Process for the preparation of pharmaceutically active thiazolidine or oxazolidine compounds by a yeast reductase

Abstract

A process for preparing a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein: T represents a substituted or unsubstituted aryl group and T 1 is O or S; which process comprises, treating a compound of formula (II), or a tautomeric form thereof and/or a salt thereof and/or a solvate thereof, wherein T and T 1 are as defined in relation to formula (I), with a microbial reductase obtained from an appropriate red yeast; and thereafter, as required, preparing a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate of the compound of formula (I) or a tautomeric form thereof; compounds prepared by such a process and the use of such compounds in medicine.

1 . A process for preparing a compound of formula (I):  
       
         
           
           
               
               
           
         
         or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein: T represents a substituted or unsubstituted aryl group and T 1  is O or S; which process comprises, treating a compound of formula (II):  
         
           
             
             
                 
                 
             
           
           or a tautomeric form thereof and/or a salt thereof and/or a solvate thereof, wherein T and T 1  are as defined in relation to formula (I), with a microbial reductase obtained from an appropriate red yeast; and  
           thereafter, as required, preparing a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate of the compound of formula (I) or a tautomeric form thereof.  
         
       
     
     
         2 . A process according to  claim 1 , wherein T represents a moiety selected from the list consisting of (Ia), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Il ), (In), (In), (Io) and (Ip):  
       
         
           
           
               
               
           
         
         wherein A 1 , A 2 , R 1  and n are as defined in relation to formula (I) of EP 0306228; 
         
           
             
             
                 
                 
             
           
         
         wherein R 2 , L 1 , L 2  and L 3  are as defined in relation to formula (I) of EP 0008203; 
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2,  R 3 , R 4 , R 5 , W and n are as defined in relation to formula of EP 0139421; 
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2  and R 3  are as defined in relation to formula (I) of of EP 032128; 
         
           
             
             
                 
                 
             
           
         
         wherein A, R, R 1  and X are as defined in relation to formula (I) of EP 0428312; 
         
           
             
             
                 
                 
             
           
         
         when A, B, R and R 1  are as defined in relation to formula (II) of EP 0428312; 
         
           
             
             
                 
                 
             
           
         
         wherein R 1  is as defined in relation to formula (I) of EP 0489663; 
         
           
             
             
                 
                 
             
           
         
         wherein R 1 , R 2 , R 3  and n are as defined in relation to formula (I) of EP 0155845; 
         
           
             
             
                 
                 
             
           
         
         when R 1  is as defined in relation to formula (I) of EP 0257781; 
         
           
             
             
                 
                 
             
           
         
         wherein Ar, R 1 , R 2 , R 3 , R 4 , R 5 , n, U and W are as defined in relation to formula (I) of U.S. Pat. No. 5,104,888; 
         
           
             
             
                 
                 
             
           
         
         when A, R 1 , R 2  and X are as defined in relation to formula (I) of EP 0208420; 
         
           
             
             
                 
                 
             
           
         
         when R 1 , R 2 , X, Z m and n are as defined in relation to formula (I) of EP 0177353; 
         
           
             
             
                 
                 
             
           
         
         according to formula (I) of EP 0319189; 
         
           
             
             
                 
                 
             
           
         
         wherein A, B, X, X 1 , X 2 , n and Z are as defined in relation to formula (I) of EP 0332331; 
         
           
             
             
                 
                 
             
           
         
         wherein V, W, X, Y, Z, Z 1  and n are as defined in EP 0332332; and  
         
           
             
             
                 
                 
             
           
         
         wherein Q and X are as defined in relation to formula (I) of International Application No. WO 92/18501.  
       
     
     
         3 . A process according to  claim 1  or  claim 2 , wherein T represents a moiety selected from the list consisting of (a), (b), (c), (d), (e), (f), (g), (h) and (i):  
       
         
           
           
               
               
           
         
       
     
     
         4 . A process to any one of  claims 1  to  3 , wherein T represents a moiety of formula (Ia).  
     
     
         5 . A process according to any one of  claims 1  to  4 , wherein T 1  represents S.  
     
     
         6 . A process according to  claim 1  for the preparition of a compound of formula (1):  
       
         
           
           
               
               
           
         
         or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: 
 A 1  represents a substituted or unsubstituted aromatic heterocyclyl group;  
 R 1  represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;  
 A 2  represents a benzene ring having in total up to five substituents; and  
 n represents an integer in the range of from 2 to 6;  
 which process comprises, treating a compound of formula (2):  
                     or a tautomeric form thereof and/or a salt thereof, and/or a solvate thereof, wherein A 1 , A 2 , R 1  and n are as defined in relation to formula (1) with a microbial reductase obtained from an appropriate red yeast; and    thereafter, as required, preparing a pharmaceutically acceptable salt, and/or a pharmaceutically acceptable solvate of the compound of formula (1) or a tautomeric form thereof.    
 
       
     
     
         7 . A process according to  claim 6 , wherein the compound of formula (1) is 5-(4-[2-N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione, or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof.  
     
     
         8 . A process according to any one of  claims 1  to  7 , wherein an appropriate red yeast is a red yeast which provides the above mentioned reduction, including known red yeasts and those red yeasts which may be produced from known red yeasts by conventional methods.  
     
     
         9 . A process according to any one of  claims 1  to  8 , wherein an appropriate red yeast is a red yeast from the species of the genera Rhodotorula, Rhodosporidium or synonyms thereof.  
     
     
         10 . A process according to any one of  claims 1  to  9  wherein an appropriate red yeast is  Rhodotorula glutinis  CBS 4406,  Rhodotorula rubra  CBS 6469,  Rhodotorula rubra  CBS 17 and  Rhodotorula glutinis  IFO 0869.  
     
     
         11 . A process according to any one of  claims 1  to  9  wherein an appropriate red yeast is  Rhodosporidium toruloides  CBS 14  
     
     
         12 . A process for the preparation of a compound of formula (I) (the ‘enantiomerically enriched compound (I)’) wherein greater than 50% w/w of said compound is in the form of a compound of formula (IA):  
       
         
           
           
               
               
           
         
         or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein T and T 1  are as defined in relation to formula (I) and the ‘**’ carbon atom is an enantiomeric carbon atom, which process comprises reacting a compound of the above defined formula (II) with a microbial reductase obtained from an appropriate red yeast and wherein the reaction is carried out at an acidic pH; and  
         thereafter, as required, preparing a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate of the enantiomerically enriched compound (I) or a tautomeric form thereof.  
       
     
     
         13 . Enantiomerically enriched compound (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein greater than 50% w/w is in the form of compound (IA)  
     
     
         14 . A compound of formula (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, in optically pure form.  
     
     
         15 . Enantiomerically enriched compound (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.  
     
     
         16 . Enantiomerically enriched compound (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia, hyperlipidaemia, hypertension, cardiovascular disease and certain eating disorders.  
     
     
         17 . A pharmaceutical composition comprising enantiomerically enriched compound (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.