Processes and compounds for the preparation of substituted naphthylindole derivatives

Abstract

The present invention provides processes for the preparation of substituted naphthylindole derivatives that can be used as inhibitors of plasminogen activator inhibitor-1 (PAI-1). In certain embodiments of the invention, the processes involve reactions that include one or more of an Oppenauer oxidation, a Fischer indole synthesis, a methyl ether cleavage, or coupling a substituted methyltetrazole with a substituted naphthol.

1 . A process comprising reacting a compound of formula (6):  
       
         
           
           
               
               
           
         
         wherein  
         R 3 , and R 4  are each, independently, hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH 2 cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, aryl of 6 to 14 carbon atoms optionally substituted with 1 to 3 R 8  groups, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms; and  
         R 8  is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH 2 cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxy, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms;  
         with an alkylmagnesium halide or an arylmagnesium halide having the formula R 9 MgBr and further with a hydride acceptor to produce a compound of formula (5):  
         
           
             
             
                 
                 
             
           
         
         wherein  
         R 9  is —CH 2 —R 5 ; or  
         reacting a compound of formula (6) consecutively with an alkyllithium having the formula R 9 Li, a magnesium salt, and a hydride acceptor to produce a compound of formula (5).  
       
     
     
         2 . The process of  claim 1  wherein the alkylmagnesium halide is hexylmagnesium bromide (HxMgBr).  
     
     
         3 . The process of  claim 1  wherein the alkyllithium is hexyllithium.  
     
     
         4 . The process of  claim 1  wherein the magnesium salt is magnesium bromide, magnesium chloride, a magnesium sulfonate, or magnesium sulfate.  
     
     
         5 . The process of  claim 1  wherein the hydride acceptor is an optionally substituted dialkylaminobenzaldehyde or an optionally substituted aminocycloalkanone.  
     
     
         6 . The process of  claim 5  wherein the hydride acceptor is 1-methyl-4-piperidone (MPP).  
     
     
         7 . The process of  claim 1  wherein the compound of formula (5) is produced by a process comprising reacting a compound of formula (6) with an alkylmagnesium halide or an arylmagnesium halide having the formula R 9 MgBr and further with a hydride acceptor.  
     
     
         8 . The process of  claim 1  further comprising reacting a compound of formula (5) with a substituted hydrazine having the formula  
       
         
           
           
               
               
           
         
         to produce a compound of formula (4):  
         
           
             
             
                 
                 
             
           
         
         wherein  
         R 1 , and R 2  are each, independently, hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH 2 cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, aryl of 6 to 14 carbon atoms optionally substituted with 1 to 3 R 8  groups, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms;  
         R 5  is hydrogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, aryl of 6 to 14 carbon atoms optionally substituted with 1 to 3 R 8  groups, alkanoyl of 2 to 7 carbon atoms, or aroyl of 7 to 15 carbon atoms optionally substituted with 1 to 3 R 8  groups; and  
         R 6  is hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 8 to 20 carbon atoms, benzyl optionally substituted with 1 to 3 R 8  groups, alkanoyl of 2 to 7 carbon atoms, or aroyl of 7 to 15 carbon atoms optionally substituted with 1 to 3 R 8  groups.  
       
     
     
         9 . The process of  claim 8  wherein the substituted hydrazine is 1-benzyl-1-phenylhydrazine hydrochloride (BPH).  
     
     
         10 . The process of  claim 8  further comprising reacting a compound of formula (4) with an ether demethylating agent to produce a compound of formula (2):  
       
         
           
           
               
               
           
         
       
     
     
         11 . The process of  claim 10  wherein the ether demethylating agent is boron tribromide (BBr 3 ).  
     
     
         12 . The process of  claim 10  further comprising reacting a compound of formula (2) with a compound of formula (3):  
       
         
           
           
               
               
           
         
         wherein  
         X is a leaving group;  
         R 7  is hydrogen, alkyl of 1 to 6 carbon atoms, alkylaryl of 7 to 20 carbon atoms, or aryl of 6 to 14 carbon atoms optionally substituted with 1 to 3 R 8  groups; and  
         n is an integer from 0 to 6;  
         and an inorganic or organic base to produce a compound of formula (1):  
         
           
             
             
                 
                 
             
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         13 . The process of  claim 12  wherein X is a halogen or a sulfonate.  
     
     
         14 . The process of  claim 12  wherein the compound of formula (3) is 5-chloromethyl-1H-tetrazole (CMT).  
     
     
         15 . The process of  claim 14  further comprising reacting the 5-chloromethyl-1H-tetrazole (CMT) with 3,4-dihydro-3H-pyran (DHP) and pyridinium p-toluene sulfonate (PPTS) to produce tetrahydropyran (THP) protected 5-chloromethyl-1H-tetrazole (CMT) prior to reaction with the compound of formula (2).  
     
     
         16 . The process of  claim 12  wherein the inorganic or organic base is an alkaline carbonate, an alkaline earth metal carbonate, an alkaline hydroxide, an alkaline earth metal hydroxide, an amine, a phosphine, or an anion exchange resin.  
     
     
         17 . The process of  claim 16  wherein the alkaline carbonate is lithium carbonate, potassium carbonate, cesium carbonate, or sodium carbonate.  
     
     
         18 . A process comprising 
 (a) reacting a compound of formula (6):                          wherein    R 3 , and R 4  are each, independently, hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH 2 cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, aryl of 6 to 14 carbon atoms optionally substituted with 1 to 3 R 8  groups, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms; and    R 8  is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, —CH 2 cycloalkyl of 4 to 6 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxy, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms;    with n-hexylmagnesium bromide (HxMgBr) and further with 1-methyl-4-piperidone (MPP) to produce a compound of formula (5):                          wherein    R 9  is n-hexyl; or    reacting a compound of formula (6) consecutively with n-hexyllithium, magnesium sulfate, and 1-methyl-4-piperidone (MPP) to produce a compound of formula (5) wherein R 9  is n-hexyl;    (b) reacting a compound of formula (5) with 1-benzyl-1-phenyl hydrazine hydrochloride (BPH) to produce a compound of formula (4):                          wherein    R 1  and R 2  are each hydrogen    R 5  is n-pentyl; and    R 6  is benzyl;    (c) reacting a compound of formula (4) with boron tribromide (BBr 3 ) to produce a compound of formula (2):                          and    (d) reacting a compound of formula (2) with 5-chloromethyl-1H-tetrazole (CMT) and cesium carbonate to produce a compound of formula (1):                          wherein n is 0 and R 7  is hydrogen;    or a pharmaceutically acceptable salt thereof.    
     
     
         19 . The process of  claim 18  further comprising reacting the 5-chloromethyl-1H-tetrazole (CMT) with 3,4-dihydro-3H-pyran (DHP) and pyridinium p-toluene sulfonate (PPTS) to produce tetrahydropyran (THP) protected 5-chloromethyl-1H-tetrazole (CMT) prior to reaction with the compound of formula (2).  
     
     
         20 . The process of  claim 18  wherein the compound of formula (5) is produced by the process comprising reacting a compound of formula (6) with hexylmagnesium bromide (HxMgBr) and further with 1-methyl-4-piperidone (MPP).  
     
     
         21 . The process of  claim 18  wherein the compound of formula (1) is a compound of formula (1a):  
       
         
           
           
               
               
           
         
         wherein  
         R 1a , R 3a , and R 4a  are each, independently, hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, alkanoyl of 2 to 4 carbon atoms, halogen, hydroxyl, aryl of 6 to 14 carbon atoms optionally substituted with 1 to 3 R 8  groups, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms, dialkylamino of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms.  
       
     
     
         22 . The process of  claim 21  wherein the compound of formula (1a) is a compound of formula (1b):