Isoquinoline compounds

Abstract

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 a substituted or unsubstituted isoquinoline radical wherein the isoquinoline radical may be mono- or disubstituted with halogen, cyano, nitro, or C 1 -C 4  alkyl;
 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 O; 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 1 , wherein A is an unsubstituted isoquinoline radical and R 1 , R 3 , and R 5  are hydrogen. 
   
   
       4 . A compound according to  claim 1 , wherein R 1 , R 2 , R 3 , and R 5  are hydrogen and R 4  is —O—R 7 . 
   
   
       5 . A compound according to  claim 1 , wherein R 4  is carbonylamino, sulfylamino, acyl, or carboxyl. 
   
   
       6 . A compound according to  claim 1 , wherein R 1 , R 2 , and R 5  are H and one of R 3  and R 4  is carbonylamino, sulfylamino, acyl, or carboxyl. 
   
   
       7 . 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, 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 O; and 
 R 6′  is CH 2  or CH(C 1 -C 4  alkyl). 
 
   
   
       8 . A compound according to  claim 7 , wherein R 1′ , R 2′ , R 3′ , and R 5′  are hydrogen and R 4′  is —O—R 7′ . 
   
   
       9 . A compound according to  claim 7 , wherein R 4′  is carbonylamino, sulfylamino, acyl, or carboxyl. 
   
   
       10 . A compound according to  claim 9 , 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 . 
   
   
       11 . A compound according to  claim 7 , wherein R 1′ , R 2′ , and R 5′  are H and one of R 3′  and R 4′  is carbonylamino, sulfylamino, acyl, or carboxyl. 
   
   
       12 . A compound according  claim 7 , wherein R 2′  or R 4′  is —O—R 7′ . 
   
   
       13 . A compound according to  claim 12 , wherein R 7′  is methyl, ethyl, phenyl, benzyl, propyl, or isopropyl. 
   
   
       14 . A method for influencing the action of a G-protein-coupled receptor kinase in a cell comprising administering to or contacting with the cell at least one compound according to  claim 7 , or reducing GPCR desensitization in a cell comprising administering to or contacting with the cell a therapeutically effective amount of a compound according to  claim 7 , or inhibiting the action of a G-protein-coupled receptor kinase comprising applying to a medium or contacting with a cell an effective inhibitory amount of a compound according to  claim 7 . 
   
   
       15 . The method according to  claim 14 , wherein R 1′ , R 3′ , and R 5′  are hydrogen. 
   
   
       16 . The method according to  claim 14 , wherein R 2′  or R 4′  is —O—R 7′ . 
   
   
       17 . The method according to  claim 14 , wherein R 7′  is methyl, ethyl, phenyl, benzyl, propyl, or isopropyl. 
   
   
       18 . The method according to  claim 14 , wherein R 2′  or R 4′  is carbonylamino. 
   
   
       19 . The method according to  claim 18 , wherein the carbonylamino moiety is selected from C(O)NHphenyl, C(O)NY-m-pyridyl, C(O)NY-o-pyridyl, C(O)NY-p-pyridyl, C(O)NH 2 , or C(O)NHCH 3 . 
   
   
       20 . The method according to  claim 14 , wherein the G-protein-coupled receptor kinase is GRK-2, GRK-3, GRK-5, or GRK-6. 
   
   
       21 . The method according to  claim 14 , wherein the G-protein-coupled receptor kinase is GRK-2. 
   
   
       22 . A pharmaceutical composition comprising:
 (a) a compound according to  claim 7 ; and   (b) a carrier.   
   
   
       23 . The composition of  claim 22 , wherein the carrier is selected from the group consisting of systemic and topical carriers. 
   
   
       24 . The composition of  claim 22 , wherein the composition comprises about 0.01% to 10% of the isoquinoline derivative and about 90 to 99.99% of the systemic carrier. 
   
   
       25 . A method of treating a condition comprising administering to a subject in need of treatment a safe and effective amount of an isoquinoline derivative, wherein the condition is selected from the group consisting of eye disease, bone disorder, heart disease, hepatic disease, renal disease, pancreatitis, cancer, myocardial infarct, gastric disturbance, hypertension, fertility control, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, and dermatological disorder, wherein the isoquinoline derivative is a compound according to  claim 1 . 
   
   
       26 . The method of  claim 25 , wherein the condition comprises eye disease. 
   
   
       27 . The method of  claim 26 , wherein the condition comprise glaucoma. 
   
   
       28 . The method of  claim 25 , wherein R 1 , R 2 , R 3 , R 4 , and R 5  are not phenoxy. 
   
   
       29 . The method of  claim 25 , wherein the isoquinoline derivative is 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 O; and 
 R 6  is CH 2  or CH(C 1 -C 4  alkyl).