Nitrogen-containing heteroaryl compounds and their use in increasing endogeneous erythropoietin

A technology of heteroaryl compounds, applied in the field of nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin, capable of solving problems such as tissue damage

Active Publication Date: 2013-03-20
FIBROGEN (CHINA) MEDICAL TECHNOLOGY DEVELOPMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Stabilize the condition with other drugs, including digoxin, diuretics, amrinone, beta-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, none of which can Acts directly on tissue damage resulting from ischemia and hypoxia

Method used

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  • Nitrogen-containing heteroaryl compounds and their use in increasing endogeneous erythropoietin
  • Nitrogen-containing heteroaryl compounds and their use in increasing endogeneous erythropoietin
  • Nitrogen-containing heteroaryl compounds and their use in increasing endogeneous erythropoietin

Examples

Experimental program
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example

[0684] The invention may be further understood by reference to the following examples, which are intended purely to demonstrate the invention. The present invention is not limited to the scope of the exemplary embodiment, which is only used as an illustration of a single aspect of the present invention. Any functionally equivalent methods are intended to be within the scope of this invention. Various modifications of the invention in addition to the modifications described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are within the scope of the appended claims.

[0685] All temperatures are in degrees Celsius unless otherwise stated. Also, abbreviations appearing in these examples and elsewhere have the following meanings:

[0686] μl = microliter

[0687] amu = atomic mass unit

[0688] atm = atmospheric pressure

[0689] bs = broad singlet

[0690] ClCO 2 iBu = isobutyl chloroform...

example A-1

[0741] (S)-2-[(6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-propionic acid

[0742] a.(S)-2-[(6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester

[0743] In 15ml CH at room temperature 2 Cl 2 0.33 g of 6-benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid (available according to Weidmann et al. US Patent 6,093,730, 10 / 1998), 0.5 ml of triethylamine, 0.38 g HATU and 0.151 g of commercially available L-alanine methyl ester hydrochloride for 18 h yielded (S)-2-[(6 -Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-propionic acid methyl ester 0.220g, MS-(+)-ion, M+1=415.8amu.

[0744] b. (S)-2-[(6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-propionic acid

[0745]0.200 g of the (S) methyl ester described in Example A-1a) and 15 ml of a 1.5M NaOH solution in methanol were stirred at room temperature for 3 h and concentrated. The residue was dissolved in water and extracted with EtOAc....

example A-2

[0747] (R)-2-[(1-Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-3-hydroxy-propionic acid

[0748] a. (1,3-Dioxy-1,3-dihydro-isoindol-2-yl)-butyl acetate

[0749] A mixture of 160ml butanol, 20.0g (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid (94.6mmol) and 2.0ml concentrated sulfuric acid was refluxed for 24h under stirring. Then 5 g of sodium bicarbonate were added in portions, stirring was continued for 5 min at room temperature and the solvent was evaporated in vacuo. The residue was partitioned between 100 mL of water and 100 mL of ethyl acetate. The organic phase was washed with 100 ml brine, dried over sodium sulfate and evaporated in vacuo to give a yellowish oil which then solidified. 24.02 g of the title compound were obtained; MS-(+)-ion:

[0750] b. Butyl 1,4-dihydroxy-isoquinoline-3-carboxylate

[0751] 4.41 g of sodium (190 mmol) were dissolved in 250 ml of n-butanol with stirring. After complete dissolution of the sodium, the solution was cooled to am...

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Abstract

The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.

Description

[0001] Cross References to Related Applications [0002] This application asserts U.S. Provisional Patent Application Nos. 60 / 476,811, filed June 6, 2003; 60 / 476,420, filed June 6, 2003; 60 / 476,633, filed June 6, 2003 and 60 / 476,519, filed June 6, 2003, under 35 USC § 119(e); all said applications are incorporated herein by reference in their entirety. technical field [0003] The present invention relates to methods and compounds capable of modulating the stability of the alpha subunit of hypoxia-inducible factor (HIF) and increasing endogenous erythropoietin in vitro and in vivo. Background technique [0004] An early response to tissue hypoxia is the induction of hypoxia-inducible factor (HIF), a basic helix-loop-helix (bHLH) PAS (Per / Arnt / Sim) transcriptional activator whose regulation follows Changes in gene expression associated with changes in cellular oxygen concentration. HIF is a heterodimer containing an oxygen-regulated α subunit (HIFα) and a constitutively exp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26C07D401/04C07D401/12A61K31/472A61K31/4725A61P7/06A61P25/00A61P25/08A61P17/02A61P25/28A61P9/10A61P1/16A61P13/12A61P11/00C07D221/08C07D401/06C07D403/12
CPCC07D403/12C07D217/26C07D221/08C07D401/06A61K38/1816C07D401/12A61K31/472C07D401/04C07D217/24A61K31/4725A61K31/473A61P1/04A61P1/16A61P11/00A61P13/12A61P17/00A61P17/02A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P43/00A61P7/00A61P7/06A61P9/00A61P9/10A61P9/14A61K2300/00
Inventor 迈克尔·P·阿兰德李·A·弗利平福尔克马·京茨勒-普卡尔何文彬埃里克·D·图尔托杜晓辉
Owner FIBROGEN (CHINA) MEDICAL TECHNOLOGY DEVELOPMENT CO LTD
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