Proline derivatives and use thereof as drugs

Abstract

The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.

1 - 11 . (canceled)  
   
   
       12 . A method for treating a disease involving DPP-IV, comprising administering to a mammal in need thereof a therapeutically effective amount of an L-proline derivative of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 X is —NR 1 R 2  wherein one of R 1  and R 2  is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and the other is a hydrogen atom, alkyl, cycloalkyl or aryl, Y is CH 2 , CH—OH, S, S═O or SO 2 ,  
 Z is a hydrogen atom or a cyano, and  
 of the above-mentioned groups, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and cycloalkylalkyl each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       13 . The method of  claim 12 , wherein X is a group of the formula (IV) or (V):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 22  is a hydrogen atom, alkyl, cycloalkyl, or aryl,  
 R 23  and R 24  are the same or different and each is independently a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, haloalkyl, cyano, nitro, —NR 25 R 26 , —NHSO 2 R 27 , OR 28 , —COOR 29 , —CONHSO 2 R 30 , —SO 2  OR 31 , —SO 2 R 32  or —CONR 33 R 34  wherein R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33  and R 34  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R 25  and R 26 , and R 33  and R 34  may be bonded to each other to form heterocycles each optionally containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 a, b, c, d, e, f and g are all carbon atoms, or any one or two thereof is(are) nitrogen atom(s) and the rest is a carbon atom,  
 n is 0, 1, 2 or 3, and  
 of the above-mentioned groups, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       14 . The method of  claim 12 , wherein X is phenylamino optionally having substituents, 2-pyridylamino optionally having substituents, 3-pyridazinylamino optionally having substituents or 2-pyrimidinylamino optionally having substituents, and the asymmetric carbon, to which X is bonded, is expressed by an S configuration,  
     or a pharmaceutically acceptable salt thereof.  
   
   
       15 . A method for treating a disease involving DPP-IV, comprising administering to a mammal in need thereof a therapeutically effective amount of an L-proline derivative of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 X is a group of the formula (III)  
                     wherein    R 12  is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NR 14 R 15 , —OR 16 , —COR 17 , —CO 2 R 18 , —CONR 19 R 20  or —SO 2 R 21  wherein R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20  and R 21  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R 14  and R 15 , and R 19  and R 20  may be bonded to each other to form heterocycles each optionally containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally being condensed with an aromatic ring optionally having substituents, and R 13  is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,    
 Y is CH 2 , CH—OH, S, S═O or SO 2 ,  
 Z is a hydrogen atom or a cyano, and  
 of the above-mentioned groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocycle each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       16 . A method for treating a disease involving DPP-IV, comprising administering to a mammal in need thereof a therapeutically effective amount of an L-proline derivative of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 X is —NR 1 R 2  wherein R 1  and R 2  may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, 
 —NR 3  COR 4  wherein R 3  and R 4  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,  
 —NR 5  CONR 6 R 7  or —NR 5  CH 2 CH 2 NR 6 R 7  wherein R 5 , R 6  and R 7  are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6  and R 7  may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 —NR 8 SO 2 R 9  wherein R 8  and R 9  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or  
 —OR 10  or —OCOR 11  wherein R 10  and R 11  are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,  
 
 Y is CH 2 , CH—OH, S, S═O or SO 2 ,  
 Z is a hydrogen atom or a cyano, and  
 of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       17 . The method of  claim 16 , wherein X of the formula (I) is a group of the formula (II):  
     
       
         
         
             
             
         
       
     
     wherein  
     
       
         
         
             
             
         
       
     
     is a single bond or a double bond, 
 R 12  is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NR 14 R 15 , —OR 16 , —COR 17 , —CO 2 R 18 , —CONR 19 R 20  or —SO 2 R 21  wherein R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20  and R 21  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R 14  and R 15 , and R 19  and R 20  may be bonded to each other to form heterocycles each optionally containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 m is 1 or 2, and  
 A is a carbon atom or a nitrogen atom,  
 provided that i) when A is a carbon atom, A may be substituted by a hydroxyl group, carboxyl or alkoxycarbonyl, and ii) when A is a nitrogen atom,  
                     
 is a single bond,  
 of the above-mentioned groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocycle each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       18 . The method of  claim 16 , wherein X of the formula (I) is a group of the formula (VI) or (VII):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 23  and R 24  are the same or different and each is independently a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, haloalkyl, cyano, nitro, —NR 25 R 26 , —NHSO 2 R 27 , —OR 28 , —COOR 29 , —CONHSO 2 R 30 , —SO 2 OR 31 , —SO 2 R 32  or —CONR 33 R 34  wherein R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33  and R 34  are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R 25  and R 26 , and R 33  and R 34  may be bonded to each other to form heterocycles each optionally containing 1 or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally being condensed with an aromatic ring optionally having substituents,  
 a, b, c, d, e, f and g are all carbon atoms, or any one or two thereof is(are) nitrogen atom(s) and the rest is a carbon atom, and  
 A is a carbon atom or a nitrogen atom,  
 provided that when A is a carbon atom, A may be substituted by a hydroxyl group, carboxyl or alkoxycarbonyl, and  
 of the above-mentioned groups, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       19 . The method of  claim 18 , wherein, in the formula (I), the asymmetric carbon, to which X is bonded, is expressed by an S configuration, X is a group of the formula (VI) or (VII), R 23  and R 24  are the same or different and each is nitro, cyano, C 1-6 alkyl, C 1-6 alkyloxy, halogen or haloalkyl, Y is a sulfur atom and Z is a hydrogen atom,  
     or a pharmaceutically acceptable salt thereof.  
   
   
       20 . The method of  claim 16 , wherein the L-proline derivative is 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride.  
   
   
       21 . The method of  claim 16 , wherein the L-proline derivative is 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine or a salt thereof.