Antidiabetic oxazolidinediones and thiazolidinediones
View Patent ↗Phenoxyphenyl and phenoxybenzyl oxazolidine-2,4-diones and thiazolidine-2,4-diones 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:
A is O or S;
X is a bond or —C(R 7 ) 2 —;
R 1 is selected from the group consisting of H and C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-3 halogens;
each R 2 is independently 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 are optionally substituted with 1-3 halogens;
R 3 is selected from the group consisting of
Y is selected from the group consisting of ═O and ═N—OH;
D and Z are each independently selected from the group consisting of ═C(R 7 )— and ═N—;
B is selected from the group consisting of —N(R 7 )—, —O— and —S—;
each R 4 is independently selected from the group consisting of halogen, —OH, C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —OC(═O)C 1 -C 3 alkyl, and —S(O) q C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —OC(═O)C 1 -C 3 alkyl, and —S(O) q C 1 -C 3 alkyl are optionally substituted with 1-5 halogens;
each R 5 is independently 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 are optionally substituted with 1-3 halogens;
R 6 is selected from the group consisting of C 2 -C 5 alkyl, —CH 2 Cyclopropyl, C 3 -C 6 cycloalkyl, —OC 2 -C 5 alkyl and —C(═O)C 1 -C 3 alkyl, wherein the alkyl, cyclopropyl, and cycloalkyl groups of said R 6 substituent are optionally substituted with 1-3 halogens;
each R 7 is independently selected from the group consisting of H and C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-3 F;
m is an integer from 0-4;
n is an integer from 0-5;
p is an integer from 0-3; and
q is an integer from 0-2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is a bond or CH 2 ;
R 1 is selected from the group consisting of H and C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is optionally substituted with 1-3 F;
each R 2 is independently selected from the group consisting of F, Cl, CH 3 , CF 3 , —OCH 3 , and —OCF 3 ;
each R 4 is independently selected from the group consisting of halogen, —OH, C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —OC(═O)C 1 -C 3 alkyl, and —S(O) q C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —OC(═O)C 1 -C 3 alkyl, and —S(O) q C 1 -C 3 alkyl are optionally substituted with 1-3 F;
each R 5 is independently selected from the group consisting of F, Cl, CH 3 , —OCH 3 , CF 3 , and —OCF 3 ;
R 6 is selected from the group consisting of C 2 -C 5 alkyl, —CH 2 Cyclopropyl, and —C(═O)C 1 -C 3 alkyl, wherein any alkyl or cycloalkyl groups of said R 6 substituent is optionally substituted with 1-3 F;
R 7 is selected from the group consisting of H and C 1 -C 3 alkyl;
m is an integer selected from 0 and 1;
n is an integer from 0-3; and
p is an integer from 0-2.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is O.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from the group consisting of F, Cl, —OH, CH 3 , CF 3 , —OCH 3 , —OCHF 2 , —OC 2 H 5 , —OC(═O)CH 3 , and —S(O) q CH 3 , wherein q is 0, 1 or 2, and n is 1 or 2.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 2 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of n-C 3 H 7 , —CH 2 Cyclopropyl, and —C(═O)C 2 H 5 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is n-C 3 H 7 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 2.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
A is O;
X is a bond or CH 2 ;
R 1 is CH 3 ;
each R 4 is independently selected from the group consisting of F, Cl, —OH, CH 3 , CF 3 , —OCH 3 , —OCF 3 , —OCH 2 CH 3 , —OC(═O)CH 3 , —OCHF 2 , and —S(O) q CH 3 ;
R 5 is Cl or F;
R 6 is selected from the group consisting of n-C 3 H 7 , —CH 2 Cyclopropyl, and —C(═O)C 2 H 5 ;
R 7 is selected from H and CH 3 ;
m is 0;
n is an integer from 1-2;
p is 0 or 1; and
q is an integer from 0-2.
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
14. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
15. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
16. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
17. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
18. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
19. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method for treating type 2 diabetes in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. The compound of claim 12 , selected from the compounds listed below, or a pharmaceutically acceptable salt thereof: