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Diethylcarbamyl-substituted thiazole dihydropyrimidine

A technology of alkyl and methylene, which is applied in the field of drugs for the composition, treatment and prevention of hepatitis B virus infection, and can solve problems such as side effects and rebound effects

Active Publication Date: 2011-05-25
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, interferons are only moderately active and have deleterious side effects; although lamivudine has good activity, resistance develops rapidly during treatment and rebound effects often occur after cessation of treatment, IC of lamivudine (3-TC) > 50 Value is 300nM (Science, 299(2003), 893-896)

Method used

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  • Diethylcarbamyl-substituted thiazole dihydropyrimidine
  • Diethylcarbamyl-substituted thiazole dihydropyrimidine
  • Diethylcarbamyl-substituted thiazole dihydropyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Ethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate

[0116]

[0117] With 10.0g (57.1mmol) of2,4-dichlorobenzaldehyde, 7.4g (57.1mmol) ethyl acetoacetic acid, 9.3g (57.1mmol) 2-amidino-thiazole hydrochloride and 5.7g (69.5mmol) acetic acid Sodium was dissolved or suspended in 500ml of ethanol and boiled under reflux for 16 hours. Cool to room temperature, filter with suction, and wash the residue with water to remove inorganic salts. 11.8 g (52.5%) of the product were obtained. Melting point: 164-166°C.

Embodiment 2

[0119] Ethyl 6-bromomethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

[0120]

[0121] 8.0g (20.2mmol) ethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine prepared in Example 1 -5-Carboxylate was added to 140ml of carbon tetrachloride and heated to 50°C under argon atmosphere to obtain a clear solution. At this temperature, 4.36 g (24.2 mmol) of N-bromosuccinimide were added and mixing was maintained at this temperature for 10 minutes. Cool immediately, filter under vacuum at room temperature, and concentrate under reduced pressure. The purity of the product detected by HPLC was higher than 90%, and it was used as the raw material for the next step.

[0122] Rf=0.68 (petroleum ether / ethyl acetate=8:2)

[0123] B. Preparation Examples

Embodiment 3

[0125] Ethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate

[0126]

[0127] 5.0 g of the newly prepared ethyl-6-bromomethyl-4-(2-chloro4-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5 -Carboxylate was added to 60ml of methanol to form a solution, mixed with 5 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solution was diluted with water and extracted with ethyl acetate.

[0128] Yield: 4.1g

[0129] Melting point: 155-157°C.

[0130] R f =0.48 (petroleum ether / ethyl acetate=8:2)

[0131] The enantiomers obtained in Example 3 were separated on a chiral column (Daicel Chiralpak AS-H, mobile phase: n-hexane / ethanol=99 / 1)

[0132] The anti-HBV active compounds in Example 3 are all enantiomers with longer retention time.

[0133] The list of activity data of the compounds of the present invention is as follows:

[0134]

[0135] Treatment of Hepatitis B virus producing He...

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Abstract

The invention relates to a novel ethoxycarbonyl-substituted thiazolyldihydropyrimidine applicable to acting against hepatitis B virus (HBV) infection and a composition of the same and other antiviral agents.

Description

technical field [0001] The present invention relates to a new ethoxycarbonyl-substituted thiazole dihydropyrimidine, its preparation method and its use as a medicine, especially as a medicine for treating and preventing hepatitis B virus infection. The invention also relates to compositions of these dihydropyrimidines with other antiviral agents and, where appropriate, immunomodulators, and medicaments containing these compositions, especially for the treatment and prevention of HBV infections such as hepatitis B. Background technique [0002] Hepatitis B virus belongs to the Hepaviridae family. It can cause acute and or persistent / progressive chronic disease. Hepatitis B virus also causes many other clinical signs in the pathomorphology - notably chronic inflammation of the liver, cirrhosis and canceration of hepatocellular cells. In addition, co-infection with hepatitis D can have detrimental effects during the development of the disease. [0003] Interferon and lamivud...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/5377A61P1/16A61P31/12A61K31/506C07D417/04
CPCC07D417/04C07D417/14A61P1/16A61P31/12
Inventor S·戈尔德曼李静刘遗松
Owner SUNSHINE LAKE PHARM CO LTD