Diazepinone derivatives and their use in the treatment of hepatitis b infections

A compound, heterocycloalkyl technology, applied in the field of diazepinone derivatives and its use in the treatment of hepatitis B infection, can solve the problems of inability to provide cure, difficulty in complete inhibition, low cure rate, etc.

Inactive Publication Date: 2019-04-16
NOVIRA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Despite the availability of preventive HBV vaccines, the burden of chronic HBV infection remains a major and unaddressed worldwide medical problem due to suboptimal treatment options and persistent new infection rates in large parts of the developing world
Current treatments offer no cure and are limited to only two classes of agents (interferon alpha and nucleoside analogs / inhibitors of viral polymerase); drug tolerance, low efficacy, and resistance issues limit their impact
The low cure rate of HBV is due at least in part to the fact that complete suppression of viral production is difficult to achieve with a single antiviral agent

Method used

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  • Diazepinone derivatives and their use in the treatment of hepatitis b infections
  • Diazepinone derivatives and their use in the treatment of hepatitis b infections
  • Diazepinone derivatives and their use in the treatment of hepatitis b infections

Examples

Experimental program
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preparation example Construction

[0547] Preparation of the optically active form is accomplished in any suitable manner, including, by way of non-limiting examples, resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or use of a chiral stationary phase Perform chromatographic separation. In one embodiment, a mixture of one or more isomers is used as the disclosed compounds described herein. In another embodiment, the compounds described herein contain one or more chiral centers. The 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 achieved by any means including, by way of non-limiting examples, chemical methods, enzymatic methods, fractional crystallization, distillation and chromatography.

[0548] It is also to be understood that those compounds which have the same molec...

Embodiment

[0631] Exemplary compounds useful in the methods of the invention will now be described with reference to exemplary synthetic schemes for their general preparation below and the specific examples that follow. Those skilled in the art will recognize that to obtain the various compounds herein, starting materials can be appropriately selected so that, protected or unprotected as required, throughout the reaction schemes will carry the ultimately desired substituents to provide desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group which can be run through the reaction scheme and replaced with the desired substituent where appropriate. Unless otherwise indicated, variables are as defined above for formula (I). The reaction can be carried out between the melting point of the solvent and the reflux temperature, and preferably between 0°C and the reflux temperature of the solvent. The reaction can be heated u...

preparation example

[0640] Exemplary compounds useful in the methods of the invention will now be described with reference to exemplary synthetic schemes for their general preparation below and for the specific illustrations that follow.

[0641] plan 1

[0642]

[0643] According to Scheme 1, a commercially available or synthetically obtained compound of formula (Xa) is synthesized with an alkylating agent such as ethyl prop-2-enoate, ethyl 2-(bromomethyl)prop-2-enoate, etc. (where R a for C 1-6 Alkyl or C 1-6 Haloalkyl, and PG is a suitable nitrogen protecting group, such as BOC, Bn, etc.) Alkylation to provide compounds of formula (XI) (wherein R b is optionally co- 2 C replaced by Me 2-6 alkylene). The compound of formula (Xa) (wherein R a for CH 3 or CH 2 CHF 2 , and PG is BOC) alkylation, for example, with or without such as NaH, Cs 2 CO 3 、K 2 CO 3 base, etc., in a suitable solvent such as THF, DMF, etc., with an alkylating agent such as ethyl 2-(bromomethyl)prop-2-enoat...

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Abstract

Provided herein are compounds of formula (I) and (V) useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

Description

[0001] Related Patent Applications [0002] This patent application claims the benefit of U.S. Provisional Patent Application 62 / 356,489, filed June 29, 2016; and U.S. Provisional Patent Application 62 / 511,573, filed May 26, 2017; each of which is incorporated by reference in its entirety Incorporated into this article. Background technique [0003] Chronic hepatitis B virus (HBV) infection is a major global health problem, affecting more than 5% of the world's population (more than 350 million people worldwide and 1.25 million individuals in the United States). [0004] Despite the availability of preventive HBV vaccines, the burden of chronic HBV infection remains a major and unaddressed worldwide medical problem due to suboptimal treatment options and persistent rates of new infections in large parts of the developing world. Current treatments offer no cure and are limited to only two classes of agents (interferon alpha and nucleoside analogs / inhibitors of viral polymeras...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/551A61P31/12
CPCC07D471/14A61P31/20C07D471/04A61P31/12A61P43/00
Inventor S.库德克G.D.哈特曼
Owner NOVIRA THERAPEUTICS
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