Acylamide compounds having secretagogue or inducer activity of adiponectin

Abstract

The present invention provides acylamide compounds, prodrugs thereof, or pharmaceutically acceptable salts thereof; and an adiponectin inducer or secretagogue, and therapeutic methods by administering the same.

1 . A method of treating a metabolic syndrome in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       2 . The method of  claim 1 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 1 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       4 . The method according to  claim 1 , wherein, in the formula (1), R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 is a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, cyclic alkyl group having 3 to 10 carbon atoms, aryl group having 6 to 8 carbon atoms, heteroaryl group having 1 to 8 carbon atoms, arylalkyl group having 7 to 17 carbon atoms, heteroarylalkyl group having 2 to 8 carbon atoms or alkylthioalkyl group having 2 to 4 carbon atoms; R3 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R4 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and X is an oxygen atom. 
   
   
       5 . The method according to  claim 4 , wherein, in the formula (1), R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 is a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, phenylalkyl group having 7 to 8 carbon atoms or alkylthioalkyl group having 2 to 4 carbon atoms; R3 is a hydrogen atom; R4 is a hydrogen atom; and R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond. 
   
   
       6 . The method according to  claim 4 , wherein, in the formula (1), R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 is a methyl group, isopropyl group, isobutyl group, sec-butyl group, phenylmethyl group or methylthioethyl group; R3 is a hydrogen atom; R4 is a hydrogen atom; and R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond. 
   
   
       7 . The method according to  claim 4 , wherein, in the formula (1), R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 is a straight- or branched-chain alkyl group having 1 to 4 carbon atoms, phenylalkyl group having 7 to 8 carbon atoms or alkylthioalkyl group having 2 to 4 carbon atoms; R3 is an alkyl group having 1 to 4 carbon atoms; R4 is a hydrogen atom; and R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond. 
   
   
       8 . The method according to  claim 1 , wherein, in the formula (1), R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 is a straight- or branched-chain alkyl group having 1 to 4 carbon atoms; R3 is a hydrogen atom; R4 is a hydrogen atom or a straight-chain having 1 to 16 carbon atoms, branched-chain having 1 to 16 carbon atoms or cyclic alkyl group having 3 to 16 carbon atoms; R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and X is NH. 
   
   
       9 . A method of treating hyperlipemia in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       10 . The method of  claim 9 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       11 . The method of  claim 9 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       12 . A method of treating diabetes in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       13 . The method of  claim 12 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       14 . The method of  claim 12 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       15 . A method for improving glucose tolerance in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
     
     wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
 R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
 R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
 R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
 R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
 X is an oxygen atom or NH. 
 
   
   
       16 . The method of  claim 15 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 15 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       18 . A method of improving insulin resistance or enhancing insulin sensitivity in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       19 . The method of  claim 18 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       20 . The method of  claim 18 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       21 . A method of treating hypertension in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       22 . The method of  claim 21 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       23 . The method of  claim 21 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       24 . A method of treating a disorder selected from the group consisting of hepatic inflammation, fatty liver, hepatic fibrosis and liver cirrhosis in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       25 . The method of  claim 24 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       26 . The method of  claim 24 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       27 . A method of treating non-alcoholic/nonviral steatohepatitis (NASH) or non-alcoholic/nonviral fatty liver disease (NAFLD) in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       28 . The method of  claim 27 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       29 . The method of  claim 27 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       30 . A method of treating obesity in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       31 . The method of  claim 30 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       32 . The method of  claim 30 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.   
   
   
       33 . A method of treating hypoadiponectinemia in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an acylamide compound, or pharmaceutically acceptable salt thereof, of the formula (1): 
     
       
         
         
             
             
         
       
       wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; 
       R2 is an alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, arylalkyl group having 7 to 20 carbon atoms, heteroarylalkyl group having 2 to 11 carbon atoms or alkylthioalkyl group having 2 to 6 carbon atoms; 
       R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 may bond each other to form a ring; 
       R4 is a hydrogen atom or an alkyl group having 1 to 16 carbon atoms; 
       R5 is a straight-chain hydrocarbon group having 5 to 21 carbon atoms which may have 1 to 3 double bond(s); and 
       X is an oxygen atom or NH. 
     
   
   
       34 . The method of  claim 33 , wherein the compound of formula (1) is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       35 . The method of  claim 33 , wherein, in the formula (1),
 R1 is a hydrogen atom;   R3 is a hydrogen atom;   R4 is a hydrogen atom;   X is an oxygen atom;   R5 is a straight-chain alkyl group having 5 to 21 carbon atoms which may have one double bond; and   R2 is either one of the following substituents:   a tert-butyl group;   2,2,2,2′,2′,2′-hexafluoroisopropyl group;   cyclohexyl group; or   diphenylmethyl group,   except for a compound wherein R2 is a tert-butyl group, and R5 is a normal dodecyl group or 10-decenyl group.