Chroman carboxylic acid derivatives for the treatment of diabetes and lipid disorders

1. A compound having the Formula I:

wherein R 1 , R 1 ′, R 2 , R 3 and R 3 ′ are independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, and halogen, wherein alkyl, alkenyl and alkynyl are linear or branched and are optionally substituted with substituents selected from 1 to 7 halogen atoms and 1-3-OC 1-3 alkyl groups; R 4 and R 5 are independently selected from H, halogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, —OH, and —OC 1-5 alkyl; R 6 and R 7 are independently selected from H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl and an optionally substituted phenyl; Y is ═O; W is selected from the group of consisting of —OR a , —NR a R b , —NR a SO 2 R b wherein R a and R b are independently selected from the group consisting of H, C 1-4 alkyl and aryl where in all instances, alkyl is linear or branched and are optionally substituted with 1-7 halogen atoms; m and n are independently 0-6; and pharmaceutically acceptable salts thereof.

2. A compound having Formula 1 as recited in claim 1 , wherein R 1 , R 1 ′, R 2 , R 3 , R 3 ′, R 4 and R 5 are hydrogen.

3. A compound having the Formula 1 as recited in claim 1 , wherein R 6 is selected from the group consisting of H, Me and Ph.

4. A compound having the Formula 1 as recited in claim 1 , wherein R 7 is selected from the group consisting of H, Me, Et, Ph, optionally substituted with 1-3 halogens or phenyl.

5. A compound having the Formula 1 as recited in claim 1 , wherein W is a group that is easily removed under physiological conditions during or after administration to a mammalian patient to yield a carboxylic acid selected from the group consisting of —OR a , —NR a R b , wherein R a and R b are independently selected from Me and Et.

6. A compound as recited in claim 1 , wherein the stereochemistry at the C 3 position of the chroman ring is R.

7. A compound as recited in claims 1 , wherein the stereochemistry at the C 3 position of the chroman ring is S.

8. A compound as recited in claim 1 , wherein the compound of the Formula I is selected from the following structures

9. A compound as recited in claim 8 , wherein the stereochemistry at the C 3 position of the chroman ring is R.

10. A compound as recited in claim 8 , wherein the stereochemistry at the C 3 position of the chroman ring is S.

11. A compound as recited in claim 1 , wherein R 1 , R 1 ′, R 2 , R 3 , R 3 ′, R 4 and R 5 are all hydrogens, R 6 is methyl, R 7 is phenyl, m is 2, n is 0 and W is —OH and the C 3 position of the chroman ring is R, as shown below:

12. A compound as recited in claim 1 , wherein R 1 , R 1 ′, R 2 , R 3 , R 3 ′, R 4 and R 5 are all hydrogens, R 6 is methyl, R 7 is phenyl, m is 2, n is 0 and W is —OH and the C 3 position of the chroman ring is S, as shown below:

13. A compound as recited in claim 8 , wherein said compound is in form of a pharmaceutically acceptable salt in which the carboxylic group exist as the anion and the counter cation is selected from Na, K, biguanide, arginine, lysine and histidine.

14. A pharmaceutical composition comprising an effective amount of compounds of Formula I of claim 1 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising an effective amount of compounds of Formula I of claim 5 and a pharmaceutically acceptable carrier.

16. A method for treating or controlling non-insulin dependent (Type II) diabetes mellitus in a mammalian patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound of Formula I of claim 1 .

17. A method for treating or controlling hyperglycaemia in a mammalian patient in need of such treatment which comprises administering to said patient a therapeutically effective amount of a compound of Formula I of claim 1 .

18. A method of treating or controlling one or more diseases, disorders, or conditions selected form the group consisting of non-insulin dependent diabetes mellitus (NIDDM) and hyperglycemia comprising the administration of an effective amount of a compound of Formula I of claim 1 .

19. The method in accordance with claim 18 , additionally comprising the administration of an effective amount one or more of the compounds selected from the group consisting of:

(a) an insulin sensitizer selected from the group consisting of (i) biguanides including metformin and fenformin, (ii) PPARγ agonist including pioglitazone, rosiglitazone and englitazone, (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors, and (iv) dipeptidyl peptidase IV inhibitors and

(b) insulin.