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:
ring A represents a phenyl or naphthyl group;
each R 1 and R 2 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 3 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, and
R 4 represents H or C 1-4 alkyl optionally substituted with 1-3 halo atoms up to perhalo and 1 phenyl ring.
2. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A represents phenyl.
3. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A represents naphthyl.
4. 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 fluoro; chloro; SCH 3 ; CN, C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy,
wherein the alkyl and alkenyl portions of SCH 3 , C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy are optionally substituted with 1-3 fluoro atoms.
5. A compound in accordance with claim 4 wherein each R 1 represents H or is selected from the group consisting of fluoro, chloro; SCH 3 ; CN, C 1-4 alkyl and OCH 3 ,
wherein the alkyl portions of SCH 3 , C 1-4 alkyl and OCH 3 are optionally substituted with 1-3 fluoro atoms.
6. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 represents H or is selected from the group consisting of: fluoro; chloro; SCH 3 ; CN, C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy,
wherein the alkyl and alkenyl portions of SCH 3 , C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy are optionally substituted with 1-3 fluoro atoms.
7. A compound in accordance with claim 6 , or a pharmaceutically acceptable salt thereof, wherein each R 2 represents H or is selected from the group consisting of fluoro, chloro; SCH 3 ; CN, C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy,
wherein the alkyl and alkenyl portions of SCH 3 , C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy are optionally substituted with 1-3 fluoro atoms.
8. A compound in accordance with claim 7 , or a pharmaceutically acceptable salt thereof, wherein each R 2 represents H or is selected from the group consisting of fluoro, chloro; SCH 3 ; CN, C 1-4 alkyl and OCH 3 ,
wherein the alkyl portions of SCH 3 , C 1-4 alkyl and OCH 3 are optionally substituted with 1-3 fluoro atoms.
9. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 represents a member selected from the group consisting of: CH 3 , ethyl, n-propyl, n-, s- and t-butyl, and allyl.
10. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of: H, methyl, ethyl, n-propyl, n-butyl and benzyl.
11. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A represents a phenyl or naphthyl group;
each R 1 and R 2 represents H or is selected from the group consisting of halo selected from fluoro and chloro; SCH 3 ; CN, C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy,
wherein the alkyl and alkenyl portions of SCH 3 , C 1-6 alkyl, C 2-4 alkenyl and C 1-6 alkoxy are optionally substituted with 1-3 fluoro atoms;
R 3 represents a member selected from the group consisting of: methyl, ethyl, n-propyl, n-, s- and t-butyl, and allyl, and
R 4 is selected from the group consisting of: H, methyl, ethyl, n-propyl, n-butyl and benzyl.
12. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
TABLE A
TABLE 1
EXAMPLE
R 1
R 2
3
H
4-MeO
4
5-Cl
4-MeO
5
7-Cl
4-MeO
6
6-Cl
4-MeO
7
5-CF 3 O
4-MeO
8
5-Bu, 7-Me
4-MeO
9
5-Me, 7-F
4-MeO
10
5,7-diCl
4-MeO
11
7-Me
4-MeO
12
5,7-diMe
4-MeO
13
5-CF 3 O
4-Cl
14
5,7-diCl
4-CF 3 O
15
4,6-diCl
4-CF 3 O
16
5,7-diCl
2-CF 3 , 4-Cl
17
7-Cl
4-Cl
18
6,7-diCl
4-Cl
19
7-Cl
4-CF 3 O
20
6,7-diCl
3,4-diCl
21
5,7-diF
3,4-diCl
22
5,7-diCl
3-CF 3 O
23
6,7-diCl
3-CF 3 O
24
5,7-diF
3-CF 3 O
25
5-Me, 7-F
3-CF 3
26
6,7-diCl
4-CF 3 O
27
5-Me, 7-F
4-CF 3 O
28
5,7-diCl
3,4-diCl
29
5-Me, 7-F
3,4-diCl
30
7-Cl
3,4-diCl
31
7-Cl
3,4-diF
32
6,7-diCl
3,4-diF
33
5,7-diF
3,4-diF
34
7-F
3,4-diCl
35
5,7-diCl
3,4-diF
36
5-CN
4-Cl
37
5-MeS
4-Cl
38
5,7-diCl
3-Cl
39
5-Me
4-Cl
40
5-Cl, 7-Me
4-Cl
41
6,7-diCl
3-Cl
42
5,7-diMe
4-Cl
43
7-F
4-Cl
44
5,7-diF
4-Cl
45
7-Cl
3-Cl
46
5-Me, 7-F
3-Cl
47
7-CF 3
3-Cl
48
5,7-diF
3-Cl
49
5,7-diCl
3-CF 3
50
6,7-diCl
3-CF 3
51
5,7-diF
3-CF 3
52
5-Me, 7-F
3,4-diF
53
5,7-diCl
4-CF 3
54
5,7-diF
4-CF 3
55
5-Me, 7-F
4-CF 3
56
5-Cl
4-CF 3
57
5,7-diCl
3-F, 4-Cl
58
5-Me, 7-F
3-F, 4-Cl
59
5-Me, 7-F
3,5-diF
60
5,7-diCl
3,5-diF
61
5,7-diCl
4-Me
62
5-Me, 7-F
4-Me
63
5-Cl, 7-Me
4-Me
64
5,7-diCl
3,4-diMe
65
5-Me, 7-F
3,4-diMe
66
5-Cl, 7-Me
3,4-diMe
67
5-Cl, 7-F
4-Cl
68
5-CF 3 O
4-MeO, 3-Cl
TABLE 2
EXAMPLE
R 1
R 2
69
5-CF 3 O
4-MeO
70
5,7-diCl
4-MeO
71
7-CF 3
4-MeO
72
4,7-diCl
4-MeO
73
5,7-diF
4-MeO
74
7-Et
4-MeO
75
5-Cl, 7-Me
4-MeO
76
5-Bu, 7-Me
4-MeO
77
5-Me, 7-F
4-MeO
78
6,7-diCl
4-MeO
79
5,7-diCl
4-Cl
80
5-Me, 7-F
4-Cl
81
5-Me, 7-F
H
82
5,7-diCl
3,4-diF
TABLE 3
EXAMPLE
R 1
R 2
R 3
83
5-CF 3 O
4-Cl
Me
84
5-CF 3 O
4-MeO
Me
85
7-CF 3 O
4-Cl
Me
86
6-CF 3 O
4-Cl
Me
87
5-CF 3 O
4-MeO
Et
88
5,7-diCl
4-MeO
CF 3 (CH 2 ) 3 —
(racemic)
89
5,7-diCl
4-Cl
Et
90
5-Me, 7-F
4-Cl
Et
TABLE 4
EXAMPLE
R
95
3-cyclohex-1-enyl
96
3-cyclohexyl
97
4-(4′- t Bu-cyclohex-1′-enyl)
98
4-(4′- t Bu-cyclohexyl)
99
4-hex-1-enyl
100
4-hexyl
TABLE 5
EXAMPLE
R 1
R 2
R 3
R 4
103
Me
4-Cl
Bn
H
(racemic)
104
n-Pr
4-Cl
n-Pr
5,7-diCl
(racemic)
105
n-Pr
4-CF 3 O
Me
5,7-diCl
(enantiomer 1)
106
n-Pr
4-CF 3 O
Me
5,7-diCl
(enantiomer 2)
107
n-Bu
4-MeO
Me
5,7-diCl
(enantiomer 1)
108
n-Bu
4-MeO
Me
5,7-diCl
(enantiomer 2)
TABLE 6
EXAMPLE
R 1
109
7-Cl
110
5-Cl
111
5-CF 3 O
112
5,7-diCl
113
6,7-diCl
114
5-Me, 7-F
115
7-CF 3
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
14. 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 therapeutically effective to treat said type 2 diabetes mellitus.
15. A method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof.
16. 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 , or a pharmaceutically acceptable salt thereof.
17. A compound of the structural formula:
or a pharmaceutically acceptable salt thereof.
18. A compound of the structural formula:
19. A pharmaceutical composition comprised of a compound in accordance with claim 17 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprised of a compound in accordance with claim 18 in combination with a pharmaceutically acceptable carrier.