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NEP inhibitor and medicine composition thereof

A technology for solvates and compounds, which is applied in the directions of drug combination, separation of optically active compounds, and pharmaceutical formulations to achieve the effects of high bioavailability, good solubility, and good pharmacokinetic activity

Inactive Publication Date: 2017-03-01
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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  • NEP inhibitor and medicine composition thereof
  • NEP inhibitor and medicine composition thereof
  • NEP inhibitor and medicine composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The first step: the preparation of 1-chloroethyl isopropyl carbonate

[0070]

[0071] Compound 1-chloroethyl chloroformate (3ml, 27.8mmol) was diluted with DCM (25ml), cooled to 0°C, and isopropanol (2.1ml, 27.8mmol) diluted with DCM (25ml) was dropped with constant pressure Slowly add the liquid funnel, and react for about 15 minutes. Pyridine (2.4ml, 30.6mmol) diluted with DCM (5ml) is also slowly added using the constant pressure dropping funnel. Overnight, then diluted with water, extracted with DCM, the organic phase was dried and concentrated to obtain 3.74 g of light yellow liquid with a yield of 81%.

[0072] 1 HNMR: (400MHz, CDCl 3 ), 6.36(q,1H), 4.88(m,1H), 1.759(dm,3H), 1.26(t,6H).

[0073] The second step: the preparation of 1-iodoethyl isopropyl carbonate

[0074]

[0075] Compound 1-chloro-ethyl ester isopropyl carbonate (3.74g, 22.4mmol) was dissolved in acetonitrile (20ml), sodium iodide (16.8g, 112.2mmol) was added, and the temperature was ra...

Embodiment 2

[0100] The first step: (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-6-isopropyl-2,9-dimethyl-4,8,13 - Preparation of tricarbonyl-3,5,7-trioxa-12-azahexadecane-16-acid

[0101]

[0102] Compound (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (1410mg, 2.98mmol) was dissolved in 10mL N,N -Dimethylformamide with addition of Cs 2 CO 3 (580mg, 1.79mmol), stirred at room temperature for 1 hour, added KI (1240mg, 7.44mmol), 1-chloro-2-methylpropyl isopropyl carbonate (1450mg, 7.44mmol), heated at 65°C for 24 hours. Reversed-phase column chromatography separated 745 mg of crude product (containing ring-closing by-products). It was then dissolved in 10 mL of methanol, 80 mg of palladium / carbon was added, and hydrogenated at room temperature and pressure for 5 hours. Filtration, concentration, separation by reverse phase column chromatography, white foamy solid (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-6-isopropyl-2 , 9-Dimethyl-4,8,13-tricarbony...

experiment example 1

[0116] (Rat pharmacokinetic study test)

[0117] 1. Research purpose

[0118] Taking rats as test animals, study the pharmacokinetic behavior of NEP series prodrug compound (6), compound (1-6R), compound (2-6R), compound (2-6S) in rats, and evaluate its pharmacokinetic characteristics.

[0119] 2. Test plan

[0120] 2.1 Test animals

[0121] Three SD rats, male, were used in each case, provided by Xipuer-Bikai Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2008-0016.

[0122] 2.2 Drug preparation

[0123] Take all the samples (according to 30mg), add 1ml of ethanol to dissolve, then add 1ml of Solutol HS15 and 8ml of pH 4.63 acetate buffer in order to make a 3mg / ml solution, and keep the remaining liquid as a sample for quantitative analysis.

[0124] 2.3 Administration

[0125] Three SD rats, male, were administered intragastrically after fasting overnight, with a dose of 30 mg / kg and a volume of 10 ml / kg.

[0126] 2.4 Sample Collection ...

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Abstract

The invention relates to an NEP inhibitor and a medicine composition thereof, and in particular, relates to a (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(3-carboxylpropionylamino)-2-methylpentanoate derivative represented as the formula (I), and a stereoisomer, a hydrate or a solvate thereof, and a medicine composition thereof, wherein the substituent groups in the formula (I) are defined as same as the specification. The series of the compounds in the invention have significant NEP inhibition activity, good solubility and high bioavailability, and can be used for developing medicines used in therapy or prevention of hypertension, pulmonary arterial hypertension, heart failure, kidney diseases and the like, which are related to NEP abnormality, so that it is hopeful to develop a new-generation NEP inhibitor.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to a NEP inhibitor (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(3-carboxypropionylamino)- 2-methylvalerate derivatives and pharmaceutical compositions 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 in the world, accounting for about 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 applic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C231/20C07B57/00A61K31/265A61P9/12A61P9/04A61P11/00A61P13/12
CPCC07B57/00C07B2200/07C07C231/20C07C233/47
Inventor 杨飞仝朝龙李成海包如迪喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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