Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs

Abstract

The present invention comprises a group of compounds that effectively inhibit angiogenesis. More specifically, nitrogen-substituted thalidomide analogs and di-substituted thalidomide analogs have been shown to inhibit angiogenesis. Importantly, these compounds can be administered orally.

1 . A method of treating undesired angiogenesis in a human or animal comprising the step of administering to the human or animal a composition comprising an effective amount of an angiogenesis-inhibiting compound selected from the following compounds:  
     
       
         
         
             
             
         
       
     
     or combinations thereof, wherein: 
 R 1  is independently selected from —H, —OH, —CH 3 , —CH 2 OZ (ethers), —CH 2 OCOZ (esters), —CH 2 OCONZ (carbamates), or —CH 2 Z (alkyls), wherein Z is selected from H or —(CH 2 ) n —H, where n is 1-10);  
 R 2  is independently selected from —NH—NH 2  hydrazine), —NH—OH (hydroxalamine), —NH—OR 3 , —N═N—R 3 , —NH 2 , —N(R 3 ) 2 , —NHCOH, —NHCOCH 3 , pyrazolidine, pyrazoline, tetrazole, imidazole, pyrazole, piprazine, or imidazoline; and  
 R 3  is independently selected from pyrazolidine, pyrazoline, tetrazole, imidazole, pyrazole, piprazine, or imidazoline.  
 
   
   
       2 . The method of  claim 1 , wherein the compound has the following formula:  
     
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 1 , wherein the compound has the following formula:  
     
       
         
         
             
             
         
       
     
   
   
       4 . The method of  claim 1 , wherein the compound has the following formula:  
     
       
         
         
             
             
         
       
     
   
   
       5 . The method of  claim 1 , wherein the undesired angiogenesis is associated with retinal/choroidal neovascularization.  
   
   
       6 . The method of  claim 5 , wherein the retinal/choroidal newvascularization is associated with diabetic retinopathy.  
   
   
       7 . The method of  claim 5 , wherein the retinal/choroidal newvascularization is associated with macular degeneration.  
   
   
       8 . The method of  claim 1 , wherein the undesired angiogenesis is associated with corneal neovascularization.  
   
   
       9 . The method of  claim 1 , wherein the compound is delivered in a pharmaceutically acceptable carrier.  
   
   
       10 . A method of treating undesired angiogenesis in a human or animal comprising the step of administering to the human or animal a composition comprising an effective amount of an angiogenesis-inhibiting compound selected from the following compound:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is selected from  
                     
 or —CH 2 —;  
 R 2  is independently selected from —NH—NH 2  hydrazine), —NH—OH (hydroxalamine), —NH—OR 3 , —N═N—R 3 , —NH 2 , —N(R 3 ) 2 , —NHCOH, —NHCOCH 3 , pyrazolidine, pyrazoline, tetrazole, imidazole, pyrazole, piprazine, or imidazoline;  
 R 3  is independently selected from pyrazolidine, pyrazoline, tetrazole, imidazole, pyrazole, piprazine, or imidazoline; and  
 R 4 , R 5 , and R 6  may be the same or different and are independently selected from —NH 2 , —OH, —CH 3 , —H, —OCH 3 , —O(CH 2 ) m —H, where m is 1-7, —Cl, —Br, —F, —I, —CH 2 OCONZ (carbamates), —CH 2 Z (alkyls), —CH 2 OZ (ethers), —CH 2 OCOZ (esters), wherein Z is selected from H or —(CH 2 ) n —H, where n is 1-10, —NH—NH 2  (hydrazine), —NH—OH (hydroxalamine), —NH—OR 3 , N═N—R 3 , —N(R 3 ) 2 , —NHCOH, —NHCOCH 3 , pyrazolidine, pyrazoline, tetrazole, imidazole, pyrazole, piprazine, or imidazoline.  
 
   
   
       11 . The method of  claim 1 , wherein the compound comprises 34-diamino-thalidomide.  
   
   
       12 . The method of  claim 10 , wherein the undesired angiogenesis is associated with retinal/choroidal neovascularization.  
   
   
       13 . The method of  claim 12 , wherein the retinal/choroidal newvascularization is associated with diabetic retinopathy.  
   
   
       14 . The method of  claim 12 , wherein the retinal/choroidal newvascularization is associated with macular degeneration.  
   
   
       15 . The method of  claim 10 , wherein the undesired angiogenesis is associated with corneal neovascularization.  
   
   
       16 . The method of  claim 10 , wherein the compound is delivered in a pharmaceutically acceptable carrier.