Diabetes and metabolic syndrome treatment with a novel dual modulator of soluble epoxide hydrolase and peroxisome proliferator-activated receptors

Patent metadata

Field	Value
Publication number	US-11447445-B2
Application number	US-202017132310-A
Country	US
Kind code	B2
Filing date	Dec 23, 2020
Priority date	Jul 2, 2015
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

N-benzylbenzamides that act as dual soluble epoxide hydrolase (sEH)/peroxisome proliferator-activated receptor γ (PPARγ) modulators and are useful as medications in the treatment of Metabolic Syndrome (MetS) cluster diseases, including diabetes. Methods of making and using the same are further provided.

First claim

What is claimed is:

1. A compound having the structure:

wherein: X—Y is CH═C or CH 2 -CH; R 1 is CH 2 CH 3 , CH 3 or H; and R 3 is a fluoro-substituted aryl group; or a salt thereof.

2. The compound according to claim 1 , wherein the fluoro-substituted aryl group at R 3 is a phenyl group comprising a trifluoromethyl- or trifluoromethoxy-substitution.

3. The compound according to claim 2 , wherein the trifluoromethyl- or trifluoromethoxy-substitution is at said phenyl group's ortho position.

4. The compound according to claim 1 , wherein R 3 is:

5. The compound of claim 1 , wherein R 3 is:

6. The compound according to claim 1 , wherein X—Y is CH 2 -CH and R 1 is CH 2 CH 3 .

7. The compound according to claim 1 , wherein X—Y is CH═C and R 1 is CH 2 CH 3 .

8. The compound according to claim 1 , wherein X—Y is CH 2 -CH and R 1 is H.

9. The compound according to claim 1 , wherein X—Y is CH═CH and R 1 is H.

10. The compound according to claim 1 , wherein the compound exhibits a half maximal inhibitory concentration (IC 50 ) for soluble epoxide hydrolase (sEH) and a half maximal effective concentration (EC 50 ) for peroxisome proliferator-activated receptor gamma (PPARγ) that are less than 1.0 micromolar when administered to a subject.

11. A composition comprising: (a) a compound according to claim 1 ; and (b) a pharmaceutically acceptable carrier.

12. The composition of claim 11 formulated as an oral dosage.

13. A method of treating metabolic syndrome in a subject, comprising administering to a subject a therapeutically effective amount of a compound according to claim 1 , wherein soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor gamma (PPARγ) are simultaneously-modulated by the compound thereby treating metabolic syndrome in said subject.

14. The method of claim 13 , wherein said therapeutically effective amount provides a half maximal inhibitory concentration (IC 50 ) for sEH and a half maximal effective concentration (EC 50 ) for PPARγ that are less than 1.0 micromolar in the subject.

15. A method of treating diabetes in a subject, comprising administering to a subject a therapeutically effective amount of a compound according to claim 1 , wherein soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor gamma (PPARγ) are simultaneously-modulated by the compound thereby treating diabetes in said subject.

16. The method of claim 15 , wherein said therapeutically effective amount provides a half maximal inhibitory concentration (IC 50 ) for sEH and a half maximal effective concentration (EC 50 ) for PPARγ that are less than 1.0 micromolar in the subject.

17. A method of simultaneously-modulating soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor gamma (PPARγ) activities in a subject, comprising administering to a subject a therapeutically effective amount of a compound according to claim 1 , wherein sEH and peroxisome proliferator-activated receptor gamma PPARγ activities are simultaneously-modulated by the compound in the subject.

18. The method of claim 17 , wherein said therapeutically effective amount provides a half maximal inhibitory concentration (IC 50 ) for sEH and a half maximal effective concentration (EC 50 ) for PPARγ that are less than 1.0 micromolar in the subject.

19. The method of claim 13 , wherein X—Y is CH 2 CH, R 1 is H, and R 3 is

20. The method of claim 15 , wherein X—Y is CH 2 CH, R 1 is H, and R 3 is

21. The method of claim 17 , wherein X—Y is CH 2 CH, R 1 is H, and R 3 is

22. The compound of claim 1 , wherein X—Y is CH 2 CH, R 1 is H, and R 3 is

Assignees

• Medical College Wisconsin Inc
• Johann Wolfgang Goethe Univ Frankfurt

Inventors

• Imig John David
• Khan Md Abdul Hye
• Proschak Eugen
• Blocher Rene

Classifications

• C07C233/65 Primary

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61M25/0127

  Magnetic means; Magnetic markers · CPC title

• C07C233/73

  of a carbon skeleton containing six-membered aromatic rings · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title