Triazole derivative and use thereof

Abstract

The present invention relates to a novel triazole derivative or a salt thereof. The triazole derivative or the salt thereof according to the present invention induces or promotes browning of white adipocytes, and differentiates stem cells, embryonic cells, or preadipocytes to brown adipocytes or beige adipocytes. A composition comprising the triazole derivative or the salt thereof according to the present invention can treat, prevent or alleviate obesity, obesity complications, diabetes, dyslipidemia, fatty liver, hypertension, metabolic syndrome, and insulin resistance syndrome.

What is claimed is: 
     
         1 . A compound represented by Formula 1 or a pharmaceutically or sitologically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is 
 
       
       
         
           
           
               
               
           
         
         
            C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or C3-10 heteroaryl or heterocycloalkyl having one or more hetero atoms selected from N, O and S unsubstituted or substituted with R 5 ,
 R 4  is 1 to 5 substituents each independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6 alkyl, —OR 6 , —O(CO)R 6 , —NO 2 , —N(R 6 ) 2 , —CN, —COR 6 , —NH(CO)R 6 , —NH(CO)NHR 6 , —NH(CS)NHR 6 , —NH(SO 2 )R 6 , —SH, —SR 6 , —SOR 6 , —S(CO)R 6 , —CO 2 R 6 , —CON(R 6 ) 2 , —S 3 H, —SO 2 N(R 6 ) 2  and —CF 3 , and is bonded to one or more of ortho, meta and para positions, 
 R 6  is each independently a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 
 
         
       
       
         
           
           
               
               
           
         
         
           
              or C3-10 heteroaryl or heterocycloalkyl having one or more hetero atoms selected from N, O and S, 
             R 12  is —NHR 13 , —N(R 13 ) 2 , —OR 13 , 
           
         
       
       
         
           
           
               
               
           
         
         
           
              or morpholin, wherein R 13  is a hydrogen atom or C1-C6 alkyl, 
             X is a hydrogen atom, NH 2  or OH, and n is 0, 1, 2 or 3, 
             R 5  is 1 to 5 substituents each independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6 alkyl, —OR 7 , —O(CO)R 7 , —NO 2 , —N(R 7 ) 2 , —CN, —COR 7 , —NH(CO)R 7 , —NH(CO)NHR 7 , —NH(CS)NHR 7 , —NH(SO 2 )R 7 , —SH, —SR 7 , —SOR 7 , —S(CO)R 7 , —CO 2 R 7 , —CON(R 7 ) 2 , —SO 3 H, —SO 2 N(R 7 ) 2  and —CF 3 , and is bonded to one or more of ortho, meta and para positions, 
             R 7  is each independently a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or C3-10 heteroaryl or heterocycloalkyl having one or more hetero atoms selected from N, O and S; 
           
           R 2  is a hydrogen atom or NH 2 ; 
           R 3  is 
         
       
       
         
           
           
               
               
           
         
         
            C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or C3-10 heteroaryl or heterocycloalkyl having one or more hetero atoms selected from N, O and S unsubstituted or substituted with R 9 ,
 R 8  is 1 to 5 substituents each independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6 alkyl, —OR 10 , —O(CO)R 10 , —NO 2 , —N(R 10 ) 2 , —CN, —COR 10 , —NH(CO)R 10 , —NH(CO)NHR 10 , —NH(CS)NHR 10 , —NH(SO 2 )R 10 , —SH, —SR 10 , —SOR 10 , —S(CO)R 10 , —CO 2 R 10 , —CON(R 10 ) 2 , —S 3 H, —SO 2 N(R 10 ) 2  and —CF 3 , and is bonded to one or more of ortho, meta and para positions, 
 R 10  is each independently a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, 
 
         
       
       
         
           
           
               
               
           
         
         
           
              or C3-10 heteroaryl or heterocycloalkyl having one or more hetero atoms selected from N, O and S, 
             R 12  is —NHR 13 , —N(R 13 ) 2 , —OR 13 , 
           
         
       
       
         
           
           
               
               
           
         
         
           
              or morpholin, wherein R 13  is a hydrogen atom or C1-C6 alkyl, 
             X is a hydrogen atom, NH 2  or OH, and n is 0, 1, 2 or 3, 
             R 9  is 1 to 5 substituents each independently selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6 alkyl, —OR 11 , —O(CO)R 11 , —NO 2 , —N(R 11 ) 2 , —CN, —COR 11 , —NH(CO)R 11 , —NH(CO)NHR 11 , —NH(CS)NHR 11 , —NH(SO 2 )R 11 , —SH, —SR 11 , —SOR 11 , —S(CO)R 11 , —CO 2 R 11 , —CON(R 11 ) 2 , —S 3 H, —SO 2 N(R 11 ) 2  and —CF 3 , and is bonded to one or more of ortho, meta and para positions, 
             R 11  is each independently a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or C3-10 heteroaryl or heterocycloalkyl having one or more hetero atoms selected from N, O and S. 
           
         
       
     
     
         2 . The compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 , wherein the compound represented by Formula 2: 
       
         
           
           
               
               
           
         
         wherein R 2 , R 3  and R 4  are as described in  claim 1 . 
       
     
     
         3 . The compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 , wherein the compound represented by Formula 3: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 8  are as described in  claim 1 . 
     
     
         4 . The compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 , wherein the compound is selected from the group consisting of:
 4-(1-(2,4-dimethoxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-fluorophenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-hydroxy-3-methylphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   (E)-N-(4-chlorophenethyl)-3-(3,4-dihydroxyphenyl)acrylamide;   4-(1-(3-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(3,4-difluorophenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(2-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-fluoro-3-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(3-fluorophenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(3-fluoro-4-methoxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(2-fluorophenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(2,3-difluoro-4-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-(2-hydroxyethoxy)phenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol;   4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol hydrochloride;   4-(1-(4-(3-(dimethylamino)-2-hydroxypropoxy)phenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol hydrochloride;   N-(2-(diethylamino)ethyl)-4-(4-(3,4-dihydroxyphenyl)-1H-1,2,3-triazole-1-yl)benzamide hydrochloride;   N-(3-(diethylamino)propyl)-4-(4-(3,4-dihydroxyphenyl)-1H-1,2,3-triazole-1-yl)benzamide hydrochloride;   1-(3,4-dimethoxyphenyl)-4-phenyl-1H-1,2,3-triazole-5-amine;   4-(5-amino-4-phenyl-1H-1,2,3-triazole-1-yl)benzene-1,2-diol;   4-(benzo[d][1,3]dioxol-5-yl)-1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole-5-amine;   4-(4-chlorophenyl)-1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole-5-amine;   4-(5-amino-4-(4-chlorophenyl)-1H-1,2,3-triazole-1-yl)benzene-1,2-diol;   4-(5-amino-1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)benzene-1,2-diol; and   4-(5-amino-1-(3,4-dihydroxyphenyl)-1H-1,2,3-triazole-4-yl)-N-(2-(diethylamino)ethyl)benzamide hydrochloride.   
     
     
         5 . A composition for inducing or promoting browning of white adipocytes, comprising the compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 . 
     
     
         6 . The composition according to  claim 5 , wherein the white adipocytes are transdifferentiated into beige adipocytes or brown adipocytes. 
     
     
         7 . A composition for inducing or promoting differentiation of stem cells, embryonic cells or preadipocytes into brown adipocytes or beige adipocytes, comprising the compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 . 
     
     
         8 . A composition comprising the compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 , wherein the composition increases the expression of UCP1. 
     
     
         9 . A composition comprising the compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 , wherein the composition is a pharmaceutical composition for treating or preventing one or more selected from the group consisting of obesity, obesity complications, diabetes, dyslipidemia, fatty liver, hypertension, metabolic syndrome and insulin resistance syndrome. 
     
     
         10 . A composition comprising the compound or pharmaceutically or sitologically acceptable salt thereof according to  claim 1 , wherein the composition is a food composition for alleviating or preventing one or more selected from the group consisting of obesity, obesity complications, diabetes, dyslipidemia, fatty liver, hypertension, metabolic syndrome and insulin resistance syndrome.