Use of a Compound for Inducing Differentiation of Mesenchymal Stem Cells into Cartilage Cells

Abstract

Use of a compound of Formula 1 for inducing differentiation of mesenchymal stem cells to chondrocytes, and a pharmaceutical composition for treating a cartilage disease, which includes chondrocytes in which differentiation from mesenchymal stem cells is induced by the compound of Formula 1, are provided. Differentiation of the mesenchymal stem cells treated with the compound of Formula 1 to chondrocytes is specifically induced, and thus the compound can be used to effectively treat a cartilage disease such as arthritis, cartilage damage, and a cartilage defect.

1 . A composition for inducing differentiation of mesenchymal stem cells to chondrocytes, comprising a compound of Formula 1: 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  are each independently hydrogen, C 6-12  aryl, C 1-12  alkyl, C 1-12  alkoxy, hydroxyl, carboxyl, or halogen, or R 1  and R 2  or R 2  and R 3  are joined together to form an aryl or heteroaryl ring having 5 to 12 carbon atoms; 
         R 4  and R 5  are each independently hydrogen, C 1-12  alkyl, C 1-12  alkoxy, hydroxyl, carboxyl, or halogen; 
         R 6  is C 6-12  aryl, C 3-12  cycloalkyl, or C 1-4  alkyl substituted with C 6-12  aryl; 
         R 7  is hydrogen or C 1-4  alkyl, and 
         R 1  to R 6  are each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl group, hydroxyl C 1-4  alkyl, nitro, carboxyl, and halogen. 
       
     
     
         2 . The composition of  claim 1 , wherein R 1  to R 3  are each independently hydrogen, phenyl, C 1-4  alkyl, or halogen, or R 1  and R 2  or R 2  and R 3  are joined together to form a pyridine or benzene ring;
 R 4  and R 5  are each independently hydrogen, C 1-4  alkyl, or halogen;   R 6  is phenyl group, naphthalyl, C 3-12  cycloalkyl, or C 1-4  alkyl substituted with phenyl;   R 7  is hydrogen or C 1-4  alkyl, and   R 1  to R 6  is each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl, hydroxyl C 1-4  alkyl, nitro group, carboxyl, and halogen.   
     
     
         3 . The composition of  claim 1 , wherein R 1  and R 2  are each independently hydrogen, or are joined together to form a pyridine ring;
 R 3  is hydrogen, phenyl, or C 1-4  alkyl, or is joined together with R 2  to form a benzene ring;   R 4  and R 5  are each independently hydrogen,   R 6  is phenyl, naphthalyl, C 5-10  cycloalkyl, or C 1-4  alkyl substituted with phenyl,   R 7  is hydrogen or C 1-4  alkyl, and   R 1  to R 6  is each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl, hydroxyl C 1-4  alkyl, nitro, carboxyl, and halogen.   
     
     
         4 . The composition of  claim 1 , wherein the compound of Formula 1 is at least one compound selected from the group consisting of:
 1) quinoline-8-sulfonic acid (4-hydroxy-phenyl)-amide;   2) quinoline-8-sulfonic acid (7-hydroxy-naphthalen-1-yl)-amide;   3) 2-hydroxy-5-(quinoline-8-sulfonylamino)-benzoic acid;   4) 5-(4-tert-butyl-benzenesulfonylamino)-2-hydroxy-benzoic acid;   5) biphenyl-4-sulfonic acid (5-hydroxy-naphthalen-1-yl)-amide;   6) N-(4-hydroxy-naphthalen-1-yl)-4-methyl-benzenesulfonamide;   7) naphthalene-2-sulfonic acid (4-hydroxyl-phenyl)-amide;   8) N-(5-hydroxyl-naphthalen-1-yl)-4-methyl-benzenesulfonamide;   9) N-(7-hydroxyl-naphthalen-1-yl)-4-methyl-benzenesulfonamide;   10) 4-tert-butyl-N-(3-hydroxyl-phenyl)-benzenesulfonamide;   11) 4-tert-butyl-N-(2-chloro-4-hydroxyl-phenyl)-benzenesulfonamide;   12) biphenyl-4-sulfonic acid (2-chloro-4-hydroxyl-phenyl)-amide;   13) naphthalene-2-sulfonic acid (2-chloro-4-hydroxyl-phenyl)-amide;   14) 4-tert-butyl-N-(2-fluoro-4-hydroxyl-phenyl)-benzenesulfonamide;   15) biphenyl-4-sulfonic acid (2-fluoro-4-hydroxyl-phenyl)-amide;   16) naphthalene-2-sulfonic acid (2-fluoro-4-hydroxyl-phenyl)-amide;   17) 4-tert-butyl-N-(3-fluoro-4-hydroxyl-phenyl)-benzenesulfonamide;   18) biphenyl-4-sulfonic acid (3-fluoro-4-hydroxyl-phenyl)-amide;   19) naphthalene-2-sulfonic acid (3-fluoro-4-hydroxyl-phenyl)-amide;   20) naphthalene-2-sulfonic acid (3-nitro-4-hydroxyl-phenyl)-amide;   21) 4-tert-butyl-N-[2-(3,4-dihydroxyl-phenyl)-ethyl]-benzenesulfonamide;   22) biphenyl-4-sulfonic acid [2-(3,4-dihydroxyl-phenyl)-ethyl]-amide;   23) naphthalene-2-sulfonic acid [2-(3,4-dihydroxyl-phenyl)-ethyl]-amide;   24) 4-tert-butyl-N-ethyl-N-(5-hydroxyl-2-methyl-phenyl)-benzenesulfonamide;   25) naphthalene-2-sulfonic acid ethyl-(5-hydroxyl-2-methyl-phenyl)-amide;   26) 4-tert-butyl-N-[4-(2-hydroxyl-ethyl)-cyclohexyl]-benzenesulfonamide;   27) biphenyl-4-sulfonic acid [4-(2-hydroxyl-ethyl)-cyclohexyl]-amide; and   28) naphthalene-2-sulfonic acid [4-(2-hydroxyl-ethyl)-cyclohexyl]-amide.   
     
     
         5 . A pharmaceutical composition for treating a cartilage disease, comprising:
 the chondrocytes in which differentiation from the mesenchymal stem cells is induced using the composition defined in  claim 1 .   
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the cartilage disease is arthritis, cartilage damage, or a cartilage defect. 
     
     
         7 . A compound of the following Formula 1: 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  are each independently hydrogen, C 6-12  aryl, C 1-12  alkyl, C 1-12  alkoxy, hydroxyl, carboxyl, or halogen, or R 1  and R 2  or R 2  and R 3  are joined together to form an aryl or heteroaryl ring having 5 to 12 carbon atoms; 
         R 4  and R 5  are each independently hydrogen, C 1-12  alkyl, C 1-12  alkoxy, hydroxyl, carboxyl, or halogen; 
         R 6  is C 6-12  aryl, C 3-12  cycloalkyl, or C 1-4  alkyl substituted with C 6-12  aryl; 
         R 7  is hydrogen or C 1-4  alkyl, and 
         R 1  to R 6  are each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl, hydroxyl C 1-4  alkyl, nitro, carboxyl, and halogen. 
       
     
     
         8 . The compound of  claim 7 , wherein R 1  to R 3  are each independently hydrogen, phenyl, C 1-4  alkyl, or halogen, or R 1  and R 2  or R 2  and R 3  are joined together to form a pyridine or benzene ring;
 R 4  and R 5  are each independently hydrogen, C 1-4  alkyl, or halogen;   R 6  is phenyl, naphthalyl, C 3-12  cycloalkyl, or C 1-4  alkyl substituted with phenyl;   R 7  is hydrogen or C 1-4  alkyl, and   R 1  to R 6  is each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl, hydroxyl C 1-4  alkyl, nitro, carboxyl, and halogen.   
     
     
         9 . The compound of  claim 7 , wherein R 1  and R 2  are each independently hydrogen, or are joined together to form a pyridine ring;
 R 3  is hydrogen, phenyl, or C 1-4  alkyl, or is joined together with R 2  to form a benzene ring;   R 4  and R 5  are each independently hydrogen,   R 6  is phenyl, naphthalyl, C 5-10  cycloalkyl, or C 1-4  alkyl substituted with phenyl,   R 7  is hydrogen or C 1-4  alkyl, and   R 1  to R 6  is each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl, hydroxyl C 1-4  alkyl, nitro, carboxyl, and halogen.   
     
     
         10 . The compound of  claim 7 , which is selected from the group consisting of:
 1) quinoline-8-sulfonic acid (4-hydroxy-phenyl)-amide;   2) quinoline-8-sulfonic acid (7-hydroxy-naphthalen-1-yl)-amide;   3) 2-hydroxy-5-(quinoline-8-sulfonylamino)-benzoic acid;   4) 5-(4-tert-butyl-benzenesulfonylamino)-2-hydroxy-benzoic acid;   5) biphenyl-4-sulfonic acid (5-hydroxy-naphthalen-1-yl)-amide;   6) N-(4-hydroxy-naphthalen-1-yl)-4-methyl-benzenesulfonamide;   7) naphthalene-2-sulfonic acid (4-hydroxyl-phenyl)-amide;   8) N-(5-hydroxyl-naphthalen-1-yl)-4-methyl-benzenesulfonamide;   9) N-(7-hydroxyl-naphthalen-1-yl)-4-methyl-benzenesulfonamide;   10) 4-tert-butyl-N-(3-hydroxyl-phenyl)-benzenesulfonamide;   11) 4-tert-butyl-N-(2-chloro-4-hydroxyl-phenyl)-benzenesulfonamide;   12) biphenyl-4-sulfonic acid (2-chloro-4-hydroxyl-phenyl)-amide;   13) naphthalene-2-sulfonic acid (2-chloro-4-hydroxyl-phenyl)-amide;   14) 4-tert-butyl-N-(2-fluoro-4-hydroxyl-phenyl)-benzenesulfonamide;   15) biphenyl-4-sulfonic acid (2-fluoro-4-hydroxyl-phenyl)-amide;   16) naphthalene-2-sulfonic acid (2-fluoro-4-hydroxyl-phenyl)-amide;   17) 4-tert-butyl-N-(3-fluoro-4-hydroxyl-phenyl)-benzenesulfonamide;   18) biphenyl-4-sulfonic acid (3-fluoro-4-hydroxyl-phenyl)-amide;   19) naphthalene-2-sulfonic acid (3-fluoro-4-hydroxyl-phenyl)-amide;   20) naphthalene-2-sulfonic acid (3-nitro-4-hydroxyl-phenyl)-amide;   21) 4-tert-butyl-N-[2-(3,4-dihydroxyl-phenyl)-ethyl]-benzenesulfonamide;   22) biphenyl-4-sulfonic acid [2-(3,4-dihydroxyl-phenyl)-ethyl]-amide;   23) naphthalene-2-sulfonic acid [2-(3,4-dihydroxyl-phenyl)-ethyl]-amide;   24) 4-tert-butyl-N-ethyl-N-(5-hydroxyl-2-methyl-phenyl)-benzenesulfonamide;   25) naphthalene-2-sulfonic acid ethyl-(5-hydroxyl-2-methyl-phenyl)-amide;   26) 4-tert-butyl-N-[4-(2-hydroxyl-ethyl)-cyclohexyl]-benzenesulfonamide;   27) biphenyl-4-sulfonic acid [4-(2-hydroxyl-ethyl)-cyclohexyl]-amide; and   28) naphthalene-2-sulfonic acid [4-(2-hydroxyl-ethyl)-cyclohexyl]-amide.   
     
     
         11 . A method of preparing the compound of Formula 1 according to  claim 7 , comprising: reacting a compound of Formula 2 with a compound of Formula 3 to prepare the compound of Formula 1: 
       
         
           
           
               
               
           
         
         wherein R 1  to R 3  are each independently hydrogen, C 6-12  aryl, C 1-12  alkyl, C 1-12  alkoxy, hydroxyl, carboxyl, or halogen, or R 1  and R 2  or R 2  and R 3  are joined together to form an aryl or heteroaryl ring having 5 to 12 carbon atoms; 
         R 4  and R 5  are each independently hydrogen, C 1-12  alkyl, C 1-12  alkoxy, hydroxyl, carboxyl, or halogen; 
         R 6  is C 6-12  aryl, C 3-12  cycloalkyl, or C 1-4  alkyl substituted with C 6-12  aryl; 
         R 7  is hydrogen or C 1-4  alkyl, and 
         R 1  to R 6  are each independently unsubstituted, or further substituted with at least one substituent selected from the group consisting of C 1-4  alkyl, hydroxyl, hydroxyl C 1-4  alkyl, nitro, carboxyl, and halogen.