Melanocortin receptor ligands

Abstract

Disclosed are MC-3/MC-4 receptor ligands, the ligands having the following formula: wherein A has the formula: W is a unit which preferable comprises D-(4-fluorophenyl)alanine, Y comprises at least one nitrogen heteroatom, and Z comprises an aromatic carbocyclic ring. Also disclosed are pharmaceutical compositions comprising the ligands of the invention as well as methods of treating diseases mediated through MC-3/MC-4 receptors.

1 . A compound, or all enatiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein A is a conformationally restricted ring system having the formula:  
     
       
         
         
             
             
         
       
       W has the formula:  
       
         
           
           
               
               
           
         
       
       R is phenyl or phenyl substituted with one or more halogen units, said halogen units chosen from fluoro, chloro, and bromo;  
       wherein R 2 , R 3 , and R 4  units are independently selected from the group:  
       a) rings consisting of: 
 i) substituted or unsubstituted aromatic carbocyclic rings, said rings selected from phenyl, benzyl, α-naphthyl, or β-naphthyl;  
 ii) substituted or unsubstituted aromatic heterocyclic rings, said rings selected from 1-quinolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl;  
 iii) and mixtures thereof;  
 
       b) hydrogen;  
       c) a unit selected from the group consisting of —CH 2 C(O)CH 3 , —NHC(O)CH 3 , —NHC(O)CH 2 CH 3 , and —NHC(O)CH 2 CH 2 CH 3 ; and  
       d) two of R 2 , R 3 , or R 4  can be taken together to form a ring consisting of: 
 i) substituted or unsubstituted aromatic carbocyclic rings, said rings selected from phenyl, α-naphthyl, or β-naphthyl;  
 ii) substituted or unsubstituted aromatic heterocyclic rings, said rings selected from 1-quinolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl;  
 
       Y is a pendant unit having the formula:  
         —(CH 2 ) b —R 15    
       wherein R 15  contains at least one nitrogen heteroatom; the index b is from 1 to 4;  
       Z is a pendant unit, which contains an aromatic carbocyclic ring; said unit having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 8  is hydrogen; R 9  is phenyl, benzyl, 1-naphthyl, 2-naphthyl, 1-naphthylmethyl, or 2-naphthylmethyl; R 10  is hydrogen, —C(O) 2 R 17 , —C(O)N(R 16 ) 2 , —N(R 16 ) 2 , or —NR 16 C(O)R 17 ; R 16  is hydrogen, or C 1 -C 10  alkyl; R 17  is C 1 -C 4  linear or branched, alkyl unit which can be substituted by one or more halogen units.  
     
   
   
       2 . A compound according to  claim 1  wherein R is selected from the group consisting of phenyl, benzyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, and 4-hydroxyphenyl.  
   
   
       3 . A compound according to  claim 1  wherein W has the formula:  
     
       
         
         
             
             
         
       
       R 2  is a unit selected from the group consisting of —CH 2 C(O)CH 3 , —NHC(O)CH 3 , —NHC(O)CH 2 CH 3 , and —NHC(O)CH 2 CH 2 CH 3 ;  
       R 4  units are selected from the group:  
       a) rings consisting of: 
 i) substituted or unsubstituted aromatic carbocyclic rings, said rings selected from phenyl, benzyl, α-naphthyl, or β-naphthyl; or  
 ii) substituted or unsubstituted aromatic heterocyclic rings, said rings selected from 1-quinolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.  
 
     
   
   
       4 . A compound according to  claim 3  wherein R 2  is —NHC(O)CH 3 .  
   
   
       5 . A compound according to  claim 4  wherein R 4  is a unit selected from the group consisting of benzyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 4-fluorobenzyl, 4-hydroxybenzyl, and 4-acetoxybenzyl.  
   
   
       6 . A compound according to  claim 1  wherein W has the formula:  
     
       
         
         
             
             
         
       
       R is selected from the group consisting of phenyl, benzyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, and 4-hydroxyphenyl; R 4  is a unit selected from the group consisting of benzyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-acetoxybenxyl, 2-imidazolylmethyl, 4-imidazolylmethyl, 2-phenylethyl, 1-naphthylmethyl, and 2-naphthylmethyl.  
     
   
   
       7 . A compound according to  claim 1  wherein W has the formula:  
     
       
         
         
             
             
         
       
     
   
   
       8 . A compound according to  claim 7  wherein R is selected from the group consisting of phenyl, benzyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, and 4-hydroxyphenyl.  
   
   
       9 . A compound according to  claim 1  wherein R 15  is an ester or an amide.  
   
   
       10 . A compound according to  claim 9  wherein R 15  is an ester selected from the group consisting of: 
 i) —C(O)OCH 3 ;    ii) —C(O)OCH 2 CH 3 ;    iii) —C(O)OCH 2 CH 2 CH 3 ;    iv) —C(O)OCH 2 CH 2 CH 2 CH 3 ;    v) —C(O)OCH(CH 3 ) 2 ;    vi) —C(O)OCH 2 CH(CH 3 ) 2 ;    vii) —C(O)OCH 2 CH═CHCH 3 ;    viii) —C(O)OCH 2 CH 2 CH(CH 3 ) 2 ;    ix) —C(O)OCH 2 C(CH 3 ) 3 ;    x) —OC(O)CH 3 ;    xi) —OC(O)CH 2 CH 3 ;    xii) —OC(O)CH 2 CH 2 CH 3 ;    xiii) —OC(O)CH(CH 3 ) 2 ;    xiv) —OC(O)CH 2 CH 2 CH 2 CH 3 ;    xv) —OC(O)CH 2 CH(CH 3 ) 2 ;    xvi) —OC(O)CH 2 CH═CHCH 3 ;    xvii) —OC(O)CH 2 C(CH 3 ) 3 ; and    xviii) —OC(O)CH 2 CH 2 CH(CH 3 ) 2 .    
   
   
       11 . A compound according to  claim 9  wherein R 15  is an amide selected from the group consisting of: 
 i) —C(O)NHCH 3 ;    ii) —C(O)NHCH 2 CH 3 ;    iii) —C(O)NHCH 2 CH 2 CH 3 ;    iv) —C(O)NHCH 2 CH 2 CH 2 CH 3 ;    v) —C(O)NHCH(CH 3 ) 2 ;    vi) —C(O)NHCH 2 CH(CH 3 ) 2 ;    vii) —C(O)NHCH 2 CH═CHCH 3 ;    viii) —C(O)NHCH 2 CH 2 CH(CH 3 ) 2 ;    ix) —C(O)NHCH 2 C(CH 3 ) 3 ;    x) —NHC(O)CH 3 ;    xi) —NHC(O)CH 2 CH 3 ;    xii) —NHC(O)CH 2 CH 2 CH 3 ;    xiii) —NHC(O)CH(CH 3 ) 2 ;    xiv) —NHC(O)CH 2 CH 2 CH 2 CH 3 ;    xv) —NHC(O)CH 2 CH(CH 3 ) 2 ;    xvi) —NHC(O)CH 2 CH═CHCH 3 ;    xvii) —NHC(O)CH 2 C(CH 3 ) 3 ; and    xviii) —NHC(O)CH 2 CH 2 CH(CH 3 ) 2 .    
   
   
       12 . A compound according to  claim 1  wherein R 15  is a unit selected from the group consisting of: 
 a) —C(═NR 16 )N(R 16 ) 2 ;    b) —C(═NR 16 )NR 16 N(R 16 ) 2 ;    c) —NR 16 C(═NR 16 )N(R 16 ) 2 ; and    d) —NHN(R 16 ) 2 ;    wherein R 16  is hydrogen, methyl, cyano, hydroxy, and nitro.    
   
   
       13 . A compound according to  claim 12  wherein R 15  has the formula:  
     
       
         
         
             
             
         
       
     
   
   
       14 . A compound according to  claim 13  wherein Y has the formula:  
     
       
         
         
             
             
         
       
     
   
   
       15 . A compound according to  claim 1  wherein R 15  is a 5-member heterocyclic ring.  
   
   
       16 . A compound according to  claim 15  wherein R 15  is selected from the group consisting of: 
 i) triazolyl having the formula:                          ii) tetrazolyl having the formula:                          iii) thiazolyl, 2-methylthiazolyl, 4-mentylthiazolyl, 5-methylthiazolyl having the formula:                          iv) 1,3,4-thiadiazolyl, 2-methyl-1,3,4-thiadiazolyl having the formula:                          v) 1,2,5-thiadiazolyl, 3-methyl-1,2,5-thiadiazolyl having the formula:                          vi) oxazolyl, 2-methyloxazolyl, 4-methyloxazolyl, 5-methyloxazolyl having the formula:                          vii) imidazolyl, 2-methylimidazolyl, 5-methylimidazolyl having the formula:                          viii) 5-methyl-1,2,4-oxadiazolyl, 2-methyl-1,3,4-oxadiazolyl, 5-amino-1,2,4-oxadiazolyl, having the formula:                          ix) 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:                          x) 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:                          xi) 2-methyl-1,3,4-oxadiazolyl, 2-amino-1,3,4-oxadiazolyl, 2-(N,N-dimethylamino)-1,3,4-oxadiazolyl, having the formula:                          
   
   
       17 . A compound according to  claim 16  wherein Y has the formula:  
     
       
         
         
             
             
         
       
     
   
   
       18 . A compound according to  claim 1  wherein R 15  is a 6-member heterocyclic ring.  
   
   
       19 . A compound according to  claim 18  wherein R 15  is selected from the group consisting of: 
 i) pyridinyl units having the formula:                          ii) pyrimidinyl units having the formula:                          ii) piperidinyl units having the formula:                          
   
   
       20 . A compound according to  claim 1  wherein R 15  is selected from the group consisting of amino, guanidino, guanyl, amidino, pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,3-isoxazolyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl, 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-inolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolinyl, quinoxalinyl, pyrrolyl, and benzimidazolyl.  
   
   
       21 . A compound according to  claim 1  wherein R 10  is —CO 2 H, —CO 2 CH 3 , —CONHCH 3 , and —CONH 2 ,  
   
   
       22 . A compound according to  claim 21  wherein R 9  is benzyl or 2-naphthylmethyl.  
   
   
       23 . A compound according to  claim 22  wherein R 9  is phenyl or 2-naphthyl.  
   
   
       24 . A pharmaceutical composition comprising: 
 A) an effective amount of a compound according to  claim 1;  and    B) the balance carriers, excipients, and adjunct ingredients.    
   
   
       25 . A method for treating a body weight disorder selected from the group consisting of obesity, anorexia and cachexia in a subject needing treatment, the method comprising administering to said subject a compound according to  claim 1.