Patent EA-003876-B1 (EA)
Title: Inhibitors of phospholipase enzymes
Inventor: SEEHRA JASBIR
IPC: C07D403/12
Filed: 1999-02-24
Abstract: 1) A compound of the formulae: wherein R1 is selected from H, halogen, C1-C6 alkyl, S- C1-C6 alkyl, C1-C6 alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl, thienyl, benzofuranyl, wherein the aromatic or hereto-aromatic cycles are optionally substituted by trifluoromethyl, or a moiety of the formulae: R6 is selected from H; R7A is selected from -CF3, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, and isoxazolyl, the rings of these groups being optionally substituted by 1-3 substituents, selected from halogen, C1-C6 alkyl, -NO2, acetamido; R7B is selected from -CF3, C1-C6 alkyl, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, benzyl, pyrazolyl and thiazolyl, and isoxazolyl, the rings of these groups being optionally substituted by 1-3 substituents, selected from halogen, C1-C6 alkyl, -NO2, acetamido; R2 is selected from H, halogen; R3 is selected from -CH=CH-COOH, or a moiety selected from the formulae -L<1>-M<1>; wherein L<1> is a bridging or linking moiety selected from a chemical bond, (CH2)n-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-NH-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-; wherein Z is O or N; M<1> is selected from the group of -COOH, -(CH2n-COOH, -(CH2)n-C(O)-COOH, tetrazole, R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl,, -O-(CH2)n-COOH, -O-CH2-C=C-COOH, -O-C=C-CH2-COOH, and -C(O)-N-(CH2)n-COOH; with a proviso that the complete moiety created by any combination of L<1>, M<1>, shall contain at least one acidic moiety containing a -COOH or a moiety of the formulae: wherein n is an integer from 0 to 3; R4 is selected from H, lower C1-C6 alkyl, C3-C10-cycloalkyl, quinolylsulphanylmethyl; R5 is selected from groups of formulae -(CH2)n-A, wherein A is moiety n is an integer from 0 to 3; D is H; B and C are independently phenyl groups each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6)2, -NH(C1-C6), -N-C(O)-(C1-C6), -NO2, or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 wherein R4 is hydrogen, or a pharmaceutically acceptable salt thereof. 3. A compound of Claim 2 further wherein R1 is in the indole 5-position, or a pharmaceutically acceptable salt thereof. 4. A compound of Claim 3 further wherein R1 is a benzyloxy group, or a pharmaceutically acceptable salt thereof. 5. A compound of Claim 1 wherein R3 is -L<1>-M<1>, M<1> is the moiety: and L<1> and R9 are as defined in Claim 1. 6. A compound having the formulae: wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, L<1>, M<1> are defined above. 7. A compound of Claim 6, wherein: substituents R1 and R2 are in the indole ring's 5- or 6-position and defined as follows: R1 is selected from H, halogen, C1-C6 alkyl, -S-C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, S-phenyl, benzyl, -O-benzyl; R2 is selected from H, halogen; R3 is selected from a moiety selected from the formulae -L<1>-M<1>; wherein L<1> is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -(CH2)n-C(O)-,or -(CH2)n-NH-; M<1> is selected from the group of R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COON, R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, C1-C6 alkyl, -O-C1-C6 alkyl, -O-(CH2)n-COOH with a proviso that the complete moiety at the indole created by any combination of R3, L<1>, M<1>, R8, R9, shall contain at least one acidic moiety selected from or containing a carboxylic acid; n is an integer from 0 to 3; and R4 is selected from H, or methyl. 8. A compound having formulae: Wherein substituents R1 and R2 are in indole ring's 5- or 6-positions and defined as said in Claim 7, and R4 and R9 are defined in Claim 7. 9. A compound of Claim 1 which is selected from: a) 4-[(5-{[(cyclopentyloxy)carbonyl]amino}-1-propyl-1H-indol-3-yl)methyl]-3methoxybenzoic acid; b) cyclopentyl-N-{3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino}carbonyl) benzyl]-1-propyl-1 H-indol-5-yl} carbamate; c) 4-[(1-benzhydryl-5-{[(cyclopentyloxy)carbonyl]amino}-1H-indol-3yl)methyl]-3-methoxybenzoic acid; d) 4-{[5-{[(cyclopentyloxycarbonyl]amino}-1-(2-naphthylmethyl)-1H-indol-3yl]methyl}-3-methoxybenzoic acid; e) 4-{[5-{[(cyclopentyloxy)carbonyl]amino}-1-(cyclopropylmethyl)-1H-indol-3yl]methyl}-3-methoxybenzoic acid; f) 4-{[5-{((cyclopentyloxycarbonyl]amino}-1-(cyclopropylmethyl)-1H-indol-3yl]methyl}-3-methoxybenzoic acid; g) 4-{[5-{[(cyclopentyloxycarbonyl]amino}-1-(4-pyridinylmethyl)-1H-indol-3yl]methyl}-3-methoxybenzoic acid; h) 4-[(5-{[(cyclopentyloxy)carbonyl]amino}-1-isopropyl-1H-indol-3yl)methyl]-3methoxybenzoic acid; i) 4-[(1-cyclopentyl-5-{[(cyclopentyloxy)carbonyl]amino}-1H-indol-3yl)methyl]-3-methoxybenzoic acid; or j) 4-[(1-benzhydryl-5-{[(butylamino)carbonyl)amino}-1H-indol-3-yl)methyl]-3methoxybenzoic acid; or a pharmaceutically acceptable salt thereof. 10. A compound of Claim 1 which is selected from: a) 4-({1-benzhydryl-5-[(methylsulfonyl)amino]-1H-indol-3-yl}methyl)-3methoxybenzoic acid; b) 4-({1-benzhydryl-5-[(cyclopentylcarbonyl)amino)-1H-indol-3-yl}methyl)-3methoxybenzoic acid; c) 4-[(1-benzhydryl-5-nitro-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; d) 4-[(1-benzhydryl-5-fluoro-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; e) 4-[(1-benzhydryl-5-methyl-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; f) 4-[(5-benzhydryl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)methyl]-3-methoxybenzoic acid; g) 4-[(1-benzhydryl-5-cyano-1H-indol-3-yl)methyl]-3-methoxybenzoic acid; h) 4-{[1-benzhydryl-5-(methylsulfonyl)-1H-indol-3-yl]methyl}-3methoxybenzoic acid; or j) cyclopentyl-N-{1-benzhydryl-3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl] amino}carbonyl)benzyl]-1H-indol-5-yl}carbamate; or a pharmaceutically acceptable salt thereof. 11. A compound of Claim 1 which is selected from: a) cyclopentyl-N-{3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino} carbonyl)benzyl]-1-propyl-1H-indol-5-yl}carbamate; b) N-{1-(cyclopropylmethyl)-3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl] amino}carbonyl)benzyl]-1H-indol-5-yl}carbamate; c) cyclopentyl-N-[3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino] carbonyl)benzyl]-1-(4-pyridinylmethyl)-1H-indol-5-yl]carbamate; d) cyclopentyl-N-[3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino}carbonyl) benzyl]-1-(2-naphthylinethyl)-1H-indol-5-yl]carbamate; e) cyclopentyl-N-{1-isopropyl-3-(2-methoxy-4-({[(2-methylphenyl)sulfonyl] amino}carbonyl)benzyl]-1H-indol-5-yl}carbamate; f) cyclopentyl-N-{1-cyclopentyl-3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl] amino}carbonyl)benzyl]-1H-indol-5-yl}carbamate; g) cyclopentyl N-{1-benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl) sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}carbamate; h) cyclopentyl N-[1-benzhydryl-3-(2-methoxy-4-{[(methylsulfonyl)amino] carbonyl}benzyl)-1H-indol-5-yl]carbamate; i) N-{1-benzhydryl-3-[4-({[(2-chlorophenyl)sulfonyl]amino}carbonyl)-2methoxybenzyl]-1H-indol-5-yl}; or j) cyclopentyl N-(3-{4-[({[5-(acetylimino)-4-methyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]sulfonyl}amino)carbonyl]-2-methoxybenzyl}-1-benzhydryl-1H-indol-5yl)carbamate; or a pharmaceutically acceptable salt thereof. 12. A compound of Claim 1 which is selected from: a) cyclopentyl N-(1-benzhydryl-3-{4-(({[5-(dimethylamino)-1naphthyl]sulfonyl}amino)carbonyl]-2-methoxybenzyl}-1H-indol-5-yl)carbamate; b) cyclopentyl N-[1-benzhydryl-3-(4-{[(benzylsulfonyl)amino]carbonyl}-2methoxybenzyl)-1H-indol-5-yl]carbamate; c) cyclopentyl N-{1-benzhydryl-3-[4-({[(2,4-dimethyl-1,3-thiazol-5yl)sulfonyl]amino}carbonyl)-2-methoxybenzyl]-1H-indol-5-yl}carbamate; d) cyclopentyl N-{1-benzhydryl-3-[4-({[(3,5-dimethyl-4isoxazolyl)sulfonyl]amino}carbonyl)-2-methoxybenzyl]-1H-indol-5-yl}carbamate; e) cyclopentyl N-(3-{4-[({[5-(acetylamino)-1,3,4-thiadiazol-2yl]sulfonyl}amino)carbonyl]-2-methoxybenzyl}-1-benzhydryl-1H-indol-5yl)carbamate; f) cyclopentyl N-(1-benzhydryl-3-{2-methoxy-4-[({[4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)phenyl]sulfonyl}amino)carbonyl]benzyl}-1H-indol-5yl)carbamate; g) N-{4-[(1-benzhydryl-5-nitro-1H-indol-3-yl)methyl]-3-methoxybenzoyl}-2methylbenzenesulfonamide; h) N-{4-[(1-benzhydryl-5-nitro-1H-indol-3-yl)methyl]-3-methoxybenzoyl} (trifluoro)methanesulfonamide; i) N-{4-[(1-benzhydryl-5-bromo-1H-indol-3-yl)methyl]-3-methoxybenzoyl}-2methylbenzenesulfonamide; or j) N-{4-[(1-benzhydryl-5-bromo-1H-indol-3-yl)methyl]-3-methoxybenzoyl} (trifluoro)methanesulfonamide; or a pharmaceutically acceptable salt thereof. 13. A compound of Claim 1 which is selected from: a) N-{1-benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}cyclopentanecarboxamide; b) N-[4-({1-benzhydryl-5-[(methylsulfonyl)amino]-1H-indol-3-yl}methyl)-3methoxybenzoyl](trifluoro)methanesulfonamide; c) N-{4-[(1-benzhydryl-5-{[(butylamino)carbonyl]amino}-1H-indol-3yl)methyl]-3-methoxybenzoyl}(trifluoro) methane sulfonamide; d) N-{1-benzhydryl-3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}cyclopentanecarboxamide; e) 4-({5-[(cyclopentylcarbonyl)amino]-1-[phenyl(2-pyridinyl)methyl]-1H-indol3-yl}methyl)-3-methoxybenzoic acid; f) N-[4-({1-benzhydryl-5-[(benzylsulfonyl)amino]-1H-indol-3-yl}methyl)-3methoxybenzoyl](trifluoro)methanesulfonamide; g) N-{1-benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}-3-thiophenecarboxamide; h) benzyl N-{1-benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}carbamate; i) 4-[(1-benzhydryl-5-nitro-1H-indol-3-yl)methyl]benzoic acid; j) 4-[(1-benzhydryl-5-bromo-1H-indol-3-yl)methyl]benzoic acid; k) 4-[(1-benzhydryl-5-{[(cyclopentyloxy)carbonyl]amino}-1H-indol-3yl)methyl]benzoic acid; or l) cy