaction of the carboxy-protective group.
  • Suitable base includes, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali metal acetates (e.g. sodium acetate, potassium acetate), alkaline earth metal phosphates (e.g. magnesium phosphate, calcium phosphate), and alkali metal hydrogen phosphates (e.g.
  • inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate),
  • disodium hydrogen phosphate dipotassium hydrogen phosphate
  • organic bases such as trialkylamines (e.g. trimethylamine, triethyla ine) , picoline, N-methylpyrrol idine, N-methylmorphol ine, and 1, 5-diazabicyclo-
  • Suitable acid includes organic acids (e. Tormic acid, acetic acid, propionic acid) and inorganic acids (e.g. hydrochloric acid, hydrobro ic acid, sulfuric acid).
  • organic acids e. Tormic acid, acetic acid, propionic acid
  • inorganic acids e.g. hydrochloric acid, hydrobro ic acid, sulfuric acid.
  • the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and it may be selected suitably in accordance with the kind of carboxy protective group and elimination method.
  • the elimination using a Lewis acid is preferable for eliminating a substituted or unsubstituted ar( lower)alkyl ester, and carried out by reacting the compound (I-a) or a salt thereof with a Lewis acid.
  • the Lewis acid are boron trihalides (e.g. boron trichloride, boron trifluoride) , titanium tetrahalides (e.g. titanium tetrachloride, titanium tetrabromide) , tin tetrahalides (e.g. tin tetrachloride, tin tetrabromide), aluminum halides (e.g. aluminum chloride, aluminum bromide), and trihaloacetic acids (e.g.
  • This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, ni troethane), alkylene halide (e.g. methylene chloride, ethylene chloride), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction.
  • nitroalkane e.g. nitromethane, ni troethane
  • alkylene halide e.g. methylene chloride, ethylene chloride
  • diethyl ether diethyl ether
  • carbon disulfide e.g. methylene chloride, ethylene chloride
  • any other solvent which does not adversely affect the reaction.
  • the reduction elimination can be preferably conducted for eliminating a protective group such as halo( lower)alkyl (e.g. 2-iodoethyl, 2, 2, 2-trichloroethyl ) ester, and ar( lower)alkyl (e.g. benzyl) ester.
  • a protective group such as halo( lower)alkyl (e.g. 2-iodoethyl, 2, 2, 2-trichloroethyl ) ester, and ar( lower)alkyl (e.g. benzyl) ester.
  • the reduction applicable for the elimination reaction includes the reduction using a combination of a metal (e.g. zinc, zinc amalgam) or salt of chromium compound (e.g. chromous chloride, chromous acetate) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid); and conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g. palladium carbon, Raney nickel ).
  • a metal e.g. zinc, zinc amalgam
  • salt of chromium compound e.g. chromous chloride, chromous acetate
  • organic or inorganic acid e.g. acetic acid, propionic acid, hydrochloric acid
  • a conventional metallic catalyst e.g. palladium carbon, Raney nickel
  • reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof.
  • the reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction temperature] of this reaction are to be referred to those as explained in Process 1.
  • the starting compounds (IV) and (VI) include novel compounds which can be prepared by the following methods or in a conventional manner. The details of the following methods and conventional ones are shown in Preparation Examples to be mentioned below.
  • R 1 , R 2 , R 3 , A, X, Y, W 2 and W 3 are each as defined above, and W 4 and W 5 are each an acid residue.
  • Methods A and B can be carried out in a conventional manner.
  • the object compound (I) of the present invention can be isolated and purified in a conventional manner such as extraction, precipitation, fractional crystallization, recrystall ization, or chromatography.
  • the object compound (I) thus obtained can be converted to its salt by a conventional method.
  • the object compound (T; of the present invention is useful as a testosterone 5 a-reductase inhibitor and effective for testosterone 5 ⁇ -reductase mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism), androgenic alopecia (or male- pattern baldness), acne (e.g. acne vulgaris, pimple), other hyperandrogenis , and the like.
  • testosterone 5 a-reductase inhibitor and effective for testosterone 5 ⁇ -reductase mediated diseases such as prostatism, prostatic hypertrophy, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism), androgenic alopecia (or male- pattern baldness), acne (e.g. acne vulgaris, pimple), other hyperandrogenis , and the like.
  • the object compound (I) of the present invention is used in the form of a conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable, substantially non-toxic carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • the pharmaceutical preparation may be in a solid form such as tablet, granule, powder or capsule, or a liquid form such as solution, suspension, syrup, emulsion, lemonade or lotion.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, and ethylene glycol.
  • While the dosage of the compound (I) may vary depending upon age and conditions of patients, the kind of diseases or conditions, the kind of the compound (I) to be used, etc. In general, amounts between about 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used for treating diseases.
  • a solution of propyl agnesium bromide was prepared in a usual manner, using diethyl ether (10 ml), magnesium (194 mg) and 1-bromopropane (0.727 ml).
  • a solution of 3-fluoro-4- isobutylbenzaldehyde (721 mg) in diethyl ether (5 ml) was added dropwise to a Grinard solution and the mixture was stirred at 0°C for 30 minutes.
  • Aqueous ammonium chloride was added to the mixture, the organic phase was separated, washed with water and brine, dried over magnesium sulfate, and concentrated.
  • Chromium(VI) oxide (1.46 g) was added portionwise to pyridine (20 ml). After stirring for 30 minutes at room temperature, 1-(3-fluoro-4-isobutylphenyl )butanol (0.82 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture and extracted with diethyl »?tr_er. The organic solution was washed with 0.5N hydrochloric acid, water and brine, dried over magnesium sulfate, and consentrated.
  • Ethyl 4-[3-[4-[ (4-isobutylphenyl )phenylmethoxy]benzoyl ]-l- indolyl ]butyrate was prepared from 4-( isobutylphenyl )phenyl- methanol (397 mg) obtained in Pre. Ex. 3 and ethyl 4-[3-(4- hydroxybenzoyl )-l-indolyl ]butyrate (527 mg), in a manner similar to that of Ex. 1.
  • Step l To a solution of ethyl 4-[3-(4-hydroxybenzoyl )-l- indolyl ]butyrate (12.3 g) and di isopropylethylamine (7 ml) in tetrahydrofuran (100 ml) was added chloromethyl methyl ether (5 ml). The mixture was stirred for 4 hours at room temperature, evaporated and dissolved in ethyl acetate (100 ml). The solution was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel
  • Step 2 To a solution of ethyl 4-[3-(4-methoxymethoxy)- benzoyl]-l-indolyl ]butyrate (9.20 g) in ethanol (50 ml) was added IN aqueous solution of sodium hydroxide (30 ml). The mixture was stirred for 1 hour at room temperature, evaporated and dissolved in ethyl acetate (100 ml). The solution was washed with 5% aqueous solution of citric acid and water, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 4-[3-[4-(methoxymethoxy)benzoyl ]-l- indolyl ]butyric acid as a yellow gum (7.50 g).
  • Step 3 To a solution of 4-[3-[4-(methoxymethoxy)benzoyl ]- 1-indolyl ]butyric acid (3.67 g) in dichloromethane (30 ml) were added di isopropylethylamine (3 ml) and benzyl bromide (1.2ml). The mixture was stirred for 16 hours at room temperature, evaporated and dissolved in ethyl acetate (50 ml). The solution was washed with 5% aqueous solution of citric acid and water, dried over magnesium sulfate and evaporated.
  • Step 4 Trifluoroacetic acid (10 ml) and water (10 ml) were added to benzyl 4-[3-[4-(methoxymethoxy)benzoyl ]-l- indolyl ]butyrate (4.50 g) in dichloromethane (50 ml). The mixture was stirred for three days at room temperature. The mixture was washed with water and an aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated.
  • Step 5 Synthetically, to a solution of 2-hydroxy-2-(4- isobutylphenyl )acetic acid (1.0 g) in N, N-dimethyl-formamide (10 ml) were added potassium carbonate (2.0 g) and iodoethane (0.5 ml). The mixture was stirred at room temperature for 16 hours and poured into 7% hydrochloric acid in ice water. The organic layer was extracted with ethyl acetate (20 ml), washed with an aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solvent was removed in vacuo to give ethyl 2-hydroxy-2-(4-isobutylphenyl )acetate as an oil (1.00 g).
  • Step 6 To a solution of benzyl 4-[3-(4-hydroxybenzoyl )- 1-indolyl ]butyrate (0.41 g), ethyl 2-hydroxy-2-(4-isobutyl- phenyl )acetate (0.24 g) and triphenylphosphine (0.26 g) in a mixture of toluene (8 ml) and tetrahydrofuran (2 ml) was added diethyl azodicarboxylate (0.71 g) at -20 o C- The mixture was stirred at -20°c for 4 hours, and acetic acid (0.1 ml) was added to the mixture. After filtration, the solvent was removed under reduced pressure.
  • Step 7 Benzyl 4-[3-[4-[ethoxycarbonyl (4-isobutylphenyl )- methoxy]benzoyl ]-l-indolyl ]butyrate (o.20 g) was dissolved in ethanol (15 ml) and 10% palladium on carbon was added. The mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. Filtration of catalyst and evaporation of the solvent gave a yellow oil.
  • Step l To a solution of benzylmagnesium chloride (2.26 g) in diethyl ether was added 4' -isobutylbutyrophenone (3.06 g). The mixture was stirred at room temperature for 1 hour, and then aqueous ammonium chloride was added. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate to give 2-(4-isobutylphenyl )-l-phenyl-2-pentanol as an oil (2.73 g).
  • Step 2 To a solution of 2-(4-isobutylphenyl )-l-phenyl-2- pentanol (2.72 g) in pyridine (30 ml) was added thionyl chloride (5 ml) at 0°C • The mixture was stirred at 0°C for 1 hour, poured into ice water and extracted with diethyl ether. The organic layer was washed with 0.5N hydrochloric acid and water, dried over magnesium sulfate and concentrated. The residue was dissolved in a mixture of methanol (15 ml) and 1,4-dioxane (30 ml), and 10% palladium on carbon was added. The mixture was stirred under hydrogen atmosphere at room temperature for 1 hour. Removal of catalyst and evaporation of solvent gave 2- ( isobutylphenyl )-l-phenylpentane as an oil (1.64 g).
  • Step 3 To a suspension of aluminum chloride (755 mg) in dichloromethane (10 ml) was added oxalyl chloride (0.51 ml) at
  • Step 4 To a mixture of indole (2.03 g) and tetrahydro ⁇ furan (20 ml) was added 3 M solution of methylmagnesium bromide (6.6 ml). The mixture was stirred at room temperature for 1 hour, and then 4-[2-(4-isobutylphenyl )pentyl ]benzoyl chloride
  • Step 5 A mixture of 3-[4-[2-(4-isobutylphenyl )pentyl ]- benzoyl ] indole (424 mg), ethyl 4-bromobutyrate (234 mg) and potassium carbonate (415 mg) was stirred at room temperature for 6 hours. The insoluble materials were filtered off, and the filtrate was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated.
  • Isoamyl valerophenone was prepared from isoamylbenzene and valeryl chloride in a manner similar to that of Pre. Ex. 2.
  • l-(4-Isoamylphenyl )pentanol was prepared from the obtained isoamyl valerophenone in a manner similar to that of Pre. Ex. 1.
  • Ethyl 4-[3-[4-[ l-(4-isoamylphenyl )pentyloxy]benzoyl ]-l- indolyl ]butyrate was prepared from the obtained l-(4-isoamyl- phenyl )pentanol and ethyl 4-[3-(4-hydroxybenzoyl )-l-indolyl ]- butyrate, in a manner similar to that of Ex. 1.
  • Example 18 To a suspension of aluminum chloride (4.0 g) in dichloromethane (50 ml) was added valeryl chloride (3.56 ml) at 0°C • After the mixture was stirred at 0°C for 30 minutes, chlorobenzene (3.68 g) was added to the mixture. The mixture was heated under reflux for 4 hours, then cooled to room temperature, and poured into ice water. The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. Evaporation of the solvent gave 4' -chlorovalerophenone as an oil (780 mg). l-(4-Chloro ⁇ henyl )pentanol was prepared from the obtained 4' -chlorovalerophenone in a manner similar to that of Pre. Ex. 1

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Abstract

L'invention concerne un composé de la formule (I), dans laquelle R1 représente un carobxy ou un carboxy protégé, R2 représente un alkyle inférieur, haloalkyle(inférieur) ou phényle, R3 représente un alkyle inférieur, R4 représente hydrogène ou un halogène, et A représente un alkylène inférieur, à la condition que, lorsque R2 représente un alkyle inférieur, R4 représente un halogène, ainsi qu'un sel pharmaceutiquement acceptable dudit composé. Le composé de l'invention est utile comme inhibiteur de 5α-réductase de testostérone, et efficace contre des maladies induites par la 5α-réductase de testostérone telles que le prostatisme, l'hypertrophie prostatique, le cancer prostatique, l'alopécie, l'hirsutisme (par exemple l'hirsutisme féminin), l'alopécie androgène (la calvitie hippocratique), l'acné (par exemple l'acné vulgaris, les papules), d'autres hyperandrogénismes et analgogue.
PCT/JP1994/000093 1993-02-10 1994-01-24 Derives d'indole utilises comme inhibiteurs de 5-alpha-reductase WO1994018168A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP6517863A JPH08506338A (ja) 1993-02-10 1994-01-24 ５α−還元酵素阻害剤としてのインドール誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939302577A GB9302577D0 (en) 1993-02-10 1993-02-10 Indole derivatives
GB9302577.3 1993-02-10

Publications (1)

Publication Number Publication Date
WO1994018168A1 true WO1994018168A1 (fr) 1994-08-18

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/000093 WO1994018168A1 (fr) 1993-02-10 1994-01-24 Derives d'indole utilises comme inhibiteurs de 5-alpha-reductase

Country Status (3)

Country Link
JP (1) JPH08506338A (fr)
GB (1) GB9302577D0 (fr)
WO (1) WO1994018168A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole
WO1993002050A1 (fr) * 1991-07-24 1993-02-04 Pfizer Limited Indoles
WO1993005019A1 (fr) * 1991-09-11 1993-03-18 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole servant d'inhibiteur de 5-alpha-reductase
WO1993016996A1 (fr) * 1992-02-25 1993-09-02 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole utilises comme inhibiteurs de la testosterone-5-alpha-reductase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole
WO1993002050A1 (fr) * 1991-07-24 1993-02-04 Pfizer Limited Indoles
WO1993002051A1 (fr) * 1991-07-24 1993-02-04 Pfizer Limited Indoles
WO1993005019A1 (fr) * 1991-09-11 1993-03-18 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole servant d'inhibiteur de 5-alpha-reductase
WO1993016996A1 (fr) * 1992-02-25 1993-09-02 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole utilises comme inhibiteurs de la testosterone-5-alpha-reductase

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

Also Published As

Publication number Publication date
JPH08506338A (ja) 1996-07-09
GB9302577D0 (en) 1993-03-24

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