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Deuterated benzylaminopyrimidine diketone derivative and application thereof

A compound and hydrate technology, applied in the field of medicine, can solve the problem that there is no marketed drug for hypertrophic cardiomyopathy, and achieve the effects of good clinical application prospects, good metabolic stability and stable properties

Active Publication Date: 2020-05-08
QINGDAO JIAO PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no marketed drugs for hypertrophic cardiomyopathy

Method used

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  • Deuterated benzylaminopyrimidine diketone derivative and application thereof
  • Deuterated benzylaminopyrimidine diketone derivative and application thereof
  • Deuterated benzylaminopyrimidine diketone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Example 1 (S)-3-isopropyl-6-((1-(phenyl-d5)ethyl)amino)pyrimidine-2,4(1H,3H)-dione

[0149]

[0150] The first step: (R)-2-methyl-N-((phenyl-d5)methylene)propane-2-sulfinamide

[0151] Under nitrogen protection, dichloromethane in (R)-2-methylpropane-2-sulfinamide (4.91g, 40.48mmol), PPTS (339.12mg, 1.35mmol) and magnesium sulfate (16.24g, 134.95mmol) (200mL) benzaldehyde-2,3,4,5,6-d5 (3g, 26.99mmol) was added into the mixed system, stirred overnight at room temperature, TLC monitored the completion of the reaction, filtered to remove insoluble matter, and the filter cake was washed with dichloromethane ( 50 mL), the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EA (v / v)=20 / 1) to obtain 3 g of the title compound as a pale yellow solid, with a yield of 51.8%.

[0152] The second step: (R)-2-methyl-N-((S)-1-(phenyl-d5)ethyl)propane-2-sulfinamide

[0153] Under nitrogen protection, (R)-2-methyl-N-((phenyl-d5)...

Embodiment 2

[0161] Example 2 (S)-3-isopropyl-6-((1-(phenyl-4-d)ethyl)amino)pyrimidine-2,4(1H,3H)-dione

[0162]

[0163] The first step: (R)-2-methyl-N-((phenyl-4-d)methylene)propane-2-sulfinamide

[0164] Under nitrogen protection, benzaldehyde-4-d (0.7g, 6.53mmol), (R)-2-methylpropane-2-sulfinamide (1.58g, 13.07mmol) and anhydrous copper sulfate (3.13g, 19.60mmol) of dichloromethane (200mL) solution was stirred overnight at room temperature, filtered through celite to remove insoluble matter, the filter cake was washed with dichloromethane (50mL), the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EA( v / v)=20 / 1), 0.8 g of the title compound was obtained as a light yellow solid with a yield of 58.4%.

[0165] The second step: (R)-2-methyl-N-((S)-1-(phenyl-4-d)ethyl)propane-2-sulfinamide

[0166]Under nitrogen protection, (R)-2-methyl-N-((phenyl-4-d)methylene)propane-2-sulfinamide (0.8g, 3.8mmol) was dissolved in anhydrous di...

Embodiment 3

[0173] Example 3 (S)-3-(3,5-difluorophenyl)-6-((1-(phenyl-d5)ethyl)amino)pyrimidine-2,4(1H,3H)-dione

[0174]

[0175] Step 1: 1-(3,5-Difluorophenyl)urea

[0176] Slowly drop trimethylsilylisocyanate (4.45g, 38.73mmol) into a solution of 3,5-difluoroaniline (5g, 38.73mmol) in dichloromethane (100mL) at room temperature, and the resulting reaction solution was stirred overnight at room temperature . The reaction solution was cooled to 0°C, slowly dropped into methanol (40mL) to quench the reaction, the resulting reaction solution was raised to room temperature and stirred for 1 hour, then concentrated under reduced pressure, the obtained residue was stirred overnight with methanol / ether at room temperature, filtered to obtain a yellow solid The title compound is 3.2g, the yield is 48%.

[0177] The second step: 1-(3,5-difluorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione

[0178] To a solution of 1-(3,5-difluorophenyl)urea (2.3g, 13.36mmol) in methanol (40mL) was added a solut...

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Abstract

The invention discloses a deuterated benzylaminopyrimidine dione derivative and an application thereof, and a pharmaceutical composition containing the deuterated benzylaminopyrimidine dione derivative, and the deuterated benzylaminopyrimidine dione derivative and the pharmaceutical composition can be used for inhibiting the activity of myosin. The invention also relates to a method for preparingthe compound and the pharmaceutical composition, and an application of the compound and the pharmaceutical composition in treating hypertrophic cardiomyopathy and related heart diseases.

Description

technical field [0001] The invention belongs to the technical field of medicines, and specifically relates to compounds and pharmaceutical compositions for treating hypertrophic cardiomyopathy and related heart diseases, as well as their application methods and applications. In particular, the present invention describes deuterium-containing benzidine derivatives that can act as myosin inhibitors. Background technique [0002] Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy characterized by ventricular muscle hypertrophy, ventricular chamber shrinkage, and decreased diastolic compliance of the left ventricle. Interventricular septal or left ventricular wall thickness ≥ 15 mm measured by two-dimensional echocardiography, or thickness ≥ 13 mm with a clear family history, usually without dilation of the left ventricular cavity, need to exclude increased load such as hypertension, aortic stenosis And left ventricular wall thickening caused by congenital subaortic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/545C07D405/04C07D401/04A61K31/505A61K31/506A61P9/04A61P9/10A61P9/00
CPCC07D239/545C07D405/04C07D401/04A61P9/04A61P9/10A61P9/00A61K31/505A61K31/506A61K31/513C07D239/553C07D401/12C07D403/04C07D403/12C07D405/12C07D413/04
Inventor 邵长伦
Owner QINGDAO JIAO PHARMA TECH CO LTD
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