Morpholine derivative

A technology of morpholine derivatives and alkyl groups, which is applied in the field of medicine and can solve the problems of not disclosing details of morpholine compounds

Active Publication Date: 2010-03-24
MITSUBISHI TANABE PHARMA CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, 3,4-substituted piperidine compounds are disclosed (Patent Document 1), but no details about morpholine compounds are disclosed in this patent publication

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0280] 【Chemical 21】

[0281]

[0282] (2R)-2-{Cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]carbamoyl}ylmorpholine-4-carboxylic acid tert-butyl ester (reference example Compound 8 (368 mg) was dissolved in chloroform (4 ml), cooled in an ice bath, 4N hydrogen chloride / dioxane (1 ml) was added, and stirred at room temperature for 2 hours. Cool in an ice bath, add water, and separate the organic phase. Add saturated aqueous sodium bicarbonate solution to the aqueous phase to adjust the pH value to 9, then extract with chloroform. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column (column solvent: n-hexane / ethyl acetate=1 / 1→ethyl acetate) to obtain colorless oil (2R)-N-cyclopropyl-N-[4-methyl Oxy-3-(3-methoxypropoxy)benzyl]morpholine-2-carboxamide (230 mg). The obtained compound was dissolved in chloroform (1 ml), cooled with ice water, 4N hydr...

Embodiment 2

[0285] 【Chemical 22】

[0286]

[0287] (2R)-2-{[4-Benzyloxy-3-(3-methoxypropoxy)benzyl]cyclopropylcarbamoyl}morpholine-4-carboxylic acid tert-butyl ester (reference The compound of Example 9 (217 mg) was dissolved in chloroform (1 ml), cooled in an ice bath, 4N hydrogen chloride / dioxane (1 ml) was added, and then stirred at room temperature for 2 hours. After concentration under reduced pressure, water (1ml) and diethyl ether (2ml) were added to the residue and stirred gently, and the diethyl ether was removed by decantation. Then obtain colorless powder (2R)-N-[4-(benzyloxy)-3-(3-methoxypropoxy)benzyl]-N-cyclopropylmorpholine-2 by lyophilization - Formamide hydrochloride (166 mg).

[0288] APCI-MS m / z: 455[M+H] +

Embodiment 3

[0290] 【Chemical 23】

[0291]

[0292] (2R)-2-([3-Benzyloxy-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate)morpholine-4-carboxylic acid tert-butyl ester (reference example 10 Compound 150 mg) was obtained in the same manner as Example 2 to obtain colorless viscous oil (2R)-N-[3-(benzyl)-5-(3-methoxypropoxy)phenoxy]-N-cyclopropane Methyl-morpholine-2-carboxamide hydrochloride (107 mg).

[0293] APCI-MS m / z: 455[M+H] +

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Abstract

The present invention provides a morpholine derivative of the formula ¢I!; wherein R 1 is a substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclo group,a cycloalkyl group or an alkyl group; R 2 is a substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclo group, an optionally substituted alkylcarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted heterocyclo-substituted carbonyl group or a cycloalkylcarbonyl group; T is a methylene group or a carbonyl group; R 3 , R 4 ,R 5 and R 6 are the same or different and a hydrogen atom, an optionally substituted carbamoyl group or an optionally substituted alkyl group; or pharmaceutically acceptable salts thereof. These compounds are useful as a renin inhibitor.

Description

technical field [0001] The present invention relates to medicine, especially morpholine derivatives or pharmacologically acceptable salts and their intermediates as renin (renin) inhibitor drugs. Background technique [0002] It is expected to develop renin inhibitor drugs as drugs for the prevention and treatment of kidney diseases such as hypertension, arrhythmia, and diabetes. For example, 3,4-substituted piperidine compounds are disclosed (Patent Document 1), but any details about morpholine compounds are not disclosed in this laid-open patent. [0003] Patent Document 1: International Publication No. 06 / 069788 Contents of the invention [0004] The problem to be solved by the present invention [0005] The present invention finds a class of novel (novel-structured) morpholine derivatives that have a good inhibitory effect on renin. [0006] way of solving the problem [0007] In order to solve the proposed problem, the inventors worked hard to find a novel morphol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30A61K31/5375A61K31/538A61P9/04A61P9/12A61P13/12A61P43/00C07D265/36C07D413/12
CPCC07D471/04C07D413/14C07D403/04C07D265/36C07D209/08C07D413/12C07D413/04C07D417/14C07D231/56C07D209/34C07D265/30C07D209/30C07D209/14C07D209/42A61P9/04A61P9/12A61P13/12A61P43/00
Inventor 赤冢英则须釜宽淡井信将川口隆行高桥阳一饭嶋彻沈竞康夏广新谢建树
Owner MITSUBISHI TANABE PHARMA CORP
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