Thiazole derivative

Abstract

A thiazolylimidazole derivative represented by the formula or a pharmaceutically acceptable salt thereof, and an ALK5 inhibitor, an therapeutic agent for alopecia or a hair growth agent having the above as an active ingredient, wherein: X 1 and X 2 are different from each other and represent a sulfur atom or a carbon atom; R 1 represents a phenyl group; a substituted phenyl group; a phenyl group condensed with a hetero aromatic ring; a pyridyl group; or a pyridyl group condensed with a hetero aromatic ring; R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms, an alkoxy group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, or a hydroxyalkyl group having 1 to 6 carbon atoms, A represents a group which is represented by the formula. The present invention provides an inhibitory substance against ALK5 which is a TGF-β type I receptor and provides a hair growth stimulant or a hair growth agent based on its novel activities.

1 . A thiazole derivative represented by the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       X 1  and X 2  are different from each other and represent a sulfur atom or a carbon atom; 
       R 1  represents a phenyl group;
 a phenyl group substituted with 1 to 5 members selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, a hydroxy group, phenylalkoxy groups having 7 to 12 carbon atoms, and alkylamino groups having 1 to 6 carbon atoms; 
 a phenyl group condensed with a 5 to 7 membered hetero aromatic or non-aromatic ring having at least one hetero atom selected from the group consisting of N, O, and S; 
 a pyridyl group; 
 a quinolyl group; 
 an isoquinolyl group; or 
 a pyridyl group condensed with a 5 to 7 membered hetero aromatic ring having at least one hetero atom selected from the group consisting of N, O, and S; 
 
       R 2  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms, an alkoxy group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, or a hydroxyalkyl group having 1 to 5 carbon atoms; and 
       A represents a group which is represented by the formula 
     
     
       
         
         
             
             
         
       
       wherein: 
          represents the bond to the thiazole group of formula (I); 
     
     wherein:
 R 3  represents a hydrogen atom;
 a hydroxy group; 
 an alkyl group having 1 to 6 carbon atoms; 
 a phenylalkyl group having 7 to 12 carbon atoms; or 
 a phenylalkyl group having 7 to 12 carbon atoms, substituted with a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms substituted with an alkylamino group having 1 to 6 carbon atoms, 
 
 R 4  represents a phenyl group;
 a phenyl group substituted with 1 to 5 members selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, a carbamoyl group, and a cyano group; 
 a hydrogen atom; 
 an alkyl group having 1 to 12 carbon atoms; 
 an alkenyl group having 2 to 12 carbon atoms; 
 a cycloalkyl group having 3 to 7 carbon atoms; 
 an alkyl group having 1 to 12 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, a hydroxy group, an alkoxyphenylalkoxy group having 8 to 12 carbon atoms, a phthalimidoyl group, a toluenesulfonyloxy group, or a morpholino group; 
 an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms; 
 a cycloalkyl group having 3 to 9 carbon atoms substituted with an oxo group; 
 a tetrahydropyranyl group; 
 a 4-piperidinyl group; 
 a piperidinyl group substituted with an alkyl group having 1 to 6 carbon atoms or a t-butoxycarbonyl group; 
 a cyclohexanespiro-2′-(1,3-dioxoranyl) group; 
 a pyrrolidin-2-one-5-yl group; 
 a group represented by the formula —Y 1 —Z 1 —NR 5 —Z 2 —Y 2 —R 6 , 
 wherein: 
 Y 1  and Y 2  are the same or different from each other and represent a single bond or an alkylene group having 1 to 12 carbon atoms; 
 R 5  represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms; 
 Z 1  and Z 2  are the same or different from each other and represent a single bond; 
 an alkylene group having 1 to 7 carbon atoms; 
 —CO—; 
 —CO 2 —; 
 —SO 2 —; or 
 —OCO—, and 
 R 6  represents 
 a cycloalkyl group having 3 to 7 carbon atoms; 
 an alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms; 
 an alkenyl group having 2 to 6 carbon atoms; 
 an alkynyl group having 2 to 6 carbon atoms; 
 an amino group; 
 an amino group substituted with 1 to 2 groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a t-butoxycarbonyl group; 
 a piperidino group; 
 a piperidinyl group; 
 a piperidinyl group substituted with an alkyl group having 1 to 6 carbon atoms; 
 a pyrrolidinyl group; 
 
 a piperazinyl group;
 a piperazinyl group substituted with an alkyl group having 1 to 6 carbon atoms; 
 a morpholino group; 
 a hydroxy group; 
 an alkoxy group having 1 to 6 carbon atoms; 
 an alkoxy group having 1 to 6 carbon atoms substituted by a hydroxy group or an alkoxy group having 1 to 6 carbon atoms; 
 an oxetan-2-yl group; 
 a tetrahydropyranyl group; 
 a tetrahydropyranyl group; 
 a hydrogen atom; 
 a phenyl group; 
 a phenyl group substituted with an alkoxy group having 1 to 4 carbon atoms; or 
 a group that forms a ring when linked to the nitrogen atom of the above formula; or 
 a group represented by the formula —Y 3 —CO—R 41 , 
 wherein: 
 Y 3  represents a single bond or an alkylene group having 1 to 7 carbon atoms, 
 R 41  represents 
 a hydroxy group; 
 an alkoxy group having 1 to 6 carbon atoms; 
 a piperidino group; 
 a piperazin-1-yl group substituted by an alkyl group having 1 to 6 carbon atoms, a morpholinoalkyl group having 5 to 10 carbon atoms, or an alkylaminoalkyl group having 2 to 14 carbon atoms; or 
 a morpholino group. 
 
 
   
   
       2 . The thiazole derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms. 
   
   
       3 . The thiazole derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is an alkyl group having 1 to 6 carbon atoms or a trifluoromethyl group. 
   
   
       4 . The thiazole derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 2  is a methyl group or a trifluoromethyl group. 
   
   
       5 . The thiazole derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is a phenyl group condensed with a 5 to 7 membered hetero aromatic or non-aromatic ring containing at least one hetero atom selected from the group consisting of N, O, and S. 
   
   
       6 . The thiazole derivative or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein X 1  is a sulfur atom and X 2  is a carbon atom. 
   
   
       7 - 11 . (canceled) 
   
   
       12 . A thiazole derivative represented by the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       X 1  and X 2  are different from each other and represent a sulfur atom or a carbon atom; 
       R 1  represents a phenyl group;
 a phenyl group substituted by 1 to 5 members selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, a hydroxy group, phenylalkoxy groups having 7 to 12 carbon atoms, and alkylamino groups having 1 to 6 carbon atoms; 
 a phenyl group condensed with a 5 to 7 membered hetero aromatic or non-aromatic ring having at least one hetero atom selected from the group consisting of N, O, and S; 
 a pyridyl group; 
 a quinolyl group; 
 an isoquinolyl group; or 
 a pyridyl group condensed with a 5 to 7 membered hetero aromatic ring having at least one hetero atom selected from the group consisting of N, O, and S; 
 
       R 2  represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms, an alkoxy group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, or a hydroxyalkyl group having 1 to 5 carbon atoms; and 
       A 1  represents a group which is represented by the formula 
     
     
       
         
         
             
             
         
       
       
         wherein X 3  represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms. 
       
     
   
   
       13 . A method for treating glomerulonephritis, diabetic nephropathy, hepatic fibrosis, liver cirrhosis, pulmonary fibrosis, or alopeciarosis in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of the thiazole derivative or a pharmaceutically acceptable salt thereof according to  claim 1 . 
   
   
       14 . The method of  claim 13 , wherein the administration is carried out by external application.