Chemical synthesis of clopidogrel active metabolites and disulfide conjugate prodrugs

Abstract

A method of synthesizing a clopidogrel metabolite is provided. A piperidone intermediate is formed from a mandelate. An asymmetric ketone reduction of the piperidone intermediate is performed. A mercapto installation is performed on the piperidone intermediate to form a clopidogrel metabolite that includes a 4-carbon chiral center having an (R) configuration.

What is claimed is: 
     
         1 . A method of synthesizing a clopidogrel metabolite, the method comprising:
 forming a piperidone intermediate from a mandelate;   performing an asymmetric ketone reduction of the piperidone intermediate; and   performing a mercapto installation to form the clopidogrel metabolite that includes a 4-carbon chiral center having an (R) configuration.   
     
     
         2 . The method of  claim 1 , wherein a piperidone intermediate has a structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein forming the piperidone intermediate further comprises:
 reacting methyl 2-chloro-D-mandelate with nosyl chloride and triethylamine to form a first intermediate;   reacting the first intermediate with 4-piperidinol and potassium hydrogen carbonate to form a second intermediate;   reacting the second intermediate with oxalyl chloride, dimethyl sulfoxide, and triethylamine to form a third intermediate; and   forming the piperidone intermediate from the third intermediate.   
     
     
         4 . The method of  claim 3 , wherein forming the piperidone intermediate from the third intermediate further comprises:
 reacting the third intermediate with lithium diisopropylamide and ethyl glyoxalate to form the piperidone intermediate.   
     
     
         5 . The method of  claim 3 , wherein forming the piperidone intermediate from the third intermediate further comprises:
 reacting the third intermediate with lithium diisopropylamide and ethyl glyoxalate to form a fourth intermediate; and   reacting the fourth intermediate with p-toluenesulfonic acid to form the piperidone intermediate.   
     
     
         6 . The method of  claim 1 , wherein performing the asymmetric ketone reduction of the piperidone intermediate forms a structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein performing the asymmetric ketone reduction further comprises:
 using a metal ion chelation to form a fifth intermediate, wherein the 4-carbon chiral center has an (S) configuration.   
     
     
         8 . The method of  claim 1 , wherein clopidogrel metabolite has a structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein forming the clopidogrel metabolite further comprises:
 reacting a product of the asymmetric ketone reduction with methanesulfonyl chloride and diisopropylethylamine to form a sixth intermediate;   reacting the sixth intermediate with triisopropylsilanethiol and sodium hydride to form a seventh intermediate; and   reacting the seventh intermediate with hydrochloric acid to form the clopidogrel metabolite.   
     
     
         10 . The method of  claim 1 , further comprising:
 isomerizing the clopidogrel metabolite through a reversible Michael addition to form a second clopidogrel metabolite.   
     
     
         11 . The method of  claim 10 , wherein the second clopidogrel metabolite has a structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 10 , further comprising:
 converting one or more of the clopidogrel metabolite and the second clopidogrel metabolite to a stabilized mixed disulfide derivative.   
     
     
         13 . The method of  claim 12 , wherein the stabilized mixed disulfide derivative has a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and combinations thereof. 
       
     
     
         14 . The method of  claim 13 , wherein R is selected from the group consisting of an unsubstituted moiety of alkyl, alkenyl, cycloalkyl, alkynyl, arylalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and combinations thereof. 
     
     
         15 . The method of  claim 13 , wherein R is selected from the group consisting of a substituted moiety of alkyl, alkenyl, cycloalkyl, alkynyl, arylalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or combinations thereof, substituted with one or more suitable substituents. 
     
     
         16 . The method of  claim 13 , wherein R is a stabilized mixed disulfide derivative that includes a 4-carbon chiral center having an (R) configuration, and having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and combinations thereof. 
       
     
     
         17 . The method of  claim 1 , wherein each of forming, performing an asymmetric ketone reduction, and
 performing a mercapto installation is performed in one or more solvents selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, and toluene.   
     
     
         18 . A composition of matter comprising:
 a stabilized mixed disulfide derivative that includes a 4-carbon chiral center having an (R) configuration, and having a structure selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       and combinations thereof. 
     
     
         19 . The composition of  claim 18 , wherein R is any chemical moiety capable of producing, by reductive disulfide cleavage, a clopidogrel metabolite having structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and combinations thereof. 
       
     
     
         20 . The composition of matter of  claim 19 , wherein in the reductive disulfide cleavage, the R reacts with one or more bioreductive agents selected from the group consisting of endogenous glutathione (GSH), cysteine, homocysteine, and combinations thereof. 
     
     
         21 . The composition of matter of  claim 18 , wherein R is selected from the group consisting of an unsubstituted moiety of alkenyl, cycloalkyl, alkynyl, arylalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and combinations thereof. 
     
     
         22 . The composition of matter of  claim 18 , wherein R is selected from the group consisting of a substituted moiety of alkenyl, cycloalkyl, alkynyl, arylalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or combinations thereof, substituted with one or more suitable substituents. 
     
     
         23 . The composition of matter of  claim 18 , wherein R is a stabilized mixed disulfide derivative that includes a 4-carbon chiral center having an (R) configuration, and having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and combinations thereof. 
       
     
     
         24 . A method of treating a disease in a mammal, the method comprising:
 administering a pharmaceutically acceptable amount of a compound or salt thereof comprising a stabilized mixed disulfide derivative that includes a 4-carbon chiral center having an (R) configuration, and having a structure selected from the group consisting of:   
       
         
           
           
               
               
           
         
       
       and combinations thereof. 
     
     
         25 . The method of  claim 24 , wherein R is any chemical moiety capable of producing, by reductive disulfide cleavage, a clopidogrel metabolite having structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and combinations thereof. 
       
     
     
         26 . The method of  claim 25 , wherein in the reductive disulfide cleavage, the R reacts with one or more bioreductive agents selected from the group consisting of endogenous glutathione (GSH), cysteine, homocysteine, and combinations thereof. 
     
     
         27 . The method of  claim 24 , wherein R is an unsubstituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkynyl, arylalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, and combinations thereof. 
     
     
         28 . The method of  claim 24 , wherein R is a substituted moiety selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkynyl, arylalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or combinations thereof, substituted with one or more suitable substituents. 
     
     
         29 . The method of  claim 24 , wherein R is a stabilized mixed disulfide derivative that includes a 4-carbon chiral center having an (R) configuration, and having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and combinations thereof. 
       
     
     
         30 . The method of  claim 24 , wherein the disease is selected from the group consisting of, a heart disease, a metastatic cancer, a neuronal disorder, and autoimmune encephalomyelitis.