Prolyl hydroxylase inhibitors and methods of use
Inventors
Kawamoto, Richard Masaru • Wu, Shengde • Evdokimov, Artem G. • Greis, Kenneth D. • Boyer, Angelique Sun • Warshakoon, Namal C.
Assignees
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Publication Number
US-11426393-B2
Publication Date
2022-08-30
Expiration Date
Abstract
The present disclosure relates to HIF-1α prolyl hydroxylase inhibitors, compositions which comprise the HIF-1α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.
Core Innovation
The invention relates to HIF-1α prolyl hydroxylase inhibitor candidates having substituted aryl/heteroaryl amide carboxylic-acid and ester structures with a defined Formula (I) core. The Formula (I) defines a structural framework in which X is N or CH to distinguish between 2-amidopyridines and arylamides, and the amide nitrogen is substituted by R9. The compounds include an organic linking unit L and variable substituents R, R1, R2, and Y that define broad structural scope.
The disclosed structural variables include options where R2 is a hydroxyl (—OH) or a carboxylate (—O−), thereby covering carboxylic acid and ester forms. The scope further includes pharmaceutically acceptable salts, and substituent patterns on aryl/heteroaryl groups through variable definitions for R, R1, and Y. The disclosure also describes specific subgenera within the broader Formula (I) family, including methyl ester variants, and structural depictions and characterization for substituted {[3-hydroxy/5-hydroxy]pyridine-2-carbonyl}amino-acetic acids and related Formula (I) series members.
The disclosure describes therapeutic use based on HIF-1α stabilization, including stimulating angiogenic and erythropoietic pathways. HIF-1α stabilization is described as an outcome demonstrated in figure material together with an erythropoietin elevation response after dosing. The documented disease contexts include ischemia-related conditions, peripheral vascular disease, coronary artery disease, heart failure, ischemia, anemia, chronic non-healing wounds, and peripheral vascular disease.
Claims Coverage
The claims include one independent process claim covering catalytic coupling of 3-chlorophenyl boronic acid with a specified amino-acetic acid methyl ester precursor to form a compound of the formula or a pharmaceutically acceptable salt thereof. Dependent claims refine the precursor preparation, catalyst identity, reaction base, coupling reagents, and conversion of the methyl ester to the corresponding amino acetic acid.
Catalytic coupling of 3-chlorophenyl boronic acid with trifluoromethanesulfonyloxy pyridine amino acetic acid methyl ester
A process for preparing a compound having the formula, or a pharmaceutically acceptable salt thereof, comprising reacting 3-chlorophenyl boronic acid with [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]acetic acid methyl ester in the presence of a catalyst.
Precursor preparation to the trifluoromethanesulfonyloxy amino acetic acid methyl ester
Preparing [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]acetic acid methyl ester from 3,5-dichloro-2-cyanopyridine through base hydrolysis, coupling with glycine methyl ester using coupling reagents, hydrogenation with H2 with a catalyst, and reaction with N-phenyl trifluoromethanesulfonimide.
Specific palladium catalyst for the coupling step
Using [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II) as the catalyst.
Specific reaction base K3PO4
Carrying out the process with a reaction base of K3PO4.
Conversion of the methyl ester to the corresponding amino acetic acid using sodium hydroxide
Further reacting the amino acetic acid methyl ester with sodium hydroxide to form the corresponding amino acetic acid.
Coupling reagents MCI and HOBt
Using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (MCI) and 1-hydroxybenzotriazole (HOBt) as coupling reagents in precursor preparation.
The claims focus on a catalytic process for forming the target Formula (I) compound from 3-chlorophenyl boronic acid and the specified methyl ester precursor. The dependent features narrow the process with a named palladium catalyst, K3PO4, specific coupling reagents, a defined precursor route, and sodium hydroxide conversion of the methyl ester to the corresponding amino acetic acid.
Stated Advantages
Promotes vascularization/angiogenesis by increasing HIF-1α stabilization and transcription of hypoxia-inducible genes including VEGF, GAPDH, and EPO.
Improves revascularization in ischemia-related conditions.
Increases HIF-1α to stimulate angiogenic pathways.
Increases HIF-1α to stimulate erythropoietic pathways, including elevating erythropoietin.
Provides treatment utility for peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia, and anemia.
Documented Applications
Therapeutic use of human HIF-1α prolyl hydroxylase inhibitors in ischemia-related conditions including chronic non-healing wounds, peripheral vascular disease, coronary artery disease, and anemia.
Treatment of peripheral vascular disease (PVD) by increasing HIF-1α to stimulate angiogenic and erythropoietic pathways.
Treatment of coronary artery disease (CAD) by increasing HIF-1α to stimulate angiogenic and erythropoietic pathways.
Treatment of heart failure by increasing HIF-1α to stimulate angiogenic and erythropoietic pathways.
Treatment of ischemia by increasing HIF-1α to stimulate angiogenic and erythropoietic pathways.
Treatment of anemia by increasing HIF-1α to stimulate angiogenic and erythropoietic pathways.
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