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:
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;
a and b represents integers selected from 0 and 1, such that the sum of a and b is 0, 1 or 2;
R 3 represents Aryl(R d ) 3 or Heteroaryl(R d ) 3 wherein the Heteroaryl group is a 5-10 membered group containing one or two rings, said Heteroaryl group containing one to three heteroatoms, 0-3 of which are nitrogen, and 0-1 of which is oxygen or sulfur;
each R d represents H or is selected from the group consisting of:
halo, CN, OH, NO 2 , CO 2 R a , C(O)NH 2 , NR a R b , S(O) p R a , C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy, haloC 1-10 alkoxy, phenyl(R e ) 3 and HAR(R e ) 3 ;
each R e represents H or is selected from the group consisting of: halo, CN, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy.
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, 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 oxo and C 1-6 alkoxy;
p represents 0 or 2;
each R a and R b independently represents H or CH 3 .
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 chloro and fluoro, CN, NH 2 , SO 2 CH 3 , C 1-3 alkyl, C 2-3 alkenyl or C 1-3 alkoxy, the alkyl and alkenyl portions of, C 1-3 alkyl, C 2-3 alkenyl and C 1-3 alkoxy being optionally substituted with 1-3 halo atoms selected from chloro and fluoro.
4. A compound in accordance with claim 3 or a pharmaceutically acceptable salt thereof wherein:
each R 1 represents H or is selected from the group consisting of chloro, fluoro, CN, CH 3 , OCH 3 , CF 3 , OCF 3 .
5. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein:
R 2 represents C 1-4 alkyl or C 2-4 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 3-4 alkyl 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 represents —CH 2 CH 2 CH 3 or —CH 2 CH 2 CF 3 .
8. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein: a and b both equal zero; or a equals one and b equals zero; or a equals zero and b equals one, or a and b both equal one.
9. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein:
R 3 represents Aryl(R d ) 3 or Heteroaryl(R d ) 3 wherein the Aryl portion of Aryl(R d ) 3 is phenyl or naphthyl, and the Heteroaryl portion of Heteroaryl(R d ) 3 is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, thiazolyl, thiophene, quinolinyl, isoquinolinyl and benzothiazolyl.
10. A compound in accordance with claim 9 or a pharmaceutically acceptable salt thereof wherein:
R 3 represents Aryl(R d ) 3 or Heteroaryl(R d ) 3 wherein the Aryl portion of Aryl(R d ) 3 is phenyl or naphthyl, and the Heteroaryl portion of Heteroaryl(R d ) 3 is selected from the group consisting of pyridyl, pyrrolyl, thiophene, quinolinyl and benzothiazolyl.
11. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof wherein:
each R d represents H or is selected from the group consisting of:
halo, CN, C 1-10 alkyl, haloC 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkoxy, phenyl(R e ) 3 and HAR(R e ) 3 ;
wherein HAR is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, thiazolyl, thiophene, quinolinyl, isoquinolinyl and benzothiazolyl, and
each R e represents H or is selected from the group consisting of: halo, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy and halo C 1-6 alkoxy.
12. A compound in accordance with claim 11 or a pharmaceutically acceptable salt thereof wherein:
each R d represents H or is selected from the group consisting of:
halo, CN, C 1-4 -alkyl, haloC 1-4 alkyl, C 1-4 -alkoxy, haloC 1-4 alkoxy, phenyl(R e ) 3 and HAR(R e ) 3 ;
wherein HAR is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, thiazolyl, thiophene, quinolinyl, isoquinolinyl and benzothiazolyl,
and each R e represents H or is selected from the group consisting of: halo selected from Cl, Br and F, CN, C 1-4 -alkyl, haloC 1-4 -alkyl, C 1-4 -alkoxy and haloC 1-4 -alkoxy, the halo portions of which are selected from Cl and F.
13. A compound in accordance with claim 12 or a pharmaceutically acceptable salt thereof wherein:
each R d represents H or is selected from the group consisting of:
Cl, Br, F, CN, CH 3 , t-butyl, CF 3 , OCH 3 , OCHF 2 , OCF 3 , phenyl(R e ) 3 and HAR(R e ) 3 ;
wherein HAR is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, thiazolyl, thiophene, quinolinyl, isoquinolinyl and benzothiazolyl,
and each R e represents H or is selected from the group consisting of: Cl, F, CN, CH 3 , CF 3 , OCH 3 ,OCH(CH 3 ) 2 and OCF 3 .
14. 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, 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 oxo and C 1-6 alkoxy;
p represents 0 or 2;
each R a and R b independently represents H or CH 3 ,
R 2 represents C 1-4 -alkyl or C 2-4 alkenyl, each optionally substituted with 1-3 halo atoms.
a and b both equal zero; or a equals one and b equals zero; or a equals zero and b equals one, or a and b both equal one;
R 3 represents Aryl(R d ) 3 or Heteroaryl(R d ) 3 wherein the Aryl portion of Aryl(R d ) 3 is phenyl or naphthyl, and the Heteroaryl portion of Heteroaryl(R d ) 3 is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, thiazolyl, thiophene, quinolinyl, isoquinolinyl and benzothiazolyl;
each R d represents H or is selected from the group consisting of:
halo, CN, C 1-10 alkyl, haloC 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkoxy, phenyl(R e ) 3 and HAR(R e ) 3 ;
wherein HAR is selected from the group consisting of pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, thiazolyl, thiophene, quinolinyl, isoquinolinyl and benzothiazolyl, and
and each R e represents H or is selected from the group consisting of: halo, CN, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy.
15. A compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof selected from one of the following tables:
TABLE 1
EXAMPLE
R 3
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
TABLE 2
EXAMPLE
Q
Y
Z
37
H
—CN
38
H
—CN
39
H
—CN
40
H
—CN
41
H
—CN
42
H
H
43
H
H
44
H
H
45
H
H
46
H
H
47
H
H
48
H
—CN
49
H
—CN
50
H
—CN
51
H
—CN
52
—CN
H
53
—CN
H
54
—CN
H
55
—CN
H
56
—CN
H
57
—CN
H
58
—CN
H
59
—CN
H
60
H
—CN
61
H
—CN
TABLE 3
EXAMPLE
R 3
62
63
64
65
66
TABLE 4
EXAMPLE
R
79
80
81
82
83
84
85
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
17. A pharmaceutical composition in accordance with claim 16 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.
18. 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.
19. A method of delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to the patient a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof in an amount that is effective to delay the onset of said type 2 diabetes mellitus.
20. A method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient an effective amount of a compound in accordance with claim 1 or a pharmaceutically acceptable salt thereof.