5-pyridyl-1, 3-azole compounds, process for producing the same and use there of

Abstract

An optionally N-oxidized compound represented by the formula: wherein R 1 represents hydrogen, hydrocarbon, heterocycle, amino, acyl, R 2 represents an aromatic group, R 3 represents hydrogen, pyridyl, aromatic hydrocarbon, X represents oxygen, optionally oxidized sulfur, Y represents a bond, an oxygen, optionally oxidized sulfur, a group represented by the formula NR 4 (R 4 represents hydrogen, hydrocarbon or acyl) and Z represents a bond or a divalent acyclic hydrocarbon, or a salt thereof has an excellent adenosine A 3 receptor antagonistic activity and is used as an agent for preventing or treating diseases related to an adenosine A 3 receptor. Furthermore, the compound (I) or a salt thereof has p38 MAP kinase inhibitory activity and TNF-α inhibitory activity and is used as an agent for preventing or treating diseases related to p38 MAP kinase and diseases related to TNF-α.

1 . An optionally N-oxidized compound represented by the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  represents 
         (i) a hydrogen atom, 
         (ii) a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group [wherein these groups may have substituents selected from the group (substituent group A) consisting of oxo, halogen atom, C 1-3  alkylenedioxy, nitro, cyano, optionally halogenated C 1-6  alkyl, optionally halogenated C 2-6  alkenyl, carboxy C 2-6  alkenyl, optionally halogenated C 1-6  alkynyl, optionally halogenated C 3-6  cycloalkyl, C 6-14  aryl, optionally halogenated C 1-8  alkoxy, C 1-6  alkoxy-carbonyl-C 1-6  alkoxy, hydroxy, C 6-14  aryloxy, C 7-16  aralkyloxy, mercapto, optionally halogenated C 1-6  alkylthio, C 6-14  arylthio, C 7-16  aralkylthio, amino, mono-C 1-6  alkylamino, mono-C 6-14  arylamino, di-C 1-6  alkylamino di-C 6-14  arylamino, formyl, carboxy, C 1-6  alkyl-carbonyl, C 3-6  cycloalkyl-carbonyl, C 1-6  alkoxy-carbonyl, C 6-14  aryl-carbonyl, C 7-16  aralkyl-carbonyl, C 6-14  aryloxy-carbonyl, C 7-16  aralkyloxy-carbonyl, carbamoyl, thiocarbamoyl, mono-C 1-6  alkyl-carbamoyl, di-C 1-6  alkyl-carbamoyl, C 6-14  aryl-carbamoyl, C 1-6  alkylsulfonyl, C 6-14  arylsulfonyl, C 1-6  alkylsulfinyl, C 6-14  arylsulfinyl, formylamino, C 1-6  alkyl-carbonylamino, C 6-14  aryl-carbonylamino, C 1-6  alkoxy-carbonylamino, C 1-6  alkylsulfonylamino, C 6-14  arylsulfonylamino, C 1-6  alkyl-carbonyloxy, C 6-14  aryl-carbonyloxy, C 1-6  alkoxy-carbonyloxy, mono-C 1-6  alkyl-carbamoyloxy, di-C 1-6  alkyl-carbamoyloxy, C 6-14  aryl-carbamoyloxy, sulfo, sulfamoyl, sulfinamoyl and sulfinamoyl], 
         (iii) an acyl group represented by the formula:
   —(C═O)—R 5 ,—(C═O)—OR 5 , —(C═O)—NR 5 R 6 , —(C═S)—NHR 5  or —SO 2 —R 7    
 
       
       wherein R 5  represents {circle around (1)} a hydrogen atom or {circle around (2)} a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A, R 6  represents a hydrogen atom or a C 1-6  alkyl group, R 7  represents a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6 cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A, or
 (iv) an amino group optionally having substituents selected from the group consisting of {circle around (1)} a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A, {circle around (2)} an acyl group as defined in the (iii), and {circle around (3)} a C 1-6  alkylidene group optionally having substituents selected from the substituent group A, 
 R 2  represents a 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, optionally having substituents selected from the substituent group A; 
 R 3  represents {circle around (1)} a hydrogen atom or {circle around (2)} a C 6-14  aryl group optionally having substituents selected from the substituent group A; 
 X represents an optionally oxidized sulfur atom, 
 Y represents a bond, an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4 , wherein R 4  represents {circle around (1)} a hydrogen atom, {circle around (2)} a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 1-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A or {circle around (3)} an acyl group as defined in the (iii), and 
 Z represents a bond, a C 1-15  alkylene group, a C 2-16  alkenylene group or a C 2-16  alkynylene group optionally having substituents selected from the substituent group A, 
 
       or a salt thereof. 
     
     
         2 . The compound according to  claim 1 , wherein Z is a C 1-15  alkylene group, a C 2-16  alkenylene group or a C 2-16  alkynylene group optionally having substituents selected from the substituent group A. 
     
     
         3 . The compound according to  claim 1 , which is a compound represented by the formula: 
       
         
           
           
               
               
           
         
       
       wherein n represents 0 or 1, and other symbols are as defined in  claim 1 , or a salt thereof. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  represents
 (i) a hydrogen atom,   (ii) a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group [wherein these groups may have substituents selected from the substituent group A],   (iii) an acyl group represented by the formula:
   —(C═O)—R 5 ,—(C═O)—OR 5 , —(C═O)—NR 5 R 6 , —(C═S)—NHR 5  or —SO 2 —R 7    
   
       wherein R 5  represents {circle around (1)} a hydrogen atom or {circle around (2)} a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A, R 6  represents a hydrogen atom or a C 1-6  alkyl group, R 7  represents a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A, or
 (iv) an amino group, wherein the amino group may have substituents selected from the group consisting of {circle around (1)} a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl group or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A, {circle around (2)} an acyl group as defined in the (iii), and {circle around (3)} a C 1-6  alkylidene group optionally having substituents selected from the substituent group A, 
 R 2  represents a 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, optionally having substituents selected from the substituent group A; 
 R 3  represents {circle around (1)} a hydrogen atom or {circle around (2)} a C 6-14  monocyclic or fused polycyclic aromatic hydrocarbon group optionally having substituents selected from the substituent group A; 
 X represents S, SO or SO 2 ; and 
 Y represents a bond, O, S, SO, SO 2  or a group represented by the formula: NR 4 , wherein R 4  represents {circle around (1)} a hydrogen atom, {circle around (2)} a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 3-6  cycloalkyl group, a C 6-14  aryl or a C 7-16  aralkyl group optionally having substituents selected from the substituent group A or {circle around (3)} an acyl group as defined in the (iii). 
 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is an amino group, as defined in (iv) of  claim 1 . 
     
     
         6 . The compound according to  claim 1 , wherein R 1  is (i) a C 1-6  alkyl group, (ii) a C 6-14  aryl group optionally substituted with substituents selected from the group consisting of C 1-6  alkylthio, C 1-6  alkylsulfonyl and halogen atom, or (iii) an amino group optionally having 1 or 2 acyl represented by the formula: —(C═O)—R 5 ′, wherein R 5 ′ represents {circle around (1)} a C 1-6  alkyl group or {circle around (2)} a C 6-14  aryl group. 
     
     
         7 . The compound according to  claim 1 , wherein R 1  is an amino group optionally having 1 or 2 acyl group represented by —(C═O)—R 5 ″, wherein R 5 ″ represents a C 6-14  aryl group. 
     
     
         8 . (canceled) 
     
     
         9 . The compound according to  claim 1 , wherein R 2  is a 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms. 
     
     
         10 . (canceled) 
     
     
         11 . The compound according to  claim 1 , wherein R 3  is a C 6-14  aryl group optionally having substituents selected from the substituent group A. 
     
     
         12 . The compound according to  claim 1 , wherein R 3  is a C 6-14  aryl group optionally substituted with one or two C 1-6  alkyl or C 1-6  alkoxy. 
     
     
         13 . (canceled) 
     
     
         14 . The compound according to  claim 1 , wherein X is a sulfur atom. 
     
     
         15 . The compound according to  claim 1 , wherein Y is an oxygen atom or a group represented by the formula: NR 4 , wherein R 4  is as defined in  claim 1 . 
     
     
         16 . The compound according to  claim 1 , wherein Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4′ , wherein R 4′  represents a C 1-6  alkyl group. 
     
     
         17 . The compound according to  claim 1 , wherein Y is O, NH or S. 
     
     
         18 . The compound according to  claim 1 , wherein Z is a lower alkylene group optionally having substituents selected from the substituent group A. 
     
     
         19 . The compound according to  claim 1 , wherein Z is a bond or a C 1-6  alkylene group optionally having oxo. 
     
     
         20 . The compound according to  claim 1 , wherein R 1  is (i) a C 1-6  alkyl group, (ii) a C 6-14  aryl group optionally substituted with C 1-6  alkylthio, C 1-6  alkylsulfonyl or halogen atom, or (iii) an amino group optionally having 1 or 2 acyl group represented by the formula: —(C═O)—R 5′  wherein R 5′  represents {circle around (1)} a C 1-6  alkyl group or {circle around (2)} a C 6-14  aryl group;
 R 2  is a 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;   R 3  is a C 6-14  aryl group optionally substituted with 1 or 2 C 1-6  alkyl or C 1-6  alkoxy;   X is a sulfur atom;   Y is an oxygen atom, an optionally oxidized sulfur atom or a group represented by the formula: NR 4′ , wherein R 4′  represents a C 1-6  alkyl group; and   Z is a C 1-6  alkylene group optionally having oxo or C 1-6  alkyl or a bond.   
     
     
         21 . The compound according to  claim 1 , wherein R 1  is an amino group optionally having 1 or 2 acyl represented by —(C═O)—R 5 ″, wherein R 5 ″ represents a C 6-14  aryl group;
 R 2  is a 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms of one or two kinds selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms;   R 3  is a C 6-14  aryl group optionally substituted with 1 or 2 C 1-6  alkyl or C 1-6  alkoxy;   X is a sulfur atom; Y is O, NH or S; and Z is a bond or a C 1-6  alkylene group optionally having oxo.   
     
     
         22 - 24 . (canceled) 
     
     
         25 . A pharmaceutical composition which comprises the compound according to  claim 1  together with a pharmacologically acceptable carrier. 
     
     
         26 - 41 . (canceled) 
     
     
         42 . N-[4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide, 
       N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-2-thiophenecarboxamide, or 
       N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-thienylmethyl)amine, or a salt thereof.