Glycyrrhetinic acid derivatives

Abstract

The present invention relates to novel derivatives of glycyrrhetinic acid, compositions comprising said derivatives and their use in the treatment of conditions or diseases that benefits from an upregulation of PPARγ and/or a downregulation of the expression or activity of one or more specificity (Sp) proteins, such as cancer, diabetes and Huntington's disease.

We claim: 
     
         1 . A method of treating a condition or disease that benefits from an upregulation of PPARγ and/or a downregulation of the expression or activity of one or more specificity (Sp) proteins, comprising administering an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from CN, halo, NO 2 , CO 2 R 3 , C 1-6 alkyl, fluoro-substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR 3 , SR 3 , SOR 3 , SO 2 R 3 , NR 3 R 4 , C(O)NR 3 R 4 , C(O)R 3 , OC(O)R 3 , NHC(O)R 3 , P(O)R 3 R 4 , —C≡C—R 3 , —CR 3 ═CR 4 R 5 , aryl and heteroaryl; 
         R 2  is selected from OC 1-6 alkyl, fluoro-substituted OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl)(C 1-6 alkyl), SH and SC 1-6 alkyl; 
         R 3 , R 4  and R 5  are independently selected from H, C 1-6 alkyl, fluoro-substituted C 1-6 alkyl, aryl and heteroaryl; and 
         one of X and Y is C═O while the other is CH 2 , and if X is C═O then   adjacent to X represents a single bond and   adjacent to Y represents a double bond and if Y is C═O then   adjacent to Y represents a single bond and   adjacent to X represents a double bond; 
         and pharmaceutically acceptable salts, solvates and prodrugs thereof, 
         to a subject in need thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein R 1  is selected from CN, halo, NO 2 , CO 2 H, CO 2 C 1-4 alkyl, C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, OC 1-4 alkyl, fluoro-substituted OC 1-4 alkyl, OH, SH, SC 1-4 alkyl, SOC 1-4 alkyl, SO 2 C 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl)(C 1-4 alkyl), C(O)C 1-4 alkyl, OC(O)C 1-4 alkyl and NHC(O)C 1-4 alkyl. 
     
     
         3 . The method according to  claim 2 , wherein R 1  is selected from CN, halo, CO 2 H, CO 2 C 1-4 alkyl, C 1-4 alkyl, fluoro-substituted C 1-4 alkyl, OC 1-4 alkyl, fluoro-substituted OC 1-4 alkyl and OH. 
     
     
         4 . The method according to  claim 3 , wherein R 1  is selected from CN, Cl, Br, I, F, CO 2 H, CO 2 CH 3 , CH 3 , CF 3 , OCH 3 , OCF 3  and OH. 
     
     
         5 . The method according to  claim 4 , wherein R 1  is CN, CF 3  or I. 
     
     
         6 . The method according to  claim 1 , wherein R 2  is selected from OC 1-4 alkyl, fluoro-substituted OC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), SH and SC 1-4 alkyl. 
     
     
         7 . The method according to  claim 6 , wherein R 2  is selected from OC 1-4 alkyl and fluoro-substituted OC 1-4 alkyl. 
     
     
         8 . The method according to  claim 7 , wherein R 2  is selected from OCH 2 CH 3 , OCH 3  and OCF 3 . 
     
     
         9 . The method according to  claim 8 , wherein R 2  is OCH 3 . 
     
     
         10 . The method according to  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined in any one of  claims 1 - 9 , and pharmaceutically acceptable salts, solvates and prodrugs thereof. 
       
     
     
         11 . The method according to  claim 1 , wherein the compound is of the Formula 18α and 18β: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates and prodrugs thereof, and mixtures thereof in any ratio. 
       
     
     
         12 . The method according to  claim 1 , wherein the compound is selected from:
 2-cyano-3,11-dioxo-18β-oleana-1,12-dien-30-oic acid methyl ester;   2-cyano-3,11-dioxo-18α-oleana-1,12-dien-30-oic acid methyl ester;   2-iodo-3,11-dioxo-18β-oleana-1,12-dien-30-oic acid methyl ester;   2-iodo-3,11-dioxo-18α-oleana-1,12-dien-30-oic acid methyl ester;   2-trifluoromethyl-3,11-dioxo-18β-oleana-1,12-dien-30-oic acid methyl ester; and   2-trifluoromethyl-3,11-dioxo-18α-oleana-1,12-dien-30-oic acid methyl ester,   and pharmaceutically acceptable salts, solvates and prodrugs thereof, and mixtures thereof in any ratio.   
     
     
         13 . The method according to  claim 1 , wherein the compound is 2-cyano-3,11-dioxo-18β-oleana-1,12-dien-30-oic acid methyl ester, and pharmaceutically acceptable salts, solvates and prodrugs thereof, and mixtures thereof in any ratio. 
     
     
         14 . The method according to  claim 1 , wherein the condition or disease that benefits from an upregulation of PPARγ and/or a downregulation of the expression or activity of one or more specificity Sp proteins is cancer. 
     
     
         15 . The method according to  claim 14 , wherein the cancer is selected from prostate cancer and gastrointestinal cancers. 
     
     
         16 . The method according to  claim 15 , wherein the gastrointestinal cancer is selected from colon cancer and pancreatic cancer. 
     
     
         17 . The method according to  claim 1 , wherein the condition or disease that benefits from an upregulation of PPARγ and/or a downregulation of the expression or activity of one or more specificity Sp proteins is diabetes. 
     
     
         18 . The method according to  claim 17 , wherein the diabetes is insulin dependent type II diabetes. 
     
     
         19 . The method according to  claim 1 , wherein the condition or disease that benefits from an upregulation of PPARγ and/or a downregulation of the expression or activity of one or more specificity Sp proteins is Huntington's disease.