Indoles having anti-diabetic activity
View Patent ↗Indoles of Formula I having —X-aryl-(CH 2 ) x -oxazolidinedione and —X-heteroaryl-(CH 2 )x-oxazolidinedione substituents on the N atom of the indole ring, where x is 0 or 1, and —X— is a bond or —CH 2 —, and their thiazolidinedione analogs, are PPAR gamma agonists or partial agonists and are useful in the treatment and control of type II diabetes, including hyperglycemia, 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:
R 1 is selected from
(a) —X-Aryl-Y-Z, and
(b) —X-Heteroaryl-Y-Z,
wherein Aryl and Heteroaryl are optionally substituted with 1-3 groups independently selected from A, where A can be on any position of Heteroaryl when R 1 is —X-Heteroaryl-Y-Z;
Aryl is phenyl or naphthyl;
Heteroaryl is a monocyclic or fused bicyclic aromatic ring containing 1-4 heteroatoms independently selected from N, O and S, including —S(O)— and —S(O) 2 —, wherein each ring contains 5 to 6 atoms;
X and Y are independently selected from the group consisting of a bond and —CR 5 R 6 —;
Z is
Q is selected from the group consisting of S and O;
A is selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, —OC 1 -C 4 alkyl, and halogen, wherein alkyl, alkenyl, and —Oalkyl are each optionally substituted with 1-5 halogens;
R 2 is C 1 -C 4 alkyl, which is optionally substituted with 1-5 halogens;
R 3 is selected from the group consisting of
(a) Benzisoxazolyl,
(b) Aryl,
(c) —C(═O)Aryl,
(d) —OAryl, and
(e) —S(O) n Aryl,
wherein R 3 is optionally substituted with 1-3 substituent groups independently selected from 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 1-5 halogens;
R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, 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 1-5 halogens;
R 7 is selected from the group consisting of H, C 1 -C 3 alkyl, and halogen, wherein C 1 -C 3 alkyl is optionally substituted with 1-3 F;
R 8 is selected from the group consisting of H and CH 3 ;
n is an integer from 0 to 2; and
p is an integer from 0 to 3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —X-phenyl-YZ, wherein phenyl is optionally substituted with 1-2 groups independently selected from A.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X and Y are each independently selected from a bond and —CH 2 —.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of halogen, —CF 3 , —OCF 3 , —CH 3 , and —OCH 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl and —CF 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CH 3 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of —OCH 3 , —OCF 3 , —CH 3 and —CF 3 ; and p is 1.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:
(a) 3-Benzisoxazolyl,
(b) Phenyl,
(c) —C(═O)Phenyl, and
(d) —OPhenyl,
wherein R 3 is optionally substituted with 1-2 groups independently selected from halogen, —OCH 3 , —OCF 3 , CH 3 , and CF 3 .
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is —X-phenyl-YZ, wherein phenyl is optionally substituted with 1-2 groups independently selected from A;
X and Y are independently selected from a bond and —CH 2 —;
A is selected from the group consisting of F, Cl, I, —CF 3 , —OCF 3 , —CH 3 , and —OCH 3 ;
R 2 is —CH 3 ;
R 4 is selected from the group consisting of Cl, —CF 3 , —OCF 3 , —CH 3 , and —OCH 3 ;
R 7 is selected from the group consisting of H, CH 3 , and CF 3 ;
R 8 is H; and
p is 1.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Q is O, and X and Y are —CH 2 —.
12. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Q is O, X is —CH 2 —, and Y is a bond.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —X-Heteroaryl-YZ, wherein Heteroaryl is selected from the group consisting of pyridinyl, quinolyl, furyl, tetrazolyl, isoxazolyl, oxazolyl, azoxazolyl, pyrazolyl, and thiazolyl, wherein Heteroaryl is optionally substituted with 1-3 groups independently selected from A.
14. The compound of claim 1 , selected from the group of compounds represented by the structures below, or a pharmaceutically acceptable salt thereof:
15. The compound of claim 1 , selected from the group of compounds represented by the structures below, or a pharmaceutically acceptable salt thereof:
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. A method for treating non-insulin dependent (Type 2) diabetes mellitus in a patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.