Acylated Piperidine Derivatives as Melanocortin-4 Receptor Agonists
Certain novel 4 alkyl substituted N acylated piperidine derivatives are ligands of the human melanocortin receptor(s) and, in particular, are selective ligands 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 modulation of MC-4R, such as obesity, diabetes, nicotine addiction, alcoholism, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
1 . A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein:
Z is N or CR 4 ;
R 1 is selected from the group consisting of:
(1) amidino,
(2) —C 1-4 alkyliminoyl,
(3) —C 1-8 alkyl,
(4) —(CH 2 ) n N(R 8 ) 2 ,
(5) —(CH 2 ) n C 2-9 heterocycloalkyl,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n phenyl,
(8) —(CH 2 ) n naphthyl,
(9) —(CH 2 ) n heteroaryl,
(10) —(CH 2 ) n C(O)C 1-8 alkyl,
(11) —(CH 2 ) n C(O)C 3-8 cycloalkyl,
(12) —(CH 2 ) n C(O)C 2-9 heterocycloalkyl,
(13) —(CH 2 ) n C(O)phenyl,
(14) —(CH 2 ) n C(O)naphthyl,
(15) —(CH 2 ) n C(O)heteroaryl,
(16) —(CH 2 ) n CO 2 H,
(17) —(CH 2 ) n CO 2 C 1-8 alkyl,
(18) —(CH 2 ) n CO 2 C 3-8 cycloalkyl,
(19) —(CH 2 ) n CO 2 C 2-9 heterocycloalkyl,
(20) —(CH 2 ) n CO 2 -phenyl,
(21) —(CH 2 ) n CO 2 naphthyl,
(22) —(CH 2 ) n CO 2 heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 3 , and alkyl, cycloalkyl, heterocycloalkyl and (CH 2 ) n are unsubstituted or substituted with one to three substituents independently selected from R 3 and oxo;
R 2 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl, and
(3) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 10 ;
each R 3 is independently selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —(CH 2 ) n -phenyl,
(3) —(CH 2 ) n -heteroaryl,
(4) —(CH 2 ) n C 2-9 heterocycloalkyl,
(5) —(CH 2 ) n C 3-7 cycloalkyl,
(6) halogen,
(7) —OR 8 ,
(8) —(CH 2 ) n CE-N,
(9) —(CH 2 ) n N(R 8 ) 2 ,
(10) —(CH 2 ) n C(O)NR 8 ) 2 ,
(11) —(CH 2 ) n C(O)NR 8 N(R 8 ) 2 ,
(12) —(CH 2 ) n C(O)NR 8 NR 8 C(O)R 8 , and
(13) —(CH 2 ) n CF 3 ,
wherein phenyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein any alkyl, cycloalkyl, heterocycloalkyl, and methylene (CH 2 ) n carbon atom in R 3 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, or two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
R 4 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —OC 1-6 alkyl;
R 5 is selected from the group consisting of:
(1) —CF 3 ,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —OC 1-8 alkyl,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n C 2-9 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CH 2 ) n -naphthyl, and
(10) —(CH 2 ) n heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 3 , and alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 3 and oxo, and wherein any methylene (CH 2 ) in R 5 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —OC 1-6 alkyl;
R 7 is selected from the group consisting of:
(1) —(CH 2 ) n N(R 8 ) 2 ,
(2) —(CH 2 ) n NR 8 C(O)R 8 ,
(3) —(CH 2 ) n OR 8 ,
(4) —(CH 2 ) n C≡N,
(5) —(CH 2 ) n C(O)OR 8 ,
(6) —(CH 2 ) n C(O)N(R 8 ) 2 ,
(7) —(CH 2 ) n NR 8 C(O)N(R 8 ) 2 ,
(8) —(CH 2 ) n NR 8 C(O)heteroaryl,
(9) —(CH 2 ) n heteroaryl,
(10) —(CH 2 ) n NR 8 S(O) p R 8 ,
(11) —(CH 2 ) n SR 8 , and
(12) —(CH 2 ) n S(O) p R 8 ,
wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-4 alkyl, and any methylene (CH 2 ) in R 7 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl, or two C 1-4 alkyl substituents on any methylene (CH 2 ) in R 7 together with the atom to which they are attached form a 3, 4, 5, or 6-membered ring optionally containing an additional heteroatom selected from O, S, —NH, and —NC 1-4 alkyl;
each R 8 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —OC 1-8 alkyl,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n C 2-9 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CH 2 ) n -naphthyl, and
(10) —(CH 2 ) n heteroaryl,
wherein phenyl, naphthyl, and heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from —N(C 1-6 alkyl) 2 , —NH 2 , NH(C 1-6 alkyl), halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, and oxo, and wherein any methylene (CH 2 ) in R 8 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl;
each R 9 is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) C 1-8 alkyl,
(4) —OC 1-8 alkyl,
(5) halogen;
(6) —NR 5 ,
(7) —SR 5 , and
(8) —CF 3 ,
wherein two C 1-8 alkyl substituents along with the atoms to which they are attached can form a 4- to 8-membered ring;
each R 10 is independently selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —C 2-8 alkenyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -naphthyl,
(5) —(CH 2 ) n -heteroaryl,
(6) —(CH 2 ) n C 2-9 heterocycloalkyl,
(7) —(CH 2 ) n C 3-7 cycloalkyl,
(8) halogen,
(9) —OR 8 ,
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and any methylene (CH 2 ) carbon atom in R 10 are unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, or two R 10 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
r is 1 or 2;
s is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, and
p is 0, 1 or 2.
2 . A compound of claim 1 wherein R 9 is hydrogen, and pharmaceutically acceptable salts thereof.
3 . A compound of claim 1 wherein R 1 is selected from the group consisting of: amidino, —C 1-4 alkyliminoyl, —C 1-8 alkyl, —(CH 2 ) n N(R 8 ) 2 , —(CH 2 ) n C 2-9 heterocycloalkyl, —(CH 2 ) n C 3-8 cycloalkyl, —(CH 2 ) n phenyl, —(CH 2 ) n naphthyl, and —(CH 2 ) n heteroaryl, wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 3 , and alkyl, cycloalkyl and heterocycloalkyl and —(CH 2 ) n are unsubstituted or substituted with one to three substituents selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
4 . A compound of claim 1 wherein R 2 is phenyl optionally substituted with one to three groups independently selected from R 10 , and pharmaceutically acceptable salts thereof.
5 . A compound of claim 1 wherein R 6 is hydrogen, and pharmaceutically acceptable salts thereof.
6 . A compound of claim 1 wherein R 5 is selected from the group consisting of: —C 1-6 alkyl, and —(CH 2 ) 0-1 C 3-8 cycloalkyl, wherein alkyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 3 and oxo, and wherein any methylene (CH 2 ) in R 5 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl, and pharmaceutically acceptable salts thereof.
7 . A compounds of claim 1 wherein R 7 is selected from the group consisting of: —(CH 2 ) 0-2 NR 8 C(O)R 8 , —(CH 2 ) 0-2 OR 8 , —(CH 2 ) 0-2 C≡N, —(CH 2 ) 0-2 C(O)OR 8 , —(CH 2 ) n C(O)N(R 8 ) 2 , —(CH 2 ) 0-2 NR 8 C(O)N(R 8 ) 2 , —(CH 2 ) 0-2 NR 8 C(O)heteroaryl, —(CH 2 ) 0-2 heteroaryl, —(CH 2 ) n NR 8 S(O) 2 R 8 , wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-4 alkyl, and any methylene (CH 2 ) n in R 7 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl, or two C 1-4 alkyl substituents on any methylene (CH 2 ) n in R 7 together with the atom to which they are attached form a 3, 4, 5, or 6-membered ring optionally containing an additional heteroatom selected from O, S, —NH, and —NC 1-4 alkyl.
8 . A compound of claim 1 wherein R 10 is selected from the group consisting of: —C 1-8 alkyl, halogen, —OR 8 , —(CH 2 ) n C≡N, —(CH 2 ) n S(O) p R 8 , and —CF 3 , wherein any alkyl and methylene (CH 2 ) carbon atom in R 10 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy.
9 . A compound of claim 1 wherein Z is CH.
10 . A compound of claim 1 wherein Z is N.
11 . A compound of claim 1 of structural formula IIa or IIb of the indicated trans relative stereochemical configuration:
or a pharmaceutically acceptable salt thereof, wherein
Z is N or CR 4 ;
R 1 is selected from the group consisting of:
(1) amidino,
(2) —C 1-4 alkyliminoyl,
(3) —C 1-8 alkyl,
(4) —(CH 2 ) n N(R 8 ) 2 ,
(5) —(CH 2 ) n C 2-9 heterocycloalkyl,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n phenyl,
(8) —(CH 2 ) n naphthyl,
(9) —(CH 2 ) n heteroaryl,
(10) —(CH 2 ) n C(O)C 1-8 alkyl,
(11) —(CH 2 ) n C(O)C 3-8 cycloalkyl,
(12) —(CH 2 ) n C(O)C 2-9 heterocycloalkyl,
(13) —(CH 2 ) n C(O)phenyl,
(14) —(CH 2 ) n C(O)naphthyl,
(15) —(CH 2 ) n C(O)heteroaryl,
(16) —(CH 2 ) n CO 2 H,
(17) —(CH 2 ) n CO 2 C 1-8 alkyl,
(18) —(CH 2 ) n CO 2 C 3-8 cycloalkyl,
(19) —(CH 2 ) n CO 2 C 2-9 heterocycloalkyl,
(20) —(CH 2 ) n CO 2 -phenyl,
(21) —(CH 2 ) n CO 2 naphthyl,
(22) —(CH 2 ) n CO 2 heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 3 , and alkyl, cycloalkyl, heterocycloalkyl and (CH 2 ) n are unsubstituted or substituted with one to three substituents independently selected from R 3 and oxo;
R 2 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl, and
(3) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 10 ;
each R 3 is independently selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —(CH 2 ) n -phenyl,
(3) —(CH 2 ) n -heteroaryl,
(4) —(CH 2 ) n C 2-9 heterocycloalkyl,
(5) —(CH 2 ) n C 3-7 cycloalkyl,
(6) halogen,
(7) —OR 8 ,
(8) —(CH 2 ) n C≡N,
(9) —(CH 2 ) n N(R 8 ) 2 ,
(10) —(CH 2 ) n C(O)N(R 8 ) 2 ,
(11) —(CH 2 ) n C(O)NR 8 N(R 8 ) 2 ,
(12) —(CH 2 ) n C(O)NR 8 NR 8 C(O)R 8 , and
(13) —(CH 2 ) n CF 3 ,
wherein phenyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein any alkyl, cycloalkyl, heterocycloalkyl, and methylene (CH 2 ) carbon atom in R 3 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, or two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
R 4 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —OC 1-6 alkyl;
R 5 is selected from the group consisting of:
(1) —CF 3 ,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —OC 1-8 alkyl,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n C 2-9 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CF 12 ) n -naphthyl, and
(10) —(CH 2 ) n heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R 3 , and alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R 3 and oxo, and wherein any methylene (CH 2 ) in R 5 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —OC 1-6 alkyl;
R 7 is selected from the group consisting of:
(1) —(CH 2 ) n N(R 8 ) 2 ,
(2) —(CH 2 ) n NR 8 C(O)R 8 ,
(3) —(CH 2 ) n OR 8 ,
(4) —(CH 2 ) n C≡N,
(5) —(CH 2 ) n C(O)OR 8 ,
(6) —(CH 2 ) n C(O)N(R 8 ) 2 ,
(7) —(CH 2 ) n NR 8 C(O)N(R 8 ) 2 ,
(8) —(CH 2 ) n NR 8 C(O)heteroaryl,
(9) —(CH 2 ) n heteroaryl,
(10) —(CH 2 ) n NR 8 S(O) p R 8 ,
(11) —(CH 2 ) n SR 8 , and
(12) —(CH 2 ) n S(O) p R 8 ,
wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-4 alkyl, and any methylene (CH 2 ) n in R 7 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl, or two C 1-4 alkyl substituents on any methylene (CH 2 ) n in R 7 together with the atom to which they are attached form a 3, 4, 5, or 6-membered ring optionally containing an additional heteroatom selected from O, S, —NH, and —NC 1-4 alkyl;
each R 8 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —OC 1-8 alkyl,
(6) —(CH 2 ) n C 3-8 cycloalkyl,
(7) —(CH 2 ) n C 2-9 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CH 2 ) n -naphthyl, and
(10) —(CH 2 ) n heteroaryl,
wherein phenyl, naphthyl, and heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from N(C 1-6 alkyl) 2 , —NH 2 , NH(C 1-6 alkyl), halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, and oxo, and wherein any methylene (CH 2 ) in R 8 is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and C 1-4 alkyl;
each R 9 is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) C 1-8 alkyl,
(4) —OC 1-8 alkyl,
(5) halogen;
(6) —NR 5 ,
(7) —SR 5 , and
(8) —CF 3 ,
wherein two C 1-8 alkyl substituents along with the atoms to which they are attached can form a 4- to 8-membered ring;
each R11 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-8 alkenyl,
(4) —(CH 2 ) n -phenyl,
(5) —(CH 2 ) n -naphthyl,
(6) —(CH 2 ) n -heteroaryl,
(7) —(CH 2 ) n C 2-9 heterocycloalkyl,
(8) —(CH 2 ) n C 3-7 cycloalkyl,
(9) halogen, and
(10) —OR 8 ,
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and any methylene (CH 2 ) carbon atom in R 11 are unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy, or two R 11 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
r is 1 or 2;
s is 0, 1 or 2;
n is 0, 1, 2, 3 or 4, and
p is 0, 1 or 2.
12 . A compound of claim 11 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13 . A compound of claim 12 which is:
or a pharmaceutically acceptable salt thereof.
14 . A compound of claim 12 which is:
or a pharmaceutically acceptable salt thereof.
15 . A compound of claim 12 which is:
or a pharmaceutically acceptable salt thereof.
16 . A compound of claim 12 which is:
or a pharmaceutically acceptable salt thereof.
17 . A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
18 . A compound of claim 12 wherein the pharmaceutically acceptable salt thereof is the HCl salt.
19 - 23 . (canceled)
24 . A method of treating obesity in a human patient in need thereof comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective to treat obesity.