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Biaryl-substituted 4-aminobutyric acid derivatives and their preparation and use

A kind of aminobutyric acid and derivative technology, applied in biaryl-substituted 4-aminobutyric acid derivative and preparation field thereof

Active Publication Date: 2018-01-09
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Omapatrilat is a powerful ACE / NEP dual inhibitor developed by BMS, but because of side effects such as angioneurotic edema, FDA refused to approve Omapatrilat for the treatment of hypertension in July 2002, even as the last treatment for refractory patients

Method used

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  • Biaryl-substituted 4-aminobutyric acid derivatives and their preparation and use
  • Biaryl-substituted 4-aminobutyric acid derivatives and their preparation and use
  • Biaryl-substituted 4-aminobutyric acid derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Preparation of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid ethoxycarboxymethyl ester

[0115]

[0116] L-pyroglutaminol (50.0g, 0.43mol) was added to 500mL of dichloromethane, and after cooling in an ice-water bath, triethylamine (120mL, 0.86mol) and p-toluenesulfonyl chloride (90.0g, 0.47mol) were added successively, at room temperature React overnight. After filtration and concentration, the crude product was recrystallized from petroleum ether-ethyl acetate to obtain (S)-5-carbonyl-pyrrolidin-2-ylmethyltoluene-4-sulfonate (110.0 g, 95%) as an off-white solid.

[0117]

[0118] Weigh magnesium chips (10.9g, 0.45mol) and place them in a 2000mL three-necked flask, and dissolve 4-bromobiphenyl (93.2g, 0.40mol) in 400mL of tetrahydrofuran, then slowly add them dropwise into the three-necked flask for about two hours. After the addition, the reflux reaction was continued for two hours. After cooling to room temperature, 25 mL of 1,4-...

Embodiment 2

[0170] Preparation of (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid cyclohexyloxycarboxymethyl ester

[0171]

[0172] Cyclohexanol (2.50g, 25.0mmol) was added to 25mL of dichloromethane, cooled in an ice-water bath; chloromethyl chloroformate (2.2mL, 25.0mmol) was dissolved in 25mL of dichloromethane, and slowly added dropwise to the reaction system; pyridine (2.2mL , 27.5mmol) was diluted in 5mL of dichloromethane, and then slowly added dropwise into the reaction system. React overnight at room temperature. Add dichloromethane for dilution, wash with water three times, and dry over anhydrous sodium sulfate. Concentration gave cyclohexyl chloromethyl carbonate (4.80 g, 99%) as a colorless liquid.

[0173] 1 H NMR (400MHz, CDCl 3 )δ5.66 (s, 2H), 4.72-4.58 (m, 1H), 1.93-1.80 (m, 2H), 1.76-1.63 (m, 2H), 1.54-1.39 (m, 3H), 1.37-1.15 m, 3H).

[0174]

[0175] Cyclohexyl chloromethyl carbonate (4.8 g, 25.0 mmol) was dissolved in 25 mL of a...

Embodiment 3

[0185] Preparation of (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid isopropoxycarboxymethyl ester

[0186]

[0187] Isopropanol (1.9mL, 25.0mmol) was added to 25mL of dichloromethane, cooled in an ice-water bath; chloromethyl chloroformate (2.2mL, 25.0mmol) was dissolved in 25mL of dichloromethane, and slowly added dropwise to the reaction system; pyridine (2.2mL , 27.5mmol) was diluted in 5mL of dichloromethane, and then slowly added dropwise into the reaction system. React overnight at room temperature. Add dichloromethane for dilution, wash with water three times, and dry over anhydrous sodium sulfate. Concentration gave chloromethyl isopropyl carbonate (3.8 g, 99%) as a colorless liquid.

[0188] 1H NMR (400MHz, CDCl 3 )δ5.66(s, 2H), 4.89(m, 1H), 1.27(d, 6H).

[0189]

[0190] Chloromethyl isopropyl carbonate (3.8g, 25.0mmol) was dissolved in 25mL of acetonitrile, and sodium iodide (18.7g, 125.0mmol) was added to react at room temp...

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Abstract

The present invention relates to biaryl-substituted 4-aminobutyric acid derivatives, a preparation method and application thereof. Specifically, the present invention relates to a biaryl-substituted 4-aminobutyric acid derivative as shown in formula (I) and its preparation method and application, and a biaryl-substituted 4-aminobutyric acid derivative is prepared through a ring closure reaction Intermediates of compounds and pharmaceutical compositions containing biaryl-substituted 4-aminobutyric acid derivatives. These biaryl-substituted 4-aminobutyric acid derivatives have NEP inhibitory activity and can be used as NEP inhibitors.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a biaryl-substituted 4-aminobutyric acid derivative, a preparation method and application thereof. Background technique [0002] Hypertension is one of the most common cardiovascular diseases, and it is also a major risk factor leading to increased morbidity and mortality of congestive heart failure, stroke, coronary heart disease, renal failure, and aortic aneurysm. According to a recent press release issued by the International Society of Hypertension, there are 972 million people with high blood pressure or high blood pressure worldwide, accounting for 26.4% of the world's adult population. With the increasing trend of population aging, the proportion of hypertensive patients is gradually increasing. By 2025, the estimated number of people affected will reach 1.56 billion. With the successive advent and wide application of a new generation of antihypertensive drugs, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/404A61K31/4015A61P9/04
CPCC07C231/12C07C233/47C07C327/22C07D207/404C07D309/10A61P9/04A61P9/12A61P11/00A61P13/12C07C2601/14C07H15/18
Inventor 杨飞王春娟仝朝龙喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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