Dual mechanism inhibitors for the treatment of disease

Abstract

Provided are compounds that are inhibitors of both rho kinase and of a monoamine transporter (MAT) act to improve the disease state or condition. Further provided are compositions comprising the compounds. Further provided are methods for treating diseases or conditions, the methods comprising administering compounds according to the invention. One such disease may be glaucoma for which, among other beneficial effects, a marked reduction in intraocular pressure (IOP) may be achieved.

What is claimed is: 
     
         1 . A compound according to Formula II: 
       
         
           
           
               
               
           
         
       
       and salts thereof,
 wherein R 1 , R 2 , and R 3  are independently hydrogen, C 1 -C 4  alkyl, aryl, C 1 -C 4  alkyl aryl, C 1 -C 4  alkyl heteroaryl, C 1 -C 4  alkyl heterocyclyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 1 -C 4  carbonyl, C 1 -C 4  carbonylamino, C 1 -C 4  alkoxy, C 1 -C 4  sulfonyl, C 1 -C 4  sulfonylamino, C 1 -C 4  thioalkyl, C 1 -C 4  carboxyl, or form a ring with each other or with A; 
 wherein A is C 1 -C 4  alkyl, or forms a ring structure with R 1 , R 2 , or R 3 ; 
 wherein B is hydrogen, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 22  alkyl, C 1 -C 22  alkyl aryl, C 1 -C 22  alkyl heteroaryl, C 2 -C 22  alkenyl, C 2 -C 22  alkynyl, C 1 -C 22  carbonyl, C 1 -C 22  carbonylamino, C 1 -C 22  alkoxy, C 1 -C 22  sulfonyl, C 1 -C 22  sulfonylamino, C 1 -C 22  thioalkyl, or C 1 -C 22  carboxyl; 
 wherein X 1 , X 2 , and X 3  are, independently, hydrogen, hydroxyl, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, amino, aminocarbonyl, nitro, cyano, C 1 -C 4  carbonyl, C 1 -C 4  carbonylamino, C 1 -C 4  alkoxy, C 1 -C 4  sulfonyl, C 1 -C 4  sulfonylamino, C 1 -C 4  thioalkyl, or C 1 -C 4  carboxyl; 
 wherein the double circle 
 
       
         
           
           
               
               
           
         
       
       indicates an aromatic or heteroaromatic ring; and
 wherein each Z is independently a bond, C 1 -C 4  alkyl, heteroalkyl, or an O atom. 
 
     
     
         2 . A compound according to  claim 1 , wherein R 1  is hydrogen or C 1 -C 4  alkyl; B is C 1 -C 22  carbonyl; X 1 , X 2 , and X 3  are hydrogen; the double circle 
       
         
           
           
               
               
           
         
       
       indicates an aromatic or heteroaromatic ring; and Z is a bond, C 1 -C 4  alkyl, C 1 -C 4  heteroalkyl, or an O atom. 
     
     
         3 . A compound according to  claim 1 , wherein Z is a bond or —CH 2 —. 
     
     
         4 . A compound according to  claim 1 , wherein X 1 , X 2  and X 3  are each hydrogen. 
     
     
         5 . A compound according to  claim 1 , wherein A is —CH 2 CH 2 —. 
     
     
         6 . A compound according to  claim 1 , wherein R 1  and R 2  are independently hydrogen or methyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 3  is hydrogen or C 1 -C 4  alkyl. 
     
     
         8 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         9 . A method for treating a disease in a subject comprising:
 administering to a subject an effective amount of a compound according to  claim 1 ; wherein the disease comprises eye disease.   
     
     
         10 . The method of  claim 9 , wherein the eye disease comprises glaucoma or a neurodegenerative eye disease. 
     
     
         11 . A method of modulating kinase activity comprising:
 contacting a cell with a compound according to  claim 1  in an amount effective to modulate kinase activity.   
     
     
         12 . The method of  claim 11 , wherein the cell is in a subject. 
     
     
         13 . A method of reducing intraocular pressure comprising:
 contacting a cell with a compound according to  claim 1  in an amount effective to reduce intraocular pressure.   
     
     
         14 . The method of  claim 13 , wherein the cell is in a subject.