SOLUBLE EPOXIDE HYDROLASE INHIBITORS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT

• US 20110003849A1
• Filed: 02/24/2009
• Published: 01/06/2011
• Est. Priority Date: 03/04/2008
• Status: Abandoned Application

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Shen, Hong, Colletti, Steven L., Ding, Fa-Xiang
• Application Number:
  US12/919,323
• Publication Number:
  US 20110003849A1
• Time in Patent Office: Days
• US Class Current: 514/304
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 209/52 condensed with a ring other than six-membered
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 453/06 containing isoquinuclidine ring systems
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

Compounds of the formula: as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating diabetes, inflammation, atherosclerosis, hypertension, pain and the like are disclosed. Pharmaceutical compositions and methods of use are also included.

Claims

1. A compound represented by formula I:

2. A compound in accordance with claim 1 wherein R^a is selected from the group consisting of H, F, Cl, C_1-3alkyl, OC_1-3alkyl, haloC_1-3alkyl, OhaloC_1-3alkyl and Aryl, HAR or Hetcy, each of which is optionally substituted with 1-3 halo, C_1-3alkyl, haloC_1-3alkyl, OC_1-3alkyl or OhaloC_1-3alkyl groups, and 0-1 —

CO₂R^b group.

3. A compound in accordance with claim 1 wherein R^a is selected from the group consisting of:

H, Cl, F, CH₃, CF₃, OCF₃ and Aryl that is optionally substituted with 1-3 halo, C_1-3alkyl, haloC_1-3alkyl, OC_1-3alkyl or OhaloC_1-3alkyl groups, and 0-1 —

CO₂R^b group.

4. A compound in accordance with claim 1 wherein R^a is selected from the group consisting of:

H, Phenyl, C₁ and CF₃.

5. A compound in accordance with claim 1 wherein ring A represents a member selected from the group consisting of:

Aryl, HAR, C_3-7cycloalkyl, C_5-7cycloalkyl fused to an Aryl or HAR group, and Aryl or HAR fused to a C_5-7cycloalkyl group.

6. A compound in accordance with claim 1 wherein ring A represents Aryl, HAR or C_3-7cycloalkyl.

7. A compound in accordance with claim 1 wherein ring A represents a member selected from the group consisting of:

phenyl, a 5-10 membered heteroaryl group selected from the group consisting of pyridyl, pyrimidyl, pyrazolyl and thienyl and a C_3-5cycloalkyl group.

8. A compound in accordance with claim 1 wherein ring A represents a member selected from the group consisting of phenyl, pyridyl and a C_3-5cycloalkyl group.

9. A compound in accordance with claim 1 wherein ring A represents a phenyl or cyclopropyl ring.

10. A compound in accordance with claim 1 wherein ring A represents cyclopropyl.

11. A compound in accordance with claim 1 wherein ring B represents a 7-8 membered bicyclic heterocyclic group containing one nitrogen atom.

12. A compound in accordance with claim 1 wherein ring B represents a member selected from the group consisting of:

13. A compound in accordance with claim 1 wherein R¹ is selected from the group consisting of H and CH₃.

14. A compound in accordance with claim 1 wherein R² is selected from the group consisting of:

Aryl(R^x)_p in which the Aryl portion represents phenyl, p is an integer of 1-5, and each R^x is hydrogen, or 1-2 R^x groups represent halo, C_1-3allyl, haloC_1-3alkyl, OC_1-3alkyl or haloOC_1-3alkyl, and any remaining R^x groups represent hydrogen.

15. A compound in accordance with claim 1 wherein R² represents Aryl, which is phenyl, and all R^x groups represent hydrogen.

16. A compound in accordance with claim 1 wherein R² represents HAR(R^x)_q, q is an integer of from 1-4, HAR represents a 5-6 membered heteroaryl ring with one nitrogen atom, 0-1 oxygen or sulfur atom, and 0-2 additional nitrogen atoms, and each R^x group represents hydrogen, or 1-2 R^x groups represent a member selected from the group consisting of:

methyl, ethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy,

17. A compound in accordance with claim 1 wherein:

R² represents HAR(R^x)_q,

q represents an integer from 1-4;

HAR is selected from the group consisting of;

pyridyl and oxadiazolyl, and

the R^x groups represent hydrogen, or 1-2 R^x groups represent a member selected from the group consisting of;

methyl, ethyl, cyclopropyl, methylamino, dimethylamino, methoxy, ethoxy,

19. A compound in accordance with claim 1 represented by formula I:

20. A compound in accordance with claim 1 selected from Table 1:

21. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

22. A method of treating diabetes in a mammalian patient in need of such treatment comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective for treating diabetes.

18. (canceled)

23-25. -25. (canceled)