PPAR agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10550149-B2
Application number	US-201816022578-A
Country	US
Kind code	B2
Filing date	Jun 28, 2018
Priority date	Oct 8, 2014
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

Provided herein are deuterated compounds and compositions useful in increasing PPARδ activity. The compounds have a formula

where L 5 comprises at least one deuterium. Exemplary species include

The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).

First claim

We claim:

1. A method, comprising:
contacting a PPARδ protein with an effective amount of a compound, or a composition comprising the compound, wherein the compound has a formula,

wherein:
ring A is phenyl;
ring B is selected from phenyl, or pyridine;
each R 2 independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
each R 22 independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
n is from 0 to 5;
m is from 0 to 4;
X is O, NR 30 , sulfonyl, or S;
each R 30 independently is selected from H or aliphatic, aryl, or cycloaliphatic;
each L 2 is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, heterocycloalkylene or —CR 23 R 24 —;
R 23 and R 24 are each independently selected from H, deuterium, halogen, aliphatic, alkyl, —C(O)OR 25 or —C(O)NR 25 R 26 ;
R 25 and R 26 are each independently selected from hydrogen or aliphatic;
Z is R 1 L 1 C(O)—;
L 1 is a bond or —NR 30 —;
R 1 is hydrogen, aliphatic, —OR 1A , —NR 1A R 1B , —C(O)R 1A , —S(O) 2 R 1A , —C(O)OR 1A , —S(O) 2 NR 1A R 1B or —C(O)NR 1A R 1B ;
R 1A , R 1B are each independently selected from hydrogen or aliphatic;
p is 0, 1, 2, or 3;
p′ is 0;
L 4 is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, heterocycloalkylene or —CR 23 R 24 —;
R 3 is selected from —OH, —OR 3A , —NR 3A R 3B , —C(O)R 3A , —S(O) 2 R 3A , —C(O)OR 3A , —S(O) 2 NR 3A R 3B , —C(O)NR 3A R 3B , aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; and
R 3A and R 3B are independently selected from hydrogen or aliphatic;
R 31 and R 32 are independently H, D, or aliphatic;

with the provisos that
at least one of L 4 or R 3 comprises at least one deuterium; or
at least one of R 31 and R 32 is D.

2. The method according to claim 1 wherein the compound has a formula

or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a bond or —NR 30 —;
L 2 is

L 3 is a bond or C 1 -C 3 alkylene;
L 4 R 3 is isopropyl or

R 1 is hydrogen or —OR 1A ;
R 1A is hydrogen or aliphatic;
each R 2 independently is selected from deuterium, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
each R 22 independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
X is O, NR 30 , sulfonyl, or S;
m is from 0 to 4; and
n is from 0 to 4;
wherein at least one of L 3 or L 4 R 3 comprises at least one deuterium.

3. The method according to claim 1 wherein the compound has a formula

or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a bond or —NR 30 —;
L 2 is

L 3 is a bond or C 1 -C 3 alkylene;
L 4 R 3 is isopropyl,

cyclopropyl, or

R 1 is hydrogen or —OR 1A ;
R 1A is hydrogen or aliphatic;
each R 2 independently is selected from deuterium, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
each R 22 independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
X is O, NR 30 , sulfonyl, or S;
m is from 0 to 4; and
n is from 0 to 4;
wherein at least one of L 3 or L 4 R 3 comprises at least one deuterium.

4. The method according to claim 1 , wherein the PPAR protein is in a subject, and contacting comprises administering the compound or composition to the subject.

5. The method according to claim 4 , wherein administering comprises intraarticular, intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalational, transdermal, or rectal administration.

6. The method according to claim 4 , wherein one or more compounds are administered to the subject at a dose of about 1 mg/kg to about 20 mg/kg.

7. The method according to claim 4 , wherein one or more compounds are administered to the subject at a dose of about 2 mg/kg to about 5 mg/kg.

8. The method according to claim 4 , wherein the subject has a PPARδ related disease.

9. The method according to claim 8 wherein the disease is a metabolic disease, muscular disease, a demyelinating disease, or a vascular disease.

10. The method according to claim 9 wherein the metabolic disease is hyperlipidemia, dyslipidemia, hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis, disease of arterial sclerosis, disease of cardiovascular systems, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes, type I or type II, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complication, cardiac insufficiency, cardiac infarction, cardiomyopathy, hypertension, Non-alcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), thrombus, Alzheimer disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenal leukodystrophy, dermatitis, psoriasis, acne, skin aging, trichosis, inflammation, arthritis, asthma, hypersensitive intestine syndrome, ulcerative colitis, Crohn's disease, or pancreatitis.

11. The method according to claim 9 wherein the muscular disease is muscular dystrophy.

12. The method according to claim 11 wherein the disease is Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, or Emery-Dreifuss muscular dystrophydemyelinating disease.

13. The method according to claim 9 wherein the muscular disease is a muscular eye disease selected form strabismus, progressive external ophthalmoplegia,

Assignees

• Salk Inst Biological Studies
• Salk Inst For Biological Studi

Inventors

• Evans Ronald M
• Downes Michael

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• C07C2601/08

  the ring being saturated · CPC title