Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

1 - 32 . (canceled) 
     
     
         33 . A process for preparing 2-(9H-carbazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide (7): 
       
         
           
           
               
               
           
         
         the process comprising
 contacting ethyl 2,4-difluorobenzoate and 4-hydroxycarbazole to produce ethyl 2-(9H-carbazol-4-yloxy)-4-fluorobenzoate (7A): 
 
       
       
         
           
           
               
               
           
         
         
           contacting 7A with 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (3E) to produce ethyl 2-(9H-carbazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate (7B): 
         
       
       
         
           
           
               
               
           
         
         
           mixing 7B in a solution comprising dioxane and NaOH, followed by adding water and HCl to the solution, and extracting from the solution a HCl salt of 2-(9H-carbazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid (7C); 
           mixing 7C and 4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide (4A): 
         
       
       
         
           
           
               
               
           
         
         with a coupling agent and a first base to produce 7. 
       
     
     
         34 . The process of  claim 33 , wherein the coupling agent is selected from the group consisting of 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 1,1′-carbonyldiimidazole, and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate. 
     
     
         35 . The process of  claim 33 , wherein the coupling agent is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride. 
     
     
         36 . The process of  claim 33 , wherein the first base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof. 
     
     
         37 . The process of  claim 33 , wherein the first base is 4-(dimethylamino)pyridine. 
     
     
         38 . The process of  claim 33 , wherein the coupling agent is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, and the first base is 4-(dimethylamino)pyridine. 
     
     
         39 . The process of  claim 33  further comprising contacting 4-fluoro-3-nitrobenzenesulfonamide with 4-amino-N-methylpiperidine and triethylamine in tetrahydrofuran to produce 4A.