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WO1993013099A1 - CETONES D'ARYLE UTILISEES COMME INHIBITEURS DE TESTOSTERONE 5α-REDUCTASE - Google Patents

CETONES D'ARYLE UTILISEES COMME INHIBITEURS DE TESTOSTERONE 5α-REDUCTASE Download PDF

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Publication number
WO1993013099A1
WO1993013099A1 PCT/JP1992/001674 JP9201674W WO9313099A1 WO 1993013099 A1 WO1993013099 A1 WO 1993013099A1 JP 9201674 W JP9201674 W JP 9201674W WO 9313099 A1 WO9313099 A1 WO 9313099A1
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Prior art keywords
compound
salt
ethyl
ester
nmr
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PCT/JP1992/001674
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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 JP5511550A priority Critical patent/JPH08500082A/ja
Priority to EP93900373A priority patent/EP0620818A1/fr
Publication of WO1993013099A1 publication Critical patent/WO1993013099A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/44—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/30—Azulenes; Hydrogenated azulenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel heterocyclic compound. More particularly, it relates to novel heterocyclic compound or a pharmaceutically acceptable salt thereof which has pharmacological activities such as inhibitory activity on testosteron 5 ⁇ -reductase and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.
  • one object of the present invention is to provide novel heterocyclic compound or a pharmaceutically acceptable salt thereof, which is of use as a testosteron 5 ⁇ -reductase inhibitor.
  • Another object of the present invention is to provide a process for preparation of said heterocyclic compound or a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said heterocyclic compound or a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a use of said heterocyclic compound or a pharmaceutically acceptable salt thereof as a medicament such as testosteron 5 ⁇ -reductase inhibitor useful for treating or preventing testosteron 5 ⁇ -reductase-mediated diseases such as prostatomegaly, prostatism, alopecia, acnes, and the like in human being or animals.
  • heterocyclic compound of the present invention is novel and can be represented by the formula (I) :
  • R is carboxy(lower)alkyl or protected carboxy(lower)alkyl
  • X is optionally substituted arylene
  • R6 is hydrogen, lower alkyl, optionally substituted aralkyl or amino-protective group
  • A is a bivalent radical derived from imidazopyridine, azulene, thiophene, pyrrolo[2,3-bjpyridine, quinolone, indazole or dihydrobenzimidazole, each of which may be substituted by one or more suitable substituent(s) .
  • the object compound (I) and a salt thereof can be prepared by the following processes.
  • Process 1 the object compound (I) and a salt thereof can be prepared by the following processes.
  • R 1, R2, A, X and Y are each as defined above,
  • R_. is protected carboxy(lower)alkyl, and R, 1 is carboxy(lower)alkyl.
  • Suitable salts of the compound (I) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g.
  • triethylamine salt pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenz ⁇ lethylenediamine salt, etc.), etc.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g.
  • the compound (I) possesses stereoisomers such as optical isomers due to the presence of asymmetric carbon atom(s), and such isomers are also included within a scope of the present invention.
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Suitable “lower alkyl” may include straight or branched one having 1 to 6 carbon ato (s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atoms.
  • Carboxy(lower)alkyl means lower alkyl as explained above, which is substituted by a carboxy group at its optional positions, and suitable example thereof may be carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and the like, in which preferable one is carboxy(C..-C.)alkyl and the most preferable one is 3-carboxypropyl.
  • Protected carboxy(lower)alkyl means carboxy(lower)alkyl as explained above, in which the carboxy group is protected by a conventional carboxy-protective group, and suitable "protected carboxy” moiety of "protected carboxy(lower)alkyl” may include an esterified carboxy group. Suitable examples of the ester moiety of an
  • esterified carboxy may be a conventional one such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s) , for example, lower cycloalkyKlower)alkyl ester (e.g. 1-cyclopropylethyl, etc.), lower alkan ⁇ yloxy(lower)alkyl ester (e.g.
  • acetoxymethyl ester propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)- acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl este , l(or 2 or 3 or 4)-acetoxybutyl ester, l(or 2)-propionyl- oxyethyl 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 1)
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenz ⁇ l ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g.
  • phenyl ester 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
  • protected carboxy(lower)alkyl may be esterified carboxy(lower)alkyl such as lower alkoxycarbonyKlower)alkyl, more preferably 3-lower alkoxycarbonylpropyl (e.g. 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 3-propoxycarbonylpropyl,
  • Aralkyl in “optionally substituted aralkyl” means straight or branched C--C- Q , preferably C--Cg alkyl substituted by aryl, and suitable "optionally substituted aralkyl” thus defined may include aralkyl (e.g.
  • aryl e.g. phenyl, tolyl, xylyl , naphthyl, etc.
  • a idated carboxy such as carbamoyl, mono or di(lower)alkylcarbamoyl (e.g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl . diethylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, etc. )
  • lower alkylarylcarbamoyl e.g. isobutylphenylcarbamoyl, etc.
  • optionally substituted aralkyl may be benzyl, benzhydryl, trityl, phenethyl, 1-phenylethy1, methylbenzyl , isobutylbenzyl, methylphenylethyl, isobutylphenylethyl, methylphenylpropyl, isobutylphenyIpropyl, methylphenylpentyl, isobutylphenylpent 1, bis(methylphenyl)methyl, bis(propylphenyl)methyl, bis(butylphenyl)methyl, bis(isobutylphenyl)methyl, bis(chlorophenyl)methyl, (cyano) (isobutylphenyl)methyl, (carboxy) (isobutylphenyl)methyl, (benzyloxycarbony1) (isobutylphenyl)methyl, (N,N-diethylcarbamoyl) (
  • Suitable “amino-protective group” may be a conventional protective group which is used in the field of peptide chemistry, that is, may include acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), ar(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.), and the like.
  • acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoy
  • Optionally substituted arylene means a bivalent radical derived from arene, preferably c g ⁇ c * ⁇ g arene ' suc h as benzene, toluene, xylene, mesitylene, naphthalene, and the like, which may be substituted by one or more, preferably one or two suitable substituents such as halogen as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isobutoxy, butoxy, etc. ) , and the like. Suitable example thereof may be 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 5-methyl-1,3-phenylene, 2,3-dimethyl-l,4-phenylene, 1,2-naphthylene,
  • Suitable "a bivalent radical derived from imidazopyridine” may be imidazo[l,5-a]pyridin-diyl such as imidazo[l,5-a]pyridin-l,3-di ⁇ l, and the like.
  • Suitable "a bivalent radical derived from azulene” may be azulen-diyl such as azulen-l,3-diyl, and the like.
  • Suitable "a bivalent radical derived from thiophene” may be thien-diyl such as thien-2,5-diyl, and the like.
  • Suitable "a bivalent radical derived from pyrrolo[2,3-b]pyridine” may be lH-pyrrolo[2,3-b]p ⁇ ridin-diyl such as lH-pyrrolo[2,3-b]pyridin-l,3-di ⁇ l, and the like.
  • Suitable "a bivalent radical derived from guinolone” may be 4-(lH)-quinolon-diyl such as 4- ( lH) -guinolon-l , 3-diyl, and the like.
  • Suitable "a bivalent radical derived from indazole” may be lH-imidazol-diyl such as lH-indazol-l,3-diyl, and the like.
  • Suitable "a bivalent radical derived from dihydrobenzimidazole” may be 2,3-dihydro-lH-benzimidazol-diyl such as 2,3-dih ⁇ dro-lH-benzimidazol-l,3-diyl, and the like.
  • the bivalent radicals mentioned above may be substituted by one or more, preferably one to three suitable substituent(s) such as aryl (e.g. phenyl, tolyl, xylyl, naphthyl, etc. ) , lower alkyl as mentioned above, halogen as mentioned above, hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), and the like.
  • suitable "halogen” may be the same as those given in the above.
  • Suitable "protected hydroxy” may be lower alkyl, ar(lower)alkyl and acyloxy explained above, and the like.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or its reactive derivative at the hydroxy group, or a salt thereof.
  • Suitable salt of the compounds (II) and (III) or its reactive derivative at the hydroxy group may be the same that exemplified for the compound (I) .
  • Suitable "reactive derivative at the hydroxy group" of the compound (III) may include an acid residue such as halo (e.g. bromo, chloro, iodo, etc.), acyloxy (e.g. acetoxy, mesyloxy, tosyloxy, etc.), and the like. This reaction is usually carried out in a solvent such as chloroform, dichloromethane, benzene,
  • the reaction may be carried out in the presence of an inorganic or an. organic base such as an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc.], an alkali metal carbonate [e.g. sodium carboante, potassium carbonate, etc.], an alkali metal bicarbonate
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal carbonate e.g. sodium carboante, potassium carbonate, etc.
  • an alkali metal bicarbonate e.g. sodium hydroxide, potassium hydroxide, etc.
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • alkali metal hydride e.g. sodium hydride, potassium hydride, etc.
  • tri(lower)alkylamine e.g. trimethylamine, triethylamine, diisopropylethylamine , etc.
  • pyridine or its derivative e.g. picoline, lutidine
  • the base to be used is liquid, it can also be used as a solvent.
  • this reaction can be carried out in the presence of a conventional condensing agent which is capable of condensing alcohols and amines.
  • the 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 (l-b) or a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to removal reaction of the carboxy-protective ⁇ group in R cL.
  • Suitable salt of the compounds (I-a) and (l-b) may be the same as that exemplified for the compound (I) .
  • the carboxy-protective group is an ester
  • it can be removed by hydrolysis or removal using Lewis acid.
  • the hydrolysis is preferably carried out in the presence of a base or an acid.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carboante (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.
  • an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
  • Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, benzoic acid etc. ) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
  • organic acid e.g. formic acid, acetic acid, propionic acid, benzoic acid etc.
  • inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent such as alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, N,N-dimethylformamide, water or a mixed solvent thereof.
  • organic solvent such as alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, N,N-dimethylformamide, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and its may suitably be selected in accordance with the kind of the carboxy-protective group and the removing method.
  • the removal using Lewis acid is preferably to remove substituted or unsubstituted ar(lower)alkyl ester and carried out by reacting the compound (I-a) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc. ) , titanium tetrahalide (e.g. titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. tin tetrachloride, tin tetrabromide, etc.
  • This removal reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylene chloride, etc. ) , diethyl ether, carbon disulfide or any other solvent which does not adversely affect the reaction. These solvents may be used as a mixture thereof.
  • the reduction can be applied preferably for removing the protective-group such as halo(lower)alkyl (e.g. 2-iodoeth ⁇ l, 2,2,2-trichloroethyl, etc.) ester, ar(lower)alkyl (e.g. benzyl, etc.) ester or the like.
  • the reduction method applicable for the removal reaction may include, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc. ) and an organic or an inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc. ) ; and conventional catalytic reduction in the pressure of a conventional metallic catalyst (e.g. Palladium carbon, Raney nickel, etc.).
  • a metal e.g. zinc, zinc amalgam, etc.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the object compound (I) thus prepared can be iolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
  • the object compound (I) of the present invention can be converted to its salt by a conventional method.
  • the optically active compound can be prepared by a conventional optical resolution method or by selecting the optical active starting compound.
  • the starting compound (II) can be prepared by the following methods, the details of which are shown in Preparations mentioned below, or a conventional manner.
  • Ya is nitro or protected hydroxy
  • Methods A, B and C can be carried out in a conventional manner.
  • the object compound (I) of the present invention is useful as a testosteron 5 ⁇ -reductase inhibitor and effective to testosteron 5 ⁇ -reductase-mediated diseases such as prostatomegaly, prostatism, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism, etc.), androgenic alopecia (or male-pattern baldness), acne (e.g. acne vulgaris, pimple etc.), other hyperandrogenism, and the like.
  • testosteron 5 ⁇ -reductase inhibitor and effective to testosteron 5 ⁇ -reductase-mediated diseases such as prostatomegaly, prostatism, prostatic cancer, alopecia, hirsutism (e.g. female hirsutism, etc.), androgenic alopecia (or male-pattern baldness), acne (e.g. acne vulgaris, pimple etc.), other hyperandrogenism, and the like.
  • 3 1,2,6,7- H-Testosterone (85-105 Ci/mmol) 3 1,2,6,7- H-Testosterone (85-105 Ci/mmol) is a mixture 3 of 1,2,6,7- H-testosterone and testosterone which 3 includes 85-105 Ci of 1,2,6,7- H-testosterone per mmol of testosterone and is purchased from New
  • Aquazol-2 (Aquazol-2-Universal LSC Cocktail) : trademark, purchased from New England Nuclear, Boston, Mass., U.S.A.
  • the reaction solution contains 1 mM dithiothreitol
  • test Compound was added in 10 ⁇ l of 10% ethanol whereas control tubes received the same volume of 10% ethanol.
  • the reaction was started with the addition of the enzyme suspension. After incubation at 37°C for 30 inut :-, the reaction was extracted with 1 ml of ethyl acetate.
  • the object compound (I) or a pharmaceutically acceptable salt of the present invention is used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral, external and topical administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral, external and topical administration.
  • the pharmaceutical preparation may be in solid or semi-solid from such as tablet, granule, powder, capsule, suppository, cream, ointment, or liquid form such as solution, suspension, syrup, emulsion, lemonade, lotion and the like.
  • 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, ethylene glycol, and the like.
  • dosage of the compound (I) may very from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general amounts between 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 in treating diseases.
  • 3-(3-Nitrobenzoyl)-lH-p ⁇ rrolo[2,3-b]pyridine could be obtained by reacting lH-pyrrolo[2,3-b]pyridine with 3-nitrobenzoyl chloride in accordance with a similar manner to that of Preparation 4.
  • Ethyl 4-(thien-2-yl)butyrate could be obtained by reacting 4-(thien-2-yl)butyric acid with ethanol in accordance with a similar manner to that of Preparation 2-(2).
  • Ethyl 4-oxo-4-(3-phenylthien-2-yl)butyrate could be obtained by reacting 3-phenylthiophene with ethyl succinyl chloride in accordance with a similar manner to that of Preparation 3-(1) .
  • Example 10 The compounds described in the following Examples 10 to 15 could be obtained by hydrolyzing the corresponding ethyl ester with aqueous sodium hydroxide in accordance with a similar manner to that of Example 9.
  • Example 10

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Abstract

Composé hétérocyclique de la formule: R1-A-CO-X-Y-R2 dans laquelle R1 représente carboxyalkyle (inférieur) ou carboxyalkyl (inférieur) protégé, R2 représente aralkyle éventuellement substitué, X représente arylène éventuellement substitué, Y représente -O- ou (a), R6 représentant hydrogène, alkyle inférieur, aralkyle éventuellement substitué ou un groupe amino-protecteur, et A représente un radical bivalent dérivé d'imidazopyridine, d'azulène, de thiophène, de pyrrolo[2,3-b]pyridine, de quinolone, d'indazole ou de dihydrobenzimidazole, dont chacun peut être substitué par au moins un substituant approprié. Ce composé peut être utilisé comme inhibiteur de testostérone 5α-réductase.
PCT/JP1992/001674 1991-12-31 1992-12-21 CETONES D'ARYLE UTILISEES COMME INHIBITEURS DE TESTOSTERONE 5α-REDUCTASE WO1993013099A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5511550A JPH08500082A (ja) 1991-12-31 1992-12-21 テストステロン５α−レダクターゼ阻害剤としてのアリールケトン類
EP93900373A EP0620818A1 (fr) 1991-12-31 1992-12-21 CETONES D'ARYLE UTILISEES COMME INHIBITEURS DE TESTOSTERONE 5$g(a)-REDUCTASE

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GB9127531.3 1991-12-31
GB919127531A GB9127531D0 (en) 1991-12-31 1991-12-31 Heterocyclic compound

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Cited By (22)

* Cited by examiner, † Cited by third party
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WO1996010013A1 (fr) * 1994-09-27 1996-04-04 Ono Pharmaceutical Co., Ltd. Composes heterocycliques a cinq elements
GB2320715A (en) * 1996-12-25 1998-07-01 Kotobuki Seiyaku Co Ltd Derivatives of Carboxyalkyl Azulenes and Azulene-1-Carboxylic Acid
US5859042A (en) * 1995-09-27 1999-01-12 Ono Pharmaceutical Co., Ltd. Five membered heterocyclic compounds
US7173027B2 (en) 2001-01-29 2007-02-06 University Of Connecticut Receptor selective cannabimimetic aminoalkylindoles
US7241799B2 (en) 1999-10-18 2007-07-10 University Of Connecticut Cannabimimetic indole derivatives
US7456289B2 (en) 2004-12-31 2008-11-25 National Health Research Institutes Anti-tumor compounds
US7498342B2 (en) 2004-06-17 2009-03-03 Plexxikon, Inc. Compounds modulating c-kit activity
US7501438B2 (en) 2006-07-07 2009-03-10 Forest Laboratories Holdings Limited Pyridoimidazole derivatives
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
US7528165B2 (en) 2001-12-13 2009-05-05 National Health Research Institutes Indole compounds
US7598286B2 (en) 2004-11-01 2009-10-06 Wyeth [(1H-indazol-3-yl)methyl]phenols and (hydroxyphenyl)(1H-indazol-3-yl)methanones
US7632955B2 (en) 2001-12-13 2009-12-15 National Health Research Institutes Indole compounds
CN101058558B (zh) * 2007-05-28 2013-04-10 沈阳药科大学 具有醛糖还原酶抑制活性的4-氧代-1(4h)-喹啉羧酸类化合物、组合物及其制备方法
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
WO2016044445A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2016044446A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013060A1 (fr) * 1990-02-26 1991-09-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013060A1 (fr) * 1990-02-26 1991-09-05 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole
EP0458207A2 (fr) * 1990-05-21 1991-11-27 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'indole

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010013A1 (fr) * 1994-09-27 1996-04-04 Ono Pharmaceutical Co., Ltd. Composes heterocycliques a cinq elements
US5859042A (en) * 1995-09-27 1999-01-12 Ono Pharmaceutical Co., Ltd. Five membered heterocyclic compounds
GB2320715A (en) * 1996-12-25 1998-07-01 Kotobuki Seiyaku Co Ltd Derivatives of Carboxyalkyl Azulenes and Azulene-1-Carboxylic Acid
US7241799B2 (en) 1999-10-18 2007-07-10 University Of Connecticut Cannabimimetic indole derivatives
US7173027B2 (en) 2001-01-29 2007-02-06 University Of Connecticut Receptor selective cannabimimetic aminoalkylindoles
US7528165B2 (en) 2001-12-13 2009-05-05 National Health Research Institutes Indole compounds
US7632955B2 (en) 2001-12-13 2009-12-15 National Health Research Institutes Indole compounds
US7504509B2 (en) 2003-12-19 2009-03-17 Plexxikon, Inc. Compounds and methods for development of Ret modulators
US7498342B2 (en) 2004-06-17 2009-03-03 Plexxikon, Inc. Compounds modulating c-kit activity
US7598286B2 (en) 2004-11-01 2009-10-06 Wyeth [(1H-indazol-3-yl)methyl]phenols and (hydroxyphenyl)(1H-indazol-3-yl)methanones
US7456289B2 (en) 2004-12-31 2008-11-25 National Health Research Institutes Anti-tumor compounds
US7501438B2 (en) 2006-07-07 2009-03-10 Forest Laboratories Holdings Limited Pyridoimidazole derivatives
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
CN101058558B (zh) * 2007-05-28 2013-04-10 沈阳药科大学 具有醛糖还原酶抑制活性的4-氧代-1(4h)-喹啉羧酸类化合物、组合物及其制备方法
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US12076322B2 (en) 2011-02-07 2024-09-03 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
WO2016044446A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2016044445A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc

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JPH08500082A (ja) 1996-01-09
GB9127531D0 (en) 1992-02-19
EP0620818A1 (fr) 1994-10-26

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