Melanocortin receptor ligands

Abstract

The present invention relates to compounds which comprise a 4-substituted piperidine ring linked to a substituted or unsubstituted hydrocarbyl ring. The compounds, including all enatiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, have the formula: wherein preferably R is substituted aryl, W is a pendant unit having the formula: -L-Q L is a linking unit, Q is preferably a cyclic hydrocarbyl unit; W 1 is preferably a carbocyclic unit and W 2 is a heteroatom comprising unit.

1 . A compound, including all enatiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:  
       
         
           
           
               
               
           
         
         wherein R is a substituted or unsubstituted aromatic carbocyclic ring Q is a substituted or unsubstituted unit selected from:  
         i) C 1 -C 22  linear or branched alkyl;  
         ii) C 2 -C 22  linear or branched alkenyl;  
         iii) C 2 -C 22  linear or branched alkynyl; and  
         iv) C 6 -C 14  aromatic carbocyclic rings;  
         R 2  is a C 1 -C 7  non-aromatic heterocyclic ring or C 3 -C 13  aromatic heterocyclic ring.  
       
     
     
         2 . A compound according to  claim 1  wherein R is substituted or unsubstituted phenyl.  
     
     
         3 . A compound according to  claim 2  wherein R is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and 4-methylphenyl.  
     
     
         4 . A compound according to  claim 3  wherein R is 4-chlorophenyl.  
     
     
         5 . A compound according to  claim 1  wherein Q is substituted or unsubstituted C 1 -C 22  linear or branched alkyl.  
     
     
         6 . A compound according to  claim 5  wherein Q is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, and tert-butyl.  
     
     
         7 . A compound according to  claim 1  wherein Q is a substituted or unsubstituted C 6 -C 14  aromatic carbocyclic ring.  
     
     
         8 . A compound according to  claim 7  wherein Q is phenyl, 4-methylphenyl, or 4-hydroxyphenyl.  
     
     
         9 . A compound according to  claim 7  wherein Q is naphthalen-1-yl or naphthalen-2-yl.  
     
     
         10 . A compound according to  claim 1  wherein R 2  is selected from the group consisting of: 
 i) thiazolyl, 2-methylthiazolyl, 4-mentylthiazolyl, 5-methylthiazolyl having the formula:                          ii) 1,3,4-thiadiazolyl, 2-methyl-1,3,4-thiadiazolyl having the formula:                          iii) 1,2,5-thiadiazolyl, 3-methyl-1,2,5-thiadiazolyl having the formula:                          iv) oxazolyl, 2-methyloxazolyl, 4-methyloxazolyl, 5-methyloxazolyl having the formula:                          v) imidazolyl, 2-methylimidazolyl, 5-methylimidazolyl having the formula:                          vi) 5-methyl-1,2,4-oxadiazolyl, 2-methyl-1,3,4-oxadiazolyl, 5-amino-1,2,4-oxadiazolyl, having the formula:                          vii) 1,2-dihydro[1,2,4]triazol-3-one-1-yl, 2-methyl-1,2-dihydro[1,2,4]triazol-3-one-5-yl, having the formula:                          viii) oxazolidin-2-one-3-yl; 4,4-dimethyloxazolidin-2-one-3-yl; imidazolidin-2-one-1-yl; 1-methylimidazolidin-2-one-1-yl, having the formula:                          ix) 2-methyl-1,3,4-oxadiazolyl, 2-amino-1,3,4-oxadiazolyl, 2-(N,N-dimethylamino)-1,3,4-oxadiazolyl, having the formula:                          
     
     
         11 . A compound according to  claim 1  wherein R 2  is selected from the group consisting of: 
 i) triazoles having the formula:                          ii) tetrazole having the formula:                          
     
     
         12 . A compound according to  claim 1  wherein R 2  is [1,2,4]triazol-1-yl, 2H-tetrazol-5-yl, or imidazol-1-yl.  
     
     
         13 . A compound, including all enatiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R is a substituted or unsubstituted aromatic carbocyclic ring 
 Q is a substituted or unsubstituted unit selected from:  
 i) C 1 -C 22  linear or branched alkyl;  
 ii) C 2 -C 22  linear or branched alkenyl;  
 iii) C 2 -C 22  linear or branched alkynyl; and  
 iv) C 6 -C 14  aromatic carbocyclic rings;  
 R 2  is selected from —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 NHC(═NH)NH 2 , —(CH 2 ) 2 NHC(O)NH 2 , —(CH 2 ) 2 NHC(═NCH 3 )NH 2 , and —(CH 2 ) 2 NHC(═NCN)NHNO 2 .  
 
     
     
         14 . A compound according to  claim 13  wherein R is substituted or unsubstituted phenyl.  
     
     
         15 . A compound according to  claim 14  wherein R is selected from the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and 4-methylphenyl.  
     
     
         16 . A compound according to  claim 15  wherein R is 4-chlorophenyl.  
     
     
         17 . A compound according to  claim 13  wherein Q is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, and tert-butyl.  
     
     
         18 . A compound according to  claim 13  wherein Q is a phenyl, 4-methylphenyl, or 4-hydroxyphenyl.  
     
     
         19 . A compound and the salts thereof selected from the group consisting of: 
 N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-[1,2,4]triazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-methanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-ethanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-propanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-isopropanesulfonamide;    N-[1-(R)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide;    N-[1-(R)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide;    N-[1-(S)-(4-chlorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide; and    N-[1-(S)-(4-fluorobenzyl)-2-(4-cyclohexyl-4-imidazol-1-ylmethyl-piperidin-1-yl)-2-oxo-ethyl]-trifluoromethanesulfonamide.    
     
     
         20 . A composition comprising: 
 A) an effective amount of one or more melanocortin receptor ligands, said ligands having the formula:                          wherein R is a substituted or unsubstituted aromatic carbocyclic ring    Q is a substituted or unsubstituted unit selected from:    i) C 1 -C 22  linear or branched alkyl;    ii) C 2 -C 22  linear or branched alkenyl;    iii) C 2 -C 22  linear or branched alkynyl; and    iv) C 6 -C 22  aromatic carbocyclic rings;    R 2  is a C 1 -C 7  non-aromatic heterocyclic ring or C 3 -C 13  aromatic heterocyclic ring; and    B) one or more pharmaceutically acceptable excipients.