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5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, preparation method thereof and application thereof in medicines

An alkyl and pharmaceutical technology, applied in the field of 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivatives, its preparation and its application in medicine, can solve the problem of human biological utilization Low degree and other issues

Inactive Publication Date: 2011-07-13
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the renin inhibitors that have been developed so far have low bioavailability in the human body due to their large molecular weight. Therefore, improving the activity and pharmacokinetic properties of renin inhibitors will be the main research direction of renin inhibitors in the future.

Method used

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  • 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, preparation method thereof and application thereof in medicines
  • 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, preparation method thereof and application thereof in medicines
  • 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, preparation method thereof and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] (2S, 4S, 5S, 7S)-5-amino-4-hydroxy-2-isopropyl-N-((S)-2-methoxy-1-phenylethyl)-7-(4- Methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide fumarate

[0116]

[0117] first step

[0118] (S)-2-(Dibenzylamino)-2-phenyl benzyl acetate

[0119] At 45°C, potassium carbonate (2.76g, 0.02mol) and sodium hydroxide (0.80g, 0.02mol) were dissolved in 20mL of water, and (S)-2-amino-2-phenylacetic acid 1a (1.51g, 0.01 mol), benzyl bromide 1b (4.10mL, 0.035mol) was added dropwise, and the reaction was stirred for 12 hours. Add 100 mL of water to the reaction solution, extract with ethyl acetate (150 mL×3), combine the organic phases, wash with water (50 mL×2) and saturated brine (50 mL×2) successively, dry with anhydrous sodium sulfate, filter, and filtrate Concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system B in an appropriate ratio) to obtain the title product (S)-2-(dibenzylamino)-2-phenylacetate benzyl acetate 1c( 4.30g, white oil)...

Embodiment 2

[0147] (2S, 4S, 5S, 7S)-5-amino-N-((S)-2-ethoxy-1-(4-methoxyphenyl)ethyl)-4-hydroxy-2-isopropyl Base-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide

[0148]

[0149] first step

[0150] (S)-2-Amino-2-(4-hydroxyphenyl)acetate methyl ester hydrochloride

[0151] Under ice bath, dissolve ethyl chloroacetate (2.36g, 30mmol) in 50mL methanol, add (S)-2-amino-2-(4-hydroxyphenyl)acetic acid 2a (1.67g, 10mmol), stir at room temperature React for 2 hours and heat to reflux for 2 hours. 2mL of water was added to the reaction solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride 2b (1.81) g, white solid) crude product.

[0152] Second step

[0153] (S)-2-(tert-Butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate methyl ester

[0154] Under ice bath, dissolve (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride 2b (...

Embodiment 3

[0179] (2S, 4S, 5S, 7S)-5-amino-N-((S)-1-(4-fluorophenyl)-2-methoxyethyl)-4-hydroxy-2-isopropyl- 7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide

[0180]

[0181] first step

[0182] (S)-2-Amino-2-(4-fluorophenyl)acetate methyl ester hydrochloride

[0183] Under ice bath, dissolve (S)-2-amino-2-(4-fluorophenyl)acetic acid 3a (2.50g, 15mmol) in 80mL methanol, add thionyl chloride (1.50mL, 22mmol) dropwise, at room temperature The reaction was stirred for 2 hours, and the reaction was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product (S)-2-amino-2-(4-fluorophenyl)acetic acid methyl ester hydrochloride 3b (3.01 g, pale yellow solid), yield: 90.9%.

[0184] Second step

[0185] (S)-2-(tert-Butoxycarbonylamino)-2-(4-fluorophenyl)acetate methyl ester

[0186] Under an ice bath, (S)-2-amino-2-(4-fluorophenyl)acetic acid methyl ester hydrochloride 3b (3.01g, 14mmol) was dissolved in 50mL of water, and potassium carbonat...

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Abstract

The invention relates to a 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, a preparation method thereof and application thereof in medicines. Specifically, the invention relates to a novel 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative shown in a general formula (I) in the specification, a preparation method thereof, and medicinal composition containing the derivative as well as application of the medicinal composition as a therapeutical agent, particularly as a Renin inhibitor and medicaments for treating and resisting high blood pressure and diseases related to Renin activities, wherein all substituent groups in the general formula (1) are identical to those defined in the specification.

Description

Technical field [0001] The present invention relates to a new 5-amino-4-hydroxy-7-benzyl-8-methylnonanamide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially as a Renin inhibitors and use as drugs for anti-hypertension and other diseases related to renin activity. Background technique [0002] Aspartic proteinase (Aspartic Proteinase) is an important type of proteolytic enzyme, involved in the body's metabolism and biological regulation. Generally speaking, their active center consists of two highly conserved catalytic aspartic acid residues. Common aspartic proteases include: pepsin, Renin (Renin), β-secretase (β-site amyloid precursor protein cleaving enzyme, BACE), human immunodeficiency virus protease, Human T cell leukemia virus protease, etc. They are related to the occurrence of many diseases, such as: in hypertensive patients, the level of angiotensin I rises due to the catalytic effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/20C07C231/12A61K31/165A61P9/12A61P9/10A61P9/04A61P9/00A61P13/12A61P1/16A61P3/10A61P27/02A61P27/06A61P25/28A61P25/22
Inventor 邓炳初吴清泉潘耀辉申大为
Owner JIANGSU HENGRUI MEDICINE CO LTD
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