Substituted imidazole-4-carboxamides as cholecystokinin-1 receptor modulators
View Patent ↗Certain novel substituted imidazole 4-carboxamides are ligands of the human cholecystokinin receptor and, in particular, are selective ligands of the human cholecystokinin-1 receptor (CCK-1R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of CCK-1R, such as obesity, and diabetes.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof; wherein
X is N or CR 16 ;
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OH,
(4) —C 1-6 alkyl, and
(5) —C 1-6 alkoxy,
wherein alkyl and alkoxy are unsubstituted or substituted with one to five substituents independently selected from halogen, OH, C 1-6 alkyl, and C 1-6 alkoxy, or R 2 and R 3 or R 3 and R 4 together with the atoms to which they are attached form a 4-8 membered ring containing 0-2 heteroatoms ndependently selected from oxygen, and N—R 15 , and wherein the 4-8 membered ring is unsubstituted or substituted with a substituent selected from —OH, halogen, C 1-6 alkyl, and C 1-6 alkoxy;
R 5 , R 6 and R 7 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OH,
(4) —C 1-6 alkyl, and
(5) —C 1-6 alkoxy,
wherein alkyl and alkoxy are unsubstituted or substituted with one to five substituents independently selected from halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy;
R 8 is hydrogen;
each R 9 is hydrogen;
each R 10 is —C 1-6 alkyl;
each R 15 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
each R 16 is independently selected from the group consisting of: hydrogen, —OH and —C 1-6 alkyl;
each n is independently 0, 1, 2, or 3; and
p is 0, 1, or 2.
2. The compound of claim 1 wherein m is 0 and p is 0; or a pharmaceutically acceptable salts thereof.
3. The compound of claim 1 wherein X is N or CH; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 wherein X is N; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein n is 0.
6. The compound of claim 1 wherein n is 1, 2 or 3.
7. The compound of claim 1 of formula II:
or a pharmaceutically acceptable salt thereof; wherein
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OH,
(4) —C 1-6 alkyl, and
(5) —C 1-6 alkoxy,
wherein alkyl and alkoxy are unsubstituted or substituted with one to five substituents selected from halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy;
R 5 , R 6 and R 7 are each independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl, and
(4) —C 1-6 alkoxy,
wherein alkyl and alkoxy are unsubstituted or substituted with one to five substituents selected from halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy;
R 8 is hydrogen;
each R 9 is hydrogen;
each R 10 is —C 1-6 alkyl;
each n is independently 0, 1, 2, or 3.
8. The compound of claim 1 selected from the group consisting of:
(1) 1-{[2-(2,4-difluorophenyl)-1-(3-ethoxyphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(2) 1-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(3) 1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(4) 1-{[1-(3-hydroxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(5) 1-{[1-(2,3-dimethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(6) 1-{[1-(3-isopropoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(7) 1-{[1-(3-ethylphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(8) 1-{[1-(4-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(9) 1-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(10) 1-{[1-(3-ethoxyphenyl)-2-phenyl-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(11) 1-{[1-(3-ethoxyphenyl)-2-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(12) 1-{[1-(3-ethoxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(13) 1-{[1-(3-ethoxyphenyl)-2-(4-ethylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(14) 1-{[1-(3-ethoxyphenyl)-2-(4-methoxyphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(15) 1-{[1-(3-ethoxyphenyl)-2-(4-trifluoromethylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(16) 1-{[1-(3-ethoxy-5-fluorophenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(17) 1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine,
(18) 1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine,
(19) 1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine,
(20) 1-{[1-(1,3-benzodioxol-5-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine,
(21) 1-{[1-(3,4-dihydro-2H-chromen-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine, and
(22) 5-(2-(4-methylphenyl)-4-{[4-(2-naphthyl)-1-piperazinyl]carbonyl}-1H-imidazol-1-yl)indoline;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 selected from the group consisting of:
(1) 1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine,
(2) 1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine,
(3) 1-{[1-(1,3-benzodioxol-5-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine,
(4) 1-{[1-(3,4-dihydro-2H-chromen-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine, and
(5) 5-(2-(4-methylphenyl)-4-{[4-(2-naphthyl)-1-piperazinyl]carbonyl}-1H-imidazol-1-yl)indoline;
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 8 selected from the group consisting of: 1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine, or a pharmaceutically acceptable salt thereof.
11. The compound of claim 8 selected from the group consisting of: 1-{[1-(1,3-benzodioxol-5-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl-4-(2-naphthyl)piperazine, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 8 which is
(1) 1-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-4-(2 naphthyl)piperazine;
(2) 1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine;
(3) 1-{[2-(2,4-difluorophenyl)-1-(3-ethoxyphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine;
(4) 1-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine;
(5) 1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine;
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 8 which is selected from the group consisting of: 1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 8 which is selected from the group consisting of: 1-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-(2-naphthyl)piperazine; or a pharmaceutically acceptable salt thereof.
15. The compound of claim 8 wherein the pharmaceutically acceptable salt thereof is a trifluoroacetic acid salt.
16. A pharmaceutical composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.