Isoquinoline compounds
View Patent ↗Isoquinoline compounds with G are provided that influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the isoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.
1. A compound according to Formula (I):
wherein A is an unsubstituted isoquinoline radical; wherein the isoquinoline radical has the formula
R 1 , R 2 , R 3 , R 4 , and R 5 are, independently, hydrogen; halogen; C 1 -C 8 alkyl; alkoxy; phenoxy, —OR 7 ; amino; nitro; cyano; aryl; C 1 -C 4 alkylaryl; heteroaryl; C 1 -C 4 alkyl heteroaryl; carbonylamino; thioalkyl; sulfonyl; sulfonylamino; acyl; or carboxyl;
R 7 is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X is
and
R 6 is CH 2 or CH(C 1 -C 4 alkyl).
2. A compound according to claim 1 wherein R 1 , R 2 , R 3 , R 4 , and R 5 are not phenoxy.
3. A compound according to claim 2 wherein X is
4. A compound according to claim 3 wherein R 1 , R 3 , and R 5 are hydrogen.
5. A compound according to claim 3 wherein R 1 , R 2 , R 3 , and R 5 are hydrogen and R 4 is —O—R 7 .
6. A compound according to claim 3 wherein R 4 is carbonylamino, sulfylamino, acyl or carboxyl.
7. A compound according to claim 3 wherein R 1 , R 2 ,and R 5 are H and one of R 3 and R 4 is carbonylamino, sulfylamino, acyl or carboxyl.
8. A compound according to Formula II:
wherein R 1′ , R 2′ , R 3′ , R 4′ , and R 5′ are, independently, hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; —O—R 7′ ; sulfonylamino; carboxyl; acyl; or thioalkyl;
R 7′ is C 1 -C 4 alkyl, aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl;
X′ is
and
R 6′ is CH 2 or CH(C 1 -C 4 alkyl).
9. A compound according to claim 8 wherein X′ is
10. A compound according to claim 8 wherein R 1′ , R 2′ , R 3′ , and R 5′ are hydrogen and R 4′ , is —O—R 7′ .
11. A compound according to claim 8 wherein R 4′ is carbonylamino, sulfylamino, acyl or carboxyl.
12. A compound according to claim 11 wherein R 4′ is carbonylamino, and the carbonylamino is C(O)NHphenyl, C(O)NH-m-pyridyl, C(O)NH-o-pyridyl, C(O)NH-p-pyridyl, C(O)NH 2 , or C(O)NHCH 3 .
13. A compound according to claim 8 wherein R 1′ , R 2′ , and R 5′ are H and one of R 3′ and R 4′ is carbonylamino, sulfylamino, acyl or carboxyl.
14. A compound according claim 9 wherein R 2′ or R 4′ is —O—R 7′ .
15. A compound according to claim 14 wherein R 7′ is methyl, ethyl, phenyl, benzyl, propyl or isopropyl.
16. A compound according to Formula III:
wherein R 8 and R 9 are independently hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; phenoxy, benzyloxy, —O—R 10 ; sulfonylamino; carboxyl; acyl; or thioalkyl; and
R 10 is unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl;, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 4 alkaryl or C 1 -C 4 alkheteroaryl.
17. A compound according to claim 16 wherein R 8 is carbonylamino, a carboxyl, a sulfonyl amino, a cyano, or an acyl moiety, and R 9 is selected from H, methyl, cyano, or halogen.
18. A compound according to claim 17 wherein R 8 is the carbonylamino, and the carbonylamino is C(O)NHphenyl, C(O)NH-m-pyridyl, C(O)NH-o-pyridyl, C(O)NH-p-pyridyl, C(O)NH 2 , and C(O)NHCH 3 .
19. A compound according to claim 17 wherein R 8 is the carboxyl and the carboxyl is C(O)O phenyl, C(O)O-m-pyridyl, C(O)O-o-pyridyl, C(O)O-p-pyridyl, C(O)NH 2 , or C(O)OCH 3 .
20. A compound according to claim 17 wherein R 8 is the sulfonyl amino, and the sulfonyl amino is S(O)2NHphenyl, S(O)2NH-m-pyridyl, S(O)2NH-o-pyridyl, S(O)2NH-p-pyridyl, S(O)2NH 2 , or S(O)2NHCH 3 .
21. A compound according to claim 16 wherein R 9 is a carbonylamino, a carboxyl, a sulfonyl amino, a cyano, or an acyl moiety, and R 8 is H, methyl, cyano, or halogen.
22. A compound according to claim 16 wherein R 8 is alkoxy, phenoxy, benzyloxy, or —O—R 10 and R 9 is H, methyl, cyano, or halogen.
23. A compound according to claim 16 wherein R 8 and R 9 are not phenoxy.
24. A pharmaceutical composition comprising:
a) an isoquinoline derivative having the structure
wherein R 8 and R 9 are independently hydrogen; halogen; unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl; amino; nitro; cyano; carbonylamino; alkoxy; phenoxy, benzyloxy, —O—R 10 ; sulfonylamino; carboxyl; acyl; or thioalkyl; and
R 10 is unsubstituted C 1 -C 4 alkyl; substituted C 1 -C 4 alkyl;, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 4 alkaryl or C 1 -C 4 alkheteroaryl; and
b) a carrier.
25. The composition of claim 24 , wherein the carrier is selected from the group consisting of systemic and topical carriers.
26. A compound selected from the following: