Diphenyl ether derivatives

• US 7,521,465 B2
• Filed: 03/31/2005
• Issued: 04/21/2009
• Est. Priority Date: 01/17/2003
• Status: Expired due to Fees

• Current Assignee: Bexel Pharmaceuticals Inc. (Orchid Pharma Ltd.)
• Original Assignee: Bexel Pharmaceuticals Inc. (Orchid Pharma Ltd.)
• Inventors: Agarwal, Shiv Kumar, Chithra, Santhanagopalan, Badiger, Sangamesh, Pandey, Surendra Kumar, Reddy, Gaddam Om, Singh, Gajendra, Nag, Abhijeet, Dey, Debendranath, Nag, Bishwajit, Neogi, Partha
• Primary Examiner(s): Saeed; Kamal A
• Application Number:
  US11/096,718
• Publication Number:
  US 20050288341A1
• Time in Patent Office: 1,482 Days
• Field of Search: 514/369, 514/376, 548/183, 548/227, 548/317.1
• US Class Current: 514/369
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 277/20 having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 277/34 Oxygen atoms
• CPC Class Codes: C07D 277/36 Sulfur atoms

Abstract

Novel diphenyl ether derivatives are provided that exhibit activity useful for reducing glucose, cholesterol, and/or triglyceride levels in plasma, and for treatment of obesity, inflammation, immunological diseases, autoimmune diseases, diabetes and disorders associated with insulin resistance.

Claims

1. Diphenyl ether compounds of the formula (I)

2. A compound according to claim 1 wherein the ---- represents a bond.

3. A compound according to claim 1 wherein the ---- is absent.

4. A compound according to claim 2 wherein W and G represent O;

Z represents S;

R₁₃ is selected from the group consisting of H, substituted and unsubstituted (C₁-C₆) alkyl and a counterion; and

R₁₄ and R₁₅ are independently selected from the group consisting of substituted and unsubstituted (C₁-C₆) alkyl.

5. A compound according to claim 4 wherein R₂ and R₃ are independently selected from the group consisting of H, halo, nitro, substituted and unsubstituted (C₁-C₆) alkyl and substituted and unsubstituted (C₁-C₆) alkoxy.

6. A compound according to claim 3 wherein W and G represent O;

Z represents S;

R₁₃ is selected from the group consisting of H, substituted and unsubstituted (C₁-C₆) alkyl and a counterion; and

R₁₄ and R₁₅ are independently selected from the group consisting of substituted and unsubstituted (C₁-C₆) alkyl.

7. A compound according to claim 6 wherein R₂ and R₃ are independently selected from the group consisting of H, halo, substituted and unsubstituted (C₁-C₆) alkyl and substituted and unsubstituted (C₁-C₆) alkoxy.

8. A compound according to claim 2 wherein W represents O;

G and Z represent S; and

R₁₃ is selected from the group consisting of substituted and unsubstituted (C₁-C₆) alkyl.

9. A compound according to claim 8 wherein R₂ and R₃ are independently selected from the group consisting of H, halo, substituted and unsubstituted (C₁-C₆) alkyl and substituted and unsubstituted (C₁-C₆) alkoxy.

10. A compound according to claim 3 wherein W represents O;

G and Z represent S;

and R₁₃ is selected from the group consisting of substituted and unsubstituted (C₁-C₆) alkyl.

11. A compound according to claim 10 wherein R₂ and R₃ are independently selected from the group consisting of H, halo, substituted and unsubstituted (C₁-C₆) alkyl and substituted and unsubstituted (C₁-C₆) alkoxy.

12. A compound according to claim 2 wherein W represents O;

G and Z represent S; and

R₁₃ is selected from the group consisting of substituted and unsubstituted (C₁-C₆) alkyl; and

R₁ represents —

CH₂COOR.

13. A compound according to claim 12 wherein R₂ and R₃ are independently selected from the group consisting of H, halo, substituted and unsubstituted (C₁-C₆) alkyl and substituted and unsubstituted (C₁-C₆) alkoxy.

14. A compound according to claim 3 wherein W represents O;

G and Z represent S; and

R₁₃ is selected from the group consisting of substituted and unsubstituted (C₁-C₆) alkyl; and

R₁ represents —

CH₂COOR.

15. A compound according to claim 14 wherein R₂ and R₃ are independently selected from the group consisting of H and substituted and unsubstituted (C₁-C₆) alkyl.

16. A compound according to claim 4 selected from the group consisting of

(S)-2=Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-fluoro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[2-chloro-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-2-methoxy-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-2-nitro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionate dipotassium salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionate disodium salt.

17. A compound according to claim 6 selected from the group consisting of

(S)-2-Amino-3-{4-[3-chloro-4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[2-chloro-4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-2-methoxy-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-2-fluoro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionate disodium salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionate dipotassium salt

(S)-2-Amino-3-{4-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-N,N-dimethyl-propionamide hydrochloric acid salt.

18. A compound according to claim 8 selected from the group consisting of

(R,S)-2-Amino-3-{4-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[3-fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[2-fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[3-chloro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[2-chloro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[2-methoxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester

(S)-2-Amino-3-{4-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-2-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-3-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt.

19. A compound according to claim 10 selected form the group consisting of

(S)-2-Amino-3-{4-[2-methoxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(R,S)-2-Amino-3-{4-[4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester

(S)-2-Amino-3-{4-[2-chloro-4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[3-chloro-4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[3-fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[2-fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-3-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt.

20. A compound according to claim 12 selected from the group consisting of

(R,S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-3-chloro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-2-chloro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-2-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-3-fluoro-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-3-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-2-methoxy-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt.

21. A compound according to claim 14 selected from the group consisting of

(RS)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt

(S)-2-Amino-3-{4-[4-(3-carboxymethyl-4-oxo-2-thioxo-thiazolidin-5-ylmethyl)-3-trifluoromethyl-phenoxy]-phenyl}-propionic acid methyl ester hydrochloric acid salt.

22. A compound as claimed in claim 1, wherein said pharmaceutical acceptable salt is selected from the group consisting of a hydrochloride, hydrobromide, potassium and magnesium salt.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound or mixture of compounds according to any one of claims 1 to 15 and 22 and a pharmaceutically acceptable carrier sufficient to reduce in a subject the plasma level of glucose, fatty acids, cholesterol or triglycerides.

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound or mixture of compounds according to any one of claims 1 to 15 and 22 and a pharmaceutically acceptable carrier sufficient to treat obesity, autoimmune diseases, inflammation, immunological diseases, diabetes or disorders associated with insulin resistance in a subject.