Indoles having anti-diabetic activity
View Patent ↗Indoles having aryloxyalkanoic acid substituents or arylalkanoic acid substituents are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
wherein X is selected from the group consisting of a bond, O, S(O) n , CH 2 , and C 3-6 cycloalkylidene;
Y is selected from the group consisting of —OCR 7 R 8— , and —CH 2 CR 5 R 6— ;
Z is selected from the group consisting of —CO 2 H and tetrazole;
A is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkenyl, —OC 1-4 alkyl, and halogen, wherein alkyl, alkenyl, and Oalkyl are optionally substituted with 1-5 halogens;
R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, halogen, C 1 -C 5 alkyl, OC 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkenyl, C 3-6 cycloalkyl, (CH 2 ) 0-2 phenyl, —O(CH 2 ) 0-2 phenyl and CO 2 H, wherein C 1 -C 5 alkyl, OC 1 -C 5 alkyl, C 2 -C 5 alkenyl, OC 2 -C 5 alkenyl, C 3-6 cycloalkyl, and phenyl are optionally substituted with 1-5 halogens, and C 3-6 cycloalkyl and phenyl are further optionally substituted with 1-3 groups independently selected from C 1 -C 3 alkyl and OC 1 -C 3 alkyl, said C 1 -C 3 alkyl and OC 1 -C 3 alkyl being optionally substituted with 1-3 halogens;
R 2 is C 1 -C 4 alkyl, which is optionally substituted with 1-5 halogens;
R 3 is 3-benzisoxazolyl optionally substituted with 1-3 groups independently selected from halogen, C 1-3 alkyl, and OC 1-3 alkyl, wherein C 1-3 alkyl and OC 1-3 alkyl are optionally substituted with 1-5 halogens;
each R 4 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, and OC 1 -C 5 alkyl, whcrein C 1 -C 3 alkyl and OC 1 -C 5 alkyl are optionally substituted with 1-5 halogens;
n is an integer from 0-2;
p is an integer from 0-3; and
q is an integer from 0-3.
2. A compound according to claim 1 , wherein q is an integer from 1-3.
3. A compound according to claim 1 , wherein
X is selected from the group consisting of a bond, O, S(O) n , CH 2 , and C 3-6 cycloalkylidene;
Y is selected from the group consisting of OCR 7 R 8 and CH 2 CR 5 R 6 ;
Z is selected from CO 2 H and tetrazole;
A is selected from the group consisting of H, CH 3 , CF 3 , OCH 3 , OCF 3 , and halogen;
R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl, and OC 1 -C 3 alkyl, and R 8 is selected from the group consisting of halogen, C 1 -C 3 alkyl, and OC 1 -C 3 alkyl, wherein C 1 -C 3 alkyl and OC 1 -C 3 alkyl of R 5 , R 6 , R 7 , and R 8 are optionally substituted with 1-3 halogens;
R 2 is C 1 -C 3 alkyl;
R 3 is benzisoxazolyl optionally substituted with 1-3 groups independently selected from halogen, OCH 3 , OCF 3 , CH 3 , and CF 3 ;
each group R 4 is selected from OCH 3 , OCF 3 , and CF 3 ; and
p is 1.
4. A compound according to claim 3 , wherein R 5 , R 6 , and R 7 are each independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl, and OC 1 -C 3 alkyl, and R 8 is selected from the group consisting of halogen, C 1 -C 3 alkyl, and OC 1 -C 3 alkyl; and q is an integer from 1-3.
5. A compound according to claim 3 , wherein
X is selected from the group consisting of O, S(O) n , and CH 2 ;
Y is selected from the group consisting of OCR 7 R 8 and CH 2 CR 5 R 6 ;
Z is CO 2 H;
A is selected from the group consisting of H, CH 3 , CF 3 , OCH 3 , OCF 3 , and halogen;
R 5 is H;
R 6 is selected from H and OC 1 -C 3 alkyl, which is optionally substituted with 1-3 halogens;
R 7 is selected froni the group consisting of H and C 1 -C 3 alkyl;
R 8 is C 1 -C 3 alkyl;
R 2 is C 1 -C 3 alkyl; and
R 3 is benzisoxazolyl optionally substituted with 1 group independently selected from halogen, OCH 3 , OCF 3 , CH 3 , and CF 3 .
6. A compound according to claim 5 , wherein q is 1.
7. A compound according to claim 2 , wherein Y is OCR 7 R 8 ; R 7 is selected from the group consisting of H and C 1 -C 3 alkyl; and R 8 is C 1 -C 3 alkyl.
8. A compound according to claim 2 , wherein R 2 is CH 3 .
9. A compound according to claim 2 , wherein Z is CO 2 H.
10. A compound according to claim 2 , wherein R 3 is 3-benzisoxazolyl, which is optionally substituted with 1-3 substituents independently selected from halogen, OCH 3 , OCF 3 , CH 3 , and CF 3 .
11. A compound according to claim 4 , wherein R 3 is 3-benzisoxazolyl, which is optionally substituted with 1 substituent selected from halogen, OCH 3 , OCF 3 , and CF 3 .
12. A compound accoTding to claim 5 , wherein
X and YZ are meta to each other on the phenyl ring of R 1 ;
R 4 is selected from OCH 3 , OCF 3 , and CF 3 ;
X is selected from O and CH 2 ;
Y is OC*R 7 R 8 , wherein R 7 is H and R 8 is C 1 -C 3 alkyl;
R 2 is CH3; and
R 3 is 3-benzisoxazolyl, which is optionally substituted with 1 substituent selected from halogen, OCH 3 , OCF 3 , and CF 3 .
13. A compound according to claim 12 , wherein q is 1.
14. A compound according to claim 13 , wherein the asymmetric C* carbon of Y has the R configuration.
15. A compound according to claim 13 , wherein the asymmetric C* carbon of Y has the S configuration.
16. A compound according to claim 1 as named below, or a pharmaceutically acceptable salt thereof:
1
2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenoxy)propanoic acid
2
2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
3
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenoxy)propanoic acid
4
(2S)-2-(3-{[1-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenoxy)propanoic acid
5
(2R)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenoxy)propanoic acid
6
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenoxy)-4-phenylbutanoic acid
7
2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenoxy)-2-methylpropanoic acid
8
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(pentyloxy)-1H-indol-3-
yl]methyl}phenoxy)propanoic acid
9
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenyl)propanoic acid
10
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid
11
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
12
(2R)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
13
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-1H-indol-3-
yl]methyl}phenoxy)propanoic acid
14
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenyl)-2-ethoxypropanoic acid
15
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenyl)-2-(4-fluorophenoxy)propanoic acid
16
(2S)-2-(3-{1-[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]cyclopropyl}phenoxy)propanoic acid
17
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenyl)-2-ethoxypropanoic acid
18
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid
19
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenyl)propanoic acid
20
(2S)-2-(4-chloro-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
21
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenyl)-2-phenoxypropanoic acid
22
3-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}phenyl)-2-(4-fluorophenoxy)propanoic acid
23
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]thio}phenoxy)propanoic acid
24
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]sulfinyl}phenoxy)propanoic acid
25
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]sulfonyl}phenoxy)propanoic acid
26
(2S)-2-(2-chloro-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
27
(2S)-2-(2-allyl-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
28
(2S)-2-(2-allyl-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
29
(2S)-2-(3-chloro-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
30
(2S)-2-(5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}-2-fluorophenoxy)propanoic acid
31
(2R)-2-(5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}-2-fluorophenoxy)propanoic acid
32
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
4-propylphenoxy)propanoic acid
33
(2R)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
4-propylphenoxy)propanoic acid
34
7-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}chromane-2-carboxylic acid
35
7-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-2-
ethylchromane-2-carboxylic acid
36
(2R)-2-(2-chloro-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)propanoic acid
37
(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]thio}phenoxy)acetic acid
38
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]thio}phenoxy)butanoic acid
39
(2R)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]thio}phenoxy)butanoic acid
40
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}-4-fluorophenoxy)propanoic acid
41
(2R)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]methyl}-4-fluorophenoxy)propanoic acid
42
(2R)-2-(2-chloro-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)butanoic acid
43
(2-chloro-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)acetic acid
44
2-(2-chloro-5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)-3-methylbutanoic acid
45
(2S)-2-(4-chloro-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)butanoic acid
46
(2R)-2-(4-chloro-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)butanoic acid
47
2-(4-chloro-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)-3-methylbutanoic acid
48
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
4-fluorophenoxy)propanoic acid
49
(2S)-2-(5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
2-fluorophenoxy)propanoic acid
50
(2R)-2-(5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
2-fluorophenoxy)propanoic acid
51
(2S)-2-(5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
2-fluorophenoxy)butanoic acid
52
(2R)-2-(5-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
2-fluorophenoxy)butanoic acid
53
2-(4-chloro-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)pentanoic acid
54
2-(4-chloro-3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-
yl]oxy}phenoxy)pentanoic acid
55
(2S)-2-(3-{[1-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-3-yl]oxy}-
4-fluorophenoxy)butanoic acid
56
(2S)-2-(4-chloro-3-{[1-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-
3-yl]oxy}phenoxy)propanoic acid
57
(2S)-2-(4-fluoro-3-{[1-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-5-(trifluoromethoxy)-1H-indol-
3-yl]oxy}phenoxy)butanoic acid
17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.