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US 5,859,042 AGranted
Five membered heterocyclic compounds
AssigneeOno Pharmaceutical Co., Ltd.
InventorsSung Jai Lee, Takuya Seko, Manton Rodgers Frierson, Jagadish Chandra Sircar, Charles Xian Cao
Life of this patent
Estimating the term…
Abstract
The instant invention is related to 5-membered heterocyclic compounds and pharmaceutical compositions which possess inhibitory activity on 5 alpha-reductase.
Claims24
A pharmaceutical composition for the treatment of diseases induced by the excess generation of dihydrotestosterone in mammals, alopecia, acnes, hypertrophy of prostate and prostatic cancer, which comprises, as active ingredient, and effective amount of a compound of the formula (1a):
- ##STR154## wherein Z is pyrrole included nitrogen substituted by R.sup.4, thiophene, furan, imidazole included nitrogen substituted by R.sup.4, thiazole, oxazole, triazole included nitrogen substituted by R.sup.4, in which
- R.sup.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 C1-6 alkylene;
- D is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane, ##STR155## in which m is 0 or 1, or benzene fused 4-7 membered heterocyclic ring consisting of one nitrogen, one sulfur or one oxygen atom;
- R.sup.1 is hydrogen or C1-4 alkyl;
- R.sup.2 is hydrogen or C1-4 alkyl;
- n is 1-3;
- R.sup.3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
- (2)--Q--T--U--R.sup.5
- in which Q is bond or C1-6 alkylene;
- T is bond, --O--, ##STR156## --S--, --SO.sub.2 --, --NR.sup.7 -- or --NR.sup.7 CO--, in which R.sup.7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in --NR.sup.7 CO-- may be connected with --Q-- or --U--;
- U is bond, C1-6 alkylene, C2-6 alkyenylene, C2-6 alkynylene or C1-6 alkylene --O--, in which oxygen atom can be connected with R.sup.5 only;
- R.sup.5 is (i) C4-7 cycloalkyl, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring consisting of one nitrogen, one sulfur or one oxygen, or the benzene fused 4-7 membered heterocyclic ring consisting of one nitrogen, one sulfur or one oxygen,
- or rings in (i), (ii), (iii), (iv) of R.sup.5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR.sup.6, in which R.sup.6 is C1-4 alkyl, NR.sup.8 R.sup.9, in which R.sup.8 and R.sup.9 each, independently, is hydrogen or C1-4 alkyl;
- or --Q--T--U--R.sup.5 is C7-10 alkyl, C7-10 alkoxy;
- or non-toxic salts thereof,
- with the proviso that, the compounds wherein
- (i) T is --O--, or --NR.sup.7 --, and U is bond and R.sup.5 is diphenylmethyl in --Q--T--U--R.sup.5 represented by R.sup.3, when Z is thiophene, E is bond and D is benzene or naphthalene,
- (ii) T is --O--, or --NR.sup.7 --, and U is C1-6 alkylene and R.sup.5 is phenyl or diphenylmethyl in --Q--T--U--R.sup.5 represented by R.sup.3, when Z is thiophene, E is bond and D is benzene or naphthalene,
- (iii) Z is pyrrole included nitrogen substituted by R.sup.4, in which R.sup.4 is hydrogen, C1-3 alkyl or phenyl,
- A is bond or methylene,
- E is bond
- D is benzene,
- R.sup.2 is hydrogen or methyl and
- R.sup.3 each, independently, is hydrogen or halogen, are excluded;
- with a pharmaceutical carrier or coating.
24 more elements
A compound of the formula (1b):
- ##STR157## wherein Z is pyrrole included nitrogen substituted by R.sup.4, thiophene, furan, imidazole included nitrogen substituted by R.sup.4, thiazole, oxazole, triazole included nitrogen substituted by R.sup.4, in which
- R.sup.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 C1-6 alkylene;
- D is benzene, C4-7 cycloalkane, naphthalene, benzo(C4-7)cycloalkane, indene, cyclopenta(C4-7)cycloalkane, ##STR158## in which m is 0 or 1, or benzene fused 4-7 membered heterocylic ring consisting of one nitrogen, one sulfur or one oxygen atom;
- R is hydrogen or C1-4 alkyl,
- R.sup.2 is hydrogen or C1-4 alkyl;
- n is 1-3
- R.sup.3 each, independently, is (1) hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, nitro, methylthio, trifluoromethyl or cyano,
- (2) --Q--T--U--R.sup.5 in which Q is bond or C1-6 alkylene;
- T is bond, --O--, ##STR159## --S--, --S.sub.2, --NR.sup.7 -- or --NR.sup.7 CO--, in which R.sup.7 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4)alkyl and nitrogen atom in --NR.sup.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.sup.5 only;
- R.sup.5 is (i) C4-7 cycloalkyl, (ii) phenyl, (iii) diphenylmethyl or (iv) 4-7 membered heterocyclic ring consisting of one nitrogen, one sulfur or one oxygen,
- or the benzene fused 4-7 membered heterocyclic ring consisting of one nitrogen, one sulfur or one oxygen,
- or rings in (i), (ii), (iii), (iv) of R.sup.5 may be substituted by 1-3 of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, trifluoromethyl, nitro or COR.sup.6, in which R.sup.6 is C1-4 alkyl, NR.sup.8 R.sup.9, in which R.sup.8 and R.sup.9 each, independently, is hydrogen or C1-4 alkyl;
- or --Q--T--U--R.sup.5 is C7-10 alkyl, C7-10 alkoxy;
- or non-toxic salts thereof,
- with the proviso that,
- (a) compounds wherein
- (i) T is --O--, or --NR.sup.7 --, and U is bond and R.sup.5 is diphenylmethyl in --Q--T--U--R.sup.5 represented by R.sup.3, when Z is thiophene, E is bond and D is benzene or naphthalene,
- (ii) T is --O--, or --NR.sup.7 --, and U is C1-6 alkylene and R.sup.5 is phenyl or diphenylmethyl in --Q--T--U--R.sup.5 represented by R.sup.3, when Z is thiophene, E is bond and D is benzene or naphthalene, are excluded;
- (b) at least one R.sup.3 of (R.sup.3).sub.n is a substituent selected from group (2) that is --Q--T--U--R.sup.5, when E is bond and D is benzene;
- (c) all R.sup.3 of (R.sup.3).sub.n are not hydrogen at the same time, when E is bond and D is C4-7 cycloalkane, or E is methylene and D 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-1H-pyrrol-1-yl)benzoyl!thiophen-2-yl!acetic acid and methyl ester thereof are excluded;
- (e) when Z is pyrrole included nitrogen substituted by R.sub.4, pyrrole is substituted on 2 position by ##STR160##
22 more elements
A compound which is
- 2-5-(4-Iodobenzoyl)-1-methylpyrrol-2-yl!acetic acid.
A compound which is selected from the group consisting of 2-4-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl!acetic acid, 4-(4-Phenylbenzoyl)-1-methylpyrrol-2-yl carboxylic acid, and 4-(4-Phenylbenzoyl)-1H-pyrrol-2-yl carboxylic acid.
Dependencies are inferred from the claim text.