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Dihydropyrimidine derivatives and uses thereof in treatment of HBV infection or of HBV-induced diseases

A compound and selected technology, applied in medical preparations containing active ingredients, antiviral agents, antibody medical components, etc., can solve the problems of constant new infection rate, uncurable treatment, low cure rate and complete suppression of virus

Pending Publication Date: 2021-04-09
JANSSEN SCI IRELAND UC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Despite the availability of a preventive HBV vaccine, the burden of chronic HBV infection remains a major unmet global medical problem due to suboptimal treatment options and persistent rates of new infections in most parts of the developing world
[0003] Current treatments are not curative and are limited to two classes of agents (interferon alfa and nucleoside analogs / viral polymerase inhibitors); drug resistance, low efficacy and tolerability issues limit their impact
The low cure rate of HBV is due at least in part to the fact that it is difficult to completely suppress viral production with a single antiviral agent

Method used

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  • Dihydropyrimidine derivatives and uses thereof in treatment of HBV infection or of HBV-induced diseases
  • Dihydropyrimidine derivatives and uses thereof in treatment of HBV infection or of HBV-induced diseases
  • Dihydropyrimidine derivatives and uses thereof in treatment of HBV infection or of HBV-induced diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0114] The preparation of optically active forms is accomplished in any suitable manner, including, by way of non-limiting example, by resolution of racemic forms with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatography using chiral stationary phases separation. In one embodiment, a mixture of one or more isomers is used as the disclosed compound described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means including stereoselective synthesis, enantioselective synthesis or separation of enantiomeric or diastereomeric mixtures. Resolution of the compound and its isomers is accomplished by any means including, by way of non-limiting example, chemical methods, enzymatic methods, fractional crystallization, distillation, and chromatography.

[0115] When the absolute R or S stereochemistry of a compound cannot be determined, it...

example 1

[0198] General solution

[0199]

[0200] The general synthesis of compounds of general formula I is described in Scheme 1 and Scheme 2. Compounds of general formula III can be as shown in Scheme 1 (Method A 1 or method A 2 ) described synthesis, the method selection depends on the substituent R on the compound with general formula III 3 . as method A 1 As described in, an acid of general formula II is converted into an active ester by reaction with N,N-carbonyldiimidazole CDI, which is then coupled with ethyl potassium malonate under basic conditions to generate the intermediate, the The intermediates in turn undergo decarboxylation to yield ketoesters of general formula III.

[0201] The final product of general formula I can be synthesized as described in Scheme 2. The former is a chemical method of multi-component reaction with compounds of general formula III, IV and V in a solvent of choice (but not limited to ethanol EtOH) in the presence of a base (but not lim...

example 2

[1293] Example 2: Antiviral assay in HepG2.2.15 cells

[1294] 1. Materials and Equipment

[1295] 1.1. Cell Lines

[1296] HepG2.2.15 (the HepG2.2.15 cell line can be generated by transfection of the HepG2 cell line as described by Sells, Chen and Acs 1987 (Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 84:1005-1009) described, and the HepG2 cell line can be obtained from In number HB-8065 TM obtained below).

[1297] reagent

[1298] DMEM / F12(INVITROGEN-11330032)

[1299] FBS (GIBCO-10099-141)

[1300] Dimethyl sulfoxide (DMSO) (SIGMA-D2650)

[1301] Penicillin-streptomycin solution (HYCLONE-SV30010)

[1302] NEAA(INVITROGEN-1114050)

[1303] L-Glutamine (INVITROGEN-25030081)

[1304] Geneticin Selective Antibiotic (G418, 500mg / ml) (INVITROGEN-10131027)

[1305] Trypsin Digest (INVITROGEN-25300062)

[1306] CCK8(BIOLOTE-35004)

[1307] QIAamp 96 DNA Blood Kit(12)(QIAGEN-51162)

[1308] FastStart Universal Probe Mast Mix (ROCHE-0...

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Abstract

Provided herein are dihydropyrimidine derivatives which are useful in the treatment of HBV infection or HBV-induced diseases, as well as pharmaceutical or medical applications thereof.

Description

Background technique [0001] Chronic hepatitis B virus (HBV) infection is a major global health problem, affecting more than 5% of the world's population (over 350 million people worldwide and 1.25 million in the United States). [0002] Despite the availability of preventive HBV vaccines, the burden of chronic HBV infection remains a significant unmet global medical problem due to suboptimal treatment options and persistent rates of new infections in most parts of the developing world . [0003] Current treatments are not curative and are limited to two classes of agents (interferon alpha and nucleoside analogs / viral polymerase inhibitors); drug resistance, low efficacy and tolerability issues limit their impact. The low cure rate for HBV is at least partly attributable to the fact that complete suppression of virus production is difficult with a single antiviral agent. However, continued suppression of HBV DNA slows the progression of liver disease and helps prevent hepatoc...

Claims

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Application Information

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IPC IPC(8): C07D239/20C07D403/04C07D417/04A61P31/20A61K31/506
CPCC07D401/14C07D417/14A61P31/12A61K31/506A61K45/06A61P31/20A61K2300/00A61K31/517A61K31/675A61K31/7068A61K38/212A61K39/3955
Inventor 蒋益民万昭奎张荣顺刘谦邓刚梁超
Owner JANSSEN SCI IRELAND UC
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