Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists

Patent metadata

Field	Value
Publication number	US-9855274-B2
Application number	US-201715490205-A
Country	US
Kind code	B2
Filing date	Apr 18, 2017
Priority date	Dec 22, 2005
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

Phenoxy acetic acids and phenyl propionic acids and their use in treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, or obesity are provided herein. The present compounds are activators of PPARδ and may be useful for treating conditions mediated by the same.

First claim

The invention claimed is:

1. A method of reducing blood glucose levels, of reducing triglyceride levels, or of increasing insulin sensitivity in a subject suffering from type II diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof:

wherein is a double bond, with either E or Z substitution;
X 1 is C 1-6 -alkyl substituted with morpholino;
X 2 is phenylene;
X 3 is phenyl substituted with one or more halogens;
Ar is phenylene optionally substituted with methyl;
Y 1 is O;
Y 2 is O;
Z is CH 2 ;
R 1 is hydrogen; and
R 2 is hydrogen.

2. The method of claim 1 , wherein X 1 is morpholin-4-ylmethyl.

3. A method of reducing blood glucose levels, of reducing triglyceride levels, or of increasing insulin sensitivity in a subject suffering from type II diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of:
(E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl) propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid; and
(Z)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid; or
a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein the compound is (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

5. The method of claim 3 , wherein the compound is (Z)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

6. A method of reducing blood glucose levels, of reducing triglyceride levels, or of increasing insulin sensitivity in a subject suffering from type I diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein is a double bond, with either E or Z substitution;
X 1 is C 1-6 alkyl substituted with morpholino;
X 2 is phenylene;
X 3 is phenyl substituted with one or more halogens;
Ar is phenylene optionally substituted with methyl;
Y 1 is O;
Y 2 is CH 2 ;
Z is CH 2 ;
R 1 is hydrogen; and
R 2 is hydrogen.

7. The method of claim 6 , wherein X 1 is morpholin-4-ylmethyl.

8. The method of claim 6 , wherein the compound is (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

9. The method of claim 6 , wherein the compound is (Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic acid or a pharmaceutically acceptable salt thereof.

10. A method of reducing blood glucose levels, of reducing triglyceride levels, or of increasing insulin sensitivity in a subject suffering from type II diabetes or is suffering from type I diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of selected from the group consisting of:
(Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid;
(E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetic acid;
(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid;
(E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid; and
(Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid;
or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein the compound is (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

12. The method of claim 10 , wherein the compound is (E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)-allyloxy]phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

13. The method of claim 10 , wherein the compound is (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

14. The method of claim 10 , wherein the compound is (E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

15. The method of claim 10 , wherein the compound is (Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl) allyloxy]-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof.

Assignees

• Vtv Therapeutics Llc

Inventors

• Sauerberg Per
• Pihera Pavel
• Polivka Zdenek
• Havranek Miroslav
• Pettersson Ingrid
• Mogensen John Patrick

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title