Pharmaceutically active pyrrolidine ester derivatives

Abstract

The present invention is related to the use of pyrrolidine esters of formula (I) for the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to the use of pyrrolidine esters of formula (I) to modulate, notably to antagonise the oxytocin receptor. The present invention is furthermore related to novel pyrrolidine esters. X is selected from the group consisting of CR 6 R 7 , NOR 6 , NNR 6 R 7 ; R is selected from the group comprising or consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, saturated or unsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, aryl, heteroaryl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl. R 1 is selected from the group comprising or consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, 3-8-membered cycloalkyl, acyl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl group.

1 . A pharmaceutical composition comprising a pyrrolidine ester according to formula (I), or a pharmaceutically acceptable salt thereof,  
       
         
           
           
               
               
           
         
       
       as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein 
 X is selected from the group consisting of C 6 R 7 , NO 6 , NNR 6 R 7 ;  
 R is selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, aryl, C 1 -C 6 -alkyl aryl, saturated or unsaturated 3-8-membered cycloalkyl, and C 1 -C 6 -alkyl-saturated or unsaturated 3-8-membered cycloalkyl;  
 R 1  is selected from the group consisting of C 1 -C 6 -alkyl, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, acyl, C 1 -C 6 -alkyl aryl, and C 1 -C 6 -alkyl heteroaryl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, aryl or heteroaryl groups;  
 R 2 , R 3 , R 4  and R 5  are independently from each other selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl;  
 R 6  and R 7  are independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, aryl, C 1 -C 6 -alkyl aryl, C 1 -C 6 -alkyl, saturated or unsaturated 3-8-membered cycloalkyl, and C 1 -C 6 -alkyl-saturated or unsaturated 3-8-membered cycloalkyl.  
 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein X is NOR 6  and R 6  is selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, acyl, aryl, saturated or unsaturated 3-8-membered cycloalkyl, C 1 -C 6 -alkyl aryl, wherein said cycloalkyl or aryl groups may be fused with 1-2 further cycloalkyl or aryl groups.  
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein R 6  is H or CH 3 .  
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein R 1  is a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl.  
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein R 1  is a biphenyl.  
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein X is NOR 6 , R 6  is H, a C 1 -C 6 -alkyl, or aryl or C 1 -C 6 -alkyl aryl group and R 1  is selected from the group consisting of C 1 -C 6 -alkyl, aryl and C 1 -C 6 -alkyl aryl.  
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein R 6  is methyl, R is a C 1 -C 6 -alkyl group and R 1  is a biphenyl.  
     
     
         8 . A method of modulating an oxytocin receptor in vitro comprising administering to one or more cells having an oxytocin receptor the pharmaceutical composition according to  claim 1 .  
     
     
         9 . The method according to  claim 8 , wherein said modulating comprises blocking the oxytocin receptor or antagonising the binding of oxytocin to its receptor.  
     
     
         10 . A method of treating premature labor, premature birth, or dysmenorrheal comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of  claim 1 .  
     
     
         11 . A pyrrolidine ester compound of formula (I′), or a pharmaceutically acceptable salt thereof,  
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkyl aryl, and 3-8-membered cycloalkyl and R 1  is selected from the group consisting of a 1,1′-biphenyl, a pyridinyl-phenyl and a pyrimidinyl-phenyl group.  
       
     
     
         12 . A pyrrolidine ester compound according to  claim 11 , wherein R is a methyl group.  
     
     
         13 . A pyrrolidine ester compound according to  claim 11 , wherein R 1  is a 1,1′-biphenyl group.  
     
     
         14 . A pyrrolidine ester compound according to  claim 11 , wherein R 1  is a 1,1′-biphenyl group which is substituted by 1 or 2 substituents selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, and CN.  
     
     
         15 . A pyrrolidine derivative according to  claim 11 , selected from the group consisting of: 
 Methyl (2S,4EZ)-4-(methoxyimino)-1-[4-(5-pyrimidinyl)benzoyl]-2-pyrrolidine-carboxylate,    Methyl (2S,4EZ)-4-(methoxyimino)-1-[4-(2-pyridinyl)benzoyl]-2-pyrrolidine-carboxylate, and    Methyl (2S,4EZ)-4-(methoxyimino)-1-[4-(3-methyl-2-pyridinyl)benzoyl]-2-pyrrolidinecarboxylate.    
     
     
         16 . A medicament comprising the pyrrolidine derivative according to  claim 11 .  
     
     
         17 . A pharmaceutical composition comprising at least one pyrrolidine derivative according to  claim 11 , and a pharmaceutically acceptable carrier, diluent or excipient thereof.  
     
     
         18 . A process for preparing a compound according to  claim 11 , comprising: 
 reacting a compound of formula (III)                          wherein X, R 2 -R 5  are H,    with a carboxylic acid or acyl chloride of formulae (IVa) or (IVb)                          
     
     
         19 . The pharmaceutical composition of  claim 11 , wherein R is a methyl group.  
     
     
         20 . A method of treating and/or preventing premature labor, premature birth or dysmenorrheal, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of  claim 1.