Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
Compounds of formula (I) and II) are provided wherein: X is an alkali metal or a basic amine moiety; R 1 is alkyl, cycloalkyl, —CH 2 -cycloalkyl, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of these groups being optionally substituted; R 2 is H, halogen, alkyl, perfluoroalkyl, alkoxy, cycloalkyl, —CH 2 -cycloalkyl, —NH 2 , or —NO 2 ; R 3 is phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted; or a pharmaceutically acceptable salt or ester form thereof, as well as pharmaceutical compositions and methods using these compounds as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.
1. A compound of formula I:
wherein:
R 1 is C 1 –C 8 alkyl, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, wherein the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups may be optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, —O—C 1 –C 6 perfluoroalkyl, C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, hydroxy, —NH 2 , or —NO 2 ;
R 3 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, hydroxy, —NH 2 , —NO 2 , phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, wherein the rings of these groups may be optionally substituted by from 1 to 3 groups selected from phenyl, halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, —O—C 1 –C 6 perfluoroalkyl, C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ; or a pharmaceutically acceptable salt or ester form thereof.
2. A compound of claim 1 that is of formula III:
wherein:
R 1 is C 1 –C 8 alkyl, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, wherein the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups may be optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, —O—C 1 –C 6 perfluoroalkyl, C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, —NH 2 , or —NO 2 ;
R 3 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, hydroxy, —NH 2 , —NO 2 , phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, wherein the rings of these groups may be optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, —O—C 1 –C 6 perfluoroalkyl, C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ; or a pharmaceutically acceptable salt or ester form thereof.
3. A compound of claim 1 that is of formula (IV)
wherein:
R 1 is C 1 –C 8 alkyl, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, wherein the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups may be optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, —O—C 1 –C 6 perfluoroalkyl, C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, —NH 2 , or —NO 2 ;
R 3 phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 3 alkyl, C 1 –C 3 perfluoroalkyl, —O—C 1 –C 3 perfluoroalkyl, C 1 –C 3 alkoxy, —OH, —NH 2 , or —NO 2 ; or a pharmaceutically acceptable salt or ester form thereof.
4. A compound of claim 1 that is of formula (V):
wherein:
R 1 is C 1 –C 8 alkyl, preferably C 1 –C 6 alkyl, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, or benzyl, wherein the rings of the cycloalkyl and benzyl groups may be optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, —O—C 1 –C 6 perfluoroalkyl, C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, preferably —CF 3 , C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, hydroxy, —NH 2 , or —NO 2 ;
R 4 , R 5 and R 6 are each independently hydrogen, phenyl, halogen, C 1 –C 3 alkyl, C 1 –C 3 perfluoroalkyl, —O—C 1 –C 3 perfluoroalkyl, C 1 –C 3 alkoxy, —OH, —NH 2 , or —NO 2 ; or a pharmaceutically acceptable salt or ester form thereof.
5. A compound of claim 1 that is of formula VI:
wherein:
R 1 is C 1 –C 8 alkyl, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, or benzyl, wherein the rings of the cycloalkyl and benzyl groups may be optionally substituted by from 1 to 3 groups selected from halogen, C 1 –C 6 alkyl, C 1 –C 6 perfluoroalkyl, preferably —CF 3 , —O—C 1 –C 6 perfluoroalkyl, preferably —O—CF 3 , C 1 –C 6 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is hydrogen, halogen, C 1 –C 6 alkyl, C 1 –C 3 perfluoroalkyl, preferably —CF 3 , C 1 –C 6 alkoxy, C 3 –C 6 cycloalkyl, —CH 2 —C 3 –C 6 cycloalkyl, hydroxy, —NH 2 , or —NO 2 ; and
R 4 , R 5 and R 6 are each independently hydrogen, halogen, C 1 –C 3 alkyl, C 1 –C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 –C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 –C 3 alkoxy, —OH, —NH 2 , or —NO 2 ; or a pharmaceutically acceptable salt or ester form thereof.
6. The compound of claim 1 which is 9-(4-Methylbenzyl)-6-[4-(trifluoromethoxy)phenyl]-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
7. The compound of claim 1 which is 9-Benzyl-6-[4-(trifluoromethoxy)phenyl]-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
8. The compound of claim 1 which is 9-(4-Methylbenzyl)-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-b]indole-3,3-dione or a pharmaceutically acceptable salt or ester form thereof.
9. The compound of claim 1 which is 9-(4-tert-butylbenzyl)-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
10. The compound of claim 1 which is 6-(Benzyloxy)-9-(4-methylbenzyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
11. The compound of claim 1 which is 6-(Benzyloxy)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
12. The compound of claim 1 which is 6-(Benzyloxy)-9-(4-tertbutylbenzyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
13. The compound of claim 1 which is 9-(4-tertbutybenzyl)-6-hydroxy-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
14. The compound of claim 1 which is 9-benzyl-6-(4-Chlorophenyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
15. The compound of claim 1 which is 9-benzyl-6-(3-Methylphenyl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
16. The compound of claim 1 which is 9-benzyl-6-(1-1-bi-phenyl-4-yl)-1,9-dihydropyrano[3,4-b]indole-3,4-dione or a pharmaceutically acceptable salt or ester form thereof.
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutical carrier.
18. A method for treatment of thrombosis or fibrinolytic impairment in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 .
19. A method of claim 18 wherein the thrombosis or fibrinolytic impairment is associated with formation of atherosclerotic plaques, venous and arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, coagulation syndromes, pulmonary fibrosis, cerebral thrombosis, thromboembolic complications of surgery or peripheral arterial occlusion.