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

A compound and solvate technology, applied in the field of dihydropyrimidine derivatives and its application in the treatment of HBV infection or HBV-induced diseases, can solve the problem of low cure rate, complete virus suppression, unsatisfactory treatment options, drug resistance, and low curative effect And other issues

Pending Publication Date: 2021-03-16
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 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 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 the treatment of hbv infection or of hbv-induced diseases
  • Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases
  • Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0194] 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 compounds and isomers thereof is accomplished by any means including, by way of non-limiting example, chemical methods, enzymatic methods, fractional crystallization, distillation, and chromatography.

[0195] When the absolute R or S stereochemistry of a compound cannot be determined, it ca...

example 1

[0299] General scheme 1

[0300]

[0301] General scheme 2

[0302]

[0303] The general synthesis of final compounds of general formula I is described in general scheme 1. Compounds of general formula IV-1 can be synthesized using Method A. As described in Method A, for example, an acid of general formula III-1 is activated to an acyl imidazole and coupled under basic conditions with methyl (or ethyl) malonate potassium salt to generate an intermediate, which This in turn undergoes decarboxylation to yield ketoesters of general formula IV-1. The chemistry can be accomplished by a multi-component reaction (method B) of compounds of general formula IV-I, V and VI in a solvent of choice (but not limited to ethanol) in the presence of a base (but not limited to sodium acetate NaOAc) Methods Compounds of general formula VII were synthesized. The final product of general formula I can be synthesized by ester hydrolysis (method C).

[0304] The general synthesis of final ...

example 2

[2977] Example 2: Antiviral assay in HepG2.2.15 cells

[2978] 1. Materials and Equipment

[2979] 1.1. Cell Lines

[2980] 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).

[2981] reagent

[2982] DMEM / F12(INVITROGEN-11330032)

[2983] FBS (GIBCO-10099-141)

[2984] Dimethyl sulfoxide (DMSO) (SIGMA-D2650)

[2985] Penicillin-streptomycin solution (HYCLONE-SV30010)

[2986] NEAA(INVITROGEN-1114050)

[2987] L-Glutamine (INVITROGEN-25030081)

[2988] Geneticin Selective Antibiotic (G418, 500mg / ml) (INVITROGEN-10131027)

[2989] Trypsin Digest (INVITROGEN-25300062)

[2990] CCK8(BIOLOTE-35004)

[2991] QIAamp 96 DNA Blood Kit(12)(QIAGEN-51162)

[2992] FastStart Universal Probe Mast Mix (ROCHE-0...

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Abstract

The application describes dihydropyrimidine derivatives which are useful in the treatment or prevention of HBV infection or of HBV-induced diseases, more particularly of HBV chronic infection or of diseases induced by HBV chronic infection, 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 major global medical problem due to suboptimal treatment options and persistent rates of new infections in most parts of developing countries. [0003] Current treatments are not curative and are limited to two classes of agents (interferon alpha and nucleoside analogs / viral polymerase inhibitors); 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 slowed the progression of liver disease and helped prevent hepatocellular carcinoma...

Claims

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Application Information

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IPC IPC(8): C07D239/22C07D401/04C07D403/04C07D417/04C07D417/10C07D417/14A61K31/506A61P31/20
CPCA61P31/20C07D417/14A61K31/506A61K45/06
Inventor 邓刚蒋益民刘谦梁超万昭奎张荣顺程战领徐彦平
Owner JANSSEN SCI IRELAND UC
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