Bicyclic piperidine derivatives as melanocortin-4 receptor agonists
View Patent ↗Certain novel bicyclic 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
X and Y are independently selected from the group consisting of
(1) hydrogen,
(2) C 1-8 alkyl,
(3) C 2-6 alkenyl,
(4) —(CH 2 ) n C 3-8 cycloalkyl,
(5) —(CH 2 ) n -phenyl,
(6) —(CH 2 ) n -naphthyl,
(7) —(CH 2 ) n -heteroaryl,
(8) —(CH 2 ) n C 2-8 heterocycloalkyl,
(9) —(CH 2 ) n C≡N,
(10) —(CH 2 ) n CON(R 5 R 5 ),
(11) —(CH 2 ) n CO 2 R 5 ,
(12) —(CH 2 ) n COR 5 ,
(13) —(CH 2 ) n NR 5 C(O)R 5 ,
(14) —(CH 2 ) n NR 5 CO 2 R 5 ,
(15) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,
(16) —(CH 2 ) n NR 5 SO 2 R 5 ,
(17) —(CH 2 ) n S(O) p R 5 ,
(18) —(CH 2 ) n SO 2 N(R 5 )(R 5 ),
(19) —(CH 2 ) n OR 5 ,
(20) —(CH 2 ) n OC(O)R 5 ,
(21) —(CH 2 ) n OC(O)OR 5 ,
(22) —(CH 2 ) n OC(O)N(R 5 ) 2 ,
(23) —(CH 2 ) n N(R 5 )(R 5 ), and
(24) —(CH 2 ) n NR 5 SO 2 N(R 5 )(R 5 );
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;
R 1 is selected from the group consisting of
(1) hydrogen,
(2) amidino,
(3) C 1-4 alkyliminoyl,
(4) C 1-10 alkyl,
(5) —(CH 2 ) n —C 3-7 cycloalkyl,
(6) —(CH 2 ) n -phenyl,
(7) —(CH 2 ) n -naphthyl, and
(8) —(CH 2 ) n -heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl and (CH 2 ) 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
(1) C 1-6 alkyl,
(2) phenyl,
(3) naphthyl, and
(4) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;
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 -naphthyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n C 2-8 heterocycloalkyl,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) halogen,
(8) OR 4 ,
(9) —(CH 2 ) n N(R 4 ) 2 ,
(10) —(CH 2 ) n C≡N,
(11) —(CH 2 ) n CO 2 R 4 ,
(12) NO 2 ,
(13) —(CH 2 ) n NR 4 SO 2 R 4
(14) —(CH 2 ) n SO 2 N(R 4 ) 2 ,
(15) —(CH 2 ) n S(O) p R 4 ,
(16) —(CH 2 ) n NR 4 C(O)N(R 4 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 4 ) 2 ,
(18) —(CH 2 ) n NR 4 C(O)R 4 ,
(19) —(CH 2 ) n NR 4 CO 2 R 4 ,
(20) —(CH 2 ) n NR 4 C(O)-heteroaryl,
(21) —(CH 2 ) n C(O)NR 4 N(R 4 ) 2 ,
(22) —(CH 2 ) n C(O)NR 4 NR 4 C(O)R 4 ,
(23) O(CH 2 ) n C(O)N(R 4 ) 2 ,
(24) CF 3 ,
(25) CH 2 CF 3 ,
(26) OCF 3 , and
(27) OCH 2 CF 3 ,
wherein 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 (CH 2 ) 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, or wherein two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
each R 4 is independently selected from the group consisting of
(1) hydrogen,
(2) C 1-6 alkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n -naphthyl,
(6) —(CH 2 ) n C 2-8 heterocycloalkyl,
(7) —(CH 2 ) n C 3-7 cycloalkyl, and
(8) —(CH 2 ) n C 3-7 bicycloalkyl,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH 2 ) 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
(1) hydrogen,
(2) C 1-8 alkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -naphthyl,
(5) —(CH 2 ) n -heteroaryl, and
(6) —(CH 2 ) n C 3-7 cycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, (CH 2 ) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein 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;
R 6 and R 7 are each independently selected from the group consisting of
(1) hydrogen,
(2) C 1-8 alkyl,
(3) —(CH 2 ) n C 3-6 cycloalkyl,
(4) —(CH 2 ) n -aryl,
(5) hydroxy,
(6) halogen, and
(7) amino;
r is 1 or 2;
s is 0, 1, or 2;
t is 1, 2, or 3;
n is 0, 1 or 2; and
p is 0, 1, or 2.
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 wherein alkyl, cycloalkyl and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
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 , and pharmaceutically acceptable salts thereof.
4. The compound of claim 3 wherein R 2 is phenyl optionally substituted with one to three groups independently selected from R 3 , and pharmaceutically acceptable salts thereof.
5. The compound of claim 3 wherein X is selected from the group consisting of
(1) hydrogen,
(2) —(CH 2 ) n -phenyl,
(3) —(CH 2 ) n -naphthyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n C 3-8 cycloalkyl, and
(6) —(CH 2 ) n C 2-8 heterocycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
6. The compound of claim 5 wherein X is selected from the group consisting of
(1) hydrogen,
(2) —(CH 2 ) 0-1 -phenyl,
(3) —(CH 2 ) 0-1 -heteroaryl,
(4) —(CH 2 ) 0-1 —C 2-8 heterocycloalkyl, and
(5) —(CH 2 ) 0-1 —C 3-8 cycloalkyl,
wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
7. The compound of claim 1 wherein Y is selected from the group consisting of
(1) C 1-6 alkyl,
(2) —(CH 2 ) n -phenyl,
(3) —(CH 2 ) n -naphthyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n —C 3-8 cycloalkyl,
(6) —(CH 2 ) n —C 2-8 heterocycloalkyl,
(7) —(CH 2 ) n C(O)N(R 5 ) 2 ,
(8) —(CH 2 ) n CO 2 R 5 ,
(9) —(CH 2 ) n S(O) p R 5 ,
(10) —(CH 2 ) n OR 5 ,
(11) —(CH 2 ) n NR 5 C(O)R 5 , and
(12) —(CH 2 ) n NR 5 SO 2 R 5 ,
wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
8. The compound of claim 5 wherein Y is selected from the group consisting of
(1) C 1-6 alkyl,
(2) —(CH 2 ) 0-1 -phenyl,
(3) —(CH 2 ) 0-1 -heteroaryl,
(4) —(CH 2 ) 0-1 —C 3-8 cycloalkyl,
(5) —(CH 2 ) 0-1 —C 2-8 heterocycloalkyl,
(6) —(CH 2 ) 0-1 NHC(O)R 5 ,
(7) —(CH 2 ) 0-1 CO 2 R 5 ,
(8) —(CH 2 ) 0-1 C(O)N(R 5 ) 2 , and
(9) —(CH 2 ) 0-1 S(O) p R 5 ,
wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo, and pharmaceutically acceptable salts thereof.
9. The compound of claim 5 wherein R 6 and R 7 are hydrogen.
10. The compound of claim 1 wherein r is 1 and s is 1.
11. The compound of claim 1 wherein r is 2 and s is 1.
12. 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
X is selected from the group consisting of
(1) hydrogen,
(2) —(CH 2 ) n -phenyl,
(3) —(CH 2 ) n -naphthyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n C 3-8 cycloalkyl, and
(6) —(CH 2 ) n —C 2-8 heterocycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo;
Y is selected from the group consisting of:
wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;
R 1 is hydrogen, amidino, C 1-4 alkyliminoyl, C 1-6 alkyl, C 5-6 cycloalkyl, —(CH 2 ) 0-1 phenyl, —(CH 2 ) 0-1 heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl and (CH 2 ) 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
(1) C 1-8 alkyl,
(2) —(CH 2 ) n -heteroaryl,
(3) —(CH 2 ) n —C 2-8 heterocycloalkyl,
(4) halogen,
(5) OR 4 ,
(6) —(CH 2 ) n N(R 4 ) 2 ,
(7) —(CH 2 ) n C≡N,
(8) —(CH 2 ) n CO 2 R 4 ,
(9) —(CH 2 ) n NR 4 SO 2 R 4
(10) —(CH 2 ) n SO 2 N(R 4 ) 2 ,
(11) —(CH 2 ) n S(O) p R 4 ,
(12) —(CH 2 ) n NR 4 C(O)N(R 4 ) 2 ,
(13) —(CH 2 ) n C(O)N(R 4 ) 2 ,
(14) —(CH 2 ) n NR 4 C(O)R 4 ,
(15) —(CH 2 ) n NR 4 CO 2 R 4 ,
(16) —(CH 2 ) n NR 4 C(O)-heteroaryl,
(17) —(CH 2 ) n C(O)NR 4 N(R 4 ) 2 ,
(18) —(CH 2 ) n C(O)NR 4 NR 4 C(O)R 4 ,
(19) O(CH 2 ) n C(O)N(R 4 ) 2 ,
(20) CF 3 ,
(21) CH 2 CF 3 ,
(22) OCF 3 , and
(23) OCH 2 CF 3 ,
wherein 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 (CH 2 ) 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, or wherein two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
each R 4 is independently selected from the group consisting of
(1) hydrogen,
(2) C 1-8 alkyl,
(3) phenyl,
(4) heteroaryl,
(5) —(CH 2 ) n C 2-8 heterocycloalkyl, and
(6) C 3-6 cycloalkyl,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH 2 ) 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
(1) hydrogen,
(2) C 1-8 alkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -naphthyl,
(5) —(CH 2 ) n -heteroaryl, and
(6) —(CH 2 ) n C 3-7 cycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, (CH 2 ) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein 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;
R 6 and R 7 are each independently selected from the group consisting of
(1) hydrogen,
(2) C 1-8 alkyl,
(3) —(CH 2 ) n C 3-6 cycloalkyl,
(4) —(CH 2 ) n -aryl,
(5) hydroxy,
(6) halogen, and
(7) amino;
r is 1 or 2;
s is 0, 1 or 2;
t is 1, 2, or 3;
n is 0, 1, or 2; and
p is 0, 1, or 2.
13. 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
X is selected from the group consisting of
(1) hydrogen,
(2) —(CH 2 ) 0-1 -phenyl,
(3) —(CH 2 ) 0-1 -naphthyl,
(4) —(CH 2 ) 0-1 -heteroaryl,
(5) —(CH 2 ) 0-1 C 3-8 cycloalkyl, and
(6) —(CH 2 ) 0-1 C 2-8 heterocycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R 3 , and wherein cycloalkyl, heterocycloalkyl, and (CH 2 ) are optionally substituted with one to three groups independently selected from R 3 and oxo;
Y is selected from the group consisting of
wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, heterocycloalkyl, and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;
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
(1) C 1-8 alkyl,
(2) —(CH 2 ) 0-1 -heteroaryl,
(3) —(CH 2 ) 0-1 —C 2-8 heterocycloalkyl,
(4) halogen,
(5) OR 4 ,
(6) —(CH 2 ) 0-1 N(R 4 ) 2 ,
(7) —(CH 2 ) 0-1 C≡N,
(8) —(CH 2 ) 0-1 CO 2 R 4 ,
(9) —(CH 2 ) 0-1 NR 4 SO 2 R 4
(10) —(CH 2 ) 0-1 SO 2 N(R 4 ) 2 ,
(11) —(CH 2 ) 0-1 S(O) 0-3 R 4 ,
(12) —(CH 2 ) 0-1 NR 4 C(O)N(R 4 ) 2 ,
(13) —(CH 2 ) 0-1 C(O)N(R 4 ) 2 ,
(14) —(CH 2 ) 0-1 NR 4 C(O)R 4 ,
(15) —(CH 2 ) 0-1 NR 4 CO 2 R 4 ,
(16) —(CH 2 ) 0-1 NR 4 C(O)-heteroaryl,
(17) —(CH 2 ) 0-1 C(O)NR 4 N(R 4 ) 2 ,
(18) —(CH 2 ) 0-1 C(O)NR 4 NR 4 C(O)R 4 ,
(19) O(CH 2 ) 0-1 C(O)N(R 4 ) 2 ,
(20) CF 3 ,
(21) CH 2 CF 3 ,
(22) OCF 3 , and
(23) OCH 2 CF 3 ,
wherein 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 (CH 2 ) 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, or wherein two R 3 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
each R 4 is independently selected from the group consisting of
(1) hydrogen,
(2) C 1-8 alkyl,
(3) phenyl,
(4) heteroaryl,
(5) —(CH 2 ) 0-1 heterocycloalkyl, and
(6) C 3-6 cycloalkyl,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, cycloalkyl, bicycloalkyl, and (CH 2 ) 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
(1) hydrogen,
(2) C 1-8 alkyl,
(3) —(CH 2 ) 0-1 -phenyl,
(4) —(CH 2 ) 0-1 -naphthyl,
(5) —(CH 2 ) 0-1 -heteroaryl, and
(6) —(CH 2 ) 0-1 C 3-7 cycloalkyl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, (CH 2 ) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, or wherein 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;
R 6 and R 7 are each independently selected from the group consisting of
(1) hydrogen,
(2) C 1-8 alkyl,
(3) —(CH 2 ) 0-1 C 3-6 cycloalkyl,
(4) —(CH 2 ) 0-1 -aryl,
(5) hydroxy,
(6) halogen, and
(7) amino;
t is 1, 2, or 3;
r is 1 or 2; and
s is 0, 1 or 2.
14. The compound of claim 11 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 which is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 14 which is:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 14 which is:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 18 further comprising a therapeutically effective amount of a second active ingredient selected from the group consisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea, an α-glucosidase inhibitor, and a HMG-CoA reductase inhibitor.
20. The compound of claim 14 wherein the pharmaceutically acceptable salt thereof is the hydrochloride salt.
21. The compound of claim 14 wherein the pharmaceutically acceptable salt thereof is the trifluoroacetic acid salt.