Tricyclic derivatives of indole with antiangiogenic activity

Abstract

Compounds of the formula useful for treating tumors, particularly mammary carcinoma and colon carcinoma.

1 - 17 . (canceled)  
     
     
         18 . A method of treating a tumour pathology, in which the tumour is selected from the group consisting of sarcoma, carcinoma, carcinoid, bone tumour, neuroendocrine tumour, lymphoid leukemia, acute promyelocytic leukemia, myeloid leukemia, monocytic leukemia, megakaryoblastic leukemia and Hodgkin's disease, said method comprising administering to a subject a compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X═CH, N  
 X 1 ═O, S, N, CH  
 R and R 1 , which are the same or different, are selected from the group consisting of —H, OH, OR 5  in which R 5  is C 1 -C 4  alkyl or benzyl, when two groups OR 5  are vicinal R 5  is methylene; or R and R 1  are independently nitro; amino optionally mono- or di-substituted with C 1 -C 4  alkyl; carboxy; or alkoxy (C 1 -C 4 ) carbonyl;  
 R and R 1  taken together form an aliphatic or aromatic cyclic group having 5 or 6 atoms;  
 provided that when X 1 ═N or CH, then R 2  is selected from the group consisting of —H, phenyl, benzyl, linear or branched C 1 -C 6  alkyl;  
 n=is an integer of 0 to 4;  
 R 3 , which is the same as or different from R 4 , is —H, —OH, —OR 6 , wherein R 6  is linear or branched C 1 -C 4  alkyl, or when R 3 ═R 4 ═OR 6  vicinal, R 6  is isopropylidene  
                     
 R 7 ═C 1 -C 4  linear or branched alkyl optionally substituted with one or two groups OH, OR 6 , in case of 2 groups OR 6  vicinal, R 6  is isopropylidene; or R 7  is formyl (CHO), oxime (CH═NOH), their isomers and their mixtures.  
 
     
     
         19 . A method of treating tumour metastases; arthritic disease; diabetic retinopathy; psoriasis; chronic inflammatory diseases and arteriosclerosis, comprising administering to a subject a compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X═CH, N  
 X 1 ═O, S, N, CH  
 R and R 1 , which are the same or different, are selected from the group consisting of —H, OH, OR 5  in which R 5  is C 1 -C 4  alkyl or benzyl, when two groups OR 5  are vicinal R 5  is methylene; or R and R 1  are independently nitro; amino optionally mono- or di-substituted with C 1 -C 4  alkyl; carboxy; or alkoxy (C 1 -C 4 ) carbonyl;  
 R and R 1  taken together form an aliphatic or aromatic cyclic group having 5 or 6 atoms;  
 provided that when X 1 ═N or CH, then R 2  is selected from the group consisting of —H, phenyl, benzyl, linear or branched C 1 -C 6  alkyl;  
 n=is an integer of 0 to 4;  
 R 3 , which is the same as or different from R 4 , is —H, —OH, —OR 6 , wherein R 6  is linear or branched C 1 -C 4  alkyl, or when R 3 ═R 4 ═OR 6  vicinal, R 6  is isopropylidene  
                     
 R 7 ═C 1 -C 4  linear or branched alkyl optionally substituted with one or two groups OH, OR 6 , in case of 2 groups OR 6  vicinal, R 6  is isopropylidene; or R 7  is formyl (CHO), oxime (CH═NOH), their isomers and their mixtures.  
 
     
     
         20 . The method of  claim 18 , wherein an anticancer drug is also administered.  
     
     
         21 . The method of  claim 20  in which the anticancer drug is selected from the group consisting of alkylating agents, topoisomerase inhibitors, antitubulin agents, intercalating compounds, anti-metabolites, natural products such as vinca alkaloids, epipodophyllotoxins, antibiotics, enzymes, taxans, cyto-differentiating and anti-angiogenic compounds.  
     
     
         22 . The method of  claim 20 , in which the compound and the anticancer drug are administered simultaneously or sequentially.  
     
     
         23 . A method of treating mammary carcinoma or colon carcinoma comprising administering to a subject in need thereof a compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X═CH, N  
 X 1 ═O, S, N, CH  
 R and R 1 , which are the same or different, are selected from the group consisting of —H, OH, OR 5  in which R 5  is C 1 -C 4  alkyl or benzyl, when two groups OR 5  are vicinal R 5  is methylene; or R and R 1  are independently nitro; amino optionally mono- or di-substituted with C 1 -C 4  alkyl; carboxy; or alkoxy (C 1 -C 4 ) carbonyl;  
 R and R 1  taken together form an aliphatic or aromatic cyclic group having 5 or 6 atoms;  
 provided that when X 1 ═N or CH, then R 2  is selected from the group consisting of —H, phenyl, benzyl, linear or branched C 1 -C 6  alkyl;  
 n=is an integer of 0 to 4;  
 R 3 , which is the same as or different from R 4 , is —H, —OH, —OR 6 , wherein R 6  is linear or branched C 1 -C 4  alkyl, or when R 3 ═R 4 ═OR 6  vicinal, R 6  is isopropylidene  
                     
 R 7 ═C 1 -C 4  linear or branched alkyl optionally substituted with one or two groups OH, OR 6 , in case of 2 groups OR 6  vicinal, R 6  is isopropylidene; or R 7  is formyl (CHO), oxime (CH═NOH), their isomers and their mixtures.  
 
     
     
         24 . A method of treating mammary carcinoma or colon carcinoma comprising administering to a subject in need thereof a compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X═CH  
 X 1 ═N  
 R and R 1 , which are the same or different, are selected from the group consisting of —H, OH, OR 5  in which R 5  is C 1 -C 4  alkyl or benzyl, when two groups OR 5  are vicinal R 5  is methylene; or R and R 1  are independently nitro; amino optionally mono- or di-substituted with C 1 -C 4  alkyl; carboxy; or alkoxy (C 1 -C 4 ) carbonyl;  
 R and R 1  taken together form an aliphatic or aromatic cyclic group having 5 or 6 atoms;  
 R 2  is selected from the group consisting of —H, phenyl, benzyl, linear or branched C 1 -C 6  alkyl;  
 n=is an integer of 0 to 4;  
 R 3 , which is the same as or different from R 4 , is —H, —OH, —OR 6 , wherein R 6  is linear or branched C 1 -C 4  alkyl, or when R 3 ═R 4 ═OR 6  vicinal, R 6  is isopropylidene  
                     
 R 7 ═C 1 -C 4  linear or branched alkyl optionally substituted with one or two groups OH, OR 6 , in case of 2 groups OR 6  vicinal, R 6  is isopropylidene; or R 7  is formyl (CHO), oxime (CH═NOH), their isomers and their mixtures.