Methylphenidate derivatives and uses of them

Abstract

The present invention provides methods of using compounds of formula I: and salts and prodrugs thereof, wherein n, R 1 and R 2 are defined herein. The invention also provides certain novel compounds of formula I and pharmaceutical compositions comprising them.

1 . A method of inhibiting angiogenesis in an animal comprising administering to the animal an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       or a salt or a prodrug thereof,  
       where 
 n is an integer from 1 to 5,  
 each R 1  is independently aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, aryloxy, acyl, carboxyl, hydroxyl, halogen, amino, nitro, sulfo or sulfhydryl, wherein  
 each alkyl is optionally substituted with hydroxyl, amino or sulfhydryl; and  
 R 2  is hydrogen or lower alkyl.  
 
     
   
   
       2 . A method of treating an angiogenic disease or condition in an animal comprising administering to the animal an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       or a salt or a prodrug thereof,  
       where 
 n is an integer from 1 to 5,  
 each R 1  is independently aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, aryloxy, acyl, carboxyl, hydroxyl, halogen, amino, nitro, sulfo or sulfhydryl, wherein  
 each alkyl is optionally substituted with hydroxyl, amino or sulfhydryl; and  
 R 2  is hydrogen or lower alkyl.  
 
     
   
   
       3 . A method of treating an ocular angiogenic disease or condition in an animal comprising administering to the animal an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       or a salt or a prodrug thereof,  
       where 
 n is an integer from 1 to 5,  
 each R 1  is independently aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, aryloxy, acyl, carboxyl, hydroxyl, halogen, amino, nitro, sulfo or sulfhydryl, wherein each alkyl is optionally substituted with hydroxyl, amino or sulfhydryl; and  
 R 2  is hydrogen or lower alkyl.  
 
     
   
   
       4 . The method of  claim 3  wherein the ocular angiogenic disease or condition is diabetic retinopathy.  
   
   
       5 . The method of  claim 3  wherein the ocular angiogenic disease or condition is macular degeneration.  
   
   
       6 . The method of  claim 3  wherein the ocular angiogenic disease or condition is retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias or rubeosis.  
   
   
       7 . A method of treating a neoplastic disease in an animal comprising administering to the animal an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       or a salt or a prodrug thereof,  
       where 
 n is an integer from 1 to 5,  
 each R 1  is independently aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, aryloxy, acyl, carboxyl, hydroxyl, halogen, amino, nitro, sulfo or sulfhydryl, wherein each alkyl is optionally substituted with hydroxyl, amino or sulfhydryl; and  
 R 2  is hydrogen or lower alkyl.  
 
     
   
   
       8 . The method of  claim 7  wherein the neoplastic disease is a tumor.  
   
   
       9 . The method of  claim 8  wherein the tumor is a malignant tumor.  
   
   
       10 . The method of  claim 9  wherein the tumor is a tumor of the bladder, brain, breast, cervix, colon, rectum, kidney, liver, lung, ovary, pancreas, prostate, stomach or uterus.  
   
   
       11 . The method of  claim 10  wherein the tumor is a tumor of the brain, breast, colon, liver or pancreas.  
   
   
       12 . The method of  claim 11  wherein the tumor is a tumor of the brain.  
   
   
       13 . The method of  claim 12  wherein the brain tumor is a glioblastoma.  
   
   
       14 . The method of  claim 7  wherein the neoplastic disease is tumor metastasis.  
   
   
       15 . A method of treating a proliferative disorder in an animal comprising administering to the animal an effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
       or a salt or a prodrug thereof,  
       where 
 n is an integer from 1 to 5,  
 each R 1  is independently aryl, heteroaryl, alkyl, cycloalkyl, alkoxy, aryloxy, acyl, carboxyl, hydroxyl, halogen, amino, nitro, sulfo or sulfhydryl, wherein each alkyl is optionally substituted with hydroxyl, amino or sulfhydryl; and  
 R 2  is hydrogen or lower alkyl.  
 
     
   
   
       16 . The method of  claim 15  wherein the proliferative disorder is a cancer.  
   
   
       17 . The method of  claim 16  wherein the cancer is a carcinoma, a sarcoma, a lymphoma or a leukemia.  
   
   
       18 . The method of  claim 15  wherein the proliferative disorder is a mesangial cell proliferation disorder.  
   
   
       19 . The method of  claim 15  wherein the proliferative disorder is a fibrotic disorder.  
   
   
       20 . The method of  claim 15  wherein the proliferative disorder is a hyperproliferative skin disorder.  
   
   
       21 . The method of  claim 20  wherein the the hyperproliferative skin disorder is skin cancer.  
   
   
       22 . The method of any one of claims  1 - 21  wherein the compound is:  
     
       
         
         
             
             
         
       
     
   
   
       23 . A compound of formula IA:  
     
       
         
         
             
             
         
       
       where 
 n is an integer from 1 to 5;  
 each R 1  is independently a moiety of the formula —C(O)—R 8 , —OR 7  or —C(O)—O—R 3 ;  
 R 2  is hydrogen or lower alkyl;  
 R 3  is hydrogen, alkyl, cycloalkyl or aryl;  
 R 7  is aryl; and  
 R 8  is cycloalkyl or aryl.  
 
     
   
   
       24 . The compound of  claim 23  wherein R 1  is a moiety of the formula —OR 7 .  
   
   
       25 . The compound of  claim 24  wherein R 7  is phenyl.  
   
   
       26 . The compound of  claim 23  wherein n is 1 or 2.  
   
   
       27 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and compound of formula IA or a salt or a prodrug thereof:  
     
       
         
         
             
             
         
       
       where 
 n is an integer from 1 to 5;  
 each R 1  is independently a moiety of the formula —C(O)—R 8 , —OR 7  or —C(O)—O—R 3 ;  
 R 2  is hydrogen or lower alkyl;  
 R 3  is hydrogen, alkyl, cycloalkyl or aryl;  
 R 7  is aryl; and  
 R 8  is cycloalkyl or aryl.  
 
     
   
   
       28 . The compound of  claim 27  wherein R 1  is a moiety of the formula —OR 7 .  
   
   
       29 . The compound of  claim 28  wherein R 7  is phenyl.  
   
   
       30 . The compound of  claim 27  wherein n is 1 or 2.