Agonists of peroxisome proliferator-activated receptor alpha and methods of use

Patent metadata

Field	Value
Publication number	US-11447452-B2
Application number	US-201916981483-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Mar 16, 2018
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

Benzyl derivative compounds having peroxisome proliferator-activated receptor α (PPARα) agonistic activity, 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 are disclosed.

First claim

What is claimed is:

1. A compound, comprising chemical structure II:

wherein:
k is 0;
m is 1;
n is 1;
R 1 is selected from the group consisting of COOH, OC(CH 3 ) 2 COOH, B(OH) 2 , OCH 2 COOH, NHSO 2 CH 3 , SO 2 NH 2 , tetrazole, SC(CH 3 ) 2 COOH, and salts thereof;
R 2 is selected from the group consisting of hydrogen (H), CH 3 , OCH 3 , F, difluoro, Br, dibromo, Cl, dichloro, I, diiodo, CF 3 , CBr 3 , CCl 3 , CI 3 , O-para-methoxybenzyl, and O-para-fluorobenzyl;
R 3 is selected from the group consisting of H, F, difluoro, Br, dibromo, Cl, dichloro, I, diiodo, CF 3 , CBr 3 , CCl 3 , CI 3 , NO 2 , CN, CH 3 , OCH 3 , O-para-methoxybenzyl, and O-para-fluorobenzyl;
R 4 is H or CH 3 ;
R 5 is selected from the group consisting of H, F, Br, Cl, I, and CH 3 ; and

wherein the compound has PPARα agonistic activity, and with the proviso that
when R 1 ═COOH, at least one of R 2 -R 5 is not H;
when R 1 ═COOH and R 3 ═CH 3 , at least one of R 2 , R 4 , and R 5 is not H; and
when R 2 -R 5 ═H, R 1 is not tetrazole.

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

3. The composition of claim 2 , formulated to provide a delayed release, controlled release, extended release, and/or sustained release of the one or more compounds.

4. A kit, comprising the composition of claim 2 , and instructions for use thereof in a treatment of a disorder or condition in a subject.

5. The kit of claim 4 , 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.

6. 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 a compound comprising chemical structure II:

wherein:
k is 0;
m is 1;
n is 1;
R 1 is selected from the group consisting of COOH, OC(CH 3 ) 2 COOH, B(OH) 2 , OCH 2 COOH, NHSO 2 CH 3 , SO 2 NH 2 , tetrazole, SC(CH 3 ) 2 COOH, and salts thereof;
R 2 is selected from the group consisting of hydrogen (H), CH 3 , OCH 3 , F, difluoro, Br, dibromo, Cl, dichloro, I, diiodo, CF 3 , CBr 3 , CCl 3 , CI 3 , O-para-methoxybenzyl, and O-para-fluorobenzyl;
R 3 is selected from the group consisting of H, F, difluoro, Br, dibromo, Cl, dichloro, I, diiodo, CF 3 , CBr 3 , CCl 3 , CI 3 , NO 2 , CN, CH 3 , OCH 3 , O-para-methoxybenzyl, and O-para-fluorobenzyl;
R 4 is H or CH 3 ;
R 5 is selected from the group consisting of H, F, Br, Cl, I, and CH 3 ; and

wherein the compound has PPARα agonistic activity.

7. 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 a compound comprising chemical structure II:

wherein:
k is 0;
m is 1;
n is 1;
R 1 is selected from the group consisting of COOH, OC(CH 3 ) 2 COOH, B(OH) 2 , OCH 2 COOH, NHSO 2 CH 3 , SO 2 NH 2 , tetrazole, SC(CH 3 ) 2 COOH, and salts thereof;
R 2 is selected from the group consisting of hydrogen (H), CH 3 , OCH 3 , F, difluoro, Br, dibromo, Cl, dichloro, I, diiodo, CF 3 , CBr 3 , CCl 3 , CI 3 , O-para-methoxybenzyl, and O-para-fluorobenzyl;
R 3 is selected from the group consisting of H, F, difluoro, Br, dibromo, Cl, dichloro, I, diiodo, CF 3 , CBr 3 , CCl 3 , CI 3 , NO 2 , CN, CH 3 , OCH 3 , O-para-methoxybenzyl, and O-para-fluorobenzyl;
R 4 is H or CH 3 ;
R 5 is selected from the group consisting of H, F, Br, Cl, I, and CH 3 ; and

wherein the compound has PPARα agonistic activity.

8. The method of claim 7 , 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).

9. The method of claim 7 , wherein the disorder or condition is characterized by inflammation and/or angiogenesis.

10. The method of claim 7 , 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.

11. The method of claim 7 , 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.

12. The method of claim 7 , 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.

13. The method of claim 7 , wherein the compound is provided in a composition formulated to provide a delayed release, controlled release, extended release, and/or sustained release of the compound.

Assignees

• Univ Oklahoma

Inventors

• Duerfeldt Adam
• Ma Jian-Xing
• Dou Xiaozheng
• Nath Dinesh
• Shin Young-Hwa

Classifications

• C07C311/08

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07C259/10

  having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings · CPC title

• A61K31/4412

  having oxo groups directly attached to the heterocyclic ring · CPC title

• C07C229/60 Primary

  with amino and carboxyl groups bound in meta- or para- positions · CPC title