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Dihydropyrimidine-pomalidomide conjugate as well as preparation method and application thereof

A technology of pomalidomide and dihydropyrimidine, applied in the field of anti-HBV drugs, dihydropyrimidine-pomalidomide conjugates and their preparation

Pending Publication Date: 2021-10-19
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Select 6 positions as the linking site to connect the "Linker"; use "linker" with different hydrophilicity and different lengths to connect the core protein ligand and E3 ligase ligand; use E3 ligase ligand The body was used to identify E3 ligase, and a total of 15 dihydropyrimidine-pomalidomide conjugates were designed and synthesized. Such compounds have not been reported in the prior art

Method used

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  • Dihydropyrimidine-pomalidomide conjugate as well as preparation method and application thereof
  • Dihydropyrimidine-pomalidomide conjugate as well as preparation method and application thereof
  • Dihydropyrimidine-pomalidomide conjugate as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1. Preparation of compound II-2

[0053] Dissolve 3-fluorophthalic anhydride (200mg, 1.2mmol), 3-amino-2,6-piperidinedione hydrochloride (259mg, 1.2mmol) sodium acetate (118mg, 1.44mmol) in 20ml of acetic acid, 120°C Reflux 10h. After the reaction, the solvent was spin-dried to obtain a large amount of black solid, which was dissolved by adding a large amount of methanol, and then added to silica gel to mix the sample and put it on the column, separated by flash column chromatography to obtain II-2.

[0054] White solid product, yield 58%; 1 H NMR (400MHz, DMSO-d 6 )δ11.15 (s, 1H, CONHCO), 7.95 (q, J = 7.4Hz, 1H, Ph-H), 7.83–7.66 (m, 2H, Ph-H), 5.16 (dd, J = 12.8, 5.1 Hz,1H,COCHN),2.97–2.82(m,1H,CH 2 ),2.68–2.52(m,1H,CH 2 ),2.18–1.96(m,2H,CH 2 ); EI-MS: 275.06[M-H] - ;C 13 h 9 FN 2 o 4 [276.05].

Embodiment 2

[0055] Embodiment 2. Preparation of compound II-3

[0056] Add II-2 (100.00mg, 0.36mmol) and potassium carbonate (50mg, 0.36mmol) into the solvent N,N-dimethylformamide 5ml, and stir at room temperature, add iodomethane dropwise, and stir at room temperature for 24h. After the reaction, spin the solvent to dry, add water (20ml) and dichloromethane (20ml*2) for extraction, combine the organic phases, extract once with saturated sodium chloride, dry with anhydrous magnesium sulfate, and filter. The organic phase was added to silica gel to mix the sample, and separated by flash column chromatography to obtain II-3.

[0057] White solid product, yield 46%; 1 H NMR (400MHz, DMSO-d 6 )δ7.96 (tdt, J=7.4, 4.7, 2.3Hz, 1H, Ph-H), 7.83–7.70 (m, 2H, Ph-H), 5.30–5.12 (m, 1H, COCHN), 3.08–2.85 (m,3H,CH 3 ),2.85–2.73(m,1H,CH 2 ),2.66–2.51(m,1H,CH 2 ), 2.08 (tdd, J=12.7, 7.5, 4.2Hz, 1H, CH 2 ); EI-MS: 290.25[M-H] - ;C 14 h 11 FN 2 o 4 [290.07].

Embodiment 3

[0058] Embodiment 3. Preparation of Compound 2

[0059] Weigh 2-thiazole formamidine hydrochloride (1.0g, 6.11mmol), 2-bromo-4-fluorobenzaldehyde (1.86g, 9.16mmol) and sodium acetate (1.0g, 1.22mmol) were dissolved in absolute ethanol ( 100 mL), ethyl acetoacetate (1.2 mL, 9.20 mmol) was added under stirring at room temperature, and ethanol was refluxed at 80° C. for 8 h; after the reaction was completed, it was filtered to remove salts. The mother liquor was cooled to room temperature, and yellow crystals (I-2) were precipitated. Remove absolute ethanol from the remaining mother liquor under reduced pressure, add water (60mL), extract with ethyl acetate (25mL×3), collect and combine the organic phases, extract once with saturated sodium chloride (25mL), and use anhydrous magnesium sulfate for the organic phase dry. Filter, add 200 mesh silica gel, mix the sample, separate by flash column chromatography, and recrystallize to obtain compound 2. 0.75 g of yellow powder was ob...

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Abstract

The invention provides a dihydropyrimidine-pomalidomide conjugate as well as a preparation method and application thereof. The conjugate has a structure as shown in a formula I. The invention further relates to a preparation method of the compound with the structure as shown in the formula I, a pharmaceutical composition and application of the compound in preparation of anti-HBV drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a dihydropyrimidine-pomalidomide conjugate, a preparation method thereof, and an anti-HBV medicine 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 for the prevention and treatment of chronic hepatitis B 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 v...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D417/04A61K31/506A61P31/20
CPCC07D417/14C07D417/04A61P31/20Y02P20/55
Inventor 展鹏马悦刘新泳赵树洁任玉洁
Owner SHANDONG UNIV
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