Thiazolidine derivative and medicinal use thereof

Abstract

A thiazolidine derivative represented by the formula (I) wherein each symbol is as defined in the specification, and a pharmaceutically acceptable salt thereof exhibit a potent DPP-IV inhibitory activity, and can be provided as an agent for the prophylaxis or treatment of diabetes, an agent for the prophylaxis or treatment of obesity and the like.

1 . A thiazolidine derivative represented by the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein X is a substituent selected from the following formulas:  
       
         
           
           
               
               
           
         
       
       wherein 
 m is an integer of 1 or 2,  
 n is an integer of 1 to 5,  
 X′ is a hydrogen atom or an alkyl optionally having substituent(s),  
 Y′ is represented by —NR 1 R 2  (R 1  is aryl optionally having substituent(s) or heteroaryl optionally having substituent(s), R 2  is a hydrogen atom, alkyl optionally having substituent(s), aryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroaryl optionally having substituent(s) or heteroarylalkyl optionally having substituent(s), or they may be bonded to each other to form a heterocycle having carbon and at least one nitrogen, optionally having other heteroatom(s) and optionally having substituent(s), where this heterocycle is optionally substituted or condensed with an aromatic ring optionally having substituent(s)),  
   is a single bond or a double bond,  
 A is a carbon atom or a nitrogen atom, 
 wherein i) when A is a carbon atom, then A is optionally substituted by a hydroxyl group, carboxy or alkoxycarbonyl, and ii) when A is a nitrogen atom, then  
   is a single bond, and  
 
 Q is aryl or heteroaryl selected from the compounds represented by the following formulas (II)-(XII):  
                                       
 wherein  
 (i) in the formula (II), 1 to 3 from a, b, c and d is(are) nitrogen atom(s) and the rest is(are) carbon atom(s) or all of them are nitrogen atoms,  
 R 1a  is alkyl, phenyl, pyridyl, pyrimidinyl, imidazolyl or oxazolyl, wherein these groups are optionally substituted by one or more from alkyl, alkoxy, halogen and cyano,  
 R 2a  is a hydrogen atom, alkyl or haloalkyl, 
 wherein  
 (i-1) when b is a nitrogen atom, then R 2a  is not present,  
 (i-2) when c and d are both nitrogen atoms, a and b are both carbon atoms, R 1a  is phenyl and R 2a  is alkyl, then R 1a  has one or more substituents mentioned above,  
 (i-3) when a and d are both nitrogen atoms, b and c are both carbon atoms and R 1a  is phenyl without substituent, then R 2a  is alkyl or haloalkyl, and  
 (i-4) when all of a, b, c and d are nitrogen atoms and R 1a  is phenyl, then (1) A of the formula (I-b) is a carbon atom and R 1a  does not have the above-mentioned substituent, or (2) R 1a  is substituted by one or more from alkyl and halogen,  
 
 (ii) in the formula (III), one of e and f is a nitrogen atom and the other is a carbon atom, or both are carbon atoms (same as “0-1 of e and f is a nitrogen atom and the rest is(are) carbon atom(s)”), and  
 R 3  and R 4  may be the same or different and each is a hydrogen atom, alkyl, phenyl or pyridyl,  
 (iii) in the formula (IV), j is a sulfur atom, an oxygen atom or a nitrogen atom, h and i may be the same or different and each is a nitrogen atom or a carbon atom (same as “0-2 of h and i is(are) nitrogen atom(s) and the rest is(are) carbon atom(s)”),  
 R 5  and R 7  may be the same or different and each is a hydrogen atom, phenyl or pyridyl (when h is a nitrogen atom, then R 7  is absent), and  
 R 6  is a hydrogen atom or alkyl (when i is a nitrogen atom, then R 6  is absent),  
 (iv) in the formula (V), k, l and n′ may be the same or different and each is a carbon atom or a nitrogen atom, wherein at least one is a carbon atom (same as “0-2 of k, l and n′ is(are) nitrogen atom(s) and the rest is(are) carbon atom(s)”),  
 R 8  is a hydrogen atom, phenyl, pyridyl or nitro (when n′ is a nitrogen atom, then R 8  is absent), 
 R 8a  is a hydrogen atom or phenyl,  
 R 9  is a hydrogen atom, haloalkyl or cyano, and  
 R 10  is a hydrogen atom or cyano (when l is a nitrogen atom, then R 10  is absent), wherein 
 (iv-1) when k and n′ are both nitrogen atoms, (1) A of the formula (I-b) is a nitrogen atom, and R 8a , R 9  and R 10  are all hydrogen atoms, or (2) R 8a  is phenyl and R 9  is haloalkyl,  
 (iv-2) when k, l and n′ are all carbon atoms, then R 8  is phenyl or pyridyl,  
 (iv-3) when k is a nitrogen atom and l and n′ are both carbon atoms, (1) R 8  is phenyl or nitro, or (2) R 9  is cyano, and  
 (iv-4) when 1 is a nitrogen atom, then one of k and n′ is a nitrogen atom,  
 
 
 (v) in the formula (VI), p is a nitrogen atom or a carbon atom,  
 R 11  is a hydrogen atom, phenyl or pyridyl (when p is a nitrogen atom, then R 11  is phenyl or pyridyl),  
 R 12  is a hydrogen atom or alkyl (when p is a nitrogen atom, then R 12  is absent), and  
 R 13  and R 14  are both hydrogen atoms, or when one of them is a hydrogen atom, then the other is cyano, alkoxy or halogen,  
 (vi) in the formula (VII), one of r and s is a nitrogen atom and the other is a carbon atom,  
 R 15  is a hydrogen atom, alkyl or phenyl (when r is a nitrogen atom, then R 15  is absent),  
 R 16  is a hydrogen atom or alkyl (when s is a nitrogen atom, then R 16  is absent), and  
 R 17  is a hydrogen atom, haloalkyl or cyano,  
 (vii) in the formula (VIII), r′ and s′ may be the same or different and each is a carbon atom or a nitrogen atom, wherein at least one of them is a nitrogen atom (same as “1-2 of r′ and s′ is(are) nitrogen atom(s) and the rest is(are) carbon atom(s)”),  
 R 15a  is a hydrogen atom, alkyl or phenyl (when r′ is a nitrogen atom, then R 15a  is absent),  
 R 16a  is a hydrogen atom or alkyl (when r′ and s′ are both nitrogen atoms, then R 16a  is a hydrogen atom), and  
 R 17a  is a hydrogen atom, haloalkyl or cyano,  
 (viii) in the formula (IX), t is a sulfur atom or an oxygen atom,  
 u is a carbon atom or a nitrogen atom, and  
 R 18  and R 19  are both hydrogen atoms, or one of them is a hydrogen atom and the other is cyano, alkoxy or halogen, 
 wherein  
 (viii-1) when u is a carbon atom, then one of R 18  and R 19  is cyano, alkoxy or halogen (same as “R 18  and R 19  are not hydrogen atoms at the same time”),  
 (viii-2) when t is a sulfur atom, then A in the formula (I-b) is a carbon atom, R 19  is a hydrogen atom and R 18  is methoxy or cyano,  
 (viii-3) A in the formula (I-b) is a nitrogen atom, t is an oxygen atom, R 19  is a hydrogen atom, and when u is a carbon atom, then R 18  is alkoxy or halogen, and  
 (viii-4) A in the formula (I-b) is a carbon atom, R 19  is a hydrogen atom, u is a carbon atom, and when t is an oxygen atom, R 1  is halogen,  
 
 (ix) in the formula (X), v, w, x and y may be the same or different and each is a carbon atom or a nitrogen atom, wherein at least two are carbon atoms (same as “0-2 of v, w, x and y is(are) nitrogen atom(s) and the rest is(are) carbon atom(s)”), R 20 , R 21 , R 22 , R 23 , R 24 , R 25  and R 26  may be the same or different and 1 to 3 is(are) haloalkyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, hydroxy, cyano or halogen, and the rest is(are) hydrogen atom(s) (when v is a nitrogen atom, then R 20  is absent, when w is a nitrogen atom, then R 22  is absent, when x is a nitrogen atom, then R 23  is absent, when y is a nitrogen atom, then R 25  is absent),  
 wherein 
 (ix-1) when v is a nitrogen atom and w, x and y are all carbon atoms, then R 22  is haloalkyl,  
 (ix-2) when v and w are both nitrogen atoms and x and y are both carbon atoms, then R 21  is cyano, and  
 (ix-3) when w is a nitrogen atom and v, x and y are all carbon atoms, then (1) R 21  is a hydrogen atom and R 20  is cyano, (2) R 21  is haloalkyl and R 23  is hydroxy, ethoxy, isopropoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy, (3) R 21  is haloalkyl and R 23  and R 25  are both methoxy, (4) R 21  is haloalkyl and R 24  is hydroxy, chloro or trifluoromethyl, (5) R 21  is haloalkyl and R 25  is hydroxy or trifluoromethoxy, (6) R 21  is haloalkyl and R 26  is methoxy, or (7) R 21  is cyano and R 23  is methoxy, and  
 
 (x) in the formula (XI), R 27  and R 28  may be the same or different and each is haloalkyl or alkoxy;  
 Y is methylene, hydroxymethylene, a sulfur atom, sulfinyl or sulfonyl; and  
 Z is a hydrogen atom or cyano;  
 wherein when X is a substituent represented by the formula (I-a), then Z is a hydrogen atom,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The thiazolidine derivative of  claim 1 , wherein Y′ in the formula (I-a) is represented by —NR 1 R 2  [R 1  is aryl optionally having substituent(s) or heteroaryl optionally having substituent(s), R 2  is a hydrogen atom, alkyl optionally having substituent(s), aryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroaryl optionally having substituent(s) or heteroarylalkyl optionally having substituent(s), or they may be bonded to each other to form a heterocycle optionally having 1 or 2 nitrogen atom(s) or oxygen atom(s) and optionally having substituent(s), where this heterocycle is optionally substituted or condensed with an aromatic ring optionally having substituent(s)], or a pharmaceutically acceptable salt thereof.  
     
     
         3 . The thiazolidine derivative of  claim 1  or  2 , wherein, in the formula (I), X is a substituent represented by the formula (I-a) and Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The thiazolidine derivative of  claim 1 , wherein X in the formula (I) is a substituent represented by the formula (I-b), or a pharmaceutically acceptable salt thereof.  
     
     
         5 . The thiazolidine derivative of  claim 3 , wherein Y′ in the formula (I-a) is a substituent selected from the following formulas:  
       
         
           
           
               
               
           
         
         wherein  
           is a single bond or a double bond,  
         R 2  is as defined in  claim 1 ,  
         R 3a  and R 4a  are the same or different and each is independently hydrogen atom, alkyl optionally having substituent(s), aryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroaryl optionally having substituent(s), heteroarylalkyl optionally having substituent(s), halogen, haloalkyl, cyano, nitro, —NR 5a R 6a , NHSO 2 R 7a , —OR 8b , —COOR 9a , —CONHSO 2 R 10a , —SO 2 OR 11a , —SO 2 R 12a  or —CONR 13a R 14a  wherein R 5a , R 6a , R 7a , R 8b , R 9a , R 10a , R 11a , R 12a , R 13a  and R 14a  are the same or different and each is independently a hydrogen atom, alkyl optionally having substituent(s), cycloalkyl optionally having substituent(s), cycloalkylalkyl optionally having substituent(s), aryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroaryl optionally having substituent(s), heteroarylalkyl optionally having substituent(s) or haloalkyl, R 5a  and R 6a , and R 13a  and R 14a  may be bonded to each other to form a heterocycle having carbon and at least one nitrogen, optionally having other heteroatom(s) and optionally having substituent(s), where this heterocycle is optionally substituted or condensed with an aromatic ring optionally having substituent(s),  
         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(are) carbon atom(s),  
         m′ is 0, 1, 2 or 3, and  
         A′ is a carbon atom or a nitrogen atom, 
 wherein i) when A′ is a carbon atom, then A′ may be substituted by a hydroxyl group, carboxy or alkoxycarbonyl, and ii) when A′ is a nitrogen atom, then  
   is a single bond,  
 
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         6 . The thiazolidine derivative of  claim 5 , wherein R 3a  and R 4a  of the formulas (II-a), (II-b), (II-c) and (II-d) may be the same or different and each is independently a hydrogen atom, alkyl optionally having substituent(s), aryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroaryl optionally having substituent(s), heteroarylalkyl optionally having substituent(s), halogen, haloalkyl, cyano, nitro, —NR 5a R 6a , —NHSO 2 R 7a , —OR 8b , —COOR 9a , —CONHSO 2 R 10a , —SO 2 OR 11a , —SO 2 R 12a  or —CONR 13a R 14a  wherein R 5a , R 6a , R 7a , R 8b , R 9a , R 10a , R 11a , R 12a , R 13a  and R 14a  are the same or different and each is independently a hydrogen atom, alkyl optionally having substituent(s), cycloalkyl optionally having substituent(s), cycloalkylalkyl optionally having substituent(s), aryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroaryl optionally having substituent(s), heteroarylalkyl optionally having substituent(s) or haloalkyl, and R 5a  and R 6a , and R 13a  and R 14a  may be bonded to each other to form a heterocycle optionally having 1 or 2 nitrogen atom(s) or oxygen atom(s) and optionally having substituent(s), where this heterocycle is optionally substituted or condensed with an aromatic ring optionally having substituent(s), or a pharmaceutically acceptable salt thereof.  
     
     
         7 . The thiazolidine derivative of  claim 3 , wherein Y is a sulfur atom and X′ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.  
     
     
         8 . The thiazolidine derivative of  claim 3 , wherein Y is a sulfur atom, X′ is a hydrogen atom and Y′ is phenylamino optionally having substituent(s), 2-pyridylamino optionally having substituent(s) or 4-(1-isoquinolyl)-1-piperazinyl optionally having substituent(s), or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A pharmaceutical composition comprising the thiazolidine derivative of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmacologically acceptable carrier.  
     
     
         10 . A DPP-IV inhibitor comprising the thiazolidine derivative of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A therapeutic agent of a disease, in which DPP-IV is involved, which comprises the thiazolidine derivative of any of  claim 1  or a pharmaceutically acceptable salt thereof as an active ingredient.  
     
     
         12 . The therapeutic agent of  claim 11 , wherein the disease, in which DPP-IV is involved, is diabetes or obesity.  
     
     
         13 . The thiazolidine derivative of  claim 2 , wherein, in the formula (I), X is a substituent represented by the formula (I-a) and Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof.