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Dihydropyrimidine-sulfonamide derivatives, preparation method and application thereof

A technology of sulfonamide and dihydropyrimidine, applied in the field of medicine, can solve the problems of strong liver toxicity, poor water solubility, poor metabolic stability and the like

Active Publication Date: 2022-01-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are currently no drugs on the market for related targets
Aiming at the disadvantages of strong hepatotoxicity, poor water solubility and poor metabolic stability of current clinical candidate drugs, a novel class of dihydrogenases was designed and synthesized through target-based rational drug design based on the crystal complex structure of core protein and ligands. Pyrimidine-sulfonamide compounds, such compounds have no relevant reports in the prior art

Method used

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  • Dihydropyrimidine-sulfonamide derivatives, preparation method and application thereof
  • Dihydropyrimidine-sulfonamide derivatives, preparation method and application thereof
  • Dihydropyrimidine-sulfonamide derivatives, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1. Preparation of compound 2

[0044]Dissolve 2-thiazolecarboxamidine hydrochloride (0.50g, 3.05mmol) in 50mL of absolute ethanol, and add 2-bromo-4-fluorobenzaldehyde (0.93g, 4.60mmol) and ethyl acetoacetate successively at room temperature (600μL, 4.60mmol), sodium acetate (0.50g, 6.13mmol), 80 ℃ reflux reaction for 6h; 25mL x 3), combined the organic phases, washed once with saturated brine (25mL), dried over anhydrous sodium sulfate; concentrated, dry-loaded, separated on a silica gel column by flash preparative chromatography, recrystallized from a dichloromethane-n-hexane mixed solvent to obtain a yellow solid 0.75g, yield 58%; melting point 153-156°C.

[0045]

[0046] Compound 2 spectral data: 1 H NMR (400MHz, CDCl 3 )δ7.81(d, J=2.8Hz, 1H), 7.46(s, 1H), 7.38–7.28(m, 2H), 6.97(t, J=8.2Hz, 1H), 6.15(s, 1H), 4.05(q, J=7.1Hz, 2H), 2.53(s, 3H), 1.13(t, J=7.1Hz, 3H); EI-MS: 424.3[M+H] + .

Embodiment 2

[0047] Embodiment 2. Preparation of Compound 3

[0048] Intermediate 2 (0.50g, 1.17mmol) was dissolved in 50mL of carbon tetrachloride, NBS (0.22g, 1.24mmol) was slowly added, and the reaction was refluxed at 50°C for 2h; after the reaction, cooled to room temperature, the tetrachloride was removed by rotary evaporation carbonization, add water (50mL), extract three times with ethyl acetate (20mL x 3), combine the organic phases, wash once with saturated brine (25mL), dry over anhydrous sodium sulfate; concentrate, dry load, and quickly prepare a chromatography silica gel column Separation, recrystallization from dichloromethane-n-hexane mixed solvent to obtain 0.35 g of yellow solid, yield 59%; melting point 123-128°C.

[0049]

[0050] Spectral data of compound 1: 1 H NMR (400MHz, CDCl 3 )δ7.84(d,J=3.1Hz,1H),7.52(s,2H),7.44–7.35(m,1H),7.32(dd,J=8.1,2.6Hz,1H),7.02(t,J =8.0Hz,1H),6.09(s,1H),4.94(d,J=8.9Hz,1H),4.61(s,1H),4.09(d,J=7.0Hz,2H),1.16(t,J =7.1Hz, 3H); EI-MS: 50...

Embodiment 3

[0051] Embodiment 3. Preparation of Compound 4

[0052] Intermediate 3 (0.50 g, 1.00 mmol) was dissolved in 45 mL of acetone, and NaN 3 (0.13g, 2.00mmol), stirred overnight at room temperature; after the reaction, cooled to room temperature, acetone was removed by rotary evaporation, added water (50mL), extracted three times with ethyl acetate (20mL x 3), combined organic phases, washed once with saturated brine (25mL), dried over anhydrous sodium sulfate; concentrated, dry-loaded, separated by flash preparative chromatography on a silica gel column, recrystallized from a dichloromethane-n-hexane mixed solvent to obtain 0.37g of a yellow solid, yield 80%; melting point 123-126°C .

[0053]

[0054] Compound 4 spectral analysis data: 1 H NMR (400MHz, CDCl 3 )δ8.64(s,1H),7.85(d,J=3.1Hz,1H),7.55(d,J=3.1Hz,1H),7.48–7.37(m,1H),7.35–7.29(m,1H ),7.10–6.92(m,1H),6.29–6.02(m,1H),4.97(s,1H),4.60(d,J=2.6Hz,1H),4.17–4.00(m,2H),1.13( t,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl 3 )δ165....

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Abstract

The invention discloses a dihydropyrimidine-sulfonamide derivative, a preparation method and application thereof. The compound has the structure shown in formula I. The present invention also relates to a preparation method containing the compound of formula I, a pharmaceutical composition and the application of the above compound in the preparation of anti-HBV medicines.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to dihydropyrimidine-sulfonamide derivatives, a preparation method thereof and a pharmaceutical application. Background technique [0002] Viral hepatitis type B (viral hepatitis type B), referred to as hepatitis B (Hepatitis B), is a major infectious disease caused by hepatitis B virus (HBV), long-term development can lead to acute and chronic viral hepatitis, severe hepatitis, liver cirrhosis and primary hepatocellular carcinoma (hepatocellular carcinoma, HCC). The drugs currently used to prevent and treat chronic hepatitis B (CHB) mainly include vaccines, interferon, immunomodulators and DNA polymerase inhibitors. However, they have shortcomings such as drug resistance, side effects, rebound after drug withdrawal, and inability to completely remove hepatitis B virus. Therefore, it is important to develop a new generation of non-nucleoside hepatitis B virus inhibitor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D417/14A61K31/506A61P1/16A61P31/20
CPCA61P1/16A61P31/20C07D417/04C07D417/14
Inventor 刘新泳俞霁展鹏贾海永张硕
Owner SHANDONG UNIV
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