Compounds for the treatment of diabetes and disease complications arising from same

• US 10,111,880 B2
• Filed: 11/04/2014
• Issued: 10/30/2018
• Est. Priority Date: 11/05/2013
• Status: Active Grant

• Current Assignee: Neuromagen Pharma Limited
• Original Assignee: Ben Gurion University of The Negev
• Inventors: Priel, Esther
• Primary Examiner(s): Katakam, Sudhakar
• Application Number:
  US15/034,303
• Publication Number:
  US 20160263124A1
• Time in Patent Office: 1,456 Days
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/055 the aromatic ring being substituted by halogen
• CPC Class Codes: A61K 31/075 Ethers or acetals
• CPC Class Codes: A61K 31/08 acyclic, e.g. paraformaldehyde
• CPC Class Codes: A61K 31/09 having two or more such linkages
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention is directed to use of a series of tri-aryl compounds and compositions comprising the same for the treatment of diabetes and disease conditions arising as a consequence of the same.

Claims

1. A method of treating diabetes or diabetes related complications in a subject in need thereof, said method comprising administering to a subject an effective amount of a compound represented by the structure of formula I:

3. The method of claim 1, wherein said compound is represented by the structure of formula II:

4. The method of claim 3, wherein said compound is represented by the structure of formula VI:

5. The method of claim 4, wherein said compound is represented by the structure of formula VII:

6. The method of claim 4, wherein said compound is represented by the structure of formula VIII:

7. The method of claim 4, wherein said compound is represented by the structure of formula IX:

8. The method of claim 4, wherein said compound is represented by the structure of formula X:

9. The method of claim 4, wherein said compound is represented by the structure of formula XI:

10. The method of claim 4, wherein said compound is represented by the structure of formula XII:

11. The method of claim 4, wherein said compound is represented by the structure of formula XIII:

12. The method of claim 1, wherein said compound is represented by the structure of formula XIV:

13. The method of claim 1, wherein said compound is represented by the structure of formula XV:

14. The method of claim 1, wherein said compound is represented by the structure of formula XVI:

15. The method of claim 1, wherein said subject is administered a second agent, which is useful in the treatment of diabetes or diabetes related complications.

16. The method of claim 1, wherein said subject is administered a second agent, which is useful in the reduction of circulating glucose levels, reduction of insulin resistance, stimulation or increase of insulin sensitivity, stimulation or increase of pancreatic beta-cell mass, or stimulation or increase of creatinine clearance in a subject, or reduction of renal disease in said subject.

17. The method of claim 1, wherein R₁, R₃, R₄, R₆, R₇ and R₉ are the same and independently R₂, R₅ and R₈ are the same.

19. The method of claim 17, wherein Z is carbon, R₂, R₅ and R₈ are OH, and R₁₀ is C_1-4alkyl.

20. The method of claim 19, wherein R₁₀ is methyl.

2. A method of reducing circulating glucose levels, reducing insulin resistance, stimulating or increasing insulin sensitivity, stimulating or increasing pancreatic beta-cell mass, or stimulating or increasing creatinine clearance in a subject in need thereof, or reducing renal damage in a diabetic subject in need thereof, said method comprising administering to a subject an effective amount of a compound represented by the structure of formula I:

18. The method of claim 2, wherein R₁, R₃, R₄, R₆, R₇ and R₉ are the same and independently R₂, R₅ and R₈ are the same.

21. The method of claim 18, wherein Z is carbon, R₂, R₅ and R₈ are OH, and R₁₀ is C_1-4alkyl.

22. The method of claim 21, wherein R₁₀ is methyl.