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Dihydropyrimidine compound and preparation method and application thereof

A compound and solvate 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, easy operation and good safety

Active Publication Date: 2021-11-19
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 and preparation method and application thereof
  • Dihydropyrimidine compound and preparation method and application thereof
  • Dihydropyrimidine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: (S)-3-(3-(4-chlorobenzyl)-2,6-dioxa-4-(4-(pyrazin-2-ylthio)phenyl)amino)- Preparation of 3,6-dihydropyrimidin-1(2H)yl)-2-methyl-N-(methylsulfonyl)propionamide (compound 1):

[0053]

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

[0055] 2-Fluoropyrazine (51.0g, 0.52mol) and p-aminothiophenol (61.3g, 0.49mol) were dissolved in dimethyl sulfoxide (360ml), cesium carbonate (320g, 0.98mol) was added to obtain a reaction mixture, And the reaction mixture was stirred at a constant speed with a mechanical stirrer. 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 then concentrate to obtain the crude product. T...

Embodiment 2

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

[0076] Compared with the preparation method of Example 1, the preparation method of this example is replaced by equimolar 2-fluoropyridine in step 1, and the rest of the conditions are the same, and the compound 2 is obtained as a white solid, with a yield of 76.0% , with a 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-(pyridine-2-thiophenyl)amino)-3-(4-(trifluoromethyl)benzyl)-3,6 - Preparation of dihydropyrimidin-1(2H)ylmethyl)-N-(methylsulfonyl)cyclopropane-1-carboxamide (Compound 3)

[0080] Compared with Example 1, the preparation method of this example replaces 2-fluoro-pyrazine with equimolar 2-fluoropyridine in step 1, and replaces (S)-3-hydroxyl-2-methyl Methyl propionate was replaced by equimolar methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate, and the rest of the conditions were the same to obtain compound 3 as a white solid with a yield of 76.1% and a purity of 99.05%.

[0081] ESI-MS:m / z=646.1(M+H) + .

[0082] 1 H 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 and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The structure of the dihydropyrimidine compound is as shown in a formula I which is described in the specification. The invention also discloses a preparation method of the dihydropyrimidine compound. The invention provides application of a compound as shown in a formula I or a salt, a solvate, an allomer, a metabolite, nitrogen oxide and a prodrug of the compound in preparation of drugs for treating or preventing P2X3 and / or / P2X2 / 3 receptor related diseases. The antitussive action time of the compound is obviously prolonged compared with that of a compound in a contrast 1; the inhibitory activity of the compound on P2X3 is superior to that of a compound in a contrast 1 and a positive control drug gefapirant, and the compound almost has no influence on the taste of mice under 10mg / kg intravenous administration, and has a significant statistical difference from that of the positive control drug gefapirant.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, in particular to dihydropyrimidine compounds or their salts, solvates, isomers, metabolites, nitrogen oxides and prodrugs, their preparation methods, and preparation methods for treating and preventing P2X3 and / or The use in medicines for P2X2 / 3 receptor-related diseases, especially in the preparation of medicines for treating and preventing respiratory diseases. Background technique [0002] It is estimated that chronic cough lasting more than 8 weeks accounts for more than 1 / 3 of respiratory outpatient clinics, with an incidence rate of 2-10%. Patients with chronic cough are more sensitive to various triggers that do not usually induce cough in healthy subjects, such as daily activities (talking and laughing), changes in air temperature, exposure to aerosols or food odors. Chronic cough not only affects the quality of life of patients, but also creates a serious psychologic...

Claims

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Application Information

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Patent Type & Authority Applications(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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