Glucagon receptor antagonist compounds
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:
each R 1 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 up to perhalo; 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 up to perhalo; 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 up to perhalo, and further optionally substituted with 1 group selected from OH, oxo and C 1-6 alkoxy;
R 3 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 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 up to perhalo; 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 1 or a pharmaceutically acceptable salt thereof wherein R 2 represents a member selected from the group consisting of: C 1-4 alkyl and C 3-4 alkyenyl, each optionally substituted with 1-3 halo atoms.
5. A compound in accordance with claim 4 or a pharmaceutically acceptable salt thereof wherein R 2 represents C 2-4 alkyl optionally substituted with 1-3 halo atoms.
6. A compound in accordance with claim 5 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, each optionally substituted with 1-3 halo atoms selected from fluoro and chloro.
7. A compound in accordance with claim 6 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of n-propyl, n-butyl, CH 2 CH(CH 3 ) 2 and CH 2 CH 2 CF 3 .
8. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein each R 3 represents H or is selected from the group consisting of halo, CN, OH, SCH 3 , SO 2 CH 3 , C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy.
9. A compound in accordance with claim 8 or a pharmaceutically acceptable salt thereof wherein each R 3 represents H or is selected from the group consisting of halo which is selected from F, Cl and Br, CN, OH, SCH 3 , SO 2 CH 3 , 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.
10. A compound in accordance with claim 9 or a pharmaceutically acceptable salt thereof wherein each R 3 represents H, F, Cl, Br, CN, OH, CH 3 , OCH 3 , OCH 2 CH 3 , CHF 2 , CF 3 , SCH 3 , SO 2 CH 3 , OCHF 2 , and OCF 3 .
11. 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.
12. A compound in accordance with claim 11 or a pharmaceutically acceptable salt thereof wherein each R 4 represents H, F, Cl, OH, CH 3 , OCH 3 , CF 3 , and OCF 3 .
13. A compound in accordance with claim 12 or a pharmaceutically acceptable salt thereof wherein each R 4 represents H, F, CH 3 or OH.
14. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein m represents 0 and Z represents tetrazolyl.
15. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein m is 2 and Z represents CO 2 H.
16. 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;
R 2 represents a member selected from the group consisting of: C 1-4 -alkyl and C 3-4 alkyenyl, each optionally substituted with 1-3 halo atoms;
each R 3 represents H or is selected from the group consisting of halo, CN, OH, C 1-6 alkyl, SCH 3 , SO 2 CH 3 , C 1-6 alkoxy, haloC 1-6 alkyl and haloC 1-6 alkoxy;
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 is 0 and Z is tetrazolyl, or m is 2 and Z represents CO 2 H.
17. A compound in accordance with claim 1 selected from the group consisting of:
TABLE 1
Example
R 1
R 2
R 3
8
4-OCF 3
n-Pr
4-F
9
3-F, 4-Cl
n-Pr
4-F
10
4-Cl
—CH 2 CH(CH 3 ) 2
4-F
11
4-Cl
n-Bu
4-F
12
4-Me
n-Pr
4-F
13
3,4-diCl
n-Pr
4-F
14
3-Cl, 4-CN
n-Pr
4-F
15
3,4-diCN
n-Pr
4-F
16
4-F
n-Pr
4-F
17
4-Cl
—CH 2 CH 2 CF 3
4-F
18
2,4-diCl
n-Pr
4-F
19
2-Cl, 4-CN
n-Pr
4-F
20
4-Cl
n-Pr
2-Cl, 4-CN, 5-F
21
4-Cl
n-Pr
4,7-diOMe
22
4-Cl
n-Pr
2,5-diOMe
23
4-Cl
n-Pr
4-Cl
24
4-Cl
n-Pr
5-Cl
25
4-Cl
n-Pr
5-F, 6-Me
26
4-Cl
n-Pr
5-F, 8-Me
27
4-Cl
n-Pr
5-CN, 6-Me
28
4-Cl
n-Pr
5-CN, 8-Me
29
4-Cl
n-Pr
2-Cl, 4-OH, 5-F
30
4-Cl
n-Pr
2-Cl, 4-OMe, 5-F
31
4-Cl
n-Pr
2-Cl, 4-OH
32
4-Cl
n-Pr
5,7-diMe
TABLE 2
Example
R 1
R 2
R 3
33
4-Cl
n-Pr
6,8-diMe
34
4-Cl
n-Pr
6-Me, 8-CN
35
4-Cl
n-Pr
6-OEt
36
4-Cl
n-Pr
6-SMe
37
4-Cl
n-Pr
6-SO 2 CH 3
38
4-Cl
n-Pr
6-Me
39
4-Cl
n-Pr
5-CN, 6-OMe
40
4-Cl
n-Pr
4-F, 6-OMe
41
4-Cl
n-Pr
4-F, 6-CN
42
4-Cl
n-Pr
5-F, 6-Me
43
4-Cl
n-Pr
5-CN, 8-Me
44
4-Cl
n-Pr
5-CN, 6-Me
45
4-Cl
n-Pr
1-F
46
4-Cl
n-Pr
6-Me, 8-F
47
4-Cl
n-Pr
1-OH, 3-Cl
48
4-OMe
n-Pr
6-MeO
TABLE 3
EXAMPLE
Y
49
50
51
52
53
54
55
56
57
58
59
TABLE 4
EXAMPLE
Y
60
61
62
Example
Compound
63
64
65
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
19. A pharmaceutical composition in accordance with claim 18 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.
20. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in an amount that is effective to treat said type 2 diabetes mellitus.