Substituted 11-phenyl-dibenzazepine compounds useful for the treatment or prevention of diseases characterized by abnormal cell proliferation

Abstract

The present invention provides substituted 11-phenyl-dibenzazepine compounds which are specific, potent and safe inhibitors of mammalian cell proliferation. The compounds can be used to inhibit mammalian cell proliferation in situ as a therapeutic approach towards the treatment or prevention of diseases characterized by abnormal cell proliferation, such as cancer.

What is claimed is:  
     
         1 . A process for preparing a compound having the formula:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein: 
 R 1  is —R′, (C 6 -C 20 ) aryl or substituted (C 6 -C 20 ) aryl;  
 R 2  is —R′, —OR′, —SR′, halogen or trihalomethyl;  
 R 3  is —R′, —OR′, —SR′, halogen or trihalomethyl or, when taken together with R 4 , is (C 6 -C 20 ) aryleno;  
 R 4  is —R′, —OR′, —SR′, halogen or trihalomethyl or, when taken together with R 3 , is (C 6 -C 20 ) aryleno;  
 each of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13  and R 14  is independently selected from the group consisting of —R′, halogen and trihalomethyl;  
 R 15  is —R″, —C(O)R″, —C(S)R″, —C(O)OR″, —C(S)OR″, —C(O)SR″, —C(S)SR″, —C(O)N(R″) 2 , —C(S)N(R″) 2 , —C(O)C(O)R″ —C(S)C(O)R″, —C(O)C(S)R″, —C(S)C(S)R″, —C(O)C(O)OR″, —C(S)C(O)OR″, —C(O)C(S)OR″, —C(O)C(O)SR″, —C(S)C(S)OR″, —C(S)C(O)SR″, —C(O)C(S)SR″, —C(S)C(S)SR″, —C(O)C(O)N(R″) 2 , —C(S)C(O)N(R″) 2 , —C(O)C(S)N(R″) 2  or —C(S)C(S)N(R″) 2 ;  
 each R′ is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl and (C 2 -C 6 ) alkynyl;  
 each R″ is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 20 ) aryl, (C 6 -C 20 ) substituted aryl, (C 6 -C 26 ) alkaryl and substituted (C 6 -C 26 ) alkaryl; and  
 the aryl and alkaryl substituents are each independently selected from the group consisting of —CN, —OR′, —SR′, —NO 2 , —NR′R′, halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl and trihalomethyl,  
 with the provisos that when R 1  and R 15  are each —H, at least one of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13  or R 14  is other than —H, R 8  is other than —H or —Cl and at least three of R 2 , R 3 , R 4  and R 5  are other than —OCH 3 ; when R 1 -R 7  and R 9 -R 14  are —H, and R 8  is —H or —Cl, then R 15  is other than —H or —CH 3 ; when R 1 -R 7  and R 9 -R 14  are —H and R 8  is —F or —I or —Br, then R 15  is other than —H; when R 1  and R 6 -R 15  are —H, then three of R 2 , R 3 , R 4 , and R 5  are not —OCH 3  at the same time; when R 1 -R 5 , R 8  and R 10 -R 15  are —H, then at least one of R 6 , R 7  or R 9  is other than —Cl; when R 1  and R 5 -R 14  are —H, and R 15  is —CH 3 , then R 2 , R 3  and R 4  are not —OCH 3  at the same time; said method comprising: 
 a) cyclizing a diphenyl methanol compound according to Formula II:  
                     
  under acidic conditions; and optionally  
 b) if R 15  is hydrogen, said method further comprising a step for derivatizing the nitrogen of the azepine ring.  
 
 
       
     
     
         2 . The method of  claim 1  wherein said acidic conditions comprise one or more compounds selected from the group of sulfuric acid, acetic acid, methanesulfonic acid and phosphorus pentoxide.  
     
     
         3 . The method of  claim 1  wherein the derivatizing step comprises reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 14  are defined as above, with an acylating agent having the formula R″C(O)X, wherein X is Br, Cl or I and R″ is defined as above.  
     
     
         4 . The method of  claim 1  wherein the derivatizing step comprises reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 4  are defined as above, with an alkylating agent having the formula R″X, wherein X is Br, Cl or I and R″ is defined as above.  
     
     
         5 . The method of  claim 1  wherein the derivatizing step comprises reacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 4  are defined as above, with a chloroformate reagent of the formula:  
       
         
           
           
               
               
           
         
       
       wherein X is Br or Cl and R″ is defined as above.