Acylated piperidine derivatives as melanocortin-4 receptor agonists
View Patent ↗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 1;
n is 0, 1 or 2;
R 1 is NR 6 R 7 wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
or R 6 and R 7 together with the nitrogen atom to which they are attached form a 4 membered ring;
R 2 is phenyl optionally substituted with one to three groups independently selected from R 3 ;
each R 3 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy;
each R 5 is independently selected from the group consisting of
hydrogen,
C 1-8 alkyl;
Y is cyclohexyl, unsubstituted or substituted with one to three groups independently selected from alkyl; and
X is selected from the group consisting of:
(CH 2 ) n -heterocyclyl,
(CH 2 ) n C(O)N(R 5 )(R 5 ), and
(CH 2 ) n NR 5 SO 2 R 5 ,
wherein heterocyclyl is oxazolidinone, optionally substituted with one to three groups independently selected from alkyl.
2. The compound of claim 1 wherein Y is cyclohexyl and X is selected from the group consisting of:
(CH 2 ) n -heterocyclyl,
(CH 2 ) n C(O)N(R 5 )(R 5 ), and
(CH 2 ) n NR 5 SO 2 R 5 ;
wherein heterocyclyl is oxazolidinone, optionally substituted with one to three groups independently selected from alkyl.
3. 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 NR 6 R 7 wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
R 2 is phenyl optionally substituted with one to three groups independently selected from halogen;
each R 5 is independently selected from the group consisting of
hydrogen, and
C 1-5 alkyl; and
Y represents cyclohexyl.
4. A compound 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 NR 6 R 7 wherein R 6 and R 7 are each independently hydrogen, or C 1-4 alkyl;
each R 3 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy;
Y is cyclohexyl; and
X is selected from the group consisting of
5. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.