Dipeptidyl ketoamide compounds and their use for the treatment and/or prevention of fat accumulation

Abstract

The present invention relates to the use of dipeptidyl ketoamide compounds for preventing accumulation of triglycerides in adipose tissue or for reducing the amount of triglycerides in adipose tissue in a subject in need thereof and to novel dipeptidyl ketoamide compounds.

1 . A method of (i) treating and/or preventing an obesity-related condition selected from the group consisting of obesity, lipid storage disease, and hyperlipemia in a subject in need thereof, and/or (ii) reducing fat accumulation in a subject which does not suffer from obesity, said method comprising administering to said subject a therapeutically effective amount of a method of (i) treating and/or preventing an obesity-related condition selected from the group consisting of obesity, lipid storage disease, and hyperlipemia in a subject in need thereof, and/or (ii) reducing fat accumulation in a subject which does not suffer from obesity, said method comprising administering to said subject a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein
 X is selected from the group consisting of a single bond, an oxygen atom and a —NH— group; 
 when X is O, R 1  is selected from the group consisting of a) C 1-8 -alkyl, optionally substituted by one C 1-8  alkoxy group, b) C 6-10 -aryl-C 1-4 alkyl and c) C 5-10  heteroaryl-C 1-4  alkyl wherein the C 5-10  heteroaryl ring system comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, 
 when X is a single bond or a —NH— group, R 1  is selected from the group consisting of d) phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl; C 1-6  linear or branched alkoxy and halogen atoms; e) naphthyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl, C 1-6  linear or branched alkoxy and halogen atoms; f) C 5-10  heterocyclyl-C 0-2  alkyl wherein the heterocyclyl ring system is saturated or unsaturated and comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and is optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl and halogen atoms; g) C 1-6  linear or branched alkyl, optionally substituted by one C 1-8  alkoxy group and h) C 3-6  cycloalkyl-C 0-2  alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NH 2 , CN, CF 3 , C 1-6  linear or branched alkyl and halogen atoms; 
 R 2  is selected from the group consisting of i) C 1-8 -alkyl optionally substituted with 1, 2 or 3 fluor atoms, j) C 1-8 -alkoxy-O—C 1-8 -alkyl and k) C 3-6  cycloalkyl-C 0-2  alkyl wherein the cycloalkyl ring is optionally substituted with 1, 2 or 3 fluor atoms; 
 R 3  is selected from the group consisting of 1) C 1-8 -alkyl and m) benzyl optionally substituted by 1 to 3 substituents selected from the group consisting of C 1-4 -alkyl, MeO, CN and halogen atoms; 
 R 4  is selected from the group consisting of n) C 1-8 -alkyl, o) C 3-6  cycloalkyl-C 0-2  alkyl optionally substituted by C 1-4 -alkyl and p) C 1-8 -alkoxy; and 
 R 5  and R 6  are independently selected from the group consisting of hydrogen atoms and C 1-6 linear or branched alkyl groups; 
 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein:
 X is selected from the group consisting of a single bond, an oxygen atom and a —NH— group,   when X is O, R 1  is selected from the group consisting of a) C 1-8 -alkyl, b) C 6-10  aryl-C 1-4  alkyl and c) C 5-10  heteroaryl-C 1-4  alkyl wherein the C 5-10  heteroaryl ring system comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur,   when X is an single bond or a —NH— group, R 1  is selected from the group consisting of d) phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl; C 1-6  linear or branched alkoxy and halogen atoms; e) naphthyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl, C 1-6  linear or branched alkoxy and halogen atoms; f) C 5-10  heterocyclyl-C 0-2  alkyl wherein the heterocyclyl ring system is saturated or unsaturated and comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and is optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl and halogen atoms; g) C 1-6  linear or branched alkyl and h) C 3-6  cycloalkyl-C 0-2  alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl and halogen atoms;   R 2  is selected from the group consisting of i) C 1-8 -alkyl, j) C 1-8 -alkoxy-O—C 1-8 -alkyl and k) C 3-6 cycloalkyl-C 0-2 alkyl;   R 3  is selected from the group consisting of l) C 1-8 -alkyl and m) benzyl optionally substituted by 1 to 3 substituents selected from the group consisting of C 1-4 -alkyl, MeO, CN and halogen atoms;   R 4  is selected from the group consisting of n) C 1-8 -alkyl and o) C 3-6 cycloalkyl-C 0-2 alkyl optionally substituted by C 1-4 -alkyl; and   R 5  and R 6  are independently selected from the group consisting of hydrogen atoms and C 1-6  linear or branched alkyl groups.   
     
     
         3 . The method of  claim 1 , wherein X is a single bond. 
     
     
         4 . The method of  claim 1 , wherein R 1  is selected from the group consisting of d) phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl, C 1-6  linear or branched alkoxy and halogen atoms; and f) C 5-10  heterocyclyl-C 0-2  alkyl wherein the heterocyclyl ring system is saturated or unsaturated and comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur and is optionally substituted by 1 to 3 substituents selected from the group consisting of OH, NR 5 R 6 , CN, CF 3 , C 1-6  linear or branched alkyl and halogen atoms. 
     
     
         5 . The method of  claim 1 , wherein R 2  is selected from the group consisting of linear or branched C 2-5  alkyl and C 3-5  cycloalkyl. 
     
     
         6 . The method of  claim 5 , wherein R 2  is selected from the group consisting of isopropyl, propyl and cyclopropyl. 
     
     
         7 . The method of  claim 1 , wherein R 3  is benzyl optionally substituted by 1 to 3 substituents selected from the group consisting of C 1-4  alkyl, MeO, CN and halogen atoms. 
     
     
         8 . The method of  claim 1 , wherein R 3  is benzyl optionally substituted by 1 to 3 substituents selected from the group consisting of C 1-4 -alkyl, MeO, CN and halogen atoms; and R 2  is selected from the group consisting of isopropyl, propyl and cyclopropyl. 
     
     
         9 . The method of  claim 1 , wherein R 4  is selected from the group consisting of C 2-5  linear or branched alkyl and C 3-5  cycloalkyl, both optionally substituted by C 1-4 -alkyl. 
     
     
         10 . The method of  claim 9 , wherein R 4  is selected from the group consisting of ethyl, tert-butyl and cyclopropyl. 
     
     
         11 - 25 . (canceled)