Acylated piperidine derivatives as melanocortin-4 receptor agonists

Abstract

Certain novel 4-substituted N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

1 . A compound of structural formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
 wherein  
 r is 1 or 2;  
 s is 0, 1, or 2;  
 n is 0, 1 or 2;  
 p is 0, 1, or 2;  
 R 1  is selected from the group consisting of 
 hydrogen,  
 amidino,  
 C 1-4  alkyliminoyl,  
 C 1-10  alkyl,  
 (CH 2 ) n —C 3-7  cycloalkyl,  
 (CH 2 ) n -phenyl,  
 (CH 2 ) n -naphthyl, and  
 (CH 2 ) n -heteroaryl wherein heteroaryl is selected from the group consisting of 
 (1) pyridinyl,  
 (2) furyl,  
 (3) thienyl,  
 (4) pyrrolyl,  
 (5) oxazolyl,  
 (6) thiazolyl,  
 (7) imidazolyl,  
 (8) pyrazolyl,  
 (9) isoxazolyl,  
 (10) isothiazolyl,  
 (11) pyrimidinyl,  
 (12) pyrazinyl,  
 (13) pyridazinyl,  
 (14) quinolyl,  
 (15) isoquinolyl,  
 (16) benzimidazolyl,  
 (17) benzofuryl,  
 (18) benzothienyl,  
 (19) indolyl,  
 (20) benzthiazolyl, and  
 (21) benzoxazolyl;  
 
 
 in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 ; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3  and oxo;  
 R 2  is selected from the group consisting of 
 phenyl,  
 naphthyl, and  
 heteroaryl wherein heteroaryl is selected from the group consisting of 
 (1) pyridinyl,  
 (2) furyl,  
 (3) thienyl,  
 (4) pyrrolyl,  
 (5) oxazolyl,  
 (6) thiazolyl,  
 (7) imidazolyl,  
 (8) pyrazolyl,  
 (9) isoxazolyl,  
 (10) isothiazolyl,  
 (11) pyrimidinyl,  
 (12) pyrazinyl,  
 (13) pyridazinyl,  
 (14) quinolyl,  
 (15) isoquinolyl,  
 (16) benzimidazolyl,  
 (17) benzofuryl,  
 (18) benzothienyl,  
 (19) indolyl,  
 (20) benzthiazolyl, and  
 (21) benzoxazolyl;  
 
 
 in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 ;  
 each R 3  is independently selected from the group consisting of 
 C 1-6  alkyl,  
 (CH 2 ) n -phenyl,  
 (CH 2 ) n -naphthyl,  
 (CH 2 ) n -heteroaryl,  
 (CH 2 ) n -heterocyclyl,  
 (CH 2 ) n C 3-7  cycloalkyl,  
 halogen,  
 OR 4 ,  
 (CH 2 ) n N(R 4 ) 2 ,  
 (CH 2 ) n C≡N,  
 (CH 2 ) n CO 2 R 4 ,  
 NO 2 ,  
 (CH 2 ) n NR 4 SO 2 R 4    
 (CH 2 ) n SO 2 N(R 4 ) 2 ,  
 (CH 2 ) n S(O) p R 4 ,  
 (CH 2 ) n NR 4 C(O)N(R 4 ) 2 ,  
 (CH 2 ) n C(O)N(R 4 ) 2 ,  
 (CH 2 ) n NR 4 C(O)R 4 ,  
 (CH 2 ) n NR 4 CO 2 R 4 ,  
 (CH 2 ) n NR 4 C(O)-heteroaryl,  
 (CH 2 ) n C(O)NR 4 N(R 4 ) 2 ,  
 (CH 2 ) n C(O)NR 4 NR 4 C(O)R 4 ,  
 O(CH 2 ) n C(O)N(R 4 ) 2 ,  
 CF 3 ,  
 CH 2 CF 3 ,  
 OCF 3 , and  
 OCH 2 CF 3 ;  
 
 in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C 1-4  alkyl, trifluoromethyl, and C 1-4  alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;  
 each R 4  is independently selected from the group consisting of 
 hydrogen,  
 C 1-6  alkyl,  
 (CH 2 ) n -phenyl,  
 (CH 2 ) n -heteroaryl,  
 (CH 2 ) n -naphthyl,  
 (CH 2 ) n -heterocyclyl,  
 (CH 2 ) n C 3-7  cycloalkyl, and  
 (CH 2 ) n C 3-7  bicycloalkyl;  
 
 wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4  alkyl, hydroxy, and C 1-4  alkoxy; or two R 4  groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4  alkyl;  
 each R 5  is independently selected from the group consisting of 
 hydrogen,  
 C 1-8  alkyl,  
 (CH 2 ) n -phenyl,  
 (CH 2 ) n -naphthyl,  
 (CH 2 ) n -heteroaryl, and  
 (CH 2 ) n C 3-7  cycloalkyl;  
 
 wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 ; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3  and oxo; and wherein any methylene (CH 2 ) in R 5  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl; or two R 5  groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4  alkyl; and  
 X is selected from the group consisting of 
 C 1-8  alkyl,  
 (CH 2 ) n C 3-8  cycloalkyl,  
 (CH 2 ) n -phenyl,  
 (CH 2 ) n -naphthyl,  
 (CH 2 ) n -heteroaryl,  
 (CH 2 ) n heterocyclyl,  
 (CH 2 ) n C≡N,  
 (CH 2 ) n CON(R 5 R 5 ),  
 (CH 2 ) n CO 2 R 5 ,  
 (CH 2 ) n COR 5 ,  
 (CH 2 ) n NR 5 C(O)R 5 ,  
 (CH 2 ) n NR 5 CO 2 R 5 ,  
 (CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,  
 (CH 2 ) n NR 5 SO 2 R 5 ,  
 (CH 2 ) n S(O) p R 5 ,  
 (CH 2 ) n SO 2 N(R 5 )(R 5 ),  
 (CH 2 ) n OR 5 ,  
 (CH 2 ) n OC(O)R 5 ,  
 (CH 2 ) n OC(O)OR 5 ,  
 (CH 2 ) n OC(O)N(R 5 ) 2 ,  
 (CH 2 ) n N(R 5 )(R 5 ), and  
 (CH 2 ) n NR 5  SO 2 N(R 5 )(R 5 );  
 
 wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 ; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 3  and oxo; and wherein any methylene (CH 2 ) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl;  
 
     
     
         2 . The compound of  claim 1  wherein R 1  is selected from the group consisting of hydrogen, C 1-6  alkyl, (CH 2 ) 0-1 C 3-6  cycloalkyl, and (CH 2 ) 0-1 -phenyl; wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R 3 ; and alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R 3  and oxo.  
     
     
         3 . The compound of  claim 1  wherein R 2  is phenyl or thienyl optionally substituted with one to three groups independently selected from R 3 .  
     
     
         4 . The compound of  claim 3  wherein R 2  is phenyl optionally substituted with one to three groups independently selected from R 3 .  
     
     
         5 . The compound of  claim 1  wherein X is selected from the group consisting of 
 (CH 2 ) n -phenyl,  
 (CH 2 ) n -naphthyl,  
 (CH 2 ) n -heteroaryl,  
 (CH 2 ) n C 3-8  cycloalkyl, and  
 (CH 2 ) n -heterocyclyl;  
 wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 ; cycloalkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R 3  and oxo; and wherein any methylene (CH 2 ) group in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl.  
 
     
     
         6 . The compound of  claim 5  wherein X is selected from the group consisting of 
 (CH 2 ) 0-1 -phenyl,  
 (CH 2 ) 0-1 -heteroaryl, and  
 (CH 2 ) 0-1 -heterocyclyl;  
 wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 ; heterocyclyl are optionally substituted with one to three groups independently selected from R 3  and oxo; and CH 2  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl.  
 
     
     
         7 . The compound of  claim 6  wherein X is phenyl optionally substituted with one to three groups independently selected from R 3 .  
     
     
         8 . The compound of  claim 1  wherein r is 1 or 2 and s is 1.  
     
     
         9 . The compound of  claim 1  of structural formula IIa or IIb of the indicated trans relative stereochemical configuration:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
 wherein  
 r is 1 or 2;  
 n is 0, 1, or 2;  
 p is 0, 1, or 2;  
 R 1  is hydrogen, amidino, C 1-4  alkyliminoyl, C 1-6  alkyl, C 5-6  cycloalkyl, (CH 2 ) 0-1  phenyl, or (CH 2 ) 0-1  heteroaryl; wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 ; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3  and oxo;  
 R 2  is phenyl or thienyl optionally substituted with one to three groups independently selected from R 3 ;  
 each R 3  is independently selected from the group consisting of 
 C 1-6  alkyl,  
 (CH 2 ) n -heteroaryl,  
 (CH 2 ) n -heterocyclyl,  
 halogen,  
 OR 4 ,  
 (CH 2 ) n N(R 4 ) 2 ,  
 (CH 2 ) n C≡N  
 (CH 2 ) n CO 2 R 4 ,  
 (CH 2 ) n NR 4 SO 2 R 4    
 (CH 2 ) n SO 2 N(R 4 ) 2 ,  
 (CH 2 ) n S(O) p R 4 ,  
 (CH 2 ) n NR 4 C(O)N(R 4 ) 2 ,  
 (CH 2 ) n C(O)N(R 4 ) 2 ,  
 (CH 2 ) n NR 4 C(O)R 4 ,  
 (CH 2 ) n NR 4 CO 2 R 4 ,  
 (CH 2 ) n NR 4 C(O)-heteroaryl,  
 (CH 2 ) n C(O)NR 4 N(R 4 ) 2 ,  
 (CH 2 ) n C(O)NR 4 NR 4 C(O)R 4 ,  
 O(CH 2 ) n C(O)N(R 4 ) 2 ,  
 CF 3 ,  
 CH 2 CF 3 ,  
 OCF 3 , and  
 OCH 2 CF 3 ;  
 
 in which phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C 1-4  alkyl, trifluoromethyl, and C 1-4  alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;  
 each R 4  is independently selected from the group consisting of 
 hydrogen,  
 C 1-8  alkyl,  
 phenyl,  
 heteroaryl,  
 (CH 2 ) 0-1  heterocyclyl, and  
 C 3-6  cycloalkyl;  
 
 wherein alkyl, phenyl, hetroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4  alkyl, hydroxy, and C 1-4  alkoxy;  
 or two R 4  groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4 alkyl; and  
 X is phenyl or heteroaryl each of which is optionally substituted with one to three groups independently selected from R 3 .  
 
     
     
         10 . The compound of  claim 1  of structural formula IIIa or IIIb of the indicated trans relative stereochemical configuration:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;  
       wherein 
 r is 1 or 2;  
 R 1  is hydrogen, C 1-4  alkyl, or (CH 2 ) 0-1  phenyl;  
 each R 3  is independently selected from the group consisting of 
 C 1-6  alkyl,  
 (CH 2 ) 0-1 -heteroaryl,  
 (CH 2 ) 0-1 -heterocyclyl,  
 halogen,  
 OR 4 ,  
 (CH 2 ) 0-1 N(R 4 ) 2 ,  
 (CH 2 ) 0-1 C≡N,  
 (CH 2 ) 0-1 CO 2 R 4 ,  
 (CH 2 ) 0-1 NR 4 SO 2 R 4    
 (CH 2 ) 0-1 SO 2 N(R 4 ) 2 ,  
 (CH 2 ) 0-1 S(O) p R 4 ,  
 (CH 2 ) 0-1 NR 4 C(O)N(R 4 ) 2 ,  
 (CH 2 ) 0-1 C(O)N(R 4 ) 2 ,  
 (CH 2 ) 0-1 NR 4 C(O)R 4 ,  
 (CH 2 ) 0-1 NR 4 CO 2 R 4 ,  
 (CH 2 ) 0-1 NR 4 C(O)-heteroaryl,  
 (CH 2 ) 0-1 C(O)NR 4 N(R 4 ) 2 ,  
 (CH 2 ) 0-1 C(O)NR 4 NR 4 C(O)R 4 ,  
 O(CH 2 ) 0-1 C(O)N(R 4 ) 2 ,  
 CF 3 ,  
 CH 2 CF 3 ,  
 OCF 3 , and  
 OCH 2 CF 3 ;  
 
 in which phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, C 1-4  alkyl, trifluoromethyl, and C 1-4  alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3  is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4  alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; and each R 4  is independently selected from the group consisting of 
 hydrogen,  
 C 1-8  alkyl,  
 phenyl,  
 heteroaryl,  
 (CH 2 ) 0-1  heterocyclyl, and  
 C 3-6  cycloalkyl;  
 
 wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4  alkyl, hydroxy, and C 1-4  alkoxy; or two R 4  groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4  alkyl.  
 
     
     
         11 . (canceled)  
     
     
         12 . (canceled)  
     
     
         13 . (canceled)  
     
     
         14 . (canceled)  
     
     
         15 . (canceled)  
     
     
         16 . A method for the treatment or prevention of disorders, diseases or conditions responsive to the activation of the melanocortin-4 receptor in a mammal in need thereof which comprises administering to the mammal a therapeutically or prophylactically effective amount of a compound according to  claim 1 .  
     
     
         17 . A method for the treatment of obesity in a mammal in need thereof which comprises administering to the mammal a therapeutically or prophylactically effective amount of a compound according to  claim 1 .  
     
     
         18 . A method for the treatment or prevention of diabetes mellitus in a mammal in need thereof comprising administering to the mammal a therapeutically or prophylactically effective amount of a compound according to  claim 1 .  
     
     
         19 . A method for the treatment or prevention of male or female sexual dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically or prophylactically effective amount of a compound according to  claim 1 .  
     
     
         20 . A method for the treatment or prevention of erectile dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically or prophylactically effective amount of a compound according to  claim 1 .  
     
     
         21 . A pharmaceutical composition which comprises a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         22 . The pharmaceutical composition of  claim 21  further comprising a second active ingredient selected from the group consisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea, an α-glucosidase inhibitor, an HMG-CoA reductase inhibitor, an anti-obesity serotonergic agent, a β3 adrenoreceptor agonist, a neuropeptide Y1 or Y5 antagonist, a pancreatic lipase inhibitor, a melanin-concentrating hormone receptor antagonist, and a cannabinoid CB 1  receptor antagonist or inverse agonist.  
     
     
         23 . The pharmaceutical composition of  claim 21  further comprising a second active ingredient selected from the group consisting of a type V cyclic-GMP-selective phosphodiesterase inhibitor, an α 2 -adrenergic receptor antagonist, and a dopaminergic agent.  
     
     
         24 . A method of treating erectile dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the composition of  claim 23 .  
     
     
         25 . A method of treating erectile dysfunction in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of  claim 1  in combination with a type V cyclic-GMP-selective phosphodiesterase inhibitor, an α 2 -adrenergic receptor antagonist, or a dopaminergic agent.  
     
     
         26 . A method of treating diabetes or obesity in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of  claim 1  in combination with an insulin sensitizer, an insulin mimetic, a sulfonylurea, an α-glucosidase inhibitor, an HMG-CoA reductase inhibitor, an anti-obesity serotonergic agent, a β3 adrenoreceptor agonist, a neuropeptide Y1 or Y5 antagonist, a pancreatic lipase inhibitor, a melanin-concentrating hormone receptor antagonist, or a cannabinoid CB 1  receptor antagonist or inverse agonist.  
     
     
         27 . A method of treating obesity in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of the composition of  claim 22 .  
     
     
         28 . The compound of  claim 1  wherein the pharmaceutically acceptable salt thereof is the hydrochloride salt.