Ortho-substituted anthranilic acid amides and their use as pharmaceutical agents

Abstract

Ortho-substituted anthranilic acid amides and use thereof as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis are described.

1 - 7 . (canceled)  
     
     
         8 . A pharmaceutical composition which comprises at least one compound of the following formula I in an amount effective to inhibit the KDR and/or FLT tyrosine kinases:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is:  
                     
  in which: 
 R 4  is fluorine, chlorine, bromine, —CF 3 , —C≡N, CH 3 —, —OCF 3  or —CH 2 OH,  
 R 5  is chlorine, bromine or OCH 3 ,  
 R 6  is —CH 3  or chlorine,  
 R 7  is CH 3  or chlorine,  
 R 8  is CH 3 , fluorine, chlorine, or CF 3 , and  
 the * indicates the point of attachment of the R 1  group;  
 
 R 2  is pyridyl or the group  
                     where the * indicates the point of attachment of the R 2  group, and    
 R 3  is hydrogen or fluorine;  
 or a pharmaceutically acceptable salt of a compound of formula I.  
 
     
     
         9 . A pharmaceutical composition of  claim 8 , which is useful for treating: a tumor; psoriasis; arthritis; an eye disease; a renal disease; a fibrotic disease; or for inhibiting the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after mechanical devices are used to keep vessels open.  
     
     
         10 . A method for treating a disease or condition effected by inhibition of the KDR and/or FLT tyrosine kinases, which comprises administering to a patient in need thereof a pharmaceutical composition comprising a compound of the formula I:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is:  
                     
  in which: 
 R 4  is fluorine, chlorine, bromine, —CF 3 , —C≡N, CH 3 —, —OCF 3  or —CH 2 OH,  
 R 5  is chlorine, bromine or OCH 3 ,  
 R 6  is —CH 3  or chlorine,  
 R 7  is CH 3  or chlorine,  
 R 8  is CH 3 , fluorine, chlorine, or CF 3 , and  
 the * indicates the point of attachment of the R 1  group;  
 
 R 2  is pyridyl or the group  
                     where the * indicates the point of attachment of the R 2  group, and    
 R 3  is hydrogen or fluorine;  
 or a pharmaceutically acceptable salt of a compound of formula I.  
 
     
     
         11 . The method of  claim 10 , wherein the pharmaceutical composition is administered by enteral, parenteral and oral administration.  
     
     
         12 . The method of  claim 10 , wherein the disease or condition is: a tumor; psoriasis; arthritis; an eye disease; a renal disease; a fibrotic disease; the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after mechanical devices are used to keep vessels open.  
     
     
         13 . The method of  claim 10 , wherein the growth or propagation of tumors is prevented.  
     
     
         14 . The method of  claim 10 , wherein the disease or condition is: rheumatoid arthritis; hemangioma; angiofibroma; diabetic retinopathy; neovascular glaucoma; glomerulonephritis; diabetic nephropathy; malignant nephrosclerosis; thrombic microangiopathic syndrome; transplant rejection; glomerulopathy; cirrhosis of the liver; a mesangial cell proliferative disease; arteriosclerosis; a nerve tissue injury; or, the reocclusion of vessels associated with use of a stent to keep vessels open.  
     
     
         15 . The method of  claim 10 , wherein the compound of formula I is administered in a daily dose of 0.5 to 2000 mg.  
     
     
         16 . The method of  claim 13 , wherein the compound of formula I is administered in a daily dose of 50 to 1000 mg.  
     
     
         17 . A composition of  claim 8 , wherein the compound of formula I is selected from the group consisting of: 
 N-[2-oxo-2H-1-benzopyran-3-yl-]-2-[(4-pyridyl)methyl]amino-benzoic acid amide,    N-(6-chloroindazol-5-yl)-2-[(4-pyridyl)methyl]amino-benzoic acid amide, and 
 the compounds of formula I wherein R 1 , R 2  and R 3  are as follows:  
                                 R 1     R 2     R 3                                                 4-pyridyl   H                                                       H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-Pyridyl   F                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   F                                                       H                                                                                        
 where the * indicates the point of attachment of the R 1  group.  
   
     
     
         18 . The method of  claim 10 , wherein the compound of formula I is selected from the group consisting of: 
 N-[2-oxo-2H-1-benzopyran-3-yl-]-2-[(4-pyridyl)methyl]amino-benzoic acid amide,    N-(6-chloroindazol-5-yl)-2-[(4-pyridyl)methyl]amino-benzoic acid amide, and 
 the compounds of formula I wherein R 1 , R 2  and R 3  are as follows:  
                                 R 1     R 2     R 3                                                 4-pyridyl   H                                                       H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   F                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   H                                 4-pyridyl   F                                                       H                                                                                        
 where the * indicates the point of attachment of the R 1  group.