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A compound that specifically enhances the spatial coupling degree of trpv4-kca2.3 complex and its use

A compound and composition technology, applied in the field of chemical medicine, can solve problems such as many side effects

Active Publication Date: 2021-12-03
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

How to overcome the non-specific targets and side effects of current antihypertensive drugs is an urgent need to be solved

Method used

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  • A compound that specifically enhances the spatial coupling degree of trpv4-kca2.3 complex and its use
  • A compound that specifically enhances the spatial coupling degree of trpv4-kca2.3 complex and its use
  • A compound that specifically enhances the spatial coupling degree of trpv4-kca2.3 complex and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: 4-oxo-N-(3-(2-(pyridin-4-yl)acetamido)propyl)-1,4-dihydroquinazoline-2-carboxamide

[0066]

[0067] The synthesis method is as follows:

[0068]

[0069] Step a: Preparation of ethyl 4-oxo-1,4-dihydroquinazoline-2-carboxylate

[0070] Suspend 2-aminobenzamide (10g, 73.53mmol) in diethyl oxalate (100mL), slowly heat to 185°C, reflux for 5 hours, after cooling to room temperature, a solid precipitates, filter, and filter cake petroleum ether Washed and dried to obtain 13 g of white solid with a yield of 86%.

[0071] Step b: Preparation of 4-oxo-1,4-dihydroquinazoline-2-carboxylic acid

[0072] 4-Oxo-1,4-dihydroquinazoline-2-carboxylic acid ethyl ester (2g, 9.2mmol, 1.0eq) was suspended in tetrahydrofuran (20mL) and water (10mL), and potassium hydroxide ( 1.5g, 27.5mmol, 3.0eq), stirred at room temperature for 2 hours. The ethanol was removed by rotary evaporation, the reaction liquid was cooled to 0°C, and the pH was adjusted to 2-3 with dilute hydr...

Embodiment 2

[0080] Example 2: 4-oxo-N-(3-(3-(pyridin-4-yl)ureido)propyl)-1,4-dihydroquinazoline-2-carboxamide

[0081]

[0082] The synthesis method is as follows:

[0083]

[0084] Step f: Preparation of phenylpyridin-4-ylcarbamate

[0085] Dissolve 4-aminopyridine (200mg, 2.13mmol, 1.0eq) in DMF (2mL), add triethylamine (257.9mg, 2.55mmol, 1.2eq), cool to 0°C, and slowly add phenyl chloroformate ( 399mg, 2.55mmol, 1.2eq), react at 0°C for 3 hours. The reaction solution was diluted with ethyl acetate, washed three times with water, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to obtain 365 mg, yield 82%

[0086] Step g: Preparation of 4-oxo-N-(3-(3-(pyridin-4-yl)ureido)propyl)-1,4-dihydroquinazoline-2-carboxamide

[0087] N-(3-Aminopropyl)-4-oxo-1,4-dihydroquinazoline-2-carboxamide hydrochloride (100 mg, 0.353 mmol, 1.0 eq) was dissolved in DMF (2 mL), Add triethylamine (107.2mg, 1.06mmol, 3.0eq) and phenylpyridin-4-ylcarbamate (...

Embodiment 3

[0089] Example 3: N-(3-(3-(4-(((4-ethylpiperazin-1-yl)methyl)phenyl)ureido)propyl)-4-oxo-1,4 -Dihydroquinazoline-2-carboxamide

[0090]

[0091] The synthesis method is as follows:

[0092]

[0093] Step h: Preparation of phenyl (4-((4-ethylpiperazin-1-yl)methyl)phenyl)carbamate

[0094] 4-(4-Ethylpiperazine-1-methyl)-aniline (500mg, 2.28mmol, 1.0eq) was dissolved in DMF (5mL), triethylamine (345.9mg, 3.42mmol, 1.5eq) was added, Cool down to 0°C, add phenyl chloroformate (391.2mg, 2.51mmol, 1.1eq) dropwise, react at room temperature for 2h after addition, dilute the reaction solution with ethyl acetate, wash with water, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate , concentrated, and column chromatography gave 480 mg of oily substance, with a yield of 62%.

[0095] Step i: N-(3-(3-(4-(((4-ethylpiperazin-1-yl)methyl)phenyl)ureido)propyl)-4-oxo-1,4- Preparation of dihydroquinazoline-2-carboxamide

[0096] N-(3-Aminopropyl)-4-oxo-1,4-dihydro...

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Abstract

The invention discloses a compound that specifically enhances the spatial coupling degree of a TRPV4-KCa2.3 complex and an application thereof, belonging to the field of chemical medicine. The compound with the structure of general formula (I) of the present invention is mainly aimed at the uncoupling of TRPV4 and KCa2.3 in hypertensive patients, which can recouple the two uncoupled proteins to restore the normal state. Under normal circumstances, TRPV4 and KCa2.3 receive calcium ion signals from TRPV4. Due to the influx of calcium ions, it stimulates the outflow of potassium ions from the downstream KCa2.3 channel. return to normal levels.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a compound for specifically enhancing the spatial coupling degree of TRPV4-KCa2.3 complex and its application. Background technique [0002] Transient receptor potential (TRP) ion channel is a kind of non-selective cation channel protein, which was first discovered in the visual transmission system of Drosophila melanogaster. At present, nearly 30 TRP channels have been found in mammals, and they are divided into 7 subfamilies: TRPV (vanniloid), TRPM (melastatin), TRPA (ankryin), TRPML (mucolipin), TRPP (polycistin), TRPC ( caninocal) and TRPN (drosophila NOMPC). ([J]Arch.2011May; 461(5):493-498). TRP channels regulate the permeability of extracellular cations according to changes in temperature, chemical substances, pH value, osmotic pressure, etc. in the environment (.Int.J.Biochem . Cell Biol. 2016; 78:217–228.), thereby regulating cellular function. TRPV4 (tran...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D239/90C07D295/135A61K31/517A61K31/495A61P9/12A61P3/06A61P9/00A61P9/10A61P9/06
CPCC07D401/12C07D239/90C07D295/135A61P9/12A61P3/06A61P9/00A61P9/10A61P9/06
Inventor 马鑫唐春雷杨砂颖
Owner JIANGNAN UNIV
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