Compounds for inhibiting drug-resistant strains of HIV-1 integrase

A technology of HIV-1 and compounds, applied in the field of compounds for inhibiting drug-resistant HIV-1 integrase drug-resistant strains

Inactive Publication Date: 2016-05-25
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Although there are currently two FDA-approved HIV integrase inhibitors (raltegravir and elvitegravir) on the market, both have shown resistance and extensive cross-resistance to Low to moderate genetic barrier to drug resistance, which increases the need for inhibitors with improved potency against raltegravir-resistant strains

Method used

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  • Compounds for inhibiting drug-resistant strains of HIV-1 integrase
  • Compounds for inhibiting drug-resistant strains of HIV-1 integrase
  • Compounds for inhibiting drug-resistant strains of HIV-1 integrase

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0174] Scheme B. Preparation of Starting Pyridine Analogs

[0175]

[0176] Scheme C. Preparation of 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide analogs.

[0177]

[0178] Scheme D. 1-Hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide and 2-oxo-1,2-dihydro-1,8-naphthyridine- Preparation of 3-carboxamide analogues.

[0179]

[0180] Scheme E. Preparation of 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide analogs.

[0181]

[0182] Scheme F. Preparation of 4-amino-1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide analogs.

[0183]

[0184] The heck reaction: R 8 = alkenyl

[0185] Suzuki Reaction: R 8 = aryl

[0186] Sonogashira reaction: R 8 = Alkyl

[0187] Buchwald-Hartwig amination: R 8 = amine

[0188] Ullmann Response: R 8 = ether

[0189] Negishi reacts: R 8 = Alkyl

[0190] Scheme G. Preparation of 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide analogs using coupling reactions.

[019...

Embodiment

[0594] Assay protocol:

[0595] In vitro integrase assay. The integrase reaction was performed by adding drug or an equal volume of 100% dimethyl sulfoxide (DMSO; used as drug solvent) to 20 nM DNA and 400 nM integrase in 50 mM morpholine propane sulfonic acid (pH 7.2), 7.5 mM MgCl 2 and 14 mM 2-mercaptoethanol in a mixture. Reactions were performed at 37°C for 2 hours and quenched by adding an equal volume of loading buffer (formamide containing 1% sodium dodecyl sulfate, 0.25% bromophenol blue, and xylene cyanol). Reaction products were separated on a 16% polyacrylamide denaturing sequencing gel. Dried gels were visualized using a Typhoon 8600 (GE Healthcare, Piscataway, NJ). Densitometric analysis was performed using ImageQuant 5.1 software from GE Healthcare. Data analysis of at least 3 independent measurements was performed using GraphPad's Prism 5.0c software (linear regression, 50% inhibitory concentration [IC 50 ] determination, standard deviation [SD]).

[059...

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PUM

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Abstract

A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is N, C(OH), or CH; Y is H or OH; each of Z1-Z5 is independently H or halogen; R4 is H, OH, NH2, NHR8, NR8R9 or R8; R5, R6, and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, SO2NR8R9, or R5 and R6 together with the carbon atoms to which R5 and R6 are attached form an optionally-substituted carbocycle or optionally-substituted heterocycle; and R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.

Description

[0001] This application claims priority to US Provisional Application No. 61 / 824,306, filed May 16, 2013, and US Provisional Application No. 61 / 899,061, filed November 1, 2013, both of which are incorporated herein by reference. Background technique [0002] Although there are currently two FDA-approved HIV integrase inhibitors (raltegravir and elvitegravir) on the market, both have shown resistance and extensive cross-resistance to There is a low to moderate genetic barrier to drug resistance, which increases the need for inhibitors with improved potency against raltegravir-resistant strains. Contents of the invention [0003] Disclosed herein is a method for inhibiting drug-resistant HIV-1 integrase in a subject, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or ester thereof to a subject in need thereof, wherein Said compound has the following structure: [0004] [0005] wherein X is N, C(O...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4375A61K31/4704A61K31/496A61K31/5377C07D471/04A61K45/06
CPCA61K45/06A61K31/4375A61K31/4704A61K31/496A61K31/5377C07D215/58C07D215/60C07D491/147C07D471/04A61P31/18A61K2300/00
Inventor 赵学智S·史密斯M·A·麦迪菲奥特B·约翰逊C·马钱德S·休斯Y·波米尔T·R·伯克
Owner UNITED STATES OF AMERICA
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