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 bicyclic Aryl or 8-10 membered bicyclic heteroaryl group containing 1-3 heteroatoms, 0-1 of which are O or S, and 0-2 of which are N atoms;
R 1 is selected from C 1-10 alkyl and C 2-10 alkenyl, said groups being optionally substituted with: 1-5 halo groups, up to perhalo, and 1 member selected from OH, CO 2 R 4 , SO p R 5 , CN, NO 2 C(O)NR 6 R 7 , NR 6 R 7 , OC 1-6 alkyl, C 1-6 haloalkoxy, haloC 1-6 alkylthio, Aryl and Heteroaryl,
said Aryl and Heteroaryl being optionally substituted with 1-3 halo groups and 1-2 members selected from the group consisting of: OH, CO 2 R 4 , SO p R 5 , CN, NO 2 , C(O)NR 6 R 7 , NR 6 R 7 ; C 1-6 alkyl, haloC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)-haloC 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkoxy C 2-6 alkenyl, haloC 2-6 alkenyl , SC 1-6 alkyl and haloSC 1-6 alkyl;
R 2 represents hydrogen, C 1-6 alkyl or haloC 1-6 alkyl;
four R 3 groups are present as follows:
1) 0-1 R 3 group is selected from the group consisting of: Aryl, HAR, —C 1-4 Alkyl-Aryl, —C 1-4 Alkyl-HAR, —X-Aryl, —X-HAR, —X—C 1-4 Alkyl-Aryl and —X—C 1-4 Alkyl-HAR; wherein X represents O, S, S(O) or S(O) 2 ;
said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-4 halo atoms, and 1-2 members selected from: OH, CN, C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 haloalkyl, NO 2 , SO p R 5 , C 2-6 alkenyl, OC 2-6 alkenyl and NR 6 R 7 ;
2) 0-3 R 3 groups are selected from: OH, CN, oxo, NO 2 , SO p R 5 , NR 6 R 7 , C 1-8 alkyl, haloC 1-8 alkyl, OC 1-8 alkyl, OC 1-8 haloalkyl, C 2-8 alkenyl, OC 2-8 alkenyl and haloC 2-8 alkenyl, and
3) any remaining R 3 groups are H or halo atoms;
R 4 is H or C 1-6 alkyl, and
R 5 represents a member selected from the group consisting of: C 1-8 alkyl, haloC 1-6 alkyl, Aryl or Ar—C 1-4 alkyl;
R 6 and R 7 each independently represent H or C 1-6 alkyl;
p is 0, 1 or 2;
R a represents CH 2 CH 2 CO 2 R 4 , CH 2 CH(OH)CO 2 R 4 or 5-tetrazolyl; and
R b is H or is selected from the group consisting of: halo, CN, NO 2 , OH, C 1-3 alkyl, OC 1-3 alkyl, haloC 1-3 alkyl and haloC 1-3 alkoxy.
2. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of naphthyl and bicyclic 9-10 membered heteroaryl containing 1-3 heteroatoms, 0-1 of which is an oxygen or sulfur atom and 0-2 of which are nitrogen atoms.
3. A compound in accordance with claim 2 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of naphthyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzofuranyl and benzoxazolyl.
4. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents a C 1-8 alkyl group or a C 2-8 alkenyl group, said groups being optionally substituted with 1-3 halo atoms, and further optionally substituted with 1 group selected from: OH, SO p R 5 , OC 1-3 alkyl, haloC 1-3 alkoxy, Aryl and HAR,
said Aryl and HAR being optionally substituted with 1-3 halo atoms, and 1-2 groups selected from SO p R 5 , C 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 alkyl and haloC 1-6 alkoxy.
5. A compound in accordance with claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents a C 1-8 alkyl or a C 2-8 alkenyl group, said groups being optionally substituted with 1-3 halo atoms, and further optionally substituted with 1 group selected from SO p R 5 Aryl and HAR, wherein p represents 0, R 5 represents C 1-4 alkyl, and
said Aryl and HAR being optionally substituted with 1-3 halo atoms, and 1 group selected from SO p R 5 , C 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 alkyl and haloC 1-6 alkoxy.
6. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:
H, C 1-4 alkyl and haloC 1-4 alkyl.
7. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein four R 3 groups are present as follows:
1) 0-1 R 3 group is selected from the group consisting of: Aryl, HAR, —C 1-4 Alkyl-Aryl, —X—(CH 2 ) 1-4 Aryl, —C 1-4 Alkyl-HAR and —X—(CH 2 ) 1-4 HAR;
wherein X represents O or S and said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-3 halo atoms, and 1-2 members selected from: C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 haloalkyl, SO p R 5 , C 2-6 alkenyl, OC 2-6 alkenyl, and CN;
2) 0-3 R 3 groups selected from: CN, NO 2 , SO p R 5 , C 1-8 alkyl, haloC 1-8 alkyl, OC 1-8 alkyl, OC 1-8 haloalkyl and C 2-8 alkenyl , and
3) any remaining R 3 groups are H or halo atoms.
8. A compound in accordance with claim 7 , or a pharmaceutically acceptable salt thereof, wherein four R 3 groups are present as follows:
1) 0-1 R 3 group is selected from the group consisting of: Phenyl, a 5-6 membered HAR group, —(CH 2 ) 1-2 -Phenyl, —X—(CH 2 ) 1-2 -Phenyl, —(CH 2 ) 1-2 -5-6 membered HAR and —X—(CH 2 ) 1-2 -5-6 membered HAR,
wherein X represents O or S and said Aryl and HAR groups and portions of the groups above are optionally substituted with 1-3 halo atoms, and 1 member selected from: C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 haloalkyl, SO p R 5 , C 2-6 alkenyl, OC 2-6 alkenyl, and CN;
2) 0-3 R 3 groups are selected from: CN, NO 2 , SO p R 5 , C 1-8 alkyl, haloC 1-8 alkyl, OC 1-8 alkyl, OC 1-8 haloalkyl and C 2-8 alkenyl,
wherein p represents 0 and R 5 represents C 1-6 alkyl or haloC 1-6 alkyl, and 3) any remaining R 3 groups are H or halo atoms selected from Cl and F.
9. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a is selected from
10. A compound in accordance with claim 9 , or a pharmaceutically acceptable salt thereof, wherein R a represents
11. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R b represents H.
12. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from the group consisting of naphthyl and bicyclic 9-10 membered heteroaryl containing 1-3 heteroatoms, 0-1 of which is an oxygen or sulfur atom and 0-2 of which are nitrogen atoms;
R 1 represents a C 1-8 alkyl group or a C 2-8 alkenyl group, said groups being optionally substituted with 1-3 halo atoms and further optionally substituted with 1 group selected from: OH, SO p R 5 , OC 1-3 alkyl, haloC 1-3 alkoxy, Aryl and HAR,
said Aryl and HAR being optionally substituted with 1-3 halo atoms, and 1 group selected from SO p R 5 , C 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 alkyl and haloC 1-6 alkyl;
R 2 is selected from the group consisting of: H, C 1-4 alkyl and haloC 1-4 alkyl;
four R 3 groups are present as follows:
1) 0-1 R 3 group is selected from the group consisting of: Aryl, HAR, —C 1-4 Alkyl-Aryl, —X—(CH 2 ) 1-4 Aryl and —C 1-4 Alkyl-HAR;
wherein X represents O or S and said Aryl and HAR groups and portions of the groups above being optionally substituted with 1-3 halo atoms, and 1-2 members selected from: C 1-6 alkyl, OC 1-6 alkyl, haloC 1-6 alkyl, OC 1-6 haloalkyl, SO p R 5 , C 2-6 alkenyl, OC 2-6 alkenyl, and CN;
2) 0-3 R 3 groups selected from: CN, NO 2 , SO p R 5 , C 1-8 alkyl, OC 1-8 alkyl, OC 1-8 haloalkyl and C 2-8 alkenyl, and
3) any remaining R 3 groups are H or halo atoms;
R a is selected from
and
R b represents H.
13. A compound in accordance with claim 1 selected from the following tables:
TABLE 1
Example
R 3a
R 3b
R 3c
17
—OMe
H
H
18
H
H
19
H
H
20
H
H
21
-pentyl
H
H
22
H
H
23
H
H
24
H
H
25
H
H
26
H
H
27
H
H
28
H
H
29
H
H
30
H
H
31
H
H
32
H
H
33
-hexyl
H
H
34
-heptyl
H
H
35
H
H
36
H
H
37
H
H
38
H
H
39
H
H
40
-Propyl
Cl
Cl
41
-Pentyl
Cl
Cl
42
Cl
Cl
43
—SO 2 Et
H
H
44
H
H
45
—OBu
CN
Cl
46
—OCF 2 H
CN
Cl
47
—OPr
CN
Cl
48
CN
Cl
49
—SEt
CN
Cl
50
—SEt
—SEt
Cl
TABLE 2
Example ii
R 1
R 3a
R 3b
R 3c
51 iii
-allyl
—OButyl
H
H
52
-allyl
—OButyl
H
H
53
-hexyl
H
H
54
H
H
55
-pentyl
H
H
56
-Butyl
H
H
57 iv
—Bn
—OMe
H
H
58
-Propyl
H
H
59
-Propyl
H
H
60
-Propyl
H
H
61
-Propyl
H
H
62
-Propyl
H
H
63
-Propyl
H
H
64
-Propyl
—SEt
H
H
65
-Propyl
H
H
66
-Propyl
H
H
67
-Propyl
H
H
68
-Propyl
H
H
69
-Propyl
H
H
70
-Propyl
H
H
71
-Propyl
—SPr
—CF 3
H
72
-Propyl
—OBu
Cl
Cl
73
-Propyl
—OBu
—SEt
H
74
-Propyl
—OBu
—Pr
H
75
-Propyl
H
H
76
-Propyl
H
H
77
-Propyl
H
H
TABLE 3
Example
R 3a
R 3b
78
H
79
-hexyl
H
80
Cl
81
—OBu
Cl
82
—SEt
H
83
—SCF 2 H
H
TABLE 4
Example
R 1
R 3a
84
Br
85
OMe
86
n-hexyl
87
n-hexyl
88
89
90
or a salt thereof.
14. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.