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Dihydropyrimidine compounds and their preparation and use

A compound and application technology, applied in the field of medicinal chemistry, can solve the problems of failure to reach the main efficacy endpoint and high incidence of taste-related adverse events, and achieve the effects of good affinity, simple operation, and easy industrialization

Active Publication Date: 2022-06-07
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 compounds and their preparation and use
  • Dihydropyrimidine compounds and their preparation and use
  • Dihydropyrimidine compounds and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052]Example 1: Preparation of (S)-3-(3-(4-chlorobenzyl)-2,6-dioxa-4-(4-(pyrazine-2-ylthio)phenyl)amino)-3,6-dihydropyrimidine-1(2H)-2-methyl-N-(methylsulfonyl)propionamide (Compound 1)::

[0053]

[0054] Step 1: Preparation of 4-(pyrazine-2-thiol)aniline (compound b-1).

[0055] 2-Fluoropyrazine (51.0g, 0.52mol) and p-aminothiophenol (61.3g, 0.49mol) was dissolved in dimethyl sulfoxide (360ml), cesium carbonate (320g, 0.98mol) was added to give the reaction mixture, and the reaction mixture was stirred at a uniform speed with mechanical stirring. Subsequently, the internal temperature of the heating reaction system to 80 °C was 2h. Thin layer chromatography tracks the progress of the reaction, after the reaction is complete, the reaction mixture is added to three times the volume (about 1 L) of water and kept stirred. After the three extraction products of ethyl acetate were combined, dried and concentrated to obtain a crude product, the crude product was filtered after 500ml...

Embodiment 2

[0075] Example 2: (S)-3- (3-(4-chlorobenzyl)-2,6-dioxa-4-(4-(pyridin-2-ylthio)phenyl)amino)-3,6-dihydropyrimidine-1(2H)-2-methyl-N- (methylsulfonyl)propionamide (compound 2) preparation

[0076] The preparation method of the present embodiment is compared with Example 1, the 2-fluoropyrazine in step 1 is replaced with an equal molar of 2-fluoropyridine, the remaining conditions are the same, to give a white solid compound 2, yield: 76.0%, purity of 99.05%.

[0077] ESI-MS:m / z＝600.1(M+H) + 。

[0078] 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.80(s,1H),8.31(dd,J＝5.0, 2.0Hz,1H),7.99–7.89(m,1H),7.45–7.37(m,2H),7.30(d,J＝8.4Hz,2H),7.25 (m,4H),7.14–7.09(m,1H),7.03(d,J＝8.3Hz,1H), 5.42–5.15(m,2H),4.62(s, 1H),3.88(m,2H),3.01(s,3H),2.69(m,1H),0.98(m,3H)。

Embodiment 3

[0079] Example 3: 1-(2,6-Dioxo-4-(4-(pyridin-2-thiophenyl)amino)-3-(4-(trifluoromethyl)benzyl)-3,6-dihydropyrimidine-1(2H)ylmethyl)-N- (methanesulfonyl) cyclopropane-1-carboxamide (Compound 3) preparation

[0080] The preparation method of the present embodiment is compared with Example 1, the 2-fluoropyrazine in step 1 is replaced with an equal molar of 2-fluoropyridine, and the methyl ester in step 3 (S)-3-hydroxy-2-methylpropionate is replaced with an isomole of 1- (hydroxymethyl) cyclopropane-1-carboxylate methyl ester, the remaining conditions are the same, to give a white solid compound 3, yield: 76.1%, purity of 99.05%.

[0081] ESI-MS:m / z＝646.1(M+H) + 。

[0082] 1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.89(s,1H),8.35(dd,J＝5.2, 2.0Hz,1H),7.85(m,1H),7.46–7.38(m,2H),7.35(d,J＝8.4Hz,2H),7.23–7.15 (m,4H),7.15–7.09(m,1H),7.04(d,J＝8.3Hz,1H), 5.28(s,2H),4.65(s,1H),4.13 (s,2H),3.12(s,3H),1.07–0.92(m,4H).

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Abstract

The invention discloses a dihydropyrimidine compound, a preparation method and an application thereof, and belongs to the technical field of medicinal chemistry. The structure of the dihydropyrimidine compounds provided by the present invention is shown in Formula I. The invention also discloses a preparation method of the dihydropyrimidine compound. The present invention provides the application of the compound represented by formula I or its salt, solvate, isomer, metabolite, nitrogen oxide and prodrug in the preparation of medicines for treating or preventing P2X3 and / or / P2X2 / 3 receptor-related diseases . The antitussive action time of the compound of the present invention is significantly longer than that of the compound of Comparative Example 1; the inhibitory activity to P2X3 is better than that of the compound of Comparative Example 1 and the positive control drug gefapixant, and it has almost no effect on the taste of mice under 10mg / kg intravenous administration, which is comparable to that of the compound of Comparative Example 1. The positive control drug gefapixant had a statistically significant difference.

Description

Technical field [0001] The present invention relates to the field of medicinal chemical techniques, specifically to dihydropyrimidine compounds or salts thereof, solvates, isomers, metabolites, nitrogen oxides and prodrugs thereof, methods of preparation thereof, and in the preparation of drugs for the treatment and prevention of diseases associated with P2X3 and / or P2X2 / 3 receptors, in particular in the preparation of drugs for the treatment and prevention of respiratory diseases. Background [0002] Chronic cough, which lasts > 8 weeks, accounts for more than 1 / 3 of respiratory clinics, with an incidence of 2-10%. Patients with chronic cough are more sensitive to various triggers that do not normally cause cough in healthy subjects, such as daily activities (talking and laughing), temperature changes, exposure to aerosols, or food odors. Chronic cough not only affects the patient's quality of life, but also produces a serious psychological burden. In the prior art, the t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D401/12C07D417/12C07D413/12C07D487/04C07D239/545A61P11/06A61P11/14A61P29/00A61P11/00A61K31/513
CPCC07D403/12C07D401/12C07D417/12C07D413/12C07D487/04C07D239/545A61P11/06A61P11/14A61P29/00A61P11/00Y02P20/55
Inventor 曾燕群朱绪成黄龙朱涛牟霞付海霞
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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