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-11883386-B2
Publication Date
2024-01-30
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 a therapeutic rationale for HIF-1α prolyl hydroxylase inhibitors in treating ischemia-related diseases and promoting angiogenesis/vascularization. It associates this approach with chronic non-healing wounds, peripheral vascular disease (PVD), peripheral vascular disorders, coronary artery disease (CAD)/heart failure, diabetes and hypertension contexts, and anemia and VEGF/EPO-associated disorders.
The disclosure further frames formulation composition aspects for HIF-1α prolyl hydroxylase inhibitors, including excipients and salt or physiological release forms. It provides stated dose ranges and references compound-specific potency relationships, with compounds represented by multiple numbered structures including methyl ester variants and salts and substituent analogs such as cyano, halo, methyl, fluoro, and methoxy.
The invention also relates to a process for preparing a compound having the formula as defined in the claims. The process includes reacting a 4-chlorophenyl boronic acid with methyl 4-bromo-2-methoxybenzoate in the presence of a catalyst to form 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester, converting the resulting methyl ester to 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid using lithium hydroxide, and reacting that acid with glycine ethyl ester in the presence of coupling agents to form [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester.
Claims Coverage
The consolidated claim coverage identifies two independent inventive themes across the provided content: a therapeutic use/formulation theme for HIF-1α prolyl hydroxylase inhibitors, and a multi-step chemical preparation theme for an [(…carbonyl)-amino]-acetic acid ethyl ester product. In total, the provided independent claims support six inventive features, with dependent refinements specifying particular catalyst, base, coupling reagents, and an additional BBr3 conversion step.
Therapeutic use of HIF-1α prolyl hydroxylase inhibitors
Use of HIF-1α prolyl hydroxylase inhibitors for treating ischemia-related diseases and promoting angiogenesis/vascularization, including chronic non-healing wounds, peripheral vascular disease (PVD), peripheral vascular disorders, coronary artery disease (CAD)/heart failure, diabetes and hypertension contexts, and anemia and VEGF/EPO-associated disorders.
Formulation composition and release forms
Formulation aspects including excipients and salt or physiological release forms for HIF-1α prolyl hydroxylase inhibitors, with dose ranges and compound-specific potency relationships.
Catalyzed formation of biphenyl carboxylic acid methyl ester
Reacting a 4-chlorophenyl boronic acid with methyl 4-bromo-2-methoxybenzoate in the presence of a catalyst to form 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester.
Lithium hydroxide conversion to carboxylic acid
Reacting 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid methyl ester with lithium hydroxide to form 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid.
Coupling with glycine ethyl ester using coupling agents
Reacting 4′-chloro-3-methoxy-biphenyl-4-carboxylic acid with glycine ethyl ester in the presence of coupling agents to form [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester.
BBr3 conversion to hydroxy-acid derivative
Reacting [(4′-chloro-3-methoxy-biphenyl-4-carbonyl)-amino]-acetic acid ethyl ester with BBr3 to form [(4′-Chloro-3-hydroxy-biphenyl-4-carbonyl)-amino]-acetic acid.
The claims coverage combines a therapeutic/formulation set directed to HIF-1α prolyl hydroxylase inhibitors with a defined synthetic sequence to make an [(…carbonyl)-amino]-acetic acid ethyl ester: biphenyl methyl ester formation from a 4-chlorophenyl boronic acid and methyl 4-bromo-2-methoxybenzoate, ester-to-acid conversion with lithium hydroxide, and coupling with glycine ethyl ester using coupling agents. Dependent coverage specifies a palladium catalyst, K3PO4, EDCl and HOBt, and an additional BBr3 conversion to a hydroxy derivative.
Stated Advantages
Treat ischemia-related diseases and promote angiogenesis/vascularization.
Associated with treating chronic non-healing wounds.
Associated with treating peripheral vascular disease (PVD) and peripheral vascular disorders.
Associated with treating coronary artery disease (CAD)/heart failure.
Associated with treating diabetes and hypertension-related contexts.
Associated with treating anemia and VEGF/EPO-associated disorders.
Stabilizes HIF-1α through inhibition of EGLIN/prolyl hydroxylases.
Promotes angiogenic response.
Promotes erythropoietic pathways, including elevation of erythropoietin (EPO).
Documented Applications
Treatment of ischemia-related diseases with promotion of angiogenesis/vascularization.
Treatment of chronic non-healing wounds.
Treatment of peripheral vascular disease (PVD) and peripheral vascular disorders.
Treatment of coronary artery disease (CAD)/heart failure.
Treatment associated with diabetes and hypertension-related contexts.
Treatment associated with anemia and VEGF/EPO-associated disorders.
Therapeutic treatment/targeting of peripheral vascular disease (PVD).
Therapeutic treatment/targeting of coronary artery disease (CAD).
Therapeutic treatment/targeting of heart failure.
Therapeutic treatment/targeting of ischemia.
Therapeutic treatment/targeting of anemia.
Demonstration of HIF-1α stabilization (immunoblot) associated with the disclosed compounds, reported in Fig. 1.
Elevation of erythropoietin (EPO) after oral dosing, reported in Fig. 2.
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