Deuterated GFT-505

• US 10,442,761 B2
• Filed: 02/16/2017
• Issued: 10/15/2019
• Est. Priority Date: 02/16/2016
• Status: Active Grant

• Current Assignee: Sun Pharmaceutical Industries, Inc. (Sun Pharmaceutical Industries Limited)
• Original Assignee: Concert Pharmaceuticals Inc.
• Inventors: Tung, Roger D.
• Primary Examiner(s): Vajda, Kristin A
• Application Number:
  US16/076,620
• Publication Number:
  US 20190047949A1
• Time in Patent Office: 971 Days
• Field of Search: 514571
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 323/22 containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Abstract

This invention relates to novel deuterated forms of GFT-505, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are characterized by reduced PPAR-alpha and/or PPAR-delta activity.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein each of R¹, R², R³, R^4a and R^4b is independently selected from —

CH₃ and —

CD₃.

3. The compound of claim 2, wherein at least one of R¹, R², or R³ is —

CD₃.

4. The compound of claim 3, wherein at least one of R¹, R², or R³ is —

CH₃.

5. The compound of claim 2, wherein at least two of R¹, R², or R³ is —

CD₃.

6. The compound of claim 2, wherein each of R¹, R² and R³ is —

CD₃.

7. The compound of any one of claims 1, wherein R^4a and R^4b are the same.

8. The compound of claim 7, wherein R^4a and R^4b are both —

CD₃.

9. The compound of claim 7, wherein R^4a and R^4b are both —

CH₃.

10. The compound of any one of claims 1, wherein each of Y¹ and Y² are the same.

11. The compound of claim 10, wherein Y¹ and Y² are both hydrogen.

12. The compound of claim 1, wherein R^4a and R^4b are the same;

Y¹ and Y² are the same; and

the compound is selected from any one of the compounds set forth below;

13. The compound of any one of claims 1, wherein each position in Formula I that is designated as containing deuterium has at least 90% deuterium incorporation at that position.

14. The compound of any one of claims 1, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

15. A pharmaceutical composition comprising a compound of claim 1;

and a pharmaceutically acceptable carrier.

16. A method of agonizing PPAR-α

and/or PPAR-δ

in a mammalian cell comprising the step of contacting the cell with a compound of claim 1.

17. A method of treating a liver disorder characterized by the pathological disruption, inflammation, degeneration, and/or proliferation of liver cells, wherein the plasma level of Alanine aminotransferase (ALAT), Aspartate aminotransfersase (ASAT), Alkaline Phosphatase (AP), Gamma Glutamyl transpeptidase (GGT), Cytokeratin-18 (CK-18), Resistin or a combination thereof is elevated when compared to normal plasma levels comprising the step of administering to a subject in need thereof the composition of claim 15.

18. A method of treating a disease or condition selected from fatty liver disease, atherosclerosis, type 2 diabetes, dyslipidemia, insulin resistance, impaired glucose tolerance, non-alcoholic steatohepatitis, liver cancer, cirrhosis, and hepatic fibrosis comprising the step of administering to a subject in need thereof the composition of claim 15.

19. The method of claim 18, wherein the disease or condition is selected from type 2 diabetes, atherogenic dyslipidemia, insulin resistance, impaired glucose tolerance, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease.

20. A method of agonizing PPAR-α

and/or PPAR-δ

in a mammalian cell comprising the step of contacting the cell with pharmaceutical composition of claim 15.

21. The compound of claim 1, wherein each position in Formula I that is designated as containing deuterium has at least 95% deuterium incorporation at that position.

22. The compound of claim 1, wherein each position in Formula I that is designated as containing deuterium has at least 97% deuterium incorporation at that position.

23. The compound of claim 1, wherein R^4a and R^4b are the same;

Y¹ and Y² are the same; and

the compound is selected from any one of the compounds set forth below;