GLUCAGON RECEPTOR ANTAGONIST COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF USE
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 amd 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;
each 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 ; a 5-membered heteroaryl ring containing 1-3 nitrogen atoms, 0-1 oxygen or sulfur atom, and optionally substituted with 1-2 C 1-4 alkyl groups; 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; such that when m represents 0 or 1, Z represents 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 1 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 1-6 alkyl and C 3-4 alkenyl, each optionally substituted with 1-3 halo atoms.
5 . A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 represents C 2-5 alkyl optionally substituted with 1-3 halo atoms.
6 . A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and 3-methylbutyl, each optionally substituted with 1-3 halo atoms selected from fluoro and chloro.
7 . A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of ethyl, n-propyl, n-butyl, CH 2 CH(CH 3 ) 2 , CH 2 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, haloC 1-6 alkoxy and a 5-membered heteroaryl ring containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring being optionally substituted with 1-2 C 1-4 alkyl groups.
9 . 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 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, and a 5-membered heteroaryl ring containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring being optionally substituted with 1-2 C 1-4 alkyl groups.
10 . A compound in accordance with claim 1 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 , OCF 3 and a 5-membered heteroaryl ring containing 1-2 nitrogen atoms, 0-1 oxygen atom and being optionally substituted with 1 C 1-2 alkyl group.
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 1 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 1 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 or 1 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 1-6 alkyl and C 3-4 alkenyl, each optionally substituted with 1-3 halo atoms;
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, haloC 1-6 alkoxy and a 5-membered heteroaryl ring containing 1-2 nitrogen atoms and 0-1 oxygen atom, said ring being optionally substituted with 1-2 C 1-4 alkyl groups;
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; and
m is 0 or 1 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
5
4-Cl
n-Pr
H
6
4-Cl
n-Pr
5-Cl, 7-Me
7
4-Cl
n-Pr
5-Cl, 7-Br
8
4-Cl
n-Pr
2-Me
9
4-Cl
n-Pr
5-F, 7-Cl
10
4-OMe
n-Pr
H
11
3,4-diCl
n-Pr
5-Cl
12
3,4-diCl
n-Pr
5-Cl, 7-Br
13
4-Cl
n-Pr
5-F, 7-CN
14
4-Cl
n-Pr
5-Me, 7-CN
15
4-Cl
n-Pr
5-CF 3 , 7-CN
16
4-Cl
n-Pr
5,6-diF, 7-CN
17
4-Cl
n-Pr
4,5-diF, 7-CN
18
4-Cl
n-Pr
2-Me, 5-F, 7-CN
19
4-Cl
n-Pr
2-Me, 5-Cl, 7-CN
20
3,5-diF
n-Pr
5-CF 3 , 7-CN
21
3,4-diCl
n-Pr
5-Cl, 7-CN
22
4-OCF 3
n-Pr
5-F, 7-CN
23
4-OCF 3
n-Pr
5-Me, 7-CN
24
4-OCF 3
n-Pr
5-CF 3 , 7-CN
25
4-OCF 3
n-Pr
5-Cl, 7-CN
26
4-OCF 3
n-Pr
5,6-diF, 7-CN
27
4-Cl
—CH 2 CH 2 CF 3
5-Cl, 7-CN
28
4-Cl
—CH 2 CH 2 CF 3
5-Me, 7-CN
29
4-Cl
n-Bu
5-Cl, 7-CN
30
4-Cl
n-Bu
5-F, 7-CN
31
4-Cl
n-Bu
5-CF 3 , 7-CN
32
4-Cl
—CH 2 CH(CH 3 ) 2
5-Cl, 7-CN
33
4-Cl
—CH 2 CH(CH 3 ) 2
5-F, 7-CN
34
4-Cl
Et
5-Cl, 7-CN
35
4-Cl
n-Pr
36
4-OCF 3
n-Pr
37
4-Cl
n-Bu
38
4-Cl
n-Pr
TABLE 2
EXAMPLE
Y
39
40
41
42
43
44
TABLE 3
EXAMPLE
R 1
R 2
R 3
45
4-Cl
n-Pr
H
46
4-Cl
n-Pr
5-Cl
47
4-Cl
n-Pr
7-Cl
48
4-OMe
n-Pr
5-Cl
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.
21 - 29 . (canceled)