New substituted 2,4-thiazolidinedione derivatives, processes for producing them and pharmaceutical compositions containing them

Abstract

The present invention generally relates to a process for producing Compounds of formula I: wherein D, X, A, and n are defined herein.

1 . New 5-phenoxyalkyl-2,4-thiazolidinediones of general formula I:  
       
         
           
           
               
               
           
         
       
       in which A represents a linear or branched alkylene group comprising from 2 to 16 carbon atoms 
 D represents a homo- or heterocarbon mono-, di- or tricyclic aromatic structure which may include one or more heteroatoms  
 X represents a substituent of the aromatic structure, chosen from hydrogen, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl groups are defined as above, an aryl group defined as an aromatic cyclic structure comprising one or two rings optionally including one or two heteroatoms in the ring, an aralkyl group in which the alkyl group is defined as above and the aryl group is defined as above and optionally comprises one or more substituents, an aralkylaryl group in which the aralkyl and aryl groups are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxyl, a nitro, an amino, a carboxyl, an alkoxycarbonyl, a carboxamide, a sulfonyl, a sulfone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino, a trifluoromethoxy  
 n is an integer ranging from 1 to 3 with the proviso that if A represents the butyl radical  
                     
  does not represent the 4-chlorophenyl group in free or salified form.  
 
     
     
         2 . Tautomeric forms of the compounds of general formula I according to  claim 1 .  
     
     
         3 . Enantiomers of the compounds of general formula I according to  claim 1 .  
     
     
         4 . Diastereoisomers of the compounds of general formula I according to  claim 1 .  
     
     
         5 . Epimers of the compounds of general formula I according to  claim 1 .  
     
     
         6 . Solvates with water or an organic solvent of the compounds of general formula I according to  claim 1 .  
     
     
         7 . Pharmacologically acceptable basic salts of the compounds of general formula I according to  claim 1 .  
     
     
         8 . Compound according to  claim 1 , chosen from the group consisting of: 
 5-[3-(4-fluorophenoxy)propyl]-2,4-thiazolidinedione    5-(2-phenoxyethyl)-2,4-thiazolidinedione    5-[2-(4-fluorophenoxy)ethyl]-2,4-thiazolidinedione    5-{[1-hydroxy-2-(4-fluorophenoxy)]ethyl }-2,4-thiazolidinedione    5-{[2-hydroxy-3-(4-fluorophenoxy)]propyl }-2,4-thiazolidinedione    5-[1-methyl-2-phenoxyethyl]-2,4-thiazolidinedione    5-[2-(4-cyanophenoxy)ethyl]-2,4-thiazolidinedione    5-[2-(2-fluorophenoxy)ethyl]-2,4-thiazolidinedione    5-[2-(2-naphthyloxy)ethyl]-2,4-thiazolidinedione and their pharmacologically acceptable salts.    
     
     
         9 . Process for producing the compounds of general formula I according to  claim 1:   
       
         
           
           
               
               
           
         
       
       in which D represents an aromatic structure as defined above, 
 X represents a substituent of the aromatic structure as defined above,  
 A represents a linear or branched arkylene radical comprising from 2 to 16 carbon atoms,  
 n represents an integer ranging from 1 to 3, with the proviso that if A represents the butyl radical,  
                     
 does not represent the 4-chloro-phenyl group, which consists in that a compound of formula II:  
                     
 in which X, D and n are defined as above, is subjected to the action of a dihaloalkyl of formula III:  
                     
 in which Hal represents a chlorine or bromine atom, A represents an alkylene radical defined as above, in the presence of a basic agent, to form the compound of general formula IV:  
                     
 in which X, D, n and A are defined as above, which is subjected to the action of a dialkyl malonate of formula V:  
                     
 in which R 1  and R′ 1  are alkyl radicals, in the presence of an alkali metal alcoholate, to form the compound of general formula VI:  
                     
 in which X, D, n, A, R 1  and R′ 1  are defined as above, which is subjected to halogenation by the action of a halogenating agent to form the compound of general formula VII:  
                     
 in which Hal, X, D, n, A, R 1  and R′ 1  are defined as above, which is heated under reflux in an acidic mixture to give the α-haloacid of general formula VIII:  
                     
 in which Hal, X, D, n and A are defined as above, which is reacted with thiourea to give the 2-imino-4-thiazolidinone of general formula IX:  
                     
 in which X, D, n and A are as defined above, which is hydrolysed to a 2,4-thiazolidinedione of general formula (I) in acidic medium.  
 
     
     
         10 . Process for producing the compounds of general formula (I) according to  claim 1 , in which a compound of formula X:  
       
         
           
           
               
               
           
         
       
       in which R represents an alkyl group, X, D, n and A are defined as above, is subjected to halogenation to form the α-halogenated ester of general formula XI:  
       
         
           
           
               
               
           
         
       
       in which Hal represents a chlorine or bromine atom, X, D, n and A are defined as above, which is reacted with thiourea to form the 2-imino-4-thiazolidinone of formula IX:  
       
         
           
           
               
               
           
         
       
       in which X, D, n and A are defined as above, which is hydrolysed in an acidic medium to form the compound of general formula I.  
     
     
         11 . Process for producing the compounds of general formula (I) according to  claim 1 , in which a compound of formula IV as defined above is subjected to the action of the 2,4-thiazolidinedione dianion obtained by the action of an alkali metal derivative on 2,4-thiazolidinedione, to form the compound of general formula I.  
     
     
         12 . Process for producing the compounds of general formula (I) according to  claim 1 , in which the aldehyde compound of general formula XII:  
       
         
           
           
               
               
           
         
       
       in which B represents a linear or branched alkylene group, comprising from 1 to 15 carbon atoms, X, D and n are defined as above, is subjected to the action of the 2,4-thiazolidinedione dianion obtained by the action of an alkali metal derivative on 2,4-thiazolidinedione, to form the compound of general formula XIII:  
       
         
           
           
               
               
           
         
       
       in which X, D, n and B are defined as above, which is converted to the dehydroxylated derivative of general formula I according to known methods.  
     
     
         13 . Process for producing the compounds of general formula (I) according to  claim 1 , in which an oxirane compound of general formula XIV:  
       
         
           
           
               
               
           
         
       
       in which B′ represents a linear or branched alkylene group comprising from 1 to 14 carbon atoms, X, D and n are defined as above, formed by reacting an epihalohydrin with an aromatic derivative, is subjected with [sic] the 2,4-thiazolidinedione dianion obtained by the action of an alkali metal derivative on 2,4-thiazolidinedione, to form the compound of general formula XV:  
       
         
           
           
               
               
           
         
       
       which is converted to the dehydroxylated derivative of general formula I according to known methods.  
     
     
         14 . Process for producing the compounds of general formula (I) according to  claim 1 , in which a ketone of general formula XVI:  
       
         
           
           
               
               
           
         
       
       in which R′ represents a linear or branched alkyl group, or an aryl or aralkyl group, substituted or not, X, D, n and B are defined as above, is subjected to the action of 2,4-thiazolidinedione in the presence of an organic base and then of an acidic medium to form the compound of general formula XVII:  
       
         
           
           
               
               
           
         
       
       in which X, D, n and B are defined as above, in which the double bond is then hydrogenated by the action of hydrogen in the presence of a catalyst to form the compound of general formula I, in which the akylene chain is a branched chain:  
       
         
           
           
               
               
           
         
       
       in which X, D, n, B and R′ are defined as above.  
     
     
         15 . As new products, the intermediate compounds formed during the synthesis corresponding to the general formula VII:  
       
         
           
           
               
               
           
         
       
       in which X, D, n, A, Hal, R 1  and R′ 1  have the meanings given above.  
     
     
         16 . As new products, the intermediate compounds formed during the synthesis corresponding to the general formula VIII:  
       
         
           
           
               
               
           
         
       
       in which X, D, n, A and Hal have the meanings given above.  
     
     
         17 . As new products, the intermediate compounds formed during the synthesis corresponding to the general formula IX:  
       
         
           
           
               
               
           
         
       
       in which X, D, n and A have the meanings given above.  
     
     
         18 . As new products, the intermediate compounds formed during the synthesis, chosen from the group consisting of: 
 the compounds corresponding to the general formula XIII:                          in which B represents a linear or branched alkylene group comprising from 1 to 15 carbon atoms, X, n and D have the meanings given above, and,    the compounds corresponding to the general formula XV:                          in which B′ represents a linear or branched alkylene group comprising from 1 to 14 carbon atoms, X, n and D have the meanings given above.    
     
     
         19 . As new products, the intermediate compounds formed during the synthesis corresponding to the general formula XVII:  
       
         
           
           
               
               
           
         
       
       in which X, n, B, D and R′ have the meanings given above.  
     
     
         20 . Pharmaceutical compositions characterized in that they contain, as active ingredient, at least one compound of general formula I according to  claim 1:   
       
         
           
           
               
               
           
         
       
       in which A represents a linear or branched alkylene group comprising from 2 to 16 carbon atoms, 
 D represents a homo- or heterocarbon mono-, di- or tricyclic aromatic structure which may include one or more heteroatoms,  
 X represents the substituent of the aromatic structure, chosen from hydrogen,,an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl groups are defined as above, an aryl group defined as an aromatic cyclic structure comprising one or two rings optionally including one or two heteroatoms in the ring, an aralkyl group in which the alkyl group is defined as above and the aryl group is defined as above and optionally comprises one or more substituents, an aralkylaryl group in which the aralkyl and aryl groups are defined as above, a halogen, a trifluoromethyl, a cyano, a hydroxyl, a nitro, an amino, a carboxyl, an alkoxycarbonyl, a carboxamide, a sulfonyl, a sulfone, a sulfonamide, a sulfamoyl, an alkylsulfonylamino, an acylamino, a trifluoromethoxy,  
 n is an integer ranging from 1 to 3, with the proviso that if A represents the butyl radical  
                     
 does not represent the 4-chlorophenyl group in free or salified form, in combination or mixed with a pharmaceutically acceptable non-toxic inert vehicle or excipient.  
 
     
     
         21 . Pharmaceutical composition according to  claim 20 , in which the vehicle or excipient is one of those which are suitable for administration by the parenteral, digestive, rectal, permucosal or percutaneous route.  
     
     
         22 . Pharmaceutical composition according to  claim 20 , in which the active ingredient content varies from 1 to 200 mg per unit dose.