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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 antitussive effect, easy operation, and strong antagonistic effect

Active Publication Date: 2021-11-09
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

[0053] 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-methylpropionamide (Compound 1)

[0054]

[0055] Step 1: Preparation of 4-(pyrazine-2-oxyl)aniline (compound b-1)

[0056] 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. Then the internal temperature of the reaction system was raised to 80° C. for 2 h. 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 slurried with 500ml of water for...

Embodiment 2

[0076] Example 2: 3-(3-(4-chlorobenzyl)-2,6-dioxo-4-(4-(pyrazine-2-oxyl)phenyl)amino)-3,6-dihydro Preparation of pyrimidin-1(2H)-yl)-N-ethyl-2,2-dimethylpropionamide (compound 2)

[0077] Compared with Example 1, the preparation method of this example replaces (S)-3-hydroxyl-2-methyl propionate methyl ester with equimolar 3-hydroxyl-2,2-dimethyl propionate in step 3 Acid methyl ester, and the ammonium chloride in step 6 was replaced by equimolar ethylamine, and the rest of the conditions were the same; Compound 2 was obtained as a white solid, with a yield of 66.5% and a purity of 99.78%.

[0078] ESI-MS:m / z=549.2(M+H) + .

[0079] 1HNMR (400MHz, DMSO-d6) δ9.52(s, 1H), δ8.66(s, 1H), δ8.16(s, 1H), 7.85–7.76(m, 1H), 7.48–7.38(m, 1H),7.35–7.26(m,2H),7.16(m,4H),7.14–7.11(m,1H),7.04(d,J=8.3Hz,1H),5.42–5.15(s,2H),4.62 (s, 1H), 3.92 (s, 2H), 3.22-3.16 (m, 2H), 1.09 (s, 6H), 1.02-0.96 (m, 3H).

Embodiment 3

[0080] Example 3: (S)-3-(3-(4-chlorobenzyl)-4-(4-(2-cyanopyrimidine-5-oxyl)phenyl)-amino)-2,6-di Preparation of oxo-3,6-dihydropyrimidin-1(2H)-yl)-2-methylpropionamide (compound 3)

[0081] Compared with Example 1, the preparation method of this example is that 2-fluoropyrazine in step 1 is replaced by equimolar 5-fluoro-2-cyanopyrimidine, and the rest of the conditions are the same. Compound 3 was obtained with a yield of 67.3% and a purity of 99.76%.

[0082] ESI-MS:m / z=532.2(M+H) + .

[0083] 1 HNMR (400MHz, DMSO-d6) δ8.63(s, 1H), δ8.11(s, 2H), 7.95(s, 2H), 7.86–7.76(m, 1H), 7.35–7.26(m, 2H) ,7.18-7.09(m,4H),7.14–7.11(m,1H),5.32(s,2H),4.62(s,1H),3.88-3.79(m,2H),2.72-2.68(m,1H) ,1.01-0.96(m,3H).

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Abstract

The invention discloses a dihydropyrimidine compound as well as a preparation method and application thereof, belongs to the technical field of medicinal chemistry, and solves the problems of poor effect and large adverse reaction of a P2X3 receptor inhibitor in the prior art. The structure of the dihydropyrimidine compound is as shown in a formula I in the specification. The invention further provides a preparation method of the compound shown in the formula I and application of the compound in preparation of drugs for treating or preventing P2X3 and / or P2X2 / 3 receptor related diseases. The dihydropyrimidine compound provided by the invention has good affinity with P2X3, has a relatively strong antagonistic effect on a P2X3 receptor, and is safe and effective.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to dihydropyrimidine compounds or their salts, solvates, isomers, metabolites, nitrogen oxides and prodrugs, as well as their preparation methods and their preparation for treatment and prevention of P2X3 and / or P2X2 / 3 receptor-related diseases in the application of drugs, especially in the preparation of drugs for the treatment and prevention of respiratory diseases. Background technique [0002] Chronic cough is one of the common clinical symptoms of the respiratory system. Chronic cough refers to a cough that lasts for more than 8 weeks without obvious evidence of lung disease on chest X-ray. Cough is often the only symptom of a patient. There are many causes of chronic cough. Patients with chronic cough are more sensitive to various triggers that do not normally cause cough in healthy subjects. There is no approved drug specifically for chronic cough in the prior a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/545C07D403/12C07D401/12C07D401/14C07D413/12C07D417/12C07D487/04A61P11/14A61P11/06A61P11/00A61P29/00A61K31/513
CPCC07D239/545C07D403/12C07D401/12C07D401/14C07D413/12C07D417/12C07D487/04A61P11/14A61P11/06A61P11/00A61P29/00Y02P20/55
Inventor 黄龙朱绪成朱涛牟霞付海霞
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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