Inhibitors of phospholipase enzymes
View Patent ↗Novel compounds are disclosed which inhibit the activity of phospholipase enzymes in a mammal, particularly cytosolic phospholipase A 2 . Pharmaceutical compositions comprising such compounds and methods of treatment using such compositions are also disclosed.
1. A compound of the formulae:
wherein:
R 1 is
R 6 is
R 7 is selected from C 3 -C 5 cycloalkyl, and phenyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NO 2 , —CF 3 , CO 2 H, or —OH;
R 2 is selected from H, halogen, —CF 3 , —OH, —C 1 -C 10 alkyl, C 1 -C 10 alkoxy, —CHO, —CN, —NO 2 , —NH 2 , —NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —N—SO 2 —C 1 -C 6 alkyl, or —SO 2 —C 1 -C 6 alkyl;
R 3 is selected from H, —CF 3 , —COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 10 cycloalkyl, —CHO, halogen, or a moiety of the formulae:
wherein n is independently selected in each appearance as an integer from 0 to 3, Y is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl morpholinyl, pyrrolidinyl, or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, —CF 3 , —OH, —C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O;
R 4 is selected from the group of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(CH 2 ) n —C 3 -C 6 cycloalkyl, —(CH 2 ) n —S—(CH 2 ) n —C 3 -C 5 cycloalkyl, —(CH 2 ) n —O—(CH 2 ) n —C 3 -C 5 cycloalkyl,or the groups of:
a) —(CH 2 ) n -phenyl-O-phenyl, —(CH 2 ) n -phenyl-CH 2 -phenyl, —(CH 2 ) n —O-phenyl-CH 2 -phenyl, —(CH 2 ) n -phenyl-(O—CH 2 -phenyl) 2 , or a moiety of the formulae:
wherein n is independently selected in each appearance as an integer from 0 to 3, Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, —CF 3 , —OH, —C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O;
n is an integer from 0 to 3;
R 5 is
R 8 is —COOH,
R 9 is H;
R 10 is H;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein R 3 is H, or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 having the formula:
wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined as in claim 1 , or a pharmaceutically acceptable salt thereof.
4. A compound of claim 3 wherein
R 3 is H,
or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(phenethylsulfanyl)methyl]-1H-indol1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(2-furylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(4-hydroxy-6-phenyl-2-pyrimidinyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 which is 4-{[3-chloro-5-[(cyclopentylcarbonyl)amino]-2-({[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}methyl)-1H-indol-1-yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2,4-dibromophenoxy)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
10. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(cyclopentylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
11. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(propylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
12. A compound of claim 1 which is 4-({2-{[4-(tert-butyl)phenoxy]methyl}-3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
13. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-quinolinylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
14. A compound of claim 1 which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(cyclopropylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
15. A compound of claim 1 which is 4-({5-[(3-carboxypropanoyl)amino]-3-chloro-2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
16. A compound of claim 1 which is 4-[(5-[(3-carboxypropanoyl)amino]-3-chloro-2-{[(3-methylbenzyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
17. A compound of claim 1 which is 4-({2-({[4-(tert-butyl)benzyl]sulfanyl}methyl)-5-[(3-carboxypropanoyl)amino]-3-chloro-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
18. A compound of claim 1 which is 4-({5-{[(benzylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
19. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
20. A compound of claim 1 which is 4-({5-{[(benzyloxy)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
21. A compound of claim 1 which is 4-({3-chloro-5-{[(cyclopentyloxy)carbonyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
22. A compound of claim 1 which is 4-({5-(benzylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
23. A compound of claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenoxybenzyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
24. A compound of claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl) (methyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
25. A compound of claim 1 which is 4-({5-[acetyl(benzyl)amino]-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
26. A compound of claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenylpropanoyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
27. A compound of claim 1 which is 4-({3-benzoyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.