Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
View Patent ↗Glucagon receptor antagonist compounds are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt thereof wherein:
a is an integer selected from 1, 2 and 3, and b is an integer selected from 0 and 1, such that the sum of a and b is 2 or 3;
each R l represents H or is selected from the group consisting of: halo, CN, OH, NO 2 , CO 2 R a , NR a R b , S(O) p R a , C 1-10 alkyl, C 2-10 alkenyl or C 1-10 alkoxy, the alkyl and alkenyl portions of C 1-10 alkyl, C 2-10 alkenyl and C 1-10 alkoxy being optionally substituted with 1-5 halo atoms; and further optionally substituted with 1 group selected from OH, oxo and C 1-6 alkoxy;
p represents 0, 1 or 2;
each R a and R b independently represents H or C 1-4 alkyl optionally substituted with 1-5 halo atoms; and further optionally substituted with 1 group selected from OH, oxo and C 1-6 alkoxy;
R 2 represents C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted with 1-5 halo atoms, and further optionally substituted with 1 group selected from OH, oxo and C 1-6 alkoxy;
each R 3 represents H or halo, or 1-3 R 3 groups represent H or halo and the remainder represent a member selected from the group consisting of: CN; OH; NO 2 ; CO 2 R a ; NR a R b ; S(O) p R a ; phenyl or 5-6 membered heteroaryl containing 1-3 nitrogen atoms and 0-1 oxygen or sulfur atom, said phenyl and heteroaryl being optionally substituted with 1-3 halo atoms and 1-2 members selected from the group consisting of: C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy; C 1-10 alkyl; C 2-10 alkenyl and C 1-10 alkoxy, the alkyl and alkenyl portions of C 1-10 alkyl, C 2-10 alkenyl and C 1-10 alkoxy being optionally substituted with 1-5 halo atoms; and further optionally substituted with 1 group selected from OH, oxo, NR a R b , and C 1-6 alkoxy;
each R 4 independently represents H or is selected from the group consisting of: halo, OH, C 1-4 alkyl, OC 1-4 alkyl, haloC 1-4 alkyl and haloOC 1-4 alkyl;
m represents 0, 1 or 2; when m represents 0, Z represents tetrazolyl;
when m represents 1, Z represents a member selected from the group consisting of: CO 2 H, SO 3 H, C(O)NH 2 and tetrazolyl; and when m represents 2, Z represents a member selected from the group consisting of: CO 2 H, SO 3 H and C(O)NH 2 .
2. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R 1 represents H or is selected from the group consisting of: halo, CN, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy.
3. A compound in accordance with claim 2 or a pharmaceutically acceptable salt thereof wherein each R 1 represents H or is selected from the group consisting of: halo selected from fluoro and chloro; CN; CH 3 ; OCH 3 ; CF 3 and OCF 3 .
4. A compound in accordance with claim 3 or a pharmaceutically acceptable salt thereof wherein each R 1 represents H, halo selected from fluoro and chloro; CN; CH 3 ; or CF 3 .
5. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 represents a member selected from the group consisting of: C 1-6 alkyl and C 3-4 alkenyl, each optionally substituted with 1-3 halo atoms.
6. A compound in accordance with claim 5 or a pharmaceutically acceptable salt thereof wherein R 2 represents C 2-5 alkyl optionally substituted with 1-3 halo atoms.
7. A compound in accordance with claim 6 or a pharmaceutically acceptable salt thereof wherein R 2 represents n-propyl, optionally substituted with 1-3 halo atoms selected from fluoro and chloro.
8. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R 3 represents H or halo, or 1-3 R 3 groups represent H or halo and the remainder represent a member selected from the group consisting of: CN; OH; CO 2 R a ; NR a R b ; S(O) p R a ; phenyl or 5-6 membered heteroaryl containing 1-2 nitrogen atoms, said phenyl and heteroaryl being optionally substituted with 1-3 halo atoms and 1-2 members selected from the group consisting of: C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy; C 1-6 alkyl and C 1-6 alkoxy, the alkyl portions of C 1-6 alkyl and C 1-6 alkoxy being optionally substituted with 1-5 halo atoms.
9. A compound in accordance with claim 8 or a pharmaceutically acceptable salt thereof wherein each R 3 represents H or halo selected from fluoro, chloro and bromo, or 1-3 R 3 groups represent H or halo selected from fluoro, chloro and bromo, and the remainder represent a member selected from the group consisting of: CN; S(O) p R a ; phenyl or 5-6 membered heteroaryl selected from the group consisting of: pyrazolyl, imidazolyl, pyridyl, pyrimidinyl and pyrazinyl, said phenyl and heteroaryl being optionally substituted with 1-3 fluoro or chloro atoms and 1-2 members selected from the group consisting of: C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy; C 1-3 alkyl and C 1-3 alkoxy, the alkyl portions of C 1-3 alkyl and C 1-3 alkoxy being optionally substituted with 1-3 fluoro or chloro atoms.
10. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R 4 represents H, halo selected from F and Cl, OH, C 1-2 alkyl, C 1-2 alkoxy, haloC 1-2 alkyl and haloC 1-2 alkoxy wherein the halo portion of haloC 1-2 alkyl and haloC 1-2 alkoxy is selected from F and Cl.
11. A compound in accordance with claim 10 or a pharmaceutically acceptable salt thereof wherein each R 4 represents H, F, Cl, OH and CH 3 .
12. A compound in accordance with claim 11 or a pharmaceutically acceptable salt thereof wherein each R 4 represents H, F, CH 3 or OH.
13. A compound in accordance with claim 1 represented by formula I:
or a pharmaceutically acceptable salt thereof wherein:
a represents 1 or 2, and b represents 1, such that the sum of a and b is 2 or 3;
each R l represents H or is selected from the group consisting of: halo, CN, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;
R 2 represents a member selected from the group consisting of: C 1-6 alkyl and C 3-4 alkenyl, each optionally substituted with 1-3 halo atoms;
each R 3 represents H or halo, or 1-3 R 3 groups represent H or halo and the remainder represent a member selected from the group consisting of: CN; OH; CO 2 R a ; NR a R b ; S(O) p R a ; phenyl or 5-6 membered heteroaryl containing 1-2 nitrogen atoms, said phenyl and heteroaryl being optionally substituted with 1-3 halo atoms and 1-2 members selected from the group consisting of: C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy; C 1-6 alkyl and C 1-6 alkoxy, the alkyl portions of C 1-6 alkyl and C 1-6 alkoxy being optionally substituted with 1-5 halo atoms;
each R 4 represents H, halo selected from F and Cl, OH, C 1-2 alkyl, C 1-2 alkoxy, haloC 1-2 alkyl and haloC 1-2 alkoxy wherein the halo portion of haloC 1-2 alkyl and haloC 1-2 alkoxy is selected from F and Cl;
m represents 0 or 1 and Z represents tetrazolyl, or m is 1 or 2 and Z represents CO 2 H, SO 3 H or C(O)NH 2 .
14. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof, selected from the following tables:
TABLE 1
EXAMPLE
R 1
R 3
6
4-CF 3
CF 3
7
3-F, 5-F
CF 3
8
4-CF 3
9
3-F, 5-F
10
4-Cl
F
11
4-Cl
12
4-Cl
13
4-Cl
14
4-Cl
OCF 3
15
4-Cl
16
4-Cl
17
4-Cl
OCH 3
18
4-Cl
Cl
19
4-Cl
20
4-Cl
21
4-Cl
22
4-Cl
23
4-Cl
24
4-Cl
25
4-Cl
26
4-Cl
27
4-Cl
28
4-Cl
29
4-Cl
30
4-Cl
31
4-Cl
32
4-Cl
33
4-Cl
34
4-Cl
H
35
4-Cl
CF 3
36
4-Cl
CN
37
4-Cl
CH 3
38
4-Cl
Br
39
4-Cl
40
4-Cl
41
4-Cl
42
4-Cl
43
4-Cl
44
4-Cl
45
4-Cl
46
4-Cl
47
4-Cl
TABLE 2
EXAMPLE
R 3
48
4-OCH 3
49
4-CH 3
50
4-CF 3
51
4-Cl, 7-Cl
52
4-Cl, 5-Cl
53
4-Cl
54
5-Cl, 6-Cl
55
4-Cl, 6-Cl
56
4-F
TABLE 3
EXAMPLE
R 3
57
58
59
60
CN
61
CH 3
62
Br
63
TABLE 4
EXAMPLE
R 1
R 3
64
4-CF 3
CF 3
65
3-F, 5-F
CF 3
66
4-Cl
67
4-Cl
68
4-Cl
Cl
69
4-Cl
70
4-Cl
71
4-Cl
72
4-Cl
73
4-Cl
74
4-Cl
75
4-Cl
76
4-Cl
77
4-Cl
78
4-Cl
79
4-Cl
OCH 3
80
4-Cl
CF 3
81
4-Cl
CN
82
4-Cl
CH 3
83
4-Cl
OCF 3
84
4-Cl
SCH 3
85
4-Cl
Br
86
4-Cl
F
87
4-Cl
H
TABLE 5
EXAMPLE
R 3
88
7-(4-CH 3 —C 6 H 4 )
89
7-(4-Cl—C 6 H 4 )
90
7-(4-OCH 3 —C 6 H 4 )
91
5-Cl
92
7-CH 3
93
7-F
94
7-Cl
95
7-CF 3
96
6-OCH 3 , 7-OCH 3
97
7-Br
98
7-Cl, 8-Cl
TABLE 6
EXAMPLE
R 3
Y
99
OCF 3
100
OCF 3
101
OCF 3
102
OCF 3
103
OCF 3
104
OCF 3
105
CH 3
106
Br
107
CF 3
108
109
15. A pharmaceutical composition comprising a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
16. A pharmaceutical composition in accordance with claim 15 further comprised of a member selected from the group consisting of: simvastatin, mevastatin, ezetimibe, atorvastatin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, losartan, hydrochlorothiazide, buformin, phenformin, troglitazone, pioglitazone, rosiglitazone, insulin, somatostatin, voglibose, miglitol, acarbose, sitagliptin, vildagliptin, saxagliptin, alogliptin, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide, gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide, repaglinide, rimonabant and taranabant.