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

Patent metadata

Field	Value
Publication number	US-2021024469-A1
Application number	US-201916981483-A
Country	US
Kind code	A1
Filing date	Mar 15, 2019
Priority date	Mar 16, 2018
Publication date	Jan 28, 2021
Grant date	—

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, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms;
m is 1, 2, 3, 4, 5, or 0 carbon atoms;
n is 1, 2, 3, 4, 5, or 0 carbon atoms;
R 2 is selected from the group: hydrogen (H), CH 3 , O-para-alkoxybenzyls, 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, 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: OCH 3 , F, Cl, Br, I, NO 2 , H, CH 3 , CH 2 CH 3 , branched or unbranched alkyl chains with 3-10 carbon atoms, 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;
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;
R 1 is selected from the group consisting of COOH, carboxylic acids, carboxylic acid isosteres, hydroxamic acids, hydroxamic esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, acyl sulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidine diones, oxazolidine diones, oxadiazol-5(4H)-ones, thiadiazol-5(4H)-ones, oxathiadiazole-2-oxides, oxadiazol-5(4H)-thiones, isoxazoles, tetramic acids, cyclopentane 1,3-diones, cyclopentane 1,2-diones, squaric acids, substituted phenols, heteroarenes, amidines, hydroxyamides, alkyl hydroxyamidines, and

and salts thereof,
R 8 and R 9 are independently selected from the group consisting of H, F, Cl, Br, I, alkyl, alkoxy, and cycloalkyl comprising R 8 is linked to R 9 ;
R 10 and R 11 are independently selected from the group consisting of H, alkyl, and cycloalkyl wherein R 10 is linked to R 11 ); and
X is O, NH, S, or CH 2 ; 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; and when R 1 ═COOH and R 3 ═CH 3 , at least one of R 2 , R 4 , and R 5 is not H.

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, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms;
m is 1, 2, 3, 4, 5, or 0 carbon atoms;
n is 1, 2, 3, 4, 5, or 0 carbon atoms;
R 2 is selected from the group: hydrogen (H), CH 3 , O-para-alkoxybenzyls, 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, 0-para-alkylbenzyls, 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: OCH 3 , F, Cl, Br, I, NO 2 , H, CH 3 , CH 2 CH 3 , branched or unbranched alkyl chains with 3-10 carbon atoms, OCH 2 CH 3 , branched or unbranched alkoxy chains with 3-10 carbon atoms, haloalkyls, haloalkoxyls, cycloalkyls, halocycloalkyls, 0-para-alkylbenzyls, O-para-alkoxybenzyls, 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;
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-alkoxybenzyls, 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;
R 1 is selected from the group consisting of COOH, carboxylic acids, carboxylic acid isosteres, hydroxamic acids, hydroxamic esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, acyl sulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidine diones, oxazolidine diones, oxadiazol-5(4H)-ones, thiadiazol-5(4H)-ones, oxathiadiazole-2-oxides, oxadiazol-5(4H)-thiones, isoxazoles, tetramic acids, cyclopentane 1,3-diones, cyclopentane 1,2-diones, squaric acids, substituted phenols, heteroarenes, amidines, hydroxyamides, alkyl hydroxyamidines, and

and salts thereof,
R 8 and R 9 are independently sel

Assignees

• Univ Oklahoma

Inventors

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

Classifications

• C07C311/39

  having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom · CPC title

• C07D257/04

  Five-membered rings · CPC title

• C07C217/84

  the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom · CPC title

• C07C323/52

  the carbon skeleton being acyclic and saturated · CPC title

• C07D213/65

  attached in position 3 or 5 · CPC title