Therapeutic compounds

Abstract

The invention provides novel JAK-3 inhibitors that are useful for treating leukemia and lymphoma. The compounds are also useful to treat or prevent skin cancer, as well as sunburn and UVB-induced skin inflammation. In addition, the compounds of the present invention prevent the immunosuppressive effects of UVB radiation, and are useful to treat or prevent autoimmune diseases, inflammation, and transplant rejection. The invention also provides pharmaceutical compositions comprising compounds of the invention, as well as therapeutic methods for their use.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is HN, R 11 N, S, O, CH 2 , or R 11 CH;  
 R 11  is hydrogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkanoyl;  
 R 1 -R 8  are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo; wherein two adjacent groups of R 1 -R 5  together with the phenyl ring to which they are attached may optionally form a fused ring, for example forming a naphthyl or a tetrahydronaphthyl ring; and further wherein the ring formed by the two adjacent groups of R 1 -R 5  may optionally be substituted by 1, 2, 3, or 4 hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo; and  
 R 9  and R 10  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo, or (C 1 -C 4 )alkanoyl; or R 9  and R 10  together are methylenedioxy; or a pharmaceutically acceptable salt thereof;  
 provided the compound is not 4-(4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline.  
 
   
   
       2 . The compound of  claim 1  wherein X is R 11 N.  
   
   
       3 . The compound of  claim 1  wherein X is HN.  
   
   
       4 . The compound of  claim 1  wherein each of R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 10  is H.  
   
   
       5 . The compound of  claim 1  wherein R 3  is (C 1 -C 4 )alkoxy, hydroxy, nitro, halo, trifluoromethyl, or NR 12 R 13  wherein R 12  and R 13  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl, (C 1 -C 4 )alkynyl, (C 3 -C 8 )cycloalkyl, or heterocycle.  
   
   
       6 . The compound of  claim 1  wherein R 3  is hydroxy.  
   
   
       7 . The compound of  claim 1  wherein R 2  or R 3  is hydroxy.  
   
   
       8 . The compound of  claim 1  wherein R 2  or R 3  is hydroxy; and one of R 1 -R 5  is halo.  
   
   
       9 . The compound of  claim 1  wherein R 2  or R 3  is hydroxy.  
   
   
       10  The compound of  claim 1  wherein R 8  is (C 1 -C 4 )alkoxy.  
   
   
       11 . The compound of  claim 1  wherein R 9  is (C 1 -C 4 )alkoxy.  
   
   
       12 . The compound of  claim 1  which is 4-(3′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline; 4-(3′,5′-dibromo4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline or 4-(3′-bromo4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
   
   
       13 . A pharmaceutical composition comprising a compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is HN, R 11 N, S, O, CH 2 , or R 11 CH;  
 R 11  is hydrogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkanoyl;  
 R 1 -R 8  are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo; wherein two adjacent groups of R 1 -R 5  together with the phenyl ring to which they are attached may optionally form a fused ring, for example forming a naphthyl or a tetrahydronaphthyl ring; and further wherein the ring formed by the two adjacent groups of R 1 -R 5  may optionally be substituted by 1, 2, 3, or 4 hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo; and  
 R 9  and R 10  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo, or (C 1 -C 4 )alkanoyl; or R 9  and R 10  together are methylenedioxy; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.  
 
   
   
       14 . The composition of  claim 13  wherein R 2  or R 3  is hydroxy.  
   
   
       15 . The composition of  claim 13  wherein R 2  or R 3  is hydroxy; and one of R 1 -R 5  is halo.  
   
   
       16 . The composition of  claim 13  wherein the compound of formula I is 4-(3′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline; 4-(3′,5′-dibromo-4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline or 4-(3′-bromo-4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
   
   
       17 . A pharmaceutical composition comprising 4-(4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.  
   
   
       18 . A therapeutic method for treating leukemia or lymphoma in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       19 . A therapeutic method for treating or preventing organ transplant rejection in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       20 . A therapeutic method for preventing or reducing ultraviolet B radiation-induced inflammatory response in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       21 . A therapeutic method for inhibiting the release of prostaglandin E 2  in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       22 . A therapeutic method for preventing or reducing UVB-induced skin edema or vascular permeability changes in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       23 . A therapeutic method for preventing or reducing ultraviolet B radiation-induced damage to epithelial cells or mutation frequency in skin in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       24 . A therapeutic method for protecting a mammal from tumorigenic effects of UVB light comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       25 . A therapeutic method for inhibiting T-cell activity in a mammal comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       26 . A therapeutic method for preventing or treating an autoimmune disease comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       27 . A therapeutic method for preventing or treating graft-verses host disease comprising administering to the mammal in need thereof an effective amount of a JAK-3 inhibitor.  
   
   
       28 . The method of any one of claims  18 - 27  wherein the compound is a compound of  claim 1 .  
   
   
       29 . The method of any one of claims  18 - 27  wherein the JAK-3 inhibitor is 4-(4′-hydroxyl-phenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.