+

WO1996010013A1 - Five membered heterocyclic compounds - Google Patents

Five membered heterocyclic compounds Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
methylpyrrol
acetic acid
benzoyl
alkyl
bond
Prior art date
Application number
PCT/US1995/011962
Other languages
French (fr)
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 JP8511867A priority Critical patent/JPH10506892A/en
Priority to KR1019970701970A priority patent/KR970706250A/en
Priority to EP95934464A priority patent/EP0783488A4/en
Priority to US08/793,983 priority patent/US5859042A/en
Publication of WO1996010013A1 publication Critical patent/WO1996010013A1/en

Links

Classifications

    • 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
    • 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
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • 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
    • A61K31/335—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
    • 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
    • A61K31/38—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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61K31/4172—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

This invention is related to: (1) an inhibitory agent on 5α-reductase which comprises a five membered heterocyclic compound of formula (Ia), and non-toxic salts thereof as active ingredient; (2) a five membered heterocyclic compound of formula (Ib), and non-toxic salts thereof; (3) process for the preparation of a five membered heterocyclic ring compound of formula (Ib) and non-toxic salts thereof. The compounds of formula (Ia) are useful for the prevention and treatment of diseases induced by the excess generation of dihydrotestosterone in mammals, for example, alopecia (androgenic alopecia), acnes, hypertrophy of prostate and prostatic cancer.

Description

FIVE MEMBERED HETEROCYCLIC COMPOUNDS
Summary
This invention is related to five membered heterocyclic compounds. More particularly, this invention is related to :
(1) An inhibitory agent on 5α-reductase which comprises a five membered heterocyclic compound of the formula (la):
Figure imgf000003_0001
wherein all the symbols are the same meaning as hereafter defined, and non-toxic salts thereof as active ingredient,
(2) a five membered heterocyclic compound of the formula (lb):
Figure imgf000003_0002
wherein all the symbols are the same meaning as hereafter defined, and non-toxic salts thereof,
(3) process for the preparation of a five membered heterocyclic ring compound of the formula (lb) and non-toxic salts thereof.
Background
So far as the origin of androgenic alopecia, many theories are exposited such as (1) imbalance of hormones, (2) genetics, (3) circulatory failure, (4) nutrition. And it has been suggested that testosterone (androgenic hormone) played an important role on the generation of hairs. The relation between testosterone and androgenic alopecia is as follows:
(i) first, testosterone biosynthesized in testis is converted into dihydrotestosterone(DHT) by 5α-reductase existed in hair follicle, sebaceous gland etc. at the head,
(ii) DHT reduces the activities of adenyl cyclase remarkably,
(iii) it induces fall of the level of cyciic-AMP in cells,
(iv) last, it induces lowering of energy generation of hairs and the limbus and suppressing of protein synthesis [Biochem. Biophys. Res. Commun., 41 , 884(1970)].
Large quantities of metabolites by 5α-reductase such as DHT etc. in hair follicles of androgenic alopecia-patent exist more than that in females or healthy males. [J. Clin. Endocr., 38, 811 (1974)].
It was reported that DHT converted from testosterone by 5α-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)].
It has been clear that 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)].
And, it is thought that DHT is also related to prostatic cancer.
Recently, it was confirmed that the existence of at least two 5α-reductase isozymes (I type and II type) in human. There are differences between these isozymes about gene formation, of course, biochemical properties, expression styles, hereditary properties and pharmacological properties. [Nature, 354, 159-161 (1991) ; J. Clin, Invest., 89,293-300(1992)]. Among two type isozymes, it is considered that II type one exists more than I type one in human testis.
Therefore, it was confirmed that inhibition of a change from testosterone to DHT by 5α-reductase inhibitor is useful for above diseases. Now, research and development of 5α-reductase inhibitors are carried out energetically. Many kinds of compounds are synthesized and tested. 5α-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.
Figure imgf000005_0001
As a non-steroidal compound, ONO-3805 shown below formula is known.
Figure imgf000005_0002
Related Arts
Non-steroidal compounds possessing 5α-reductase inhibitory activity, for example, are the following:
(1) In the specification of WO9324442, benzoic acid derivatives are disclosed.
(2) In the specification of European Patent Publication Number 458207, WO9303012, WO 9305019 and WO9316996, indole derivatives are disclosed.
(3) In the specification of European Patent Publication Number 519353, indolizine derivatives are disclosed.
(4) In the specification of WO9313099, the compound of the formula (A) is disclosed.
R1A-AA-CO-XA-YA-R2A (A)
wherein R1A is carboxy (lower) alkyl or protected carboxy(lower)alkyl,
R2A is optionally substituted aralkyl, XA is optionally substituted arylene,
YA is -O- or -NR6A- ,
in which R6A is hydrogen, lower alkyl, optionally substituted aralkyl or amino- protective group, and
AA 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).
(5) On the 24th National Medicinal Chemistry Symposium (June 21-24, 1994), it was discussed that benzoic acid derivatives and indole derivatives having 5α- reductase inhibitory activity.
Meanwhile, (6) in the specification of GB1195628, the compound of the formula (B):
Figure imgf000006_0001
wherein ArB is phenyl, phenyl substituted by one or more halogen, lower alkyl, lower alkoxy, NO2, NH2, CN or SCH3; RB is hydrogen, lower alkyl; R 1B is hydrogen, lower alkyl, benzyl; R2B is CN, COOH, COO(lower alkyl), CONH2, CONH(lower alkyl),
CON(lower alkyl)2,
is disclosed to be useful as antiinflammatory. For example, the compound of the formula:
Figure imgf000006_0002
which is available in the market as an antiinflammatory agent (Tolmetin), is disclosed. (7) In the specification of GB1327308, the compound of the formula (C):
Figure imgf000007_0001
wherein Ar2C is thienyl, 5-methylthienyl or substituted phenyl; R3C is COOH,
COO(lower alkyl) etc.; R4C is lower alkyl; R5C is lower alkyl; R6C is hydrogen, lower alkyl,
is disclosed to be useful as antiinflammatory. For example, the compound of the formula:
Figure imgf000007_0002
which is available in the market as an analgesic, antiinflammatory agent (Zomepirac), is disclosed.
(8) In the specification of GB 1331505, the compound of the formula (D):
Figure imgf000007_0003
wherein RD is hydrogen, C1-4 alkyl; R1D is hydrogen, C1-4 alkyl; R2D is hydrogen, lower alkyl etc.; ArD is phenyl, cyclohexyl, heterocyclic group,
is disclosed to be useful as antiinflammatory.
(9) In the specification of US 3801605, the compound of the formula (E):
Figure imgf000007_0004
wherein RE is COOH, (C1-5 alkoxy)carbonyl, CN, CONH2; ArE is phenyl, phenyl substituted by halogen, SCH3, C1-5 alkyl or alkoxy,
is disclosed to be useful as antiphlogistics.
(10) In the specification of GB1390866, the compound of the formula (F):
Figure imgf000008_0001
wherein RF is hydrogen, lower alkyl; R1 F is hydrogen, methyl; R2F is hydrogen, methyl; r3f is -COOH, -COO(lower alkyl); R4F is benzyl, cyclopentyl, cyclohexyl,
is disclosed to be useful as antiinflammatory. For example, the compounds of the formulae:
Figure imgf000008_0002
and ethyl ester thereof are disclosed.
(11) The compounds of the formulae:
Figure imgf000008_0003
and methyl ester thereof are disclosed to be useful as antiinflammatory (Farmaco Ed. Sc., 41(4), 281-289 (1986)). (12) In the specification of DE4325204, published on February 2, 1995, the compound of the formula (G-l), (G-ll), (G-lll), (G-IV):
Figure imgf000009_0001
wherein R1 G is -COOH or XG-COOH in which XG is C1-8 alkyl, C2-8 alkenyl or alkynyl etc.; R3G is -CO-CH3, -CO-YG or -COYG-Aryl in which YG is C2-19 alkyl, alkenyl or alkynyl etc., R2G, R4G, R5G is hydrogen, C1-20 alkyl, C2-20 alkenyl or alkynyl, Aryl, -ZG-Aryl etc., in which ZG is C1-20 alkyl, C2-10 alkenyl or alkynyl etc;
is disclosed to be useful as phospholipase A2 inhibitors.
(13) In the specification of JP Kokai Hei 7-138227 published on May 30,1995, the compounds of the formula (H):
Figure imgf000009_0002
wherein R 1H is (i) hydrogen, (ii) C1-3 saturated or unsaturated alkyl optionally substituted by OH, SH, halogen, COOH, alkoxy, alkoxycarbonyl or aryloxycarbonyl,
(iii) COOH, alkoxycarbonyl, aryloxycarbonyl, (iv) benzoyi optionally substituted by halogen, (v) phenyl or tosyl, (vi) carbonyl group connected with alkoxycarbonylethyl; R2H and R5H 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;
R3H and R4H 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. Purpose of Invention
Energetic investigation have been carried out in order to discover compounds of non-steroidal formula having 5α-reductase inhibitory activity, the present inventors have found that compounds of the formula (la) having 5α-reductase inhibitory activity and have accomplished the present invention.
Comparison with the Related Arts
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.
In case of XA is phenylene or naphthalene and AA is thiophene, the compound of the formula (A) in the specification of WO9313099 of the related arts (4) is the compound of the following formula (Aa):
Figure imgf000010_0001
wherein the all symbols are the same meaning as hereinbefore defined.
The compounds which
Figure imgf000010_0003
is thiophene in the formula (la) of the present invention are following thiophene compounds.
(Ie)
Figure imgf000010_0002
However, those compounds of the formula (le) in the present invention are not overlapped with the above compounds of the formula (Aa). In the specification of WO9313099, the following two thiophene compounds are described.
Figure imgf000011_0001
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 5α-reductase inhibitory activity. It is not able to expect at all that the compounds having pyrrole ring, thiophene ring or furan ring possess 5α-reductase inhibitory activity. The compounds wherein
Figure imgf000011_0002
is pyrrole included nitrogen substituted by R4; E is C1-6 alkylene;
Figure imgf000011_0003
is benzene; R1 is hydrogen; R3 is R3-1; R3-1 is hydrogen, C1- 6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl; the other symbols are the same meaning as hereinbefore defined; in the formula (la) of the present invention represents the following compounds of the formula (If).
Figure imgf000011_0004
These compounds of the formula (If) are broadly overlapped with the compounds wherein R3G is -CO-YG-Aryl in the formula (G-l), (G-ll) and (G-lll) in the specification of DE-4325204 of the related art (12). However, in the specification of DE 4325204, the only one example compound wherein R3G is -CO-YG-Aryl is disclosed, but is not included in the extent of the present invention. Moreover, the compounds in the specification of DE4325204 are disclosed to be useful as phospholipase A2 inhibitors. There is no description that the compounds in the specification of DE4325204 possess 5α-reductase inhibitory activity. The compounds of the present invention are not overlapped with the compound of JP Kokai Hei 7-138227 of the related art (13). Disclosure of the Invention
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.
Accordingly, the present invention is related to
1) An inhibitory agent on 5α-reductase which comprises a compound of the formula (la):
Figure imgf000012_0001
wherein
Figure imgf000012_0003
is pyrrole included nitrogen substituted by R4, thiophene, furan, imidazole included nitrogen substituted by R4, thiazole, oxazole, triazole included nitrogen substituted by R4, in which R4 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;
Figure imgf000012_0004
is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta (C4-7) cycloalkane,
Figure imgf000012_0002
, in Which m is 0 or 1 , or benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom;
R1 is hydrogen or C1-4 alkyl;
R2 is hydrogen or C1-4 alkyl;
n is 1-3;
R3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
(2) -Q-T-U-R5
in which Q is bond or C1-6 alkylene; T is bond, -O- ,
Figure imgf000013_0002
-S- , -SO2- ,-NR7- or -NR7CO- , in which R7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in -NR7CO- 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 R5 only;
R5 is (i) C4-7 cycloalkyl, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or the benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or rings in (i), (ii), (iii), (iv) of R5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR6 , in which R6 is C1-4 alkyl, NR8R9, in which R8 and R9 each, independently, is hydrogen or C1-4 alkyl;
or -Q-T-U-R5 is C7-10 alkyl, C7-10 alkoxy;
or non-toxic salts thereof,
with the proviso that, the compounds wherein
(i) T is -O- , or -NR7- , and U is bond and R5 is diphenylmethyl in -Q-T-U-R5 represented by R3, when
Figure imgf000013_0003
is thiophene, E is bond and
Figure imgf000013_0004
is benzene or napthalene,
(ii) T is -O- , or -NR7- , and U is C 1-6 alkylene and R5 is phenyl or diphenylmethyl in
-Q-T-U-R5 represented by R3, when
Figure imgf000013_0005
is thiophene, E is bond and
Figure imgf000013_0006
is benzene or naphthalene, (iii)
Figure imgf000013_0007
is pyrrole included nitrogen substituted by R4, in which R4 is hydrogen, C1-3 alkyl or phenyl,
A is bond or methylene,
E is bond,
Figure imgf000013_0001
is benzene,
R2 is hydrogen or methyl and
R3 each, independently, is hydrogen or halogen,
are excluded,
2) a compound of the formula (lb):
Figure imgf000014_0001
wherein
Figure imgf000014_0004
is pyrrole included nitrogen substituted by R4, thiophene, furan, imidazole included nitrogen substituted by R4, thiazole, oxazole, triazole included nitrogen substituted by R4, in which R4 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;
Figure imgf000014_0002
is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane,
Figure imgf000014_0003
in whjch m is 0 or 1 , or benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom;
R1 is hydrogen or C 1-4 alkyl;
R2 is hydrogen or C 1-4 alkyl;
n is 1-3;
R3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
(2) -Q-T-U-R5
in which Q is bond or C 1-6 alkylene;
T is bond, -O- ,
Figure imgf000014_0005
-S- , -SO2- ,-NR7- or -NR7CO- , in which R7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in -NR7CO- 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 R5 only;
R5 is (i) C4-7 cycloalkyi, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or the benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen, or rings in (i), (ii), (iii), (iv) of R5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR6 , in which R6 is C1-4 alkyl, NR8R9, in which R8 and R9 each, independently, is hydrogen or C1-4 alkyl;
or -Q-T-U-R5 is C7-10 alkyl, C7-10 alkoxy;
or non-toxic salts thereof,
with the proviso that,
(a) compounds wherein
(i) T is -O- , or -NR7- , and U is bond and R5 is diphenylmethyl in -Q-T-U-R5 represented by R3, when
Figure imgf000015_0004
is thiophene, E is bond and
Figure imgf000015_0005
is benzene or napththalene,
(ii) T is -O- , or -NR7- , and U is C1-6 alkylene and R5 is phenyl or diphenylmethyl in
-Q-T-U-R5 represented by R3, when
Figure imgf000015_0007
is thiophene, E is bond and
Figure imgf000015_0006
is benzene or napthalene,
are excluded;
(b) at least one R3 of (R3)n is a substituent selected from group (2) that is -Q-T-U-R5, when E is bond and
Figure imgf000015_0008
s benzene;
(c) all R3 of (R3)n are not hydrogen at the same time, when E is bond and
Figure imgf000015_0001
is
C4-7 cycloalkane, or E is methylene and
Figure imgf000015_0002
is benzene;
(d) 2-[5-[2-chloro-4-(1H-pyrrol-1-yl)benzoyl]thiophen-2-yl] acetic acid and methyl ester thereof and
2-[5-[2-chloro-4-(2,5-dimethyl-1 H-pyrrol-1-yl)benzoyl]thiophen-2-yl] acetic acid and methyl ester thereof are excluded.
3) process for the preparation of a compound of the formula (lb) and non-toxic salts thereof.
In the present invention, C4-7 cycloalkane of the following formula:
Figure imgf000015_0003
means cyclobutane, cyclopentane, cyclohexane, cycloheptane. In the present invention, benzo(C4-7)cycloalkane of the following formula:
Figure imgf000016_0001
means benzocyclobutane, 2,3-dihydroindene, 1 ,2,3,4-tetrahydronaphthalene, 1 ,2,3,4,5-pentahydrobenzocycloheptene.
In the present invention, cyclopenta(C4-7)cycloalkane of the following formula:
Figure imgf000016_0002
means cyclopentacyclobutane, cyclopentacyclopentane, cyclopentacyclohexane, cyclopentacycloheptane.
In the present invention,
of the following formula:
means
Figure imgf000016_0003
In the present invention, 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 R1, R2, R4 R6 R7, R8 or R9 mean methyl, ethyl, propyl, butyl and isomeric groups thereof.
C1-6 alkyl represented by R3 means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomeric groups thereof.
C1-6 alkoxy represented by R3 means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isomeric groups thereof. Halogen represented by R3 means fluorine, chlorine, bromine and iodine.
Phenyl(C1-4)alkyl represented by R4 or R7 means methyl, ethyl, propyl, butyl and isomeric groups thereof substituted by 1 of phenyl.
C4-7 cycloalkyi represented by R5 means cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
4-7 membered heterocyclic ring containing one nitrogen represented by R5 means, for example, pyrrole, pyridine, azepine and partially or fully saturated ring thereof.
Benzene fused 4-7 membered heterocyclic ring containing one nitrogen represented by R5 or
Figure imgf000017_0001
means, for example, indole, isoindole, quinoline, isoquinoline, benzoazepine and partially or fully saturated ring thereof (e.g. indoline, isoindoline).
4-7 membered heterocyclic ring containing one sulfur represented by R5 means, for example, thiophene, thiain, thiepin and partially or fully saturated ring thereof.
Benzene fused 4-7 membered heterocyclic ring containing one sulfur represented by R5 or
Figure imgf000017_0002
means, for example, benzothiophene, benzothiain, benzothiepin and partially or fully saturated ring thereof.
4-7 membered heterocyclic ring containing one oxygen represented by R5 means, for example, furan, pyran, oxepin and partially or fully saturated ring thereof.
Benzene fused 4-7 membered heterocyclic ring containing one oxygen represented by R5 or
Figure imgf000017_0003
means, for example, benzofuran, benzopyran, benzoxepine and partially or fully saturated ring thereof (e.g. chroman, isochroman).
C1-10 alkyl as substituents of rings in groups represented by R5 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 R5 means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomeric groups thereof.
Halogen as substituents of rings in groups represented by R5 means fluorine, chlorine, bromine and iodine. C7-10 alkyl represented by -Q-T-U-R5 means heptyl, octyl, nonyl, decyl and isomeric groups thereof.
C7-10 alkoxy represented by -Q-T-U-R5 means heptyloxy, octyloxy, nonyloxy, decyloxy and isomeric groups thereof.
Preferable Compounds
In the compound of the present invention of the formula (la), 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.
Figure imgf000018_0001
Figure imgf000019_0001
wherein all the symbols are the same meaning as hereinbefore defined.
And the compounds of the following formula (la-H), (la-l), (la-J) and non-toxic salts thereof are preferable.
Figure imgf000019_0002
wherein all the symbols are the same meaning as hereinbefore defined.
More specifically, the compounds of the following formula (la-1), (la-2), (la-3), (la-4), (la-5), (la-6), (la-7), (la-8), (la-9), (la-10), (la-11 ), (la-12) and non-toxic salts thereof are preferable.
Figure imgf000020_0001
wherein all the symbols are the same meaning as hereinbefore defined.
Especially preferable compounds are the compounds described in Example and the following compounds and non-toxic salts thereof.
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
In the present invention, it is able to formulate using each active ingredient or combination of more than two active ingredients.
Unless otherwise specified, all isomers are included in the invention. For example, 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.
Salts
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.
Process for the preparation
A compound of the formula (Ic):
Figure imgf000034_0001
wherein all the symbols are the same meaning as hereinbefore defined,
in a compound of the present invention of the formula (la), may be prepared:
(1) by hydrolyzing an ester of the formula (Id):
Figure imgf000034_0002
wherein R1a is C1-4 alkyl and the other symbols are the same meaning as hereinbefore defined, or
(2) by hydrolyzing a compound of the formula (II):
Figure imgf000034_0003
wherein all the symbols are the same meaning as hereinbefore defined.
The compound of the formula (Id) among the compounds of the present invention, may be prepared:
(3) by reacting a compound of the formula (III):
Figure imgf000035_0001
wherein X is halogen, the other symbols are the same meaning as hereinbefore defined,
with a compound of the formula (IV)
Figure imgf000035_0002
wherein all the symbols are the same meaning as hereinbefore defined.
Compounds of the formula (la) wherein R4 is hydrogen and /or R7 is hydrogen, may be prepared:
(i) by using a compound of the formula (III) and (IV) wherein hydrogen represented by R4 and R7 is replaced by benzyloxycarbonyl (protecting group) as a staring material, (ii) by reacting above compounds,
(iii) by hydrolyzing a compound obtained in above reaction (ii) using an acid (hydrochloric acid, trifluoroacetic acid etc.),
(iv) 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.
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.
Starting materials and reagents
The starting materials and reagents in the present invention are known per se or may be prepared by known methods.
For example, a compound of the formula (II) may be prepared by using a reaction depicted in following scheme:
Figure imgf000036_0001
wherein all the symbols are the same meaning as hereinbefore defined.
For example, a compound included in the formula (III) of the formula:
Figure imgf000037_0001
is on the market.
For example, a compound included in the formula (IV) of the formula:
Figure imgf000037_0002
is on the market.
For example, a compound included in the formula (V) of the formula:
Figure imgf000037_0003
is on the market.
Pharmacological Activities
A compound of the formula (la) of the present invention possess an inhibitory activity on 5α-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 5α-reductase of the present invention is confirmed by the screening system described hereafter
(1) Preparation of 5α-reductase from human prostates
Frozen human prostates were thawed on ice and minced with scissors into small pieces (~1mm3). 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, 50μM 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 μM NADPH and 1 mM dithiothreitol. An appropriate aliquot of this suspension was used as the source of 5α-reductase.
(2) Assay
5α-reductase activity was determined by following the conversion of testosterone to 5α-dihydrotestosterone (DHT). In brief, buffer (100mM Tris-citrate, pH5.0), 1 mM NADPH and human prostatic 5α-reductase (0.4-1 mg protein) were placed in test tubes. After addition of test compounds (dissolved in 5μl in DMSO or EtOH) or solvents to the tubes, the solutions were preincubated at room temperature for 10 min. The reactions were initiated by addition of 1μM 14C-testosterone to a final volume of 0.5 ml. Following 30 min incubation at 37°C , the reactions were stopped by addition of 5ml dichloromethane. After centrifugation at 1000 rpm for 5min, the organic phase (bottom) was collected and the volume reduced to -100μl in a 42°C water bath down to -100 μl. 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.
The results are shown in the table 1 and 2.
Figure imgf000039_0001
Toxicity
The toxicity of a compound of the present invention of the formula (la) are very low and therefore, it may be estimated to be safe for pharmaceutical use.
Application for Pharmaceuticals
A compound of the present invention of the formula (la) and non-toxic salts thereof are useful for 5α-reductase inhibitors.
5α-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.
For the purpose above described, 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. In the human adult, the doses per person are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 100 μg 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.
As mentioned above, 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.
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.
In such compositions, 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.
Liquid compositions for oral administration include pharmaceutically- acceptable emulsions, solutions, syrups and elixirs. In such compositions, 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.). Besides inert diluents, such compositions may also comprise adjuvants (such as wetting agents, suspending agents, etc.), sweetening agents, flavouring agents, perfuming agents, and preserving agents.
Other 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.). For preparation of such spray compositions, for example, the method described in the United States Patent No. 2,868,691 or 3,095,355 may be used.
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.).
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.
Other 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.
Reference example and Example
The following examples illustrate the present invention, but not limit the present invention.
The solvents in the parentheses show the developing or eluting solvents and the rations of the solvents used are by volume in chromatographic separations.
Unless otherwise specified, "NMR" was measured in a d-chloroform (CDCI3) solution and "IR" was measured by the KBr disk method respectively.
Figure imgf000042_0001
To a mixture of 15.0 g of aluminum chloride in 100 ml of chloroform was added 10.9 g of 4-biphenyl carbonyl chloride. Slowly, 5.3 ml of 2-thiophenylacetonitrile was added to the mixture. The precipitate which formed was broken up, and the mixture was heated to reflux. After approximately four hours, heating was stopped. The mixture was then poured onto ice, and 300 ml of chloroform followed by 50 ml of cone, hydrochloric acid was added. The mixture was stirred to break up as much residue as possible. The organic layer separated was washed with dilute hydrochloric acid, followed by dilute sodium bicarbonate solution, dried over anhydrous potassium carbonate, and filtered. The filtrate was concentrated and purified on silica gel chromatography to obtain after trituration with ether 3.7 g of the desired product.
mp = 181-183°C
NMR : δ 3.99 (s, 2H), 7.17 (d, 1H), 7.36-7.77 (m, 8H), 7.87-7.98 (m, 2H).
Figure imgf000043_0002
To a solution of 2.26 g of 4'-ethyl-4-biphenyl carboxylic acid in 50.0 ml of chloroform was added 1.0 ml of oxalyl chloride, followed by two drops of
dimethylformamide. The mixture was heated to reflux with the exclusion of moisture. After a period of one hour, the mixture was concentrated. To the concentrate was added 1.53 g of methyl 1-methyl-2-pyrroleacetate and 20.0 ml of anhydrous m-xylene. The mixture was again heated to reflux with the exclusion of moisture. After a period of 24 hours, heating was stopped. The mixture was then concentrated, taken up in chloroform, washed with dilute sodium hydroxide solution, dried over potassium carbonate, and concentrated. This concentrate was purified on silica gel eluted with chloroform to yield 1.47 g of the desired product.
mp = 124-126°C
NMR : δ 1.28 (t, 3H), 2.71 (q, 2H), 3.73 (s, 2H), 3.75 (s, 3H), 3.97 (s, 3H), 6.13 (d, 1H), 6.74 (d, 1H), 7.30 (d, 2H), 7.51-7.70 (m, 4H), 7.87 (d, 2H).
Figure imgf000043_0001
To a solution of 1.25 g of the compound obtained in example 1 in 90.0 ml of methanol was added 7.0 ml of 1.0 N sodium hydroxide solution, and the mixture was stirred overnight. The mixture was then concentrated. The concentrate was taken up in warm water, treated with 10.0 ml of 1.0 N hydrochloric acid, and extracted with chloroform. The organic extract was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and triturated in ether - hexane to yield 1.0 g of the desired product.
mp= 194-196°C
NMR : δ 1.29 (t, 3H), 2.72 (q, 2H), 3.80 (s, 2H), 3.99 (s, 3H), 6.18 (d, 1H), 6.77 (d, 1H), 7.31 (d, 2H), 7.51-7.72 (m, 4H), 7.88 (d, 2H).
IR:v3020, 1694, 1628, 1600, 1481, 1458, 1380, 1267, 1239, 1194 cm-1.
Example 3(1)-3(93)
The following compounds were obtained by the same procedure as a series of reaction of example 1→ example 2, using a corresponding carboxylic acid or the compound of reference example 1 or a corresponding nitrile compound instead of 4'- ethyl-4-biphenyl carboxylic acid and a corresponding compound instead of methyl 1- methyl-2-pyrroleacetate in example 1.
Figure imgf000044_0001
NMR : δ 1.43 (m, 5H), 1.87 (m, 5H), 2.58 (m, 1H), 3.77 (s, 2H), 3.95
(s, 3H), 6.15 (d, 1H), 6.70 (d, 1H), 7.26 (d, 2H), 7.72 (d, 2H).
IR : v 2925, 1696, 1609, 1481 , 1453, 1375, 1262, 886, 756 cm-1.
Figure imgf000044_0002
NMR : δ3.79 (s, 2H), 3.99 (s, 3H), 6.17 (d, 1H), 6.76 (d, 1H), 7.34-
7.53 (m, 3H), 7.60-7.72 (m, 4H), 7.85-7.93 (m, 2H).
IR:v 3030, 1715, 1624, 1603, 1488, 1456, 1378, 1266 cm-1.
Figure imgf000045_0001
NMR : 53.77 (s, 2H), 3.96 (s, 3H), 4.06 (s, 2H), 6.14 (d, 1H), 6.69 (d, 1H), 7.14-7.40 (m, 7H), 7.67-7.80 (m, 2H).
IR:v3030, 1711, 1628, 1481, 1455, 1371, 1265, 1231 cm"-*.
Figure imgf000045_0002
NMR : δ 3.78 (s, 2H), 3.98 (s, 3H), 6.15 (d, 1H), 6.70 (d, 1H), 7.42-7.63 (m, 4H), 7.79 (d, 2H), 7.96 (m, 2H), 8.16 (s, 1H).
IR: V3060J705, 1654, 1629, 1487, 1453, 1377, 1252 cm-1
Figure imgf000045_0003
NMR : δ3.79 (s, 2H), 4.00 (s, 3H), 6.18 (d, 1H), 6.71 (d, 1H), 7.42-7.90 (m, 9H). IR : v3060, 1694, 1651, 1628, 1492, 1456, 1398, 1278 cm-1.
Figure imgf000045_0004
NMR : δ 3.75 (s, 2H), 3.94 (s, 3H), 6.12 (d, 1H), 6.69 (d, 1H), 7.00-7.55 (m, 9H). IR : V3200, 1730, 1697, 1609, 1575, 1487, 1453, 1375, 1269, 1240, 1197, 1140 cm -1
Figure imgf000046_0001
NMR : δ3.77 (s, 2H), 3.94 (s, 3H), 6.14 (d, 1H), 6.69 (d, 1H), 6.95-7.46 (m, 7H), 7.81 (m, 2H).
IR :v2950, 1720, 1593, 1561, 1485, 1448, 1376, 1238, 1179 cm-1.
Figure imgf000046_0002
NMR : δ3.77 (s, 2H), 3.94 (s, 3H), 5.14 (s, 2H), 6.13 (d, 1H), 6.68 (d, 1H), 7.04 (d, 2H), 7.43 (m, 5H), 7.83 (d, 2H).
IR : v 3065-2915, 1697, 1656, 1622, 1262, 888, 760 cm-1.
Figure imgf000046_0003
NMR (DMSO-de) : δ7.72 (2H, d), 7.38 (2H, d), 7.24 (2H, d), 7.11 (2H, d), 6.56 (1H, d), 6.09 (1H, d), 5.15 (2H, s), 3.80 (3H, s), 3.76 (2H, s), 2.61 (2H, q), 1.18 (3H, t).
IR : V3015, 2870, 1695, 1622, 1601, 1482, 1458, 1380, 1271, 1241
cm-1.
Figure imgf000046_0004
NMR : δ7.82 (2H, d), 7.37 (2H, d), 7.27 (2H, d), 7.02 (2H, d), 6.67 (1H, d), 6.13 (1H, d), 5.09 (2H, s), 3.93 (3H, s), 3.79 (2H, s), 2.93 (1H, m), 1.26 (6H,d). IR : V3425, 2960, 1697, 1622, 1601, 1481, 1456, 1379, 1270, 1243, 880, 759 cm-1.
Figure imgf000047_0001
NMR (DMSO-d6): δ7.73 (2H, d), 7.37 (2H, d), 7.23 (2H, d), 7.12 (2H, d), 6.57 (1H, d), 6.11 (1H, d), 5.15 (2H, s), 3.80 (3H, s), 3.78 (3H, s), 2.59 (2H, t), 1.56 (2H, m), 1.32 (2H, m), 0.90 (3H, t).
IR : V3015, 2855, 1695, 1622, 1601, 1482, 1458, 1396, 1272, 1241
cm-1.
Figure imgf000047_0002
NMR : δ 7.83 (2H, d), 7.41 (4H, m), 7.01 (2H, d), 6.68 (1H, d), 6.15 (1H, d), 5.10 (2H, S), 3.94 (3H, s), 3.77 (2H, s), 1.38 (9H, s).
IR:v2965, 1710, 1617, 1478, 1454, 1376, 1302, 1267, 1243, 1152, 1015, 886, 818, 756 cm-1.
Figure imgf000047_0003
NMR :δ 3.71 (s, 2H), 3.87 (s, 3H), 4.10 (s, 2H), 6.15 (d, 1H,),7.H (d, 1H),
7.27-7.63 (m, 9H).
IR :v3030, 1734, 1559, 1487, 1450, 1375, 1186, 1154 cm-1.
Figure imgf000048_0001
NMR : δ 3.81 (s, 2H), 4.01 (s, 3H), 6.18 (d, 1 H), 6.76 (d, 1 H), 7.56 (m, 2H), 7.91 (m, 4H), 8.32 (s, 1H).
IR : v 3050, 2950, 1696, 1619, 1484, 1457, 1378, 1279, 1238, 770, 738 cm-1.
Figure imgf000048_0002
NMR : δ 3.75 (s, 2H), 3.91 (s, 3H), 3.95 (s, 3H), 5J9 (s, 2H), 6.08 (d, 1 H), 6.50 (d, 1H), 6.92 (m, 1H), 7.26-7.52 (m, 7H).
Figure imgf000048_0003
NMR : δ 7.55-7.20 (6H, m),6.87-6.74 (2H, m), 6.47 (1H, d,), 6.09 (1 H, d), 5.10 (2H, s), 3.99 (3H, s), 3.76 (3H, s), 2.38 (3H, s).
IR : v 3035,2920, 1711, 1616, 1570, 1497, 1452, 1421, 1397, 1377, 1311,
1263, 1235, 1192, 1102, 993, 870, 847, 752 cm-1.
Figure imgf000048_0004
NMR : δ 7.50-7.30 (5H, m),7.20 (2H, d), 6.75 (2H, d), 6.46 (1 H, d), 6.07 (1 H, d), 5.11 (2H, s), 4.01 (3H, s), 3.75 (3H, s), 2.27 (3H, s), 2.25 (3H, s). IR : V3030, 1721, 1630, 1592, 1480, 1455, 1370, 1261, 1238, 1217, 1187, 1067,795,761,736 cm-1.
Figure imgf000049_0001
NMR : δ3.97 (s, 2H), 7.07 (d, 1H), 7.38-7.56 (m, 3H), 7.57-7.79 (m, 5H), 7.90-8.02 (m, 2H).
IR : v 3060, 2920, 1696, 1619, 1450, 1405, 1315, 1222 cm-1.
Figure imgf000049_0002
NMR (CDCl3/DMSO-d6 (2 drops)): δ 3.83 (s, 2H), 6.65 (d, 1H), 7.23 (d, 1H), 7.30-8.09 (m, 9H).
Figure imgf000049_0003
NMR : δ3.78 (s, 2H), 3.98 (s, 3H), 6.17(d, 1H), 6.71 (d, 1H), 7.35-7.41 (m, 1H), 7.52-7.76 (m, 4H), 7.93-8.07 (m, 2H).
IR:v 1716, 1640, 1490, 1456, 1379, 1199, 1100,746 cm-1.
Figure imgf000049_0004
NMR : δ 1.95-2.13 (m, 2H), 2.64-2.81 (m, 4H), 3.70 (s, 2H), 3.88 (s, 3H), 6.09 (d, 1H), 6.86 (d, 1H), 7.19-7.28 (m, 5H).
IR :v2945, 1704, 1640, 1485, 1456, 1421, 1380, 1256, 990, 917, 701 cm-1.
Figure imgf000050_0001
NMR : δ 1.70 (m, 4H), 2.64 (t, 2H), 2.77 (t, 2H), 3.70 (s, 2H), 3.87 (s, 3H), 6.10 (d, 1H), 6.92 (d, 1H), 7.10-7.33 (m, 5H).
IR : v 2600-4000, 1693, 1646, 1458, 1258, 1259, 752, 696 cm-1 .
Figure imgf000050_0002
NMR : δ θ.89 (t, 3H), 1.32 (m, 8H), 1.68 (m, 2H), 2.65 (t, 2H), 3.79 (s, 2H), 3.98 (s, 3H), 6.17 (d, 1H), 6.75 (d, 1H), 7.26 (d, 2H), 7.57 (d, 2H), 7.65 (d, 2H), 7.85 (d, 2H).
IR : v 3000-3900, 2925, 1695, 1627, 1482, 1458, 1269, 1241 cm-1 .
Figure imgf000050_0003
NMR : δ 3.95 (s, 2H), 7.00-7.50 (m, 8H), 7.52 (d, 1 H,), 7.87 (d, 2H).
IR: v 3030, 1692, 1619, 1591, 1490, 1456, 1311 , 1264, 1166 cm-1
Figure imgf000050_0004
NMR (CDCl3/DMSO-d6): δ 3.63 (s, 2H), 3.66 (s, 3H), 6.62 (d, 1 H), 7.22 (d, 1 H),
7.30-7.54 (m, 3H), 7.60-7.76 (m, 4H), 7.85-7.96 (m, 2H).
IR : v 3055, 1717, 1610, 1590, 1518, 1430, 1353, 1251 , 1199 cm-1.
Figure imgf000051_0001
NMR (DMSO-d6) : δ 7.90-7.70 (6H, m), 7.64 (1 H, d), 7.56-7.40 (3H, m), 6.89 (1H, d), 6.74 (1H, d), 6.51 (1H, d), 4.03 (3H, s).
IR : v 3030, 1680, 1615, 1516, 1469, 1446, 1376, 1312, 1255, 1211 , 960, 888, 745 cm-1.
Figure imgf000051_0002
NMR : 57.86 (2H, d), 7.70-7.30 (7H, m), 6.72 (1H, d), 6.01 (1 H, d), 3.98 (3H, s), 3.00 (2H, m), 2.79 (2H, m).
IR : v 3425, 3030, 1697, 1615, 1481, 1451, 1406, 1374, 1263, 1224, 1152, 887, 746, 695 cm-1.
Figure imgf000051_0003
NMR : 57.85 (2H, d), 7.65 (4H, m), 7.50-7.40 (3H, m), 6.73 (1 H), 6.01 (1H, d), 3.96 (3H, s), 2.73 (2H, t), 2.50 (2H, t), 2.04 (2H, m).
IR :v 3030, 1708, 1620, 1478, 1437, 1426, 1399, 1372, 1291, 1258, 1157,
1047, 891,760 cm-1.
Figure imgf000051_0004
NMR : δ 7.88 (2H, d), 7.65 (4H, m), 7.55-7.40 (3H, m), 7.40-7.15 (3H, m), 7.02 (2H, d), 6.85 (1H, d), 6.27 (1H, d), 5.80 (2H, s), 3.65 (2H, s).
IR : v 3060, 1717, 1618, 1537, 1478, 1452, 1424, 1390, 1269, 1204, 1152, 1053, 882, 848, 746 cm-1.
Figure imgf000052_0001
NMR : δ 7.87 (2H, d), 7.65 (4H, m), 7.50-7.35 (3H, m), 6.73 (1H, d), 6.01 (1H, d), 3.96 (3H, s), 2.68 (2H, t), 2.45 (2H, t,), 1.78 (4H, m).
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.
Figure imgf000052_0002
NMR : δ 7.80 (2H, d), 7.37 (2H, d), 7.26 (2H, d), 7.01 (2H, d), 6.66 (1H, d), 5.98 (1 H, d), 5.09 (2H, s), 3.92 (3H, s), 2.93 (1H, m), 2.72 (2H, t), 2.50 (2H, t), 2.03 (2H, m), 1.26 (6H, d).
IR : v 3035, 2890. 1707, 1619, 1480, 1458, 1422, 1375, 1308, 1260, 1172,
1046, 891, 751 cm-1.
Figure imgf000052_0003
NMR : δ 7.80 (2H, d), 7.37 (2H, d), 7.26 (2H, d), 7.01 (2H, d), 6.66 (1H, d), 5.97 (1 H, d), 5.09 (2H, s), 3.91 (3H, s), 2.93 (1H, m), 2.66 (2H, t), 2.44 (2H, t), 1.76 (4H, m), 1.26 (6H,d).
IR : v 2966, 1697, 1607, 1479, 1449, 1373, 1314, 1251, 889 cm-1.
Figure imgf000053_0001
NMR : δ 3.71 (s, 2H), 3.85 (s, 3H), 6.09 (d, 1 H), 6.61 (d, 2H), 6.88-7.50 (m, 9H). IR : v 2900-3100, 1708, 1622, 1487, 1454, 1378, 1232, 747 cm-1.
Figure imgf000053_0002
NMR : δ 1.20-2.10 (m, 10H), 3.76 (s, 2H), 3.93 (s, 3H), 4.36 (m, 1H), 6.13 (d, 1H), 6.68 (d, 1H), 6.91 (d, 2H), 7.80 (d, 2H).
Figure imgf000053_0003
NMR (DMSO-de): δ 3.64 (s, 2H), 3.86 (s, 3H), 6.10 (d, 1H), 6.63 (d, 1H), 7.27 (d, 4H), 7.83 (d, 2H), 8.32 (d, 2H).
IR : v 3080, 2930, 1707, 1619, 1635, 1515, 1486, 1341, 1251 , 1165 , 887, 751 cm-1.
Figure imgf000053_0004
NMR : δ3.74 (s, 2H), 3.92 (s, 3H), 5.55 (s, 1H), 6.03 (d, 1H), 6.45 (d, 1H), 6.70 (m, 1H), 6.97 (s, 1H), 7.08-7.40 (m, 13H).
IR : v 3400-3060, 1729, 1590, 1531, 1487, 1451, 1375, 747, 700 cm-1.
Figure imgf000054_0001
NMR : δ 3.70 (s, 2H), 3.89 (s, 3H), 4.68 (s, 4H), 5.98 (d, 1 H), 6.46 (d, 1 H), 6.89 (bd, 1 H), 7.08-7.36 (m, 13H).
IR : v 3200-2900, 1745, 1717, 1595, 1569, 1492, 1451, 1364, 1261, 749, 739, 697 cm-1.
Figure imgf000054_0002
NMR : δ 3.59 (s, 4H), 3.62 (s, 2H), 3.74 (s, 2H), 3.94 (s, 3H), 6.11 (d, 1H), 6.66 (d, 1H), 7.20-7.55 (m, 12H), 7.74 (d, 2H).
IR:v3060, 1730, 1619, 1558, 1403, 1452, 1374 cm-1.
Figure imgf000054_0003
NMR (DMSO-de): δ 3.80 (s, 2H), 3.85 (s, 3H), 6.14 (d, 1H), 6.68 (s, 1 H), 7.42-7.66 (m, 5H), 7.99 (m, 3H), 8.20 (s, 1H), 10.43 (s, 1H).
IR : v 3200-2955, 1733, 1675, 1578, 1549, 1473, 1376, 1262, 1201, 748 cm-1.
Figure imgf000055_0001
NMR (DMSO-de): δ 3.80 (s, 2H), 3.83 (s, 3H), 6.14 (d, 1H), 6.62 (d, 1H), 7.58 (m, 3H), 7.77 (m, 2H), 8.00 (m, 4H), 10.53 (s, 1H).
IR : v 3500-2800, 1731 , 1653, 1596, 1518, 1488, 1263, 758, 708 cm-1.
Figure imgf000055_0002
NMR : δ 3.76 (s, 2H), 3.95 (s, 3H), 4.14 (s, 2H), 6.13 (d, 1 H), 6.65 (d, 1H), 7.17-7.42 (m, 7H), 7.70 (d, 2H).
IR : V 3060, 1701 , 1624, 1482, 1377, 1264, 1232 cm'1.
Figure imgf000055_0003
NMR : δ 3.78 (s, 2H), 3.96 (s, 3H), 4.14 (s, 2H), 6.13 (d, 1 H), 6.51 (d, 1H), 7.19-7.68 (m, 9H).
Figure imgf000055_0004
NMR : δ 3.70 (s, 2H), 3.98 (s, 3H), 4.11 (s, 2H), 6.14 (d, 1 H), 6.62 (d, 1 H), 7.04 (d, 2H), 7.42-7.49 (m, 5H), 7.66 (d, 2H).
IR:v1719, 1626, 1480, 1375, 1261, 1209, 1045,885,750 cm-1.
Figure imgf000056_0001
NMR : 53.77 (s, 2H), 3.94 (s, 3H), 4.10 (s, 2H), 6.12 (d, 1 H), 6.53 (d, 1H), 7.13-7.75 (m, 9H).
IR:v1724, 1618, 1616, 1591, 1489, 1451, 1379, 1273, 1179,753 cm-1.
Figure imgf000056_0002
NMR : 57.72 (2H, d), 7.32-7.15 (7H, m), 6.68 (1H, d), 6.14 (1H, d), 3.97 (3H, s), 3.77 (2H, s), 2.97 (4H, m).
IR : v 3065, 2965, 1716, 1622, 1559, 1487, 1457, 1421 , 1376, 1267, 1232, 886 cm-1.
Figure imgf000056_0003
NMR : δ 3.70 (2, 2H), 3.87 (s, 3H), 6.15 (d, 1H), 6.68 (d, 1H), 7.37 (m, 3H), 7.54 (m, 2H), 7.57 (d, 2H), 7.78 (d, 2H).
IR : v 3015, 1698, 1620, 1592, 1486, 1456, 1378, 1264 cm-1 .
Figure imgf000056_0004
NMR : δ 7.75-7.65 (6H, m), 7.46-7.32 (5H, m), 6.64 (1 H, d), 6.15 (1H, d), 3.86 (3H, s), 3.82 (2H, s). IR : V 3030, 1732, 1700, 1570, 1541, 1489, 1457, 1420, 1398, 1268, 1242, 960, 887, 762, 685 cm-1.
Figure imgf000057_0001
NMR : δ 1.35-1.48 (m, 2H), 1.60-1.80 (m, 4H), 2.61 (t, 2H), 2.75 (t, 2H), 3.71 (s, 2H), 3.88 (s, 3H), 6.10 (d, 1H), 6.92 (d, 1H), 7.15-7.30 (m, 5H).
IR : v 2930, 1698, 1635, 1490, 1462, 1420, 1238, 917, 774, 746, 694 cm-1.
Figure imgf000057_0002
NMR : 53.79 (s, 2H), 3.99 (s, 3H), 6.16 (d, 1H), 6.36 (t, 2H), 6.72 (d, 1H), 7.13 (t,
2H), 7.43-7.68 (m, 3H), 7.81 (s, 1H).
IR: V 2955, 1743, 1572, 1490, 1380, 1242, 1168, 746 cm-1
Figure imgf000057_0003
NMR . 53.78 (s, 2H), 3.98 (s, 3H), 6.19 (d, 1H), 6.40 (m, 2H), 6.73 (d, 1H), 7.17 (m, 2H), 7.48 (d, 2H), 7.92 (d, 2H).
IR : v 3100-2955, 1698, 1646, 1621, 1331 , 1267, 884, 758, 717 cm-1.
Figure imgf000057_0004
NMR (DMSO-de): δ 3.24 (s, 2H), 3.81 (s, 3H), 4.71 (s, 4H), 5.87 (d, 1H), 6.49 (d, 1H), 6.73 (d, 2H), 7.29-7.43 (m, 4H), 7.73 (d, 2H). IR : v 3500-2800, 1606, 1471 , 1367, 1274, 1181 , 1148, 883, 758 cm-1.
Figure imgf000058_0001
NMR : δ 2.07 (s, 6H), 3.80 (s, 2H), 3.99 (s, 3H), 5.93 (s, 2H), 6.18 (d, 1H), 6.76 (d, 1H), 7.28 (d, 2H), 7.90 (d, 2H).
IR: V 3200, 2800, 1718, 1616, 1406, 1263, 1226, 884 cm-1
Figure imgf000058_0002
NMR : δ 3.78 (s, 2H), 3.99 (s, 3H), 6.15 (d, 1H), 6.73 (d, 1H), 7.07 (m, 1H), 7.25-7.52 (m, 3H), 7.62-7.82 (m, 2H), 8.01 (s, 1H).
IR : v 3105, 1734, 1699, 1623, 1595, 1489, 1454, 1375 cm-1.
Figure imgf000058_0003
NMR (CDCI3/DMSO-de): δ 3.70 (s, 2H), 3.87 (s, 3H), 6.14 (d, 1H), 6.72 (d, 1H), 7.14 (M, 1 H), 7.32-7.48 (m, 2H), 7.68 (m, 2H), 7.83 (m, 2H).
IR : v 2950, 1735, 1699, 1626, 1600, 1483, 1456, 1379, 1259 cm-1.
Figure imgf000058_0004
NMR : δ 3.70 (s, 2H), 3.97 (s, 3H), 6.15 (d, 1 H), 6.70 (d, 1 H), 7.06 (d, 1 H), 7.15 (d, 1H), 7.57 (d, 2H), 7.81 (d, 2H). IR : v 1695, 1622, 1484, 1458 1429, 1379, 1268, 979, 758 cm-1 .
Figure imgf000059_0001
NMR : δ 0.82-0.93 (m, 2H), 1.22-1.39 (m, 8H), 1.59-1.75 (m, 2H), 2.66 (t, 3H), 3.77 (s, 2H), 3.96 (s, 3H), 6.14 (d, 1 H), 6.69 (d, 1 H), 7.24 (d, 2H), 7.72 (d, 2H).
IR : v 1735, 1697, 1622, 1487, 1457, 1378, 1269, 1238, 887 cm-1 .
Figure imgf000059_0002
NMR : δ θ.91 (t, 3H), 1.00-1.58 (m, 9H), 1.90 (m, 4H), 2.52 (m, 1 H), 3.77 (s, 2H), 3.96 (s, 3H), 6.14 (d, 1H), 6.70 (d, 1 H), 7.28 (d, 2H), 7.75 (d, 2H).
Figure imgf000059_0003
NMR : δ 2.41 (s, 3H), 3.79 (s, 2H), 3.98 (s, 3H), 6.16 (d, 1 H), 6.75 (d, 1 H), 7.27 (d, 2H), 7.54 (d, 2H), 7.65 (d, 2H), 7.86 (d, 2H).
IR : v 1730, 1617, 1588, 1486, 1451 , 1400, 1379, 1264, 1199, 877, 814, 761 cm-1 .
Figure imgf000059_0004
NMR: δ 2.29 (s, 3H), 3.79 (s, 2H), 3.99 (s, 3H), 6.17 (d, 1H), 6.78 (d, 1 H), 7.28 (m, 4H), 7.40 (d, 2H), 7.85 (d, 2H). IR : v 3020, 1731, 1700, 1618, 1481, 1453, 1406, 1376, 1262 cm-1.
Figure imgf000060_0001
NMR: δ 0.98 (t, 3H), 1.67 (q, 2H), 2.64 (t, 2H), 3.79 (s, 2H), 3.99 (s, 3H), 6.19 (d, 1H), 6.75 (d, 1H), 7.28 (d, 2H), 7.54-7.68 (m, 4H), 7.87 (d, 2H).
IR:v2955, 1698, 1672, 1601, 1401, 1457, 1398, 1267, 761 cm-1.
Figure imgf000060_0002
NMR (DMSO-d6): δ 3.83 (s, 5H), 3.86 (s, 3H), 6.16 (d, 1H), 6.66 (d, 1H), 7.08 (d, 2H), 7.72 (d, 2H), 7.78 (m, 4H).
IR : v3035, 2910, 1733, 1695, 1627, 1600, 1525, 1483, 1458, 1378, 1295, 1268 cm-1.
Figure imgf000060_0003
NMR : δ3.79 (s, 2H), 3.98 (s, 3H), 6.17 (d, 1H), 6.74 (d, 1H), 7.15 (m, 2H), 7.63
(m, 4H), 7.89 (m, 2H).
IR : v3020, 1732, 1698, 1624, 1484, 1456, 1378, 1266 cm-1.
Figure imgf000060_0004
NMR (DMSO-d6): δ 3.75 (s, 2H), 3.86 (s, 3H), 6.12 (d, 1H), 6.63 (d, 1H), 7.56 (d, 4H), 7.77 (d, 4H).
IR : v 3035, 1713, 1621, 1633, 1480, 1453, 1376, 1265, 885, 822, 760 cm-1.
Figure imgf000061_0001
NMR : δ3.79 (s, 2H), 3.99 (s, 3H), 6.17 (d, 1H), 6.73 (d, 1H), 7.23 (m, 1H), 7.47 (m, 1H), 7.60 (d, 2H), 7.65 (m, 1H), 7.87 (d, 2H).
IR:v3020, 1732, 1701, 1621, 1484, 1455, 1379, 1266 cm-1.
Figure imgf000061_0002
NMR : 53.80 (s, 2H), 4.00 (s, 3H), 6.18 (d, 1H), 6.74 (d, 1H), 7.53-7.96 (m, 8H). IR:v3030, 1731, 1690, 1625, 1483, 1455, 1378, 1333, 1259, 1179, 1123 cm-1.
Figure imgf000061_0003
NMR (DMSO-d6): 53.82 (s, 2H), 3.87 (s, 3H), 6.14-6.16 (d, 1H), 6.65-6.67 (d,
1H), 7.86-8.01 (m, 8H).
IR : V3050, 1713, 1620, 1486, 1454, 1397, 1376, 1325, 1265, 1168, 1124,
1072, 885, 832, 764, 737 cm-1.
Figure imgf000062_0001
NMR (DMSO-d6): δ 8.53 (1 H, d), 8.26 (2H, m), 7.96-7.80 (5H, m), 6.66 (1 H, d),
6.15 (1 H, d), 3.87 (3H, s), 3.82 (2H, s).
IR : V 3100, 2995, 1732, 1619, 1530, 1455, 1377, 1348, 1264, 886, 771 , 735 cm-1.
Figure imgf000062_0002
NMR (DMSO-d6): δ 2.63 (s, 3H), 3.79 (s, 2H), 3.86 (s, 3H), 6.14 (d, 1H), 6.65 (d, 1 H), 7.75-7.94 (m, 6H), 8.10 (d, 2H).
IR : v 3395, 2925, 1763, 1700, 1619, 1455, 1376, 1264, 885, 762 cm-1.
Figure imgf000062_0003
NMR : δ 7.85 (2H, d), 7.64 (4H, m), 7.51 (2H, d), 6.65 (1 H, d), 6.09 (1H, d), 3.97
(3H, s), 3.73 (2H, s), 3.12 (3H, broad s), 3.05 (3H, broad s).
IR : v 3445, 3030, 1731 , 1699, 1622, 1567, 1539, 1504, 1480, 1452, 1398, 1377, 1264, 885, 837, 752 cm-1.
Figure imgf000062_0004
NMR : δ 7.94 (2H, d), 7.74-7.64 (4H, m), 7.53-7.43 (3H, m), 7.08 (1H, d), 6.70 (1H, d), 4.30 (3H, s).
IR :v3060, 1702, 1653, 1630, 1601, 1507, 1447, 1372, 1258, 887, 745 cm-1.
Figure imgf000063_0001
NMR (DMSO-de) : δ 7.90-7.73 (7H, m), 7.56-7.43 (3H, m), 7.21 (1H, d), 3.94 (3H, s).
IR : v 3113, 2960, 1678, 1629, 1601, 1535, 1496, 1467, 1400, 1373, 1288, 1249, 1206, 1134, 1104, 1077, 886, 749 cm-1.
Figure imgf000063_0002
NMR (DMSO-de) : δ 7.96 (2H, d), 7.87 (2H, m), 7.79 (2H, d), 7.58-7.45 (3H, m), 6.86 (2H, m).
IR: v 3265, 1691, 1602,1406, 1273, 1211, 887, 743 cm-1.
Figure imgf000063_0003
NMR (DMSO-d6) : δ 7.93-7.75 (6H, m), 7.57-7.40 (4H, m), 7.12 (1 H, s).
IR : v 3330, 1697, 1673, 1620, 1447, 1387, 1280, 1235, 1194, 1123, 885, 746 cm-1.
Figure imgf000064_0001
NMR : 59.95 (1 H, br.), 8.18 (2H, d), 7.71-7.61 (4H, m), 7.50-7.37 (3H, m), 7.19 (1H, s), 3.87 (3H, s), 3.64 (2H, s).
IR : V 3030, 1730, 1703, 1648, 1600, 1472, 1432, 1375, 1267, 1226, 1195, 1160, 905, 752 cm-1.
Figure imgf000064_0002
NMR (CDCI3+2 drops of DMSO-d6) : 58.28 (2H, d), 7.87 (1 H, s), 7.72 (2H, d), 7.65 (2H, m), 7.52-7.40 (3H, m), 4.31 (3H, s).
IR : v 3135, 2965, 1707, 1652, 1600, 1518, 1407, 1259, 1195, 907, 752 cm-1.
Figure imgf000064_0003
NMR : 50.87 (s, 9H), 0.95-2.00 (m, 9H), 2.85-3.05 (m, 1 H), 3.71 (s, 2H), 3.88 (s,
3H), 6.10-6.12 (d, 1H), 6.96-6.98 (d, 1H).
IR : v 2945, 1700, 1646,1486, 1461 ,1417, 1384, 1296, 1254, 989, 918, 818,
765 cm-1.
Figure imgf000064_0004
NMR : δ 1.40-2.10 (m, 8H), 2.50-2.75 (m, 1 H), 3.00-3.32 (m, 1H), 3.72 (two s, 2H), 3.87 (two s, 3H), 6.12 (two d, 1 H), 7.00 (two d, 1H), 7.13-7.37 (m, 5H).
IR: v 3060, 2930, 1733, 1638, 1489, 1453, 1305, 1248 cm- 1
Figure imgf000065_0001
NMR : δ 1.72-2.08 (m, 6H), 2.56-2.81 (m,9H), 3.70 (s, 2H), 3.88 (s,3H), 6.09 (d,1 H), 6.88-7.00 (m,5H).
IR : v 2075, 1722, 1596, 1495, 1457, 1407, 1383, 1303, 1202, 1121, 1048, 930, 771, 740, 669 cm-1.
Figure imgf000065_0002
NMR (DMSO-d6) : δ 3.80 (s, 2H), 3.86 (s, 3H), 6.13 (d, 1H), 6.64 (d, 1H), 7.71 (s, 4H), 7.81 (s, 4H).
IR : v 3030, 1731 , 1701, 1620, 1475, 1452, 1374, 1261 , 882, 817, 757 cm-1.
Figure imgf000065_0003
NMR (CDCI3 +2 drops of DMSO-d6) : δ 11.44 (1H, broad), 7.92 (2H, d), 7.66 (4H, m), 7.52-7.38 (3H, m), 6.80 (1H, dd), 6.17 (1H, dd), 3.73 (2H, s).
IR : v 3275, 1713, 1593, 1494, 1425, 1275, 1238, 884, 777, 748 cm-1.
Figure imgf000066_0001
NMR (DMSO-d6): δ 3.56 (s, 2H), 3.88 (s, 3H), 6.05 (d, 1 H), 6.61 (d, 1H),
7.50-7.63 (m, 4H), 7.73-7.85 (m, 3H)
IR: V 3505, 1713, 1619, 1589, 1483, 1453, 1371 , 1261 cm-1
Figure imgf000066_0002
NMR (DMSO-d6): δ 3.63 (s, 2H), 3.89 (s, 3H), 6.08 (d, 1H), 6.61 (d, 1H),
7.65-7.95 (m, 7H).
IR: v 3445, 3065, 2950, 1714, 1618, 1585, 1481, 1451 , 1371 , 1260 cm-1
Figure imgf000066_0003
NMR: 52.32 (s, 3H), 3.79 (s, 2H), 3.98 (s, 3H), 6.17 (d, 1H), 6.77 (d, 1H), 7.25-7.50 (m, 6H), 7.62-7.75 (m, 2H).
IR: v 2950, 1725, 1586, 1484, 1448, 1396, 1370, 1253, 1175 cm-1
Figure imgf000067_0001
NMR : 53.52 (s, 3H), 3.72 (s, 2H), 3.90 (s, 3H), 6.07 (d, 1 H), 6.51 (d, 1 H),
7.05 (m, 2H), 7.18 (m, 3H), 7.34 (d, 2H), 7.55 (d, 2H).
IR: v 3055, 1730, 1618, 1587, 1489, 1372, 1295, 1275 cm-1.
Figure imgf000067_0002
NMR (DMSOd6): δ 3.83 (s, 2H), 3.89 (s, 3H) 6.17 (d, 1 H), 6.62 (d, 1H), 7.13 (m,
1H), 7.38 (m, 2H), 7.82 (m, 4H), 8.07 (m, 2H), 10.41 (s, 1H).
IR: v 3340, 3055, 1714, 1664, 1598, 1534, 1486, 1440, 1373, 1322, 1258 cm-1.
Figure imgf000067_0003
NMR (DMSOd6): δ3.89 (s, 5H), 6.01 (d, 1H), 6.45 (d, 1H), 6.54 (d, 1H), 7.35 (m,
10H), 7.72-8.10 (m, 4H), 9.43 (d, 1H).
IR: v3420, 1623, 1524, 1486, 1450, 1367, 1271, 1186 cm-1.
Figure imgf000068_0001
NMR (DMSOd6): δ 2.87 and 2.92 (singles, total 3H), 3.82 (s, 2H), 3.86 (s, 3H),
4.51 and 4.72 (singles, total, 2H), 6.14 (d, 1H), 6.63 (d, 1H), 7.16-7.87 (m, 9H).
IR : v 3025, 1722, 1619, 1597, 1488, 1450, 1402, 1375, 1258, 1199 cm-1.
Figure imgf000068_0002
NMR : δ 3.76 (s, 2H), 3.98 (s, 3H), 4.67 (d, 2H), 6.14 (d, 1 H), 6.52 (t,
1H), 6.63 (d, 1H), 7.36 (m, 4H), 7.82 (m, 5H).
IR : v 3270, 3055, 1718, 1616, 1539, 1484, 1450, 1373, 1258, 1201 cm-1.
Figure imgf000068_0003
NMR : δ 3.06 (m, 4H), 3.71 (s, 2H), 3.89 (s, 3H), 6.10 (d, 1H), 6.93
(d, 1H), 7.25 (m, 5H).
IR : v 3025, 2900, 1690, 1644, 1481 , 1455, 1345, 1223, 969, 759 cm-1.
Figure imgf000068_0004
mp 152-155°C NMR: δ 1.37 (d, 6H), 3.77 (s, 2H), 3.93 (s, 3H), 4.64 (m, 1H), 6.14 (d, 1H), 6.68 (d, 1H), 6.90 (d, 2H), 7.80 (d, 2H).
IR: v 2960, 1725, 1602, 1557, 1487, 1455, 1380, 1297, 1196, 1150, 1047, 888, 837, 756 cm-1
Figure imgf000069_0001
mp 180-185°C
NMR: δ 3.77 (s, 2H), 3.94 (s, 3H), 4.36-4.38 (m, 4H), 6.14 (d, 1H), 6.67 (d, 1H), 6.94-7.01 (m, 5H), 7.26-7.37 (m, 2H), 7.83 (d, 2H).
IR: v 2955, 1695, 1624, 1599, 1496, 1455, 1328, 1299, 1272, 1240, 1174, 945, 844, 784, 678 cm-1 .
Figure imgf000069_0002
mp 174-178°C
NMR: δ 3.80 (s, 2H), 3.94 (s, 3H), 6.22 (d, 1H), 7.08 (d, 1H), 7.43 (m, 2H), 7.87 (m, 2H), 7.96 (s, 1H).
IR: v 3039, 2955, 1697, 1609, 1511 , 1451, 1374, 1262, 1180, 749 cm-1
Figure imgf000070_0001
mp 182-183°C
NMR: δ 3.80 (s, 2H), 3.97 (s, 3H), 6.24 (d, 1H), 7.26-7.73 (m, 6H).
IR: v 3065, 2960, 1692, 1600, 1542, 1451, 1373, 1224, 1194, 1136, 850, 746 cm- 1.
Formulation example
The following components were admixed in conventional method and punched out to obtain 100 tablets each containing 50mg of active ingredient.
2-[5-(4-phenylbenzoyl)-1-methylpyrrol-2-yl] acetic acid 5g
Cellulose calcium gluconate (disintegrating agent) 0.2g
Magnesium stearate (lubricating agent) 0.1g
Microcrystalline cellulose 4.7g

Claims

What is claimed is:
1. A pharmaceutical composition for the prevention and treatment of diseases induced by the excess generation of dihydrotestosterone in mammals, alopecia (androgenic alopecia), acnes, hypertrophy of prostate and prostatic cancer, which comprises, as active ingredient, an effective amount of a compound of the formula (la):
Figure imgf000071_0001
wherein
Figure imgf000071_0002
is pyrrole included nitrogen substituted by R4, thiophene, furan, imidazole included nitrogen substituted by R4, thiazole, oxazole, triazole included nitrogen substituted by R4, in which R4 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;
Figure imgf000071_0003
is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane,
Figure imgf000071_0004
in which m is 0 or 1 , or benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom;
R1 is hydrogen or C 1-4 alkyl;
R2 is hydrogen or C 1-4 alkyl;
n is 1-3;
R3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano, (2) -Q-T-U-R5
in which Q is bond or C1-6 alkylene;
T is bond, -O- , -S- , -SO2- , -NR7- or -NR7CO- , in which R7 is hydrogen, C1 -4
Figure imgf000072_0002
alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in -NR7CO- 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 R5 only;
R5 is (i) C4-7 cycloalkyi, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or the benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or rings in (i), (ii), (iii), (iv) of R5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR6 , in which R6 is C1-4 alkyl, NR8R9, in which R8 and R9 each, independently, is hydrogen or C 1-4 alkyl;
or -Q-T-U-R5 is C7-10 alkyl, C7-10 alkoxy;
or non-toxic salts thereof,
with the proviso that, the compounds wherein
(i) T is -O- , or -NR7- , and U is bond and R5 is diphenylmethyl in -Q-T-U-R5 represented by R3, when
Figure imgf000072_0003
is thiophene, E is bond and
Figure imgf000072_0004
is benzene or naphthalene,
(ii) T is -O- , or -NR7- , and U is C1-6 alkylene and R5 is phenyl or diphenylmethyl in -
Q-T-U-R5 represented by R3, when
Figure imgf000072_0006
is thiophene, E is bond and
Figure imgf000072_0005
is benzene or naphthalene,
(iii)
Figure imgf000072_0007
is pyrrole included nitrogen substituted by R4, in which R4 is hydrogen, C1-3 alkyl or phenyl,
A is bond or methylene,
E is bond,
Figure imgf000072_0001
is benzene,
R2 is hydrogen or methyl and R3 each, independently, is hydrogen or halogen,
are excluded;
with a pharmaceutical carrier or coating.
2. A method for the prevention and treatment of diseases induced by the excess generation of dihydrotestosterone in mammals, alopecia (androgenic alopecia), acnes, hypertrophy of prostate and prostatic cancer, which comprises the administration of an effective amount of a compound of the formula (la) depicted in claim 1 or non-toxic salts thereof.
3. A compound of the formula (lb):
Figure imgf000073_0001
wherein
Figure imgf000073_0004
is pyrrole included nitrogen substituted by R4, thiophene, furan, imidazole included nitrogen substituted by R4, thiazole, oxazole, triazole included nitrogen substituted by R4, in which R4 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;
Figure imgf000073_0002
is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane,
Figure imgf000073_0003
, in which m is 0 or 1 , or benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom; R1 is hydrogen or C 1-4 alkyl;
R2 is hydrogen or C 1-4 alkyl;
n is 1-3;
R3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
(2) -Q-T-U-R5
in which Q is bond or C1-6 alkylene;
T is bond, -O- ,
Figure imgf000074_0001
-S- , -SO2- , -NR7- or -NR7CO- , in which R7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in -NR7CO- 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 R5 only;
R5 is (i) C4-7 cycloalkyi, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or the benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen,
or rings in (i), (ii), (iii), (iv) of R5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR6 , in which R6 is C1-4 alkyl, NR8R9, in which R8 and R9 each, independently, is hydrogen or C 1-4 alkyl;
or -Q-T-U-R5 is C7-10 alkyl, C7-10 alkoxy;
or non-toxic salts thereof,
with the proviso that,
(a) compounds wherein
(i) T is -O- , or -NR7- , and U is bond and R5 is diphenylmethyl in -Q-T-U-R5 represented by R3, when
Figure imgf000074_0002
is thiophene, E is bond and
Figure imgf000074_0003
is benzene or naphthalene,
(ii) T is -O- , or -NR7- , and U is C1-6 alkylene and R5 is phenyl or diphenylmethyl in -
Q-T-U-R5 represented by R3, when
Figure imgf000074_0004
is thiophene, E is bond and
Figure imgf000074_0005
is benzene or naphthalene, are excluded;
(b) at least one R3 of (R3)n is a substituent selected from group (2) that is -Q-T-U-R5 , when E is bond and
Figure imgf000075_0001
is benzene;
(c) all R3 of (R3)n are not hydrogen at the same time, when E is bond and
Figure imgf000075_0002
is C4-
7 cycloalkane, or E is methylene and
Figure imgf000075_0003
is benzene;
(d) 2-[5-[2-chloro-4-(1 H-pyrrol-1-yl)benzoyl]thiophen-2-yl] acetic acid and methyl ester thereof and
2-[5-[2-chloro-4-(2,5-dimethyl-1 H-pyrrol-1 -yl)benzoyl]thiophen-2-yl] acetic acid and methyl ester thereof are excluded.
4. A compound according to claim 3, where in
Figure imgf000075_0004
is pyrrole included nitrogen substituted by R4, in which R4 is the same meaning as defined in claim 3.
5. A compound according to claim 3, where in
Figure imgf000075_0005
is thiophene.
6. A compound according to claim 3, where in
Figure imgf000075_0006
is furan.
7. A compound according to claim 3, where in
Figure imgf000075_0007
is imidazole included nitrogen substituted by R4, in which R4 is the same meaning as defined in claim 3.
8. A compound according to claim 3, where in
Figure imgf000075_0008
is thiazole.
9 A compound according to claim 3. where in
Figure imgf000075_0009
is oxazole.
10. A compound according to claim 3, where in
Figure imgf000076_0006
is triazole included nitrogen substituted by R4, in which R4 is the same meaning as defined in claim 3.
11. A compound according to claim 3, where in
Figure imgf000076_0001
is benzene.
12. A compound according to claim 3, where in
Figure imgf000076_0002
is C4-7 cycloalkane.
13 A compound according to claim 3, where in
Figure imgf000076_0003
is naphthalene,
benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane or
Figure imgf000076_0004
, in which m is 0 or 1.
14. A compound according to claim 3, wherein is benzene fused 4-7 membered heterocyclic ring containing one nitrogen, one sulfur or one oxygen atom.
15. A compound according to claim 3, which is selected from the group consisting of
2-[5-[4-(4-Ethylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Cyclohexylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Benzylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3-Benzoylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Benzoylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3-Phenoxybenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Phenoxybenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Benzyloxybenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Ethylbenzyloxy)benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-[4-(4-lsopropylbenzyloxy)benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-[4-(4-Butylbenzyloxy)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-t-Butylbenzyloxy)benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-(4-Phenylbenzyl)carbonyl-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3-Benzyloxy-4-methoxybenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(4-Benzyloxy-2-methylbenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(4-Benzyloxy-2,3-dimethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(3-Phenylpropyl)carbonyl-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Phenylbutyl)carbonyl-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Heptylphenyl)benzoyl-1-methylpyrrol-2-yl] acetic acid,
2-[4-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
3-[5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl]-2-propenoic acid,
3-[5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl] propionic acid,
4-[5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl] butanoic acid,
2-[5-(4-Phenylbenzoyl)-1-benzylpyrrol-2-yl] acetic acid,
5-[5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl] pentanoic acid,
5-[5-[4-(4-isopropylphenyloxy)benzoyl]-1-methylpyrrol-2-yl] butanoic acid, 5-[5-[4-(4-isopropylphenyloxy)benzoyl]-1-methylpyrrol-2-yl] pentanoic acid, 2-[5-(2-Phenoxybenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Cyclohexyloxybenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Nitrophenyloxy)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3-Diphenylmethylaminobenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(3-Dibenzylaminobenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Dibenzylaminomethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(3-Phenylcarbonylaminobenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(4-Phenylcarbonylaminobenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(4-Phenylthiomethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3-Phenylthiomethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Phenylsulfonylmethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5-(3-Phenylsulf onylmethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid, 2-[5- 4-(2-Phenylethyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5- 4-(2-Phenylethynyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5- 4-(2-Phenyletheyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5- 5-(4,4'-Biphenyl)pentylcarbonyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5- 3-Pyrrolbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5- 4-Pyrrolbenzoyl)-1 -methylpyrrol-2-yl] acetic acid,
2-[5- 4-lsoindolylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5- 4-(2, 5-Dimethylpyrrol)benzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5- 3-(2-Thienyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5- 4-(2-Thienyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5- 3-(5-Bromo-2-thienyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
245- 4-Heptylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-5-[4-(4-Propylcyclohexyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Methylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(2-Methylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Propylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Methoxyphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Fluorophenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Chlorophenyl)benzoyl]-1 -methylpyrrol-2-yl] acetic acid,
2-[5-[4-(3-Chloro-4-fluorophenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(3-Trifluoromethylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Trifluoromethylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(3-Nitrophenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Methylcarbonylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(4-Dimethylaminocarbonylphenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid, 5-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl carboxylic acid,
4-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl] carboxylic acid,
5-(4-Phenylbenzoyl)-1H-pyrrol-2-yl carboxylic acid,
4-(4-Phenylbenzoyl)-1 H-ρyrrol-2-yl carboxylic acid,
2-[5-[4-(4-Bromophenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-(4-Phenylbenzoyl)-1 H-pyrrol-2-yl] acetic acid,
2-[5-[4-(2,4-Dichlorophenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(3,5-Dichlorophenyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3-Methyl-4-phenylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-[(N-methyl-N-phenyl)carbamoyl]benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-[4-(N-phenylcarbamoyl)benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-[N-(diphenylmethyl)carbamoyl]benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-[4-[(N-methyl-N-benzyl)carbamoyl]benzoyl]-1-methylpyrrol-2-yl] acetic acid, 2-[5-[4-(N-benzylcarbamoyl-benzoyl]-1-methylpyrrol-2-yl] acetic acid,
2-[5-[4-(2-phenoxyethoxy)benzoyl]-1-methylpyrrol-2-yl] acetic acid, and
5-(3-phenylpropanoyl)-1-methyl-2-pyrroleacetic acid.
16. A compound according to claim 3, which is selected from the group consisting of
2-[5-(4-t-Butylcyclohexaylcarbonyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Phenylcyclohexylcarbonyl)-1-methylpyrrol-2-yl] acetic acid, and
2-[5-[3-(1 ,2,3,4-Tetrahydro-2-naphthyl)propylcarbonyl]-1-methylpyrrol-2-yl] acetic acid.
17. A compound according to claim 3, which is
5-(2-Naphthyl)carbonyl-1-methyl-2-pyrroleacetic acid, or
5-(9-Oxofluoren-2-yl)carbonyl-1-methyl-2-pyrroleacetic acid.
18. A compound according to claim 3, which is
5-(2-benzothienyl)carbonyl-1-methyl-2-pyrroleacetic acid, or
5-(2-benzof u ranyl)carbonyl-1-methyl-2-pyrroleacetic acid.
19. A compound according to claim 3, which is
2-[5-(4-Phenylbenzoyl)-2-thienyl] acetic acid, or
2-[5-(4-Phenoxybenzoyl)-2-thienyl] acetic acid.
20. A compound according to claim 3, which is
2-[5-(4-Phenylbenzoyl)-2-furanyl] acetic acid.
21. A compound according to claim 3, which is
2-[2-(4-Phenylbenzoyl)-1-methylimidazol-5-yl] acetic acid, or
2-(4-Phenylbenzoyl)-1-methylimidazol-5-yl carboxylic acid.
22. A pharmaceutical composition according to claim 1, which is selected from the group consisting of
2-[5-(4-Methylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-t-Butylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(3,5-Di-t-butylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Hexyloxybenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Trif iuoromethylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-lsobutylbenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-Nitrobenzoyl)-1-methylpyrrol-2-yl] acetic acid,
2-[5-(4-isopropyloxybenzoyl)-1-methylpyrrol-2-yl] acetic acid, and
5-benzylcarbonyl-1-methyl-2-pyrroleacetic acid.
PCT/US1995/011962 1994-09-27 1995-09-27 Five membered heterocyclic compounds WO1996010013A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP8511867A JPH10506892A (en) 1994-09-27 1995-09-27 5-membered heterocyclic compounds, drugs containing them as active ingredients
KR1019970701970A KR970706250A (en) 1994-09-27 1995-09-27 5-membered heterocyclic compounds (FIVE MEMBERED HETEROCYCLIC COMPOUNDS)
EP95934464A EP0783488A4 (en) 1994-09-27 1995-09-27 Five membered heterocyclic compounds
US08/793,983 US5859042A (en) 1995-09-27 1995-09-27 Five membered heterocyclic compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US31345994A 1994-09-27 1994-09-27
US08/313,459 1994-09-27
US46540695A 1995-06-05 1995-06-05
US08/465,406 1995-06-05

Publications (1)

Publication Number Publication Date
WO1996010013A1 true WO1996010013A1 (en) 1996-04-04

Family

ID=26978895

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/011962 WO1996010013A1 (en) 1994-09-27 1995-09-27 Five membered heterocyclic compounds

Country Status (4)

Country Link
EP (1) EP0783488A4 (en)
JP (1) JPH10506892A (en)
KR (1) KR970706250A (en)
WO (1) WO1996010013A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2313059A (en) * 1993-03-29 1997-11-19 Bioglan Ireland Pyrrolyl-containing compositions for the topical treatment of skin disorders
CN112955439A (en) * 2018-08-24 2021-06-11 赛尼欧普罗有限责任公司 Aromatic molecules for the treatment of pathological conditions

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1195628A (en) * 1967-07-26 1970-06-17 Mcneilab Inc Aroyl-Substituted Pyrroles
GB1327308A (en) * 1970-01-26 1973-08-22 Mcneilab Inc Process for preparing aroyl-substituted pyrroles and product prepared thereby
US3801605A (en) * 1972-01-21 1974-04-02 Mc Neil Labor Inc 5-aroyl-furans
GB1390866A (en) * 1972-01-21 1975-04-16 Mcneilab Inc Cycloalkanoyl-substituted pyrroles and pharmaceutical compo sitions containing them
US3952012A (en) * 1970-01-26 1976-04-20 Mcneil Laboratories, Incorporated Aroyl-substituted pyrroles
WO1993013099A1 (en) * 1991-12-31 1993-07-08 Fujisawa Pharmaceutical Co., Ltd. ARYL KETONES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4187230A (en) * 1975-05-27 1980-02-05 Ethyl Corporation Preparation of 5-aroyl-pyrrole compounds
JPS5848553B2 (en) * 1979-03-01 1983-10-28 財団法人相模中央化学研究所 β, β, β↓-trihalo↓-α↓-hydroxyethyl-substituted↓-2↓-aroylpyrrole derivative
EP0300688A1 (en) * 1987-07-21 1989-01-25 FISONS plc Pyrrole derivatives, process for their preparation and pharmaceutical compositions containing them
DE4325204C2 (en) * 1993-07-27 2002-11-28 Matthias Lehr Acylpyrrolealcanoic acids and their derivatives as inhibitors of phospholipase A¶2¶

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1195628A (en) * 1967-07-26 1970-06-17 Mcneilab Inc Aroyl-Substituted Pyrroles
GB1327308A (en) * 1970-01-26 1973-08-22 Mcneilab Inc Process for preparing aroyl-substituted pyrroles and product prepared thereby
US3865840A (en) * 1970-01-26 1975-02-11 Mcneilab Inc Process of preparing 1,4-diloweralkyl-3-loweralkoxy-carbonyl-2-acetates
US3952012A (en) * 1970-01-26 1976-04-20 Mcneil Laboratories, Incorporated Aroyl-substituted pyrroles
US3801605A (en) * 1972-01-21 1974-04-02 Mc Neil Labor Inc 5-aroyl-furans
GB1390866A (en) * 1972-01-21 1975-04-16 Mcneilab Inc Cycloalkanoyl-substituted pyrroles and pharmaceutical compo sitions containing them
WO1993013099A1 (en) * 1991-12-31 1993-07-08 Fujisawa Pharmaceutical Co., Ltd. ARYL KETONES AS TESTOSTERONE 5α-REDUCTASE INHIBITORS

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FARMACO ED. SC., Volume 41, Number 4, issued 1986, S. MASSA et al., "Agenti Antiinflammatory Non-Steroidei", pages 281-291. *
See also references of EP0783488A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (en) * 2018-08-24 2021-06-11 赛尼欧普罗有限责任公司 Aromatic molecules for the treatment of pathological conditions

Also Published As

Publication number Publication date
JPH10506892A (en) 1998-07-07
KR970706250A (en) 1997-11-03
EP0783488A1 (en) 1997-07-16
EP0783488A4 (en) 1998-01-07

Similar Documents

Publication Publication Date Title
CA2190087C (en) Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities
US5859042A (en) Five membered heterocyclic compounds
US6835752B2 (en) Carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical agents comprising the same as active ingredient
EP0512570B1 (en) Urea derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same
CZ211596A3 (en) Metalloprotease inhibitors, process of their preparation, their use and pharmaceutical compositions containing thereof
WO1994026738A1 (en) N'-heterocyclyl-n-benzofuranyl urea derivatives and their analogs as acat inhibitors
JP2001526687A (en) Inhibition of p38 kinase activity by arylureas
BG63940B1 (en) Biphenylsulphanomide inhibitors of the matrix metalloproteinase
JP2001514244A (en) 5-Alkyl-2-arylaminophenylacetic acids and derivatives
MXPA05003847A (en) Imidazole derivatives and their use as peripherally-selective inhibitors of dopamine-beta-hydroxylase.
HRP970474A2 (en) Compounds for and a method of inhibiting matrix metalloproteinases
CA2415847C (en) Aminoalkylbenzoyl-benzofuran or benzothiophene derivatives, method for preparing same and compositions containing same
US6617357B2 (en) Compounds and their use as PDE inhibitors
JPH01156950A (en) Benzoylaminophenoxybutanoic acid derivative having 5d-reductase inhibitory activity, production thereof and drug containing said derivative
JP2000256259A (en) Maillard reaction-inhibiting agent
WO2002020462A1 (en) Benzoic acid derivatives and drugs containing the same as the active ingredient
JPH04224554A (en) Lipoxygenase suppressing compound
AU1982500A (en) Use of substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives as matrix metalloprotease inhibitors for the treatment of respiratory diseases
US4431652A (en) 4-Hydroxy-5-substituted-3(2H)-isothiazolone-1,1-dioxide derivatives useful in treating urinary tract calcium oxalate lithiasis
US4423063A (en) 2,4-Dioxo-4-substituted-1-butaoic acid derivatives useful in treating urinary track calcium oxalate lithiasis
FR2745571A1 (en) NOVEL SULFUR DERIVATIVES COMPRISING AN AMIDE BINDING, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME
EP0783488A1 (en) Five membered heterocyclic compounds
JPH0583551B2 (en)
FI81346C (en) Process for the preparation of therapeutically useful - / 10-oxy-4H-benzo / 4,5 / cyclohepta / 1,2-b / thiophen-4-ylidene / carboxylic acid derivative
JPH09249669A (en) Condensed pyrrole derivatives, and medicines containing the derivatives as active ingredients

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 08793983

Country of ref document: US

122 Ep: pct application non-entry in european phase
WWE Wipo information: entry into national phase

Ref document number: 1019970701970

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1995934464

Country of ref document: EP

122 Ep: pct application non-entry in european phase
WWP Wipo information: published in national office

Ref document number: 1995934464

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019970701970

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1995934464

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1019970701970

Country of ref document: KR

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载