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Novel renin inhibitor

A halogen and compound technology, applied in the field of new compounds, can solve problems that do not involve the details of morpholine compounds, and achieve excellent renin inhibitory effect

Active Publication Date: 2015-05-20
SHANGAI PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no details about morpholine compounds are mentioned in this published patent

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0286] [chemical formula 5]

[0287]

[0288] (1) Under ice cooling, to (3-{3-[(1R)-1-(cyclopropylamino)ethyl]-6-methyl-1H-pyrazolo[3,4-b]pyridine- 1-yl}propyl)methyl carbamate (4.00g), and (2R,6S)-4-(tert-butoxycarbonyl)-6-(methoxymethyl)morpholine-2-carboxylic acid (3.66 g) N,N-dimethylformamide (80mL) solution, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.45g), 1-hydroxy Benzotriazole (1.63 g) was then stirred at room temperature for 5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=1 / 1→ethyl acetate) to obtain (2R,6S)-2-{cyclopropyl[(1R )-1-(1-{3-[(methoxycarbonyl)amino]propyl}-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)ethyl...

Embodiment 2

[0293] [chemical formula 6]

[0294]

[0295] (1) Under ice-cooling, (2R, 6S)-4-(tert-butoxycarbonyl)-6-(methoxymethyl)morpholine-2-carboxylic acid (7.59g) in dichloromethane (70mL) To the solution, diisopropylethylamine (9.60 mL) and diphenyl chlorophosphate (5.71 mL) were added, followed by stirring for 15 minutes under ice-cooling. Under ice-cooling, methyl (3-{4-[(1R)-1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}propyl)carbamate (5.65g ) in dichloromethane (20 mL), followed by stirring at room temperature for 20 hours. Under ice-cooling, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=1 / 1→ethyl acetate) to obtain (2R,6S)-2-{cyclopropyl[(1R )-1-(2-methoxy-6-{3-[(methoxycarbo...

Embodiment 3

[0300] [chemical formula 7]

[0301]

[0302] (1) Under nitrogen flow and ice cooling, add (2R,6S)-4-(tert-butoxycarbonyl)-6-(methoxycarbonyl)morpholine-2-carboxylic acid (289mg) to a dichloromethane solution (20mL ), diisopropylamine (523 μL), diphenyl chlorophosphate (415 μL) were added, and stirred under ice cooling for 30 minutes, after which, (3-{2-bromo-5-[(1R)-1-(cyclo A solution (3 mL) of methyl propylamino)ethyl]thiophen-3-yl}propyl)carbamate (361 mg) in dichloromethane was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=75 / 25→40 / 60) to obtain (2S,6R)-6-{[(1R)-1 -(5-Bromo-4-{3-[(methoxycarbonyl)am...

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PUM

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Abstract

The invention provides a nitrogen-containing saturated heterocyclic compound useful as a renin inhibitor. A compound represented by formula [I] (in the formula, R1 represents a cycloalkyl or alkyl, R22 represents an optionally substituted aryl or the like, R represents a lower alkyl group, R3, R4, R5, and R6 are the same or different and represent a hydrogen atom, optionally substituted carbamoyl, optionally substituted alkyl, or alkoxycarbonyl) or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to a medicine, in particular to a novel compound effective as a renin inhibitor or a pharmacologically acceptable salt thereof and its use, preparation method or intermediate. Background technique [0002] Development of a renin inhibitor is expected to be used as a drug for the prevention or treatment of hypertension, heart failure, diabetic nephropathy, etc., and for example, 3,4-substituted piperidine compounds are disclosed (Patent Document 1). However, no details about morpholine compounds are mentioned in this publication. [0003] In addition, although morpholine compounds are disclosed in International Publication No. 2008 / 153182, only compounds in which R in the general formula I of the invention of the present application is hydrogen are disclosed (Patent Document 2). [0004] prior art literature [0005] patent documents [0006] Patent Document 1: International Publication No. 06 / 069788 (US Publication No. ...

Claims

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Application Information

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IPC IPC(8): C07D265/30A61K31/5377A61P9/04A61P9/12A61P13/12A61P43/00C07D413/12C07D413/14C07D417/12C07D471/04C07D487/04C07D491/048
CPCC07D265/30C07D413/12C07D413/14C07D417/12C07D471/04C07D487/04C07D491/048A61P9/04A61P9/12A61P13/10A61P13/12A61P43/00C07D417/14
Inventor 饭嶋彻高桥阳一平井未希须釜宽富樫优子沈竞康夏广新万惠新
Owner SHANGAI PHARMA GRP CO LTD
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