Synergistic compositions

Patent metadata

Field	Value
Publication number	US-9957230-B2
Application number	US-201715594795-A
Country	US
Kind code	B2
Filing date	May 15, 2017
Priority date	Jul 5, 2013
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present invention describes a synergistic composition comprising of one or more statins, or one or more dipeptidyl peptidase IV (DPP IV) inhibitor or one or more biguanide antihyperglycaemic agent and a PPAR agonist of formula (1a) for the treatment of diabetes, especially non-insulin dependent diabetes (NIDDM) or Type 2 diabetes and conditions associated with diabetes mellitus and to compositions suitable for use in such method. The invention also describes the preparation of such compositions. The present invention also relates to certain novel salts of the PPAR agonist of formula (I), processes for the preparation of: these novel salts and use thereof.

First claim

We claim:

1. A compound selected from the group consisting of:
(i) Benethamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values of ±0.2 degree at about 10.0, 10.3, 14.5, 15.1, 15.7, 16.7, 17.4, 17.9, 18.6, 19.2, 19.8, 21.3, 23.2 and 25.7 degrees;
(ii) Benzylamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values at about 14.8, 16.8, 17.5, 18.3, 19.3, 20.8, 22.6 and 24.2 ±0.2 degrees;
(iii) Dibenzylamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values at about 8.72, 16.8, 18.5, 19.1, 19.6, 20.6, 21.6, 22.5 and 24.5 ±0.2 degrees; and
(iv) Imidazole crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values at about 9.40, 14.7, 15.6, 17.3, 21.0, 21.5, 22.5 and 26.2 ±0.2 degrees.

2. The compound of claim 1 , wherein the compound is a benethamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values of ±0.2 degree at about 10.0, 10.3, 14.5, 15.1, 15.7, 16.7, 17.4, 17.9, 18.6, 19.2, 19.8, 21.3, 23.2 and 25.7 degrees.

3. The compound of claim 1 , wherein the compound is a benzylamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values at about 14.8, 16.8, 17.5, 18.3, 19.3, 20.8, 22.6 and 24.2±0.2 degrees.

4. The compound of claim 1 , wherein the compound is a dibenzylamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values of about 8.72, 16.8, 18.5, 19.1, 19.6, 20.6, 21.6, 22.5 and 24.5±0.2 degrees.

5. The compound of claim 1 , wherein the compound is a imidazole crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having an XRD pattern having a peak at 2 theta values of about 9.40, 14.7, 15.6, 17.3, 21.0, 21.5, 22.5 and 26.2±0.2 degrees.

6. The compound of claim 1 , wherein the compound is a benethamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having a powder X-ray diffraction pattern substantially as depicted in FIG. 10 .

7. The compound of claim 1 , wherein the compound is a benzylamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having a powder X-ray diffraction pattern substantially as depicted in FIG. 11 .

8. The compound of claim 1 , wherein the compound is a dibenzylamine crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having a powder X-ray diffraction pattern substantially as depicted in FIG. 12 .

9. The compound of claim 1 , wherein the compound is a imidazole crystalline salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid having a powder X-ray diffraction pattern substantially as depicted in FIG. 14 .

10. A compound selected from the group consisting of:
(i) (S)-α-4-Methylphenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(ii) (S)-α-3-Methoxyphenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(iii) (S)-α-4-Methoxyphenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(iv) (S)-α-4-Chlorophenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid; and
(v) (S)-α-Naphthylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid.

11. A compound in amorphous form selected from:
(i) Zinc salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
ii) Lithium salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(iii) Piperazine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(iv) Tromethamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(v) L-Lysine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(vi) Meglumine salt (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(vii) Benethamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(viii) Benzylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(ix) Dibenzylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(x) Arginine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xi) Imidazole salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xii) Dicyclohexylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xiii) Diethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xiv) Diphenylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xv) α-Naphthylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xvi) O-phenylenediamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xvii) 1,3-Diaminopropane salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xviii) (S)-α-Naphthylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xix) (S)-3-Methoxyphenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xx) (S)-4-Methoxyphenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxi) (S)-4-Chlorophenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxii) (S)-4-Methylphenylethylamine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxiii) Cinchonine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxiv) Cinchonidine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxv) (-)-Quinine salt of (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxvi) Benzathine salt (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-1-yl]-ethoxy}-phenyl)-propionic acid;
(xxvii) Ethanolamine salt o

Assignees

• Cadila Healthcare Ltd

Inventors

• Jain Mukul R
• Giri Suresh
• Kothari Himanshu M
• Banerjee Kaushik
• Kachhiya Rashmikant

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• C07D207/333 Primary

  Radicals substituted by oxygen or sulfur atoms · CPC title