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WO1996010013A1 - Composes heterocycliques a cinq elements - Google Patents

Composes heterocycliques a cinq elements Download PDF

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Publication number
WO1996010013A1
WO1996010013A1 PCT/US1995/011962 US9511962W WO9610013A1 WO 1996010013 A1 WO1996010013 A1 WO 1996010013A1 US 9511962 W US9511962 W US 9511962W WO 9610013 A1 WO9610013 A1 WO 9610013A1
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WO
WIPO (PCT)
Prior art keywords
methylpyrrol
acetic acid
benzoyl
alkyl
bond
Prior art date
Application number
PCT/US1995/011962
Other languages
English (en)
Inventor
Sung Jai Lee
Takuya Seko
Manton Rodgers Frierson
Jagadish Chandra Sircar
Charles Xian Cao
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to KR1019970701970A priority Critical patent/KR970706250A/ko
Priority to JP8511867A priority patent/JPH10506892A/ja
Priority to EP95934464A priority patent/EP0783488A4/fr
Priority to US08/793,983 priority patent/US5859042A/en
Publication of WO1996010013A1 publication Critical patent/WO1996010013A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention is related to five membered heterocyclic compounds. More particularly, this invention is related to :
  • testosterone androgenic hormone played an important role on the generation of hairs.
  • the relation between testosterone and androgenic alopecia is as follows:
  • testosterone biosynthesized in testis is converted into dihydrotestosterone(DHT) by 5 ⁇ -reductase existed in hair follicle, sebaceous gland etc. at the head,
  • DHT converted from testosterone by 5 ⁇ -reductase also plays an important physiological role in the generation of acnes (acne, pimple etc.) other than androgenic alopecia [Br. J. Dermatol., 91 , 123(1974) ; J. Invest. Dermatol., 56, 366(1971)].
  • DHT also plays an important role in the generation and the development of prostatic hypertrophy [J. Steroid Biochemistry, 11, 609(1979) ; J. Clinical Endocrinol and Metabolism, 56, 139(1983)].
  • DHT is also related to prostatic cancer.
  • 5 ⁇ -reductase inhibitors are largely divided into compounds having steroidal structure and compounds having non-steroidal structure.
  • a representation of steroidal compound is finasteride, shown by below formula, and the compound is available in the market.
  • ONO-3805 shown below formula is known.
  • Non-steroidal compounds possessing 5 ⁇ -reductase inhibitory activity are the following:
  • R 1A is carboxy (lower) alkyl or protected carboxy(lower)alkyl
  • R 2A is optionally substituted aralkyl
  • X A is optionally substituted arylene
  • Y A is -O- or -NR 6A - ,
  • R 6A is hydrogen, lower alkyl, optionally substituted aralkyl or amino- protective group
  • a A is a bivalent radical derived from imidazopyridine, azulene, thiophene, pyrrolo[2,3- b] pyridine, quinolone, indazole or dihydrobenzimidazole, each of which may be substituted by one or more suitable substituent(s).
  • Ar B is phenyl, phenyl substituted by one or more halogen, lower alkyl, lower alkoxy, NO 2 , NH 2 , CN or SCH 3 ;
  • R B is hydrogen, lower alkyl;
  • R 1B is hydrogen, lower alkyl, benzyl;
  • R 2B is CN, COOH, COO(lower alkyl), CONH 2 , CONH(lower alkyl),
  • R 4C is lower alkyl
  • R 5C is lower alkyl
  • R 6C is hydrogen, lower alkyl
  • R 1 G is -COOH or X G -COOH in which X G is C1-8 alkyl, C2-8 alkenyl or alkynyl etc.
  • R 3G is -CO-CH 3 , -CO-Y G or -COY G -Aryl in which Y G is C2-19 alkyl, alkenyl or alkynyl etc.
  • R 2G , R 4G , R 5G is hydrogen, C1-20 alkyl, C2-20 alkenyl or alkynyl, Aryl, -Z G -Aryl etc., in which Z G is C1-20 alkyl, C2-10 alkenyl or alkynyl etc;
  • R 1H is (i) hydrogen, (ii) C1-3 saturated or unsaturated alkyl optionally substituted by OH, SH, halogen, COOH, alkoxy, alkoxycarbonyl or aryloxycarbonyl,
  • R 2 H and R 5H is (j) hydrogen, (ii) methyl optionally substituted by OH, COOH, alkoxycarbonyl, (iii) -CHO, COOH, acethyl, propionyl, (iv) benzoyl optionally substituted by halogen (v) carbonyl group connected with alkoxycarbonylethyl, (vi) 3-alkoxycarbonyl-2-alkoxy-2-propenyl, (vii) nitrophenyl;
  • R 3H and R 4H is (i) hydrogen, (ii) aryloxycarbonyl, (iii) carbonyl group connected with methyl or ethyl substituted by alkoxycarbonyl, (iv) benzoyi optionally substituted by halogen, is disclosed to be useful as growth of hair.
  • the compounds disclosed in the related arts (1), (2), (3) and (5) are benzoic acid derivatives, indole derivatives or indolizine derivatives.
  • the compounds of the formula (la) of the present invention are pyrrole, thiophene, furan, imidazole, thiazole, oxazole and triazole derivatives. Therefore, the compounds of the present invention differ from those compounds.
  • the compounds which is thiophene in the formula (la) of the present invention are following thiophene compounds.
  • the compounds in the related arts (6), (7), (8), (9), (10) and (11) are disclosed to be useful as antiinflammatory. There are not description that the compound in the related arts (6), (7), (8), (9), (10) and (11 ) possess 5 ⁇ -reductase inhibitory activity. It is not able to expect at all that the compounds having pyrrole ring, thiophene ring or furan ring possess 5 ⁇ -reductase inhibitory activity.
  • the present invention is related to novel use of known compounds, novel compounds, use of the novel compounds and process for the preparation of the novel compounds.
  • the present invention is related to
  • R 4 is pyrrole included nitrogen substituted by R 4 , thiophene, furan, imidazole included nitrogen substituted by R 4 , thiazole, oxazole, triazole included nitrogen substituted by R 4 , in which R 4 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-
  • A is bond, C1-6 alkylene or C2-6 alkenylene
  • E is bond or C 1-6 alkylene; is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta (C4-7) cycloalkane,
  • n is 0 or 1 , or benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom;
  • R 1 is hydrogen or C1-4 alkyl
  • R 2 is hydrogen or C1-4 alkyl
  • n 1-3;
  • R 3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
  • Q is bond or C1-6 alkylene
  • T is bond, -O- , -S- , -SO 2 - ,-NR 7 - or -NR 7 CO-
  • R 7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in -NR 7 CO- may be connected with -Q- or -U-;
  • U is bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene or C1-6 alkylene -O-, in which oxygen atom can be connected with R 5 only;
  • R 5 is (i) C4-7 cycloalkyl, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
  • R 5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR 6 , in which R 6 is C1-4 alkyl, NR 8 R 9 , in which R 8 and R 9 each, independently, is hydrogen or C1-4 alkyl;
  • or -Q-T-U-R 5 is C7-10 alkyl, C7-10 alkoxy
  • T is -O- , or -NR 7 -
  • U is bond
  • R 5 is diphenylmethyl in -Q-T-U-R 5 represented by R 3 , when is thiophene, E is bond and is benzene or napthalene,
  • T is -O- , or -NR 7 - , and U is C 1-6 alkylene and R 5 is phenyl or diphenylmethyl in
  • R 3 when is thiophene, E is bond and is benzene or naphthalene, (iii) is pyrrole included nitrogen substituted by R 4 , in which R 4 is hydrogen, C1-3 alkyl or phenyl,
  • A is bond or methylene
  • E is bond, is benzene
  • R 2 is hydrogen or methyl
  • R 3 each, independently, is hydrogen or halogen
  • R 4 is pyrrole included nitrogen substituted by R 4 , thiophene, furan, imidazole included nitrogen substituted by R 4 , thiazole, oxazole, triazole included nitrogen substituted by R 4 , in which R 4 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl;
  • A is bond, C1-6 alkylene or C2-6 alkenylene
  • E is bond or C 1-6 alkylene; is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane,
  • whjch m is 0 or 1 , or benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom;
  • R 1 is hydrogen or C 1-4 alkyl
  • R 2 is hydrogen or C 1-4 alkyl
  • n 1-3;
  • R 3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
  • T is bond, -O- , -S- , -SO 2 - ,-NR 7 - or -NR 7 CO- , in which R 7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in -NR 7 CO- may be connected with -Q- or -U-;
  • U is bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene or C1-6 alkylene -O-, in which oxygen atom can be connected with R 5 only;
  • R 5 is (i) C4-7 cycloalkyi, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
  • R 5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR 6 , in which R 6 is C1-4 alkyl, NR 8 R 9 , in which R 8 and R 9 each, independently, is hydrogen or C1-4 alkyl;
  • or -Q-T-U-R 5 is C7-10 alkyl, C7-10 alkoxy
  • T is -O- , or -NR 7 -
  • U is bond and R 5 is diphenylmethyl in -Q-T-U-R 5 represented by R 3 , when is thiophene, E is bond and is benzene or napththalene,
  • T is -O- , or -NR 7 - , and U is C1-6 alkylene and R 5 is phenyl or diphenylmethyl in
  • At least one R 3 of (R 3 ) n is a substituent selected from group (2) that is -Q-T-U-R 5 , when E is bond and s benzene;
  • cyclopenta(C4-7)cycloalkane of the following formula:
  • C1-6 alkylene represented by A, E, Q or U and included in C1-6 alkylene -O- represented by U means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomeric groups thereof.
  • C2-6 alkenylene represented by A or U mean vinylene, propenylene, butenylene, pentenylene, hexenylene and isomeric groups thereof.
  • C2-6 alkynylene represented by U means ethynylene, propynylene, butenylene, pentenylene, hexenylene and isomeric groups thereof.
  • C1-4 alkyl represented by R 1 , R 2 , R 4 R 6 R 7 , R 8 or R 9 mean methyl, ethyl, propyl, butyl and isomeric groups thereof.
  • C1-6 alkyl represented by R 3 means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomeric groups thereof.
  • C1-6 alkoxy represented by R 3 means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isomeric groups thereof.
  • Halogen represented by R 3 means fluorine, chlorine, bromine and iodine.
  • Phenyl(C1-4)alkyl represented by R 4 or R 7 means methyl, ethyl, propyl, butyl and isomeric groups thereof substituted by 1 of phenyl.
  • C4-7 cycloalkyi represented by R 5 means cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 4-7 membered heterocyclic ring containing one nitrogen represented by R 5 means, for example, pyrrole, pyridine, azepine and partially or fully saturated ring thereof.
  • 4-7 membered heterocyclic ring containing one sulfur represented by R 5 means, for example, thiophene, thiain, thiepin and partially or fully saturated ring thereof.
  • R 5 4-7 membered heterocyclic ring containing one oxygen represented by R 5 means, for example, furan, pyran, oxepin and partially or fully saturated ring thereof.
  • C1-10 alkyl as substituents of rings in groups represented by R 5 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomeric groups thereof.
  • C1-10 alkoxy as substituents of rings in groups represented by R 5 means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomeric groups thereof.
  • Halogen as substituents of rings in groups represented by R 5 means fluorine, chlorine, bromine and iodine.
  • C7-10 alkyl represented by -Q-T-U-R 5 means heptyl, octyl, nonyl, decyl and isomeric groups thereof.
  • C7-10 alkoxy represented by -Q-T-U-R 5 means heptyloxy, octyloxy, nonyloxy, decyloxy and isomeric groups thereof.
  • the compounds of the following formula (la-A), (la-B), (la-C), (la-D), (la-E), (la-F), (la-G) and non-toxic salts thereof are preferable.
  • Especially preferable compounds are the compounds described in Example and the following compounds and non-toxic salts thereof.
  • alkyl, alkoxy, alkenylene and alkylene includes straight and branched ones. Double bond in alkenylene includes E, Z and EZ mixture. Isomers generated by asymmetric carbon(s) e.g. branched alkyl are included in the present invention.
  • the compounds of the formula (la) and (lb) of the present invention may be converted into the corresponding salts.
  • Non-toxic and water-soluble salts are preferable.
  • Suitable salts for example, are as follows:
  • salts of alkaline metal sodium, potassium etc.
  • salts of alkaline earth metal calcium, magnesium etc.
  • ammonium salts salts of pharmaceutically acceptable organic amine (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D- glucamine etc.).
  • the compounds of the formula (la) and (lb) may be converted into the corresponding acid addition salts.
  • Non-toxic and water-soluble salts are preferable. Suitable salts, for example, are as follows:
  • salts of inorganic acids e. g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate
  • salts of organic acids e. g. acetate, lactate, tartarate, benzoate, citrate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isedthioate, glucuronate, gluconate.
  • R 1a is C1-4 alkyl and the other symbols are the same meaning as hereinbefore defined, or
  • the compound of the formula (Id) among the compounds of the present invention may be prepared:
  • reaction (1) by hydrolyzing a compound obtained in above reaction (iii) using an aqueous solution of an alkaline (potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate etc.).
  • the reaction (1) is known, for example, it may be carried out in water miscible organic solvent (methanol, ethanol, isopropanol, tetrahydrofuran(THF), dioxane or two or more of the mixture, etc.), using an aqueous solution of an alkaline (potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate etc.) at - 10-50°C.
  • the reaction (2) is known, for example, it may be carried out in water miscible organic solvent (methanol, ethanol, isopropanol, tetrahydrofuran(THF), dioxane or two or more of the mixture, etc.), using an aqueous solution of an alkaline (potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate etc.) at 40-150°C.
  • water miscible organic solvent methanol, ethanol, isopropanol, tetrahydrofuran(THF), dioxane or two or more of the mixture, etc.
  • an alkaline potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate etc.
  • the reaction (3) is known, for example, it may be carried out in organic solvent (xylene, chloroform, methylene chloride, THF, toluene, acetonitrile etc.), in the presence or absence of Lewis acid (aluminum chloride, iron(lll) chloride, boron trifluoride diethyl etherate etc.) or an base (triethylamine, pyridine etc.) at 20 ⁇ 150°C.
  • organic solvent xylene, chloroform, methylene chloride, THF, toluene, acetonitrile etc.
  • Lewis acid aluminum chloride, iron(lll) chloride, boron trifluoride diethyl etherate etc.
  • an base triethylamine, pyridine etc.
  • the starting materials and reagents in the present invention are known per se or may be prepared by known methods.
  • a compound of the formula (II) may be prepared by using a reaction depicted in following scheme:
  • a compound of the formula (la) of the present invention possess an inhibitory activity on 5 ⁇ -reductase and therefore are useful for prevention and/or treatment of diseases induced by the excess generation of dihydrotestosterone in mammals, especially human.
  • the diseases such as above, for example, are alopecia (e.g. androgenic alopecia), acnes, hypertrophy of prostate and prostatic cancer.
  • An inhibitory activity on 5 ⁇ -reductase of the present invention is confirmed by the screening system described hereafter
  • Frozen human prostates were thawed on ice and minced with scissors into small pieces ( ⁇ 1mm 3 ).
  • the minced tissue was homogenized in 3 tissue volumes of ice cold medium A ( 20mM potassium phosphate, pH 6.5, containing 0.32 M sucrose, 1mM dithiothreitol, 50 ⁇ M NADPH, 1mM EDTA), first with a Brinkmann Polytron and then with a Dounce homogenizer.
  • the homogenate was filtered through gauze and the filtrate was centrifuged at 140,000 x g at 4°C for 60 min. The resulting pellet was washed with 3 tissue volumes of medium A.
  • the washed pellet was suspended (5-10 mg protein/ml) in 20mM potassium phosphate, pH 6.5, containing 20% glycerol, 50 ⁇ M NADPH and 1 mM dithiothreitol. An appropriate aliquot of this suspension was used as the source of 5 ⁇ -reductase.
  • 5 ⁇ -reductase activity was determined by following the conversion of testosterone to 5 ⁇ -dihydrotestosterone (DHT).
  • DHT 5 ⁇ -dihydrotestosterone
  • buffer 100mM Tris-citrate, pH5.0
  • 1 mM NADPH and human prostatic 5 ⁇ -reductase 0.4-1 mg protein
  • the organic phase (bottom) was collected and the volume reduced to -100 ⁇ l in a 42°C water bath down to -100 ⁇ l.
  • the solutions were applied to silica plates and the plates were developed in chloroform/ethyl acetate (3:1) at room temperature.
  • the radioactivity profiles were determined by a BIOSCAN imaging scanner. The silica in sections identified by BIOSCAN and counted in a scintillation counter. Enzyme activity was calculated from the percent of recovered radio label converted to the product DHT.
  • a compound of the present invention of the formula (la) and non-toxic salts thereof are useful for 5 ⁇ -reductase inhibitors.
  • 5 ⁇ -Reductase inhibitors are useful for prevention and /or treatment of diseases induced by the excess generation of dihydrotestosterone in mammals, especially human.
  • the diseases such as above, for example, are alopecia (e.g. androgenic alopecia), acnes, hypertrophy of prostate and prostatic cancer.
  • the compounds of the formula (la) and (lb), of the present invention and non-toxic salts thereof may be normally by administered systemically or locally usually by oral or parenteral administration.
  • the doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc.
  • the doses per person are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 100 ⁇ g and 100 mg, by parenteral administration (preferable intravenous administration), up to several times per day, or continuous administration between 1 and 24 hrs. per day from vein.
  • the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
  • compositions of the present invention When administration of the compounds of the present invention, it is used as solid compositions, liquid compositions or other compositions for oral administration, as injections, liniments or suppositories etc. for parenteral administration.
  • Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules.
  • Capsules include hard capsules and soft capsules.
  • one or more of the active compound(s) is or are admixed with at least one inert diluent (such as lactose, mannitol, mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.).
  • the compositions may also comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents (such as magnesium stearate etc.), disintegrating agents (such as cellulose calcium glycolate, etc.), stabilizing agents, and assisting agents for dissolving such as glutamic acid, aspartic acid etc.).
  • the tablets or pills may, if desired, be coated with a film of gastric or enteric material (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate, etc.), or be coated with more than two films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
  • a film of gastric or enteric material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate, etc.
  • coating may include containment within capsules of absorbable materials such as gelatin.
  • Liquid compositions for oral administration include pharmaceutically- acceptable emulsions, solutions, syrups and elixirs.
  • one or more of the active compound(s) is or are contained in inert diluent(s) commonly used in the art (purified water, ethanol etc.).
  • inert diluents commonly used in the art (purified water, ethanol etc.).
  • such compositions may also comprise adjuvants (such as wetting agents, suspending agents, etc.), sweetening agents, flavouring agents, perfuming agents, and preserving agents.
  • compositions for oral administration included spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s).
  • Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents (sodium sulfate etc.), isotonic buffer (sodium chloride, sodium citrate, citric acid, etc.).
  • stabilizing agents sodium sulfate etc.
  • isotonic buffer sodium chloride, sodium citrate, citric acid, etc.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
  • Aqueous solutions, suspensions include distilled water for injection and physiological salt solution.
  • Non-aqueous solutions, suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, POLYSORBATE80 (registered trade mark), etc.
  • Injections may comprise additional other than inert diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (glutamic acid, aspartic acid, etc.).
  • additional other than inert diluents e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (glutamic acid, aspartic acid, etc.).
  • They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before used.
  • compositions for parenteral administration include liquids for external use, and endermic liniments, ointment, suppositories for rectal administration and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by per se known methods.
  • the solvents in the parentheses show the developing or eluting solvents and the rations of the solvents used are by volume in chromatographic separations.
  • IR v 2925, 1696, 1609, 1481 , 1453, 1375, 1262, 886, 756 cm -1 .
  • IR v 3065-2915, 1697, 1656, 1622, 1262, 888, 760 cm -1 .
  • IR V3015, 2870, 1695, 1622, 1601, 1482, 1458, 1380, 1271, 1241
  • IR V3015, 2855, 1695, 1622, 1601, 1482, 1458, 1396, 1272, 1241
  • IR v 3050, 2950, 1696, 1619, 1484, 1457, 1378, 1279, 1238, 770, 738 cm -1 .
  • IR v 3035,2920, 1711, 1616, 1570, 1497, 1452, 1421, 1397, 1377, 1311,
  • IR v 3060, 2920, 1696, 1619, 1450, 1405, 1315, 1222 cm -1 .
  • IR v 2600-4000, 1693, 1646, 1458, 1258, 1259, 752, 696 cm -1 .
  • IR v 3000-3900, 2925, 1695, 1627, 1482, 1458, 1269, 1241 cm -1 .
  • IR v 3055, 1717, 1610, 1590, 1518, 1430, 1353, 1251 , 1199 cm -1 .
  • IR v 3030, 1680, 1615, 1516, 1469, 1446, 1376, 1312, 1255, 1211 , 960, 888, 745 cm -1 .
  • IR v 3425, 3030, 1697, 1615, 1481, 1451, 1406, 1374, 1263, 1224, 1152, 887, 746, 695 cm -1 .
  • IR v 3060, 1717, 1618, 1537, 1478, 1452, 1424, 1390, 1269, 1204, 1152, 1053, 882, 848, 746 cm -1 .
  • IR v 3025, 2875, 1699, 1610, 1479, 1456, 1432, 1406, 1374, 1314, 1257, 1207, 1174, 1035, 1005, 961 , 938, 881, 852, 786, 751 , 728, 700 cm -1 .
  • IR v 3035, 2890. 1707, 1619, 1480, 1458, 1422, 1375, 1308, 1260, 1172,
  • IR v 2966, 1697, 1607, 1479, 1449, 1373, 1314, 1251, 889 cm -1 .
  • IR v 3080, 2930, 1707, 1619, 1635, 1515, 1486, 1341, 1251 , 1165 , 887, 751 cm -1 .
  • IR v 3400-3060, 1729, 1590, 1531, 1487, 1451, 1375, 747, 700 cm -1 .
  • IR v 3200-2900, 1745, 1717, 1595, 1569, 1492, 1451, 1364, 1261, 749, 739, 697 cm -1 .
  • IR v 3200-2955, 1733, 1675, 1578, 1549, 1473, 1376, 1262, 1201, 748 cm -1 .
  • IR v 3500-2800, 1731 , 1653, 1596, 1518, 1488, 1263, 758, 708 cm -1 .
  • IR V 3060, 1701 , 1624, 1482, 1377, 1264, 1232 cm' 1 .
  • IR v 3065, 2965, 1716, 1622, 1559, 1487, 1457, 1421 , 1376, 1267, 1232, 886 cm -1 .
  • IR v 3015, 1698, 1620, 1592, 1486, 1456, 1378, 1264 cm -1 .
  • IR v 2930, 1698, 1635, 1490, 1462, 1420, 1238, 917, 774, 746, 694 cm -1 .
  • IR v 3100-2955, 1698, 1646, 1621, 1331 , 1267, 884, 758, 717 cm -1 .
  • IR v 2950, 1735, 1699, 1626, 1600, 1483, 1456, 1379, 1259 cm -1 .
  • IR v 1730, 1617, 1588, 1486, 1451 , 1400, 1379, 1264, 1199, 877, 814, 761 cm -1 .
  • IR v3035, 2910, 1733, 1695, 1627, 1600, 1525, 1483, 1458, 1378, 1295, 1268 cm -1 .
  • IR v3020, 1732, 1698, 1624, 1484, 1456, 1378, 1266 cm -1 .
  • IR v 3035, 1713, 1621, 1633, 1480, 1453, 1376, 1265, 885, 822, 760 cm -1 .
  • IR V3050, 1713, 1620, 1486, 1454, 1397, 1376, 1325, 1265, 1168, 1124,
  • IR V 3100, 2995, 1732, 1619, 1530, 1455, 1377, 1348, 1264, 886, 771 , 735 cm -1 .
  • IR v 3395, 2925, 1763, 1700, 1619, 1455, 1376, 1264, 885, 762 cm -1 .
  • IR v 3445, 3030, 1731 , 1699, 1622, 1567, 1539, 1504, 1480, 1452, 1398, 1377, 1264, 885, 837, 752 cm -1 .
  • IR v 3113, 2960, 1678, 1629, 1601, 1535, 1496, 1467, 1400, 1373, 1288, 1249, 1206, 1134, 1104, 1077, 886, 749 cm -1 .
  • IR v 3330, 1697, 1673, 1620, 1447, 1387, 1280, 1235, 1194, 1123, 885, 746 cm -1 .
  • IR V 3030, 1730, 1703, 1648, 1600, 1472, 1432, 1375, 1267, 1226, 1195, 1160, 905, 752 cm -1 .
  • IR v 3135, 2965, 1707, 1652, 1600, 1518, 1407, 1259, 1195, 907, 752 cm -1 .
  • IR v 2075, 1722, 1596, 1495, 1457, 1407, 1383, 1303, 1202, 1121, 1048, 930, 771, 740, 669 cm -1 .
  • IR v 3030, 1731 , 1701, 1620, 1475, 1452, 1374, 1261 , 882, 817, 757 cm -1 .
  • IR v 3275, 1713, 1593, 1494, 1425, 1275, 1238, 884, 777, 748 cm -1 .
  • IR v 3055, 1730, 1618, 1587, 1489, 1372, 1295, 1275 cm -1 .
  • IR v 3340, 3055, 1714, 1664, 1598, 1534, 1486, 1440, 1373, 1322, 1258 cm -1 .
  • IR v3420, 1623, 1524, 1486, 1450, 1367, 1271, 1186 cm -1 .
  • IR v 3025, 1722, 1619, 1597, 1488, 1450, 1402, 1375, 1258, 1199 cm -1 .
  • IR v 3270, 3055, 1718, 1616, 1539, 1484, 1450, 1373, 1258, 1201 cm -1 .
  • IR v 3025, 2900, 1690, 1644, 1481 , 1455, 1345, 1223, 969, 759 cm -1 .
  • IR v 2955, 1695, 1624, 1599, 1496, 1455, 1328, 1299, 1272, 1240, 1174, 945, 844, 784, 678 cm -1 .
  • IR v 3065, 2960, 1692, 1600, 1542, 1451, 1373, 1224, 1194, 1136, 850, 746 cm - 1 .
  • the following components were admixed in conventional method and punched out to obtain 100 tablets each containing 50mg of active ingredient.

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Abstract

Cette invention se rapporte: (1) à un agent inhibiteur agissant sur la 5α-réductase, cet agent comprenant comme principe actif un composé hétérocyclique à cinq éléments représenté par la formule (Ia), ainsi que des sels non toxiques de ce composé; (2) à un composé hétérocyclique à cinq éléments représenté par la formule (Ib), ainsi que des sels non toxiques de ce composé; (3) et à un procédé pour préparer un composé à chaînes fermées hétérocycliques à cinq éléments, représenté par la formule (Ib), ainsi que des sels non toxiques de ce composé. Le composé de la formule (Ia) sert à prévenir et à traiter les maladies induites par la production excessive de dihydrotestostérone chez les mammifères, telles que l'alopécie (alopécie endrogène), l'acné, l'hypertrophie de la prostate et le cancer de la prostate.
PCT/US1995/011962 1994-09-27 1995-09-27 Composes heterocycliques a cinq elements WO1996010013A1 (fr)

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KR1019970701970A KR970706250A (ko) 1994-09-27 1995-09-27 5원 헤테로시클릭 화합물(five membered heterocyclic compounds)
JP8511867A JPH10506892A (ja) 1994-09-27 1995-09-27 ５員複素環化合物、それらを有効成分として含有する薬剤
EP95934464A EP0783488A4 (fr) 1994-09-27 1995-09-27 Composes heterocycliques a cinq elements
US08/793,983 US5859042A (en) 1995-09-27 1995-09-27 Five membered heterocyclic compounds

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GB2313059A (en) * 1993-03-29 1997-11-19 Bioglan Ireland Pyrrolyl-containing compositions for the topical treatment of skin disorders
CN112955439A (zh) * 2018-08-24 2021-06-11 赛尼欧普罗有限责任公司 用于治疗病理状况的芳族分子

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GB2313059A (en) * 1993-03-29 1997-11-19 Bioglan Ireland Pyrrolyl-containing compositions for the topical treatment of skin disorders
GB2313059B (en) * 1993-03-29 1998-01-21 Bioglan Ireland Pharmaceutically useful pyrrolyl derivatives
CN112955439A (zh) * 2018-08-24 2021-06-11 赛尼欧普罗有限责任公司 用于治疗病理状况的芳族分子

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EP0783488A4 (fr) 1998-01-07
EP0783488A1 (fr) 1997-07-16
KR970706250A (ko) 1997-11-03
JPH10506892A (ja) 1998-07-07

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