Agonists of peroxisome proliferator-activated receptor alpha (PPARα) and methods of use

Patent metadata

Field	Value
Publication number	US-12319708-B2
Application number	US-202318379715-A
Country	US
Kind code	B2
Filing date	Oct 13, 2023
Priority date	Mar 16, 2018
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

Benzyl derivative compounds having peroxisome proliferator-activated receptor α (PPARα) agonistic activity, kits and compositions containing such compounds, and methods of their use in enhancing PPARα activity for treating diseases and/or conditions involving inflammation and/or angiogenesis, particularly ocular diseases and/or conditions such as but not limited to retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and diabetic macular edema.

First claim

What is claimed is:

1. A compound, comprising chemical structure III:

and salts and isomers thereof, wherein:
k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms;
m is 0, 1, 2, 3, 4, or 5 carbon atoms;
n is 0, 1, 2, 3, 4, or 5 carbon atoms;
R 1 is selected from the group: phosphate and phosphonate;
R 2 is selected from the group: CH 3 , hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO 2 ), CH 2 CH 3 , branched or unbranched alkyl chains with 3-10 carbon atoms, OCH 3 , OCH 2 CH 3 , branched or unbranched alkoxy chains with 3-10 carbon atoms, haloalkyls, haloalkoxyls, cycloalkyls, halocycloalkyls, O-para-alkylbenzyls, O-para-alkyloxybenzyls, and O-para-halobenzyls, wherein the benzene ring comprising R 2 comprises one, two, three, or four of said R 2 substituents substituted in any combination of said R 2 substituents and arranged in any pattern in the ring including ortho, meta, mono, di, tri, and tetrasubstituted;
R 3 is selected from the group: F, H, Cl, Br, I, NO 2 , CH 3 , CH 2 CH 3 , branched or unbranched alkyl chains with 3-10 carbon atoms, OCH 3 , OCH 2 CH 3 , branched or unbranched alkoxy chains with 3-10 carbon atoms, haloalkyls, haloalkoxyls, cycloalkyls, halocycloalkyls, O-para-alkylbenzyls, O-para-alkyloxybenzyls, and O-para-halobenzyls, wherein the benzene ring comprising R 3 comprises one, two, three, four, or five of said R 3 substituents substituted in any combination of said R 3 substituents and arranged in any pattern in the ring including ortho, meta, para, mono, di, tri, tetra, and pentasubstituted;
R 4 is selected from the group: H, alkyl, and acyl; and
R 5 is selected from the group: H, Cl, F, Br, I, NO 2 , CH 3 , CH 2 CH 3 , branched or unbranched alkyl chains with 3-10 carbon atoms, OCH 3 , OCH 2 CH 3 , branched or unbranched alkoxy chains with 3-10 carbon atoms, haloalkyls, haloalkoxyls, cycloalkyls, halocycloalkyls, O-para-alkylbenzyls, O-para-alkyloxybenzyls, and O-para-halobenzyls, wherein the benzene ring comprising R 5 comprises one, two, three, or four of said R 5 substituents substituted in any combination of said R 5 substituents and arranged in any pattern in the ring including ortho, meta, para, mono, di, tri, and tetrasubstituted; and
wherein the compound has PPAα a agonistic activity.

2. The compound of claim 1 , wherein R 1 is a phosphate having the chemical structure:

wherein each R X is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

3. The compound of claim 1 , wherein R 1 is a phosphonate having the chemical structure:

wherein each R X is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

4. The compound of claim 1 , having PPARα agonistic activity that is at least 1,000-fold greater than the compound's PPARγ agonistic activity or PPARδ agonistic activity.

5. A composition, comprising one or more compounds of claim 1 disposed in a pharmaceutically-acceptable carrier, vehicle, or diluent.

6. The composition of claim 5 , formulated to provide a delayed release, controlled release, extended release, and/or sustained release of the one or more compounds.

7. A kit, comprising the composition of claim 5 , and instructions for use thereof in a treatment of a disorder or condition in a subject.

8. The kit of claim 7 , wherein the disorder or condition is an ocular disorder or condition selected from the group consisting of retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), an age-related macular degeneration (AMD), macular edema, diabetic macular edema (DME), keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammations, optic neuritis, sympathetic ophthalmia, retinitis, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

9. A method of increasing peroxisome proliferator-activated receptor α (PPARα) activity in a retinal cell, comprising: administering to the retinal cell a PPARα activity-enhancing amount of the compound of claim 1 .

10. A method of treating a disorder or condition in a subject by causing an increase in peroxisome proliferator-activated receptor α (PPARα ) activity, comprising: administering to a subject in need of such therapy, a therapeutic amount of the compound of claim 1 , wherein the compound is optionally provided in a composition formulated to provide a delayed release, controlled release, extended release, and/or sustained release of the compound.

11. The method of claim 10 , wherein the disorder or condition is selected from the group consisting of retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), an age-related macular degeneration (AMD), and diabetic macular edema (DME).

12. The method of claim 10 , wherein the disorder or condition is characterized by inflammation and/or angiogenesis.

13. The method of claim 10 , wherein the disorder is selected from inflammatory bowel disease, type 1 diabetes, type 2 diabetes, Graves disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodonititis, atherosclerosis, heart failure, obesity, Alzheimer's disease, and metabolic syndrome.

14. The method of claim 10 , wherein the disorder or condition is an ocular disorder or condition selected from keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammations, optic neuritis, sympathetic ophthalmia, retinitis, macular edema, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

15. The method of claim 10 , wherein the disorder or condition is selected from retinal artery or vein occlusion, corneal graft rejection, corneal neovascularization, neovascular glaucoma, sickle cell retinopathy, cancers, skin diseases, diabetic ulcers, diabetic nephropathy, cardiovascular disease, and stroke.

16. A compound, comprising chemical structure III:

and salts and isomers thereof, wherein:
k is 0, 1, or 2 carbon atoms;
m is 0, 1, or 2 carbon atoms;
n is 0, 1, or 2 carbon atoms;
R 1 =phosphate or phosphonate;
R 2 =H, 3-F, 3-Cl, 2-CH 3 or 3-CH 3 ;
R 3 =4-F, 2,4-diF, 3,4-diF, 3,5-diF, or 4-OCH 3 ;
R 4 =H or CH 3 ; and
R 5 =H or F.

17. The

Assignees

• Univ Oklahoma

Inventors

• Duerfeldt Adam
• Dou Xiaozheng
• Hu Ziwei

Classifications

• C07F9/301

  Acyclic saturated acids which can have further substituents on alkyl · CPC title

• A61P29/00 Primary

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• C07F9/091

  with hydroxyalkyl compounds with further substituents on alkyl · CPC title

• C07F9/3808 Primary

  Acyclic saturated acids which can have further substituents on alkyl · CPC title