imidazopyridine compounds

A compound, pyridine technology, applied in organic chemistry, drug combination, blood diseases, etc., can solve problems such as undisclosed or revealed sGC activators

Active Publication Date: 2016-10-12
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this document does not disclose or suggest that sGC activators

Method used

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Examples

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Embodiment

[0276] Hereinafter, the production method of the compound of formula (I) is demonstrated in more detail based on an Example. It should be noted that the present invention is not limited to the compounds described in the following examples. In addition, the production method of the raw material compound is shown in the production example. In addition to the production methods described in the Examples shown below, the compound of formula (I) can be produced using a combination of these production methods or a method obvious to those skilled in the art.

[0277] In addition, the following abbreviations may be used in Examples, Production Examples, and Tables described later.

[0278] PEx: Production example number, Ex: Example number, No.: Compound number, Str: Structural formula, DATA: Physicochemical data (ESI+: ESI-MS[M+H] + or ESI-MS[M] + ;ESI-:ESI-MS[M-H] - ;CI+: CI-MS[M+H] + ;EI:EI[M] + ;APCI / ESI+:APCI / ESI-MS[M+H] + or APCI / ESI-MS[M] + (APCI / ESI refers to simultane...

manufacture example 1

[0291] Add 500 mg of ethyl 8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate, 0.35 ml of 2,3-difluorobenzyl bromide, and 650 mg of potassium carbonate in N,N-dimethylformaldehyde Amide (DMF) 8.6ml suspension was stirred at 60°C for 1 hour. The reaction mixture was left to cool to room temperature, then water was added and the resulting solid was collected by filtration and washed with water. The solid was washed with diisopropyl ether to obtain 650 mg of ethyl 8-[(2,3-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate.

manufacture example 2

[0293]Add 4.3ml of ethyl 2-chloro-3-oxobutyrate and 4.3ml of triethylamine to a solution of 5.8g of 3-(cyclohexylmethoxy)pyridin-2-amine in 100ml of toluene, and stir overnight under reflux . 1 ml of ethyl 2-chloro-3-oxobutyrate and 1 ml of triethylamine were added to the reaction mixture, followed by stirring under reflux for 6.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethyl acetate and hexane were added to the obtained purified product, heated and stirred, and then stirred under ice cooling. The generated solid was collected by filtration to obtain 4.0 g of ethyl 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate.

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Abstract

The present invention provides pharmaceutical compositions for the treatment or prevention of various cardiovascular diseases, which have soluble guanylate cyclase (sGC) activation and are based on improvement of cGMP signaling. The imidazo[1,2-a]pyridine skeleton represented by the formula (I) having a carbamoyl group at the 3-position and a specific ring group bonded via a methyleneoxy group at the 8-position was found. 2-a] Pyridine compound or its salt has sGC activation effect, as the treatment or prevention of sGC-related various cardiovascular diseases, especially peripheral arterial disease, intermittent claudication, severe lower extremity ischemia, hypertension and pulmonary hypertension The present invention was accomplished by using the active ingredient of the pharmaceutical composition to be useful. (where, A 1 is a cyclohexyl group, a phenyl group substituted with 1 to 3 Fs, or a 3-fluoropyridin-2-yl group; R is a group represented by any one of the following formulae (i) to (vii). )

Description

technical field [0001] The present invention relates to an imidazolo that is useful as an active ingredient of a pharmaceutical composition for treating or preventing various cardiovascular diseases, which has a soluble guanylate cyclase (sGC) activating action and is based on the improvement of cyclic guanosine monophosphate (cGMP) signaling. [1,2-a]pyridine compounds. Background technique [0002] cGMP is an important intracellular messenger, through the regulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels, it participates in various physiological phenomena such as relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, and signal transmission of nerve cells control. This cGMP is produced from guanosine triphosphate (GTP) catalyzed by guanylate cyclase in response to various extracellular and intracellular stimuli. Two groups of guanylate cyclases have been reported so far. These are membrane-bound guanylate c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61K31/444A61K31/506A61P7/02A61P9/04A61P9/08A61P9/10A61P9/12A61P11/00A61P43/00
CPCC07D471/04A61P11/00A61P43/00A61P7/02A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12
Inventor 黑崎寿夫渡边翼大根和彦石冈裕贵野泽荣典花泽毅八谷俊一郎柴田洋古贺祐司沟口亮
Owner ASTELLAS PHARMA INC
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