Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
View Patent ↗Substituted aryl and heteroaryl derivatives 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:
ring A is selected from the group consisting of: 6-10 membered aryl and 5-10 membered heteroaryl, said heteroaryl containing from 1-4 heteroatoms, 0-2 of which are O or S atoms, and 0-4 of which are N;
Y is present or absent, and when present, represents O, S, NH or CH 2 ;
X is present or absent, and when present, represents O or CH 2 ;
each R 1 is H or is selected from the group consisting of:
(a) halo, OH, CO 2 R 4 , SO p R 5 , CN, NO 2 C(O)NR 6 R 7 or NR 6 R 7 ;
(b) C 1-10 alkyl, C(O)C 1-6 alkyl or OC 1-6 alkyl, the alkyl portions being optionally substituted with: (1) 1-5 halo groups, up to perhalo, and 1-2 groups selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 C(O)NR 6 R 7 , NR 6 R 7 and phenyl optionally substituted with 1-3 halo groups and 1-2 groups selected from: OH, C 1-3 alkyl, haloC 1-3 alkyl, CN, OC 1-3 alkyl and OhaloC 1-3 alkyl;
(c) a 6-10 membered aryl or aryloxy group, said groups being optionally substituted with 1-3 halo groups and 1-2 groups selected from: OH, C 1-3 alkyl, haloC 1-3 alkyl, CN, OC 1-3 alkyl and OhaloC 1-3 alkyl;
R 2 is C 1-10 alkyl or aryl optionally substituted with 1-3 groups selected from (a), (b) and (c) above;
R 3 represents CH 2 CH 2 CO 2 R 4 , CH 2 CH(OH)CO 2 R 4 , CH 2 CF 2 CO 2 R 4 or 5-tetrazolyl;
R 4 is H or C 1-6 alkyl, and
R 5 represents a member selected from the group consisting of: C 1-10 alkyl, Aryl or Ar—C 1-10 alkyl, said C 1-10 alkyl, Aryl and Ar—C 1-10 alkyl being optionally substituted with 1-3 halo groups;
R 6 and R 7 each independently represent H or C 1-3 alkyl,
R 8 is selected from the group consisting of: H, OH, C 1-3 alkyl, haloC 1-3 alkyl, CN, OC 1-3 alkyl and OhaloC 1-3 alkyl, and
p is 0, 1 or 2.
2. A compound in accordance with claim 1 wherein ring A is selected from the group consisting of: phenyl, naphthyl, indole, 4H-1,3-benzodioxine and 1,3-benzodioxole.
3. A compound in accordance with claim 2 wherein ring A represents phenyl.
4. A compound in accordance with claim 1 wherein Y is absent or is selected from the group consisting of NH and CH 2 .
5. A compound in accordance with claim 1 wherein X is absent or represents CH 2 .
6. A compound in accordance with claim 1 wherein X is O.
7. A compound in accordance with claim 1 wherein R 2 represents C 1-10 alkyl or phenyl optionally substituted with C 1-10 alkyl or OC 1-6 alkyl, said groups being optionally substituted with 1-5 halo groups up to perhalo.
8. A compound in accordance with claim 1 wherein R 3 represents CH 2 CH 2 CO 2 H or 5-tetrazolyl.
9. A compound in accordance with claim 1 wherein each R 1 is selected from the group consisting of: (a) H, halo, CN, NR 6 R 7 , with R 6 and R 7 representing H or C 1-6 alkyl; (b) C 1-6 alkyl, OC 1-6 alkyl and SC 1-6 alkyl, each optionally substituted with 1-5 halo groups; and (c) aryl optionally substituted with 1-4 halo groups or 1-2 members selected from C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl and OC 1-6 haloalkyl.
10. A compound in accordance with claim 1 wherein R 8 represents H, halo, C 1-3 alkyl, haloC 1-3 alkyl OC 1-3 alkyl or OhaloC 1-3 alkyl.
11. A compound in accordance with claim 10 wherein R 8 represents H or halo.
12. A compound in accordance with claim 1 wherein:
A represents phenyl;
X is absent or represents CH 2 ;
Y is absent or is selected from the group consisting of; NH and CH 2 ;
each R 1 is selected from the group consisting of: (a) H, halo, CN, NR 6 R 7 , with R 6 and R 7 representing H or C 1-6 alkyl; (b) C 1-6 alkyl, OC 1-6 alkyl and SC 1-6 alkyl, each optionally substituted with 1-5 halo groups; and (c) aryl optionally substituted with 1-4 halo groups or 1-2 members selected from C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl and OC 1-6 haloalkyl;
R 2 represents C 1-10 alkyl or phenyl optionally substituted with C 1-10 alkyl or OC 1-6 alkyl, said groups being optionally substituted with 1-5 halo groups up to perhalo;
R 3 represents CH 2 CH 2 CO 2 H or 5-tetrazolyl, and R 8 represents H or halo, and
R 8 represents H or halo.
13. A compound in accordance with claim 1 wherein:
A represents phenyl;
X is O;
Y is absent or is selected from the group consisting of NH and CH 2 ;
each R 1 is selected from the group consisting of: (a) H, halo, CN, NR 6 R 7 , with R 6 and R 7 representing H or C 1-6 alkyl; (b) C 1-6 alkyl, OC 1-6 alkyl and SC 1-6 alkyl, each optionally substituted with 1-5 halo groups; and (c) aryl optionally substituted with 1-4 halo groups or 1-2 members selected from C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl and OC 1-6 haloalkyl;
R 2 represents C 1-10 alkyl or phenyl optionally substituted with C 1-10 alkyl or OC 1-6 alkyl, said groups being optionally substituted with 1-5 halo groups up to perhalo;
R 3 represents CH 2 CH 2 CO 2 H or 5-tetrazolyl and R 8 represents H or halo, within this aspect of the invention, all other variables are as originally defined with respect to formula I.
14. A compound in accordance with claim 1 selected from one of the following tables:
TABLE 1
Example
Ar
R
12
3,5-diClPh
13
3,5-diClPh
14
3,5-diClPh
15
3,5-diCF 3 Ph
16
3,5-diCF 3 Ph
17
3,5-diCF 3 Ph
18
19
20
4- i PrPh
21
4- i PrPh
22
4-CHF 2 O
23
4-CHF 2 O Ph
24
4-NMe 2 Ph
25
4-NMe 2 Ph
26
4-CF 3 SPh
27
4-CF 3 SPh
TABLE 2
Example
Ar
R
28
4-CF 3 OPh
29
4-CF 3 OPh
30
4-CF 3 OPh
TABLE 3
Example
Ar
R
31
4-CF 3 OPh
32
3,5-diMeOPh
33
3,5-diMeOPh
34
4-EtOPh
35
4-EtOPh
36
37
38
4-MeOPh
39
4-MeOPh
40
4- i Pr Ph
41
1-naphthyl
42
1-naphthyl
43
4-BnOPh
44
4-BnOPh
45
3-indolyl
46
3-indolyl
47
3,4,5-triMeOPh
48
3,4,5-triMeOPh
49
4-PentOPh
50
4-PentOPh
TABLE 4
Example
Ar
R
51
4-CF 3 OPh
52
4-CF 3 OPh
53
4-CF 3 OPh
TABLE 5
Example
Ar
R
54
4-CF 3 OPh
55
4-CF 3 OPh
56
4- t BuPh
57
4- t BuPh
58
4-MeOPh
59
4-MeOPh
60
4- n BuOPh
61
4- n BuOPh
62
63
64
4-FPh
65
4-FPh
66
4-ClPh
67
4-ClPh
68
4-BrPh
69
4-BrPh
70
2-CF 3 OPh
71
2-CF 3 OPh
72
3-CF 3 OPh
73
3-CF 3 OPh
74
4-PhOPh
75
4-PhOPh
76
3,5-diClPh
77
3,5-diClPh
TABLE 6
Example
Ar
R
78
3,5-diClPh
79
3,5-diClPh
80
4-CF 3 OPh
81
4-CF 3 OPh
TABLE 7
Example
Ar
X
R
82
3,5-diClPh
CH 2
83
3,5-diClPh
CH 2
84
4-CF 3 OPh
CH 2
85
4-CF 3 OPh
CH 2
86
4-CF 3 OPh
O
87
4-CF 3 OPh
O
or a pharmaceutically acceptable salt or solvate thereof.
15. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
16. 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 in an amount that is effective to treat said type 2 diabetes mellitus.
17. 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 in an amount that is effective to delay the onset of said type 2 diabetes mellitus.
18. 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 .
19. A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with claim 1 .