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 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, and 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 independently selected from oxygen, 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) —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;
R 9 is hydrogen;
each R 10 is independently selected from the group consisting of:
(1) Cl,
(2) —CH═CHCO 2 H,
(3) —C(O)morpholine,
(4) —C(O)pyrrolidine,
(5) —C(O)piperidine,
(6) —CO 2 H,
(7) —CO 2 CH 2 phenyl,
(8) —CO 2 CH 3 ,
(9) —(CH 2 ) 2 CO 2 H,
(10) —CO 2 tetrahydropyran,
(11) —CONH 2 ,
(12) —CONHCH 3 ,
(13) —CONHCH 2 CH 3 ,
(14) —CON(CH 2 CH 3 ) 2 ,
(15) —CON(CH 3 ) 2 ,
(16) —CONHCH(CH 3 ,) 2 ,
(17) —CONHcyclopropyl,
(18) —CONHphenyl,
(19) —C(O)NHcyclopentyl,
(20) —C(O)NH(CH 2 ) 1-6 OH,
(21) —C(O)NHtetrahydropyran,
(22) —CONHCH 2 CO 2 H,
(23) —CON(CH 3 )CH 2 CO 2 H,
(24) —CONHCOC(CH 3 ) 3 ,
(25) —C(O)NHCH(CO 2 CH 2 phenyl) 2 ,
(26) —C(O)NHCH(CO 2 CH 2 CH 3 ) 2 , and
(27) tetrazole,
wherein the alkyl, alkene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents and —(CH 2 ) n as described in the above R 10 substituents are unsubstituted or substituted with one to eight substituents selected from —C 1-6 alkyl, oxo, halogen, —C 1-6 alkoxy, —(CH 2 ) n OH, —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n SO 3 H, —(CH 2 ) n CO 2 H, —(CH 2 ) n CO 2 C 1-6 alky, and —(CH 2 ) n CO 2 C 2-6 alkene, and alkyl and alkoxy are unsubstituted or substituted with one to five substituents independently selected from halogen, —OH, —SO 3 H, —CO 2 H, and —CO 2 C 1 - 6 alkyl;
R 16 is selected from the group consisting of: hydrogen, —OH, —C 1-6 alkyl unsubstituted or substituted with —OH or phenyl, and —C 1-6 alkoxy;
each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
m is 1 and p is 0.
2. The compound of claim 1 wherein p is 0, m is 1 and R 10 is —CO 2 H; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein X is N; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein X is CH; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein X is COH; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 of formula II:
or a pharmaceutically acceptable salt thereof; wherein
R 2 , R 3 and R 4 are each 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, and 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 independently selected from oxygen, 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) —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;
R 9 is hydrogen;
each R 10 is independently selected from the group consisting of:
(1) Cl,
(2) —CH═CHCO 2 H,
(3) —C(O)morpholine,
(4) —C(O)pyrrolidine,
(5) —C(O)piperidine,
(6) —CO 2 H,
(7) —CO 2 CH 2 phenyl,
(8) —CO 2 CH 3 ,
(9) —(CH 2 ) 2 CO 2 H,
(10) —CO 2 tetrahydropyran,
(11) —CONH 2 ,
(12) —CONHCH 3 ,
(13) —CONHCH 2 CH 3 ,
(14) —CON(CH 2 CH 3 ) 2 ,
(15) —CON(CH 3 ) 2 ,
(16) —CONHCH( 3 ,) 2 ,
(17) —CONHcyclopropyl,
(18) —CONHphenyl,
(19) —C(O)NHcyclopentyl,
(20) —C(O)NH(CH 2 ) 1-6 OH,
(21) —C(O)NHtetrahydropyran,
(22) —CONHCH 2 CO 2 H,
(23) —CON(CH 3 )CH 2 CO 2 H,
(24) —CONHCOC(CH 3 ) 3 ,
(25) —C(O)NHCH(CO 2 CH 2 phenyl) 2 ,
(26) —C(O)NHCH(CO 2 CH 2 CH 3 ) 2 , and
(27) tetrazole,
wherein the alkyl, alkene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents and —(CH 2 ) n are unsubstituted or substituted with one to eight substituents selected from —C 1-6 alkyl, oxo, halogen, —C 1-6 alkoxy, —(CH 2 ) n OH, —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n SO 3 H, —(CH 2 ) n CO 2 H, —(CH 2 ) n CO 2 C 1-6 alky, and —(CH 2 ) n CO 2 C 2-6 alkene, and alkyl and alkoxy are unsubstituted or substituted with one to five substituents independently selected from halogen, —OH, —SO 3 H —CO 2 H, and —CO 2 C 1 - 6 alkyl;
each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
m is 1.
7. The compound of claim 1 of formula III:
or a pharmaceutically acceptable salt thereof; wherein
R 2 , R 3 and R 4 are each 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, and 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 independently selected from oxygen, 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) —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;
R 9 is hydrogen;
each R 10 is independently selected from the group consisting of:
(1) Cl,
(2) —CH═CHCO 2 H,
(3) —C(O)morpholine,
(4) —C(O)pyrrolidine,
(5) —C(O)piperidine,
(6) —CO 2 H,
(7) —CO 2 CH 2 phenyl,
(8) —CO 2 CH 3 ,
(9) —(CH 2 ) 2 CO 2 H,
(10) —CO 2 tetrahydropyran,
(11) —CONH 2 ,
(12) —CONHCH 3 ,
(13) —CONHCH 2 CH 3 ,
(14) —CON(CH 2 CH 3 ) 2 ,
(15) —CON(CH 3 ) 2 ,
(16) —CONHCH( 3 ,) 2 ,
(17) —CONHcyclopropyl,
(18) —CONHphenyl,
(19) —C(O)NHcyclopentyl,
(20) —C(O)NH(CH 2 ) 1-6 OH,
(21) —C(O)NHtetrahydropyran,
(22) —CONHCH 2 CO 2 H,
(23) —CON(CH 3 )CH 2 CO 2 H,
(24) —CONHCOC(CH 3 ) 3 ,
(25) —C(O)NHCH(CO 2 CH 2 phenyl) 2 ,
(26) —C(O)NHCH(CO 2 CH 2 CH 3 ) 2 , and
(27) tetrazole,
wherein the alkyl, alkene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents and —(CH 2 ) n are unsubstituted or substituted with one to eight substituents selected from —C 1-6 alkyl, oxo, halogen, —C 1-6 alkoxy, —(CH 2 ) n OH, —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n SO 3 H, —(CH 2 ) n CO 2 H, —(CH 2 ) n CO 2 C 1-6 alky, and —(CH 2 ) n CO 2 C 2-6 alkene, and alkyl and alkoxy are unsubstituted or substituted with one to five substituents independently selected from halogen, —OH, —SO 3 H —CO 2 H, and —CO 2 C 1 - 6 alkyl;
R 16 is selected from the group consisting of: hydrogen, —OH, —C 1-6 alkyl unsubstituted or substituted with —OH or phenyl, and —C 1-6 alkoxy;
each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and
m is 1.
8. The compound of claim 1 selected from the group consisting of:
(1) 3-(4-{[1-(3-ethoxyphenyl )-2-(4-methylphenyl)-1H -imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(2) 3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H -imidazol-4-yl]carbonyl}-1piperazinyl)-1-naphthoic acid,
(3) 3-(4-{[1-(3-ethoxypheny1)-2-(4-fluorophenyl)-1H -imidazol-4-yl]carbonyl}-1piperazinyl)-1-naphthoic acid,
(4) 3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H -imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(5) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(6) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(7) 1-(7-methoxy-2-naphthyl)-4-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine,
(8) 3-(4-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(9) methyl-2-(4-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoate,
(10) 6-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(11) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-isopropyl-1-naphthamide,
(12) 1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(1-pyrrolidinylcarbonyl)-2-naphthyl]piperazine,
(13) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-ethyl-1-naphthamide,
(14) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N,N-diethyl-1-naphthamide,
15-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[3-(1-pyrrolidinylcarbonyl)-2-naphthyl]piperazine,
(16) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N,N-diethyl-2-naphthamide,
(17) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-ethyl-2-naphthamide,
(18) 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-isopropyl-2-naphthamide,
(19) 3-(4-{[2-(2,4-difluorophenyl)-1-(3-ethoxyphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(20) 3-(4-{[1-(3-hydroxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(21) 3-(4-{[1-(3-ethoxyphenyl)-2-phenyl-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(22) 3-(4-{[2-(4-chlorophenyl)-1-(3-ethoxyphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(23) 3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(24) 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(25) 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(26) 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(27) 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid,
(28) 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic acid,
(29) 3-(1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinyl)-1-naphthoic acid,
(30) 3-(1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinyl)-1-naphthoic acid, and
(31) 3-(1-{[11-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-hydroxy-4-piperidinyl)-1-naphthoic acid;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 selected from the group consisting of: 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; or a pharmaceutically acceptable salt thereof.
10. The compound of claim 8 selected from the group consisting of: 3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; or a pharmaceutically acceptable salt thereof.
11. The compound of claim 8 selected from the group consisting of: 3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; or a pharmaceutically acceptable salt thereof.
12. The compound of claim 8 selected from the group consisting of: 3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl )-1-naphthoic acid; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 8 selected from the group consisting of: 3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 8 wherein the pharmaceutically acceptable salt thereof is a trifluoroacetic acid salt.
15. A pharmaceutical composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A Method for the treatment of obesity, or diabetes in a subject in need thereof which compromise administering to said subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.