Dihydropyrimidine compound as well as preparation method and application thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problems of high incidence of taste-related adverse events and failure to reach the main efficacy endpoint, and achieve good P2X3 receptor antagonism, good inhibitory effect, and long-term effect

Active Publication Date: 2021-12-17
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2 studies, the primary efficacy endpoint was not met in the gefapixant 15 mg twice daily dose group
Although the 45mg group achieved the clinical endpoint, the 45mg group had a higher frequency of discontinuation due to adverse events and a higher incidence of taste-related adverse events

Method used

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  • Dihydropyrimidine compound as well as preparation method and application thereof
  • Dihydropyrimidine compound as well as preparation method and application thereof
  • Dihydropyrimidine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2-oxyl)phenyl)amino)-3, Preparation of 6-dihydropyrimidin-1(2H)-yl)-2-methylpropanoic acid methyl ester (compound 1):

[0067]

[0068] Step 1: Preparation of 4-(pyrazine-2-oxyl)aniline (compound b-1)

[0069] 2-Fluoropyrazine (50.0g, 0.52mol) and p-aminophenol (53.5g, 0.49mol) were dissolved in dimethylsulfoxide (360ml), cesium carbonate (320g, 0.98mol) was added to obtain a reaction mixture, and mechanically Stir the reaction mixture at constant speed. Subsequently, the internal temperature of the reaction system was raised to 80° C. for 2-3 hours. The progress of the reaction was tracked by thin-layer chromatography. After the reaction was complete, the reaction mixture was added to three times the volume (about 1 L) of water and kept stirring. Then extract the product three times with ethyl acetate, combine and dry the ethyl acetate and concentrate to obtain the crude product. The crude product is s...

Embodiment 2

[0081] Example 2: S-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2-oxyl)phenyl)amino)-3,6- Preparation of dihydropyrimidin-1(2H)-yl)-2-methylpropionic acid (compound 2)

[0082] (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2-oxyl)phenyl) prepared by the method in Example 1 Amino)-3,6-dihydropyrimidin-1(2H)-yl)-2-methylpropionic acid methyl ester (522mg, 1.0mmol) was dissolved in a mixed solvent of methanol (3ml) and tetrahydrofuran (3ml), kept At a temperature around 10°C, a solution of lithium hydroxide (168mg, 4mmol) in water (3ml) was added to obtain a reaction mixture which was allowed to react overnight at RT. Thin-layer chromatography followed the reaction process. After the reaction was complete, purified by column chromatography to obtain S-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2- Oxy)phenyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)-2-methylpropionic acid (388 mg, off-white solid), yield: 76.5%, purity: 98.62%.

[0083] ESI-MS:m / z=508.1(M+H) + .

[00...

Embodiment 3

[0085] Example 3: (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2-oxyl)phenyl)amino)-3, Preparation of 6-dihydropyrimidin-1(2H)-yl)-2-methyl-N-(methylsulfonyl)propionamide (compound 3)

[0086] The S-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2-oxyl)phenyl)amino obtained by the method of Example 2 )-3,6-dihydropyrimidin-1(2H)-yl)-2-methylpropionic acid (compound 2) (288mg, 0.57mmol), DIPEA (183mg, 1.42mmol) and EDCI (130.8mg, 0.68mmol ), dissolved with dichloromethane (5ml), stirred for 15min, added methanesulfonamide (64.7mg, 0.68mmol) and DMAP (83mg, 0.68mmol) and reacted at room temperature for 2-3 hours, followed by TLC After the reaction is complete, the reaction mixture is washed with water, extracted three times with dichloromethane, combined, dried and concentrated, and purified by column chromatography to obtain (S)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4 -(4-(pyrazine-2-oxyl)phenyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)-2-methyl-N-(methylsulfonyl)propanamide ( 1...

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Abstract

The invention discloses a dihydropyrimidine compound as well as a preparation method and an application thereof, and belongs to the technical field of medicinal chemistry. The structure of the dihydropyrimidine compound provided by the invention is as shown in a formula I in the specification. The preparation method provided by the invention comprises the following steps: carrying out substitution reaction on a compound a and a compound k under the catalysis of alkali to generate a compound b; performing substitution reaction on the compound c and the compound d under an alkaline condition to obtain a compound e; carrying out Mitsunobu reaction on the compound e and f to obtain an intermediate g, and carrying out coupling reaction on the compound g and b to generate a compound h. The invention provides the application of the compound shown in the formula I or salt, solvate, allomer, metabolite, nitric oxide and prodrug thereof in preparation of drugs for treating or preventing P2X3 and/or/P2X2/3 receptor related diseases. The dihydropyrimidine compound disclosed by the invention has a good P2X3 receptor antagonism effect and better safety.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to dihydropyrimidine compounds, their preparation method and application. Background technique [0002] It is estimated that 5%-10% of adults worldwide suffer from chronic cough. A subset of these patients have refractory chronic cough (RCC) and unexplained chronic cough (UCC), which are more sensitive to various triggers that do not usually cause cough in healthy subjects, including daily activities (such as talking and laugh), changes in temperature, exposure to aerosols or food odors. To date, treatment options for these patients are extremely limited, and many patients often do not experience remission for many years. There are currently no approved medications for chronic cough. Commonly used clinical drugs such as codeine and dextromethorphan are central antitussives, and adverse reactions such as constipation and drowsiness often occur. According to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D239/545C07D403/12C07D417/12C07D487/04C07D413/12A61P11/00A61P11/06A61P11/14A61P29/00
CPCC07D401/12C07D239/545C07D403/12C07D417/12C07D487/04C07D413/12A61P11/00A61P11/06A61P11/14A61P29/00
Inventor 曾燕群黄龙朱绪成朱涛牟霞付海霞
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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