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Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

A compound and pharmaceutical technology, applied in the field of coupling compounds or their salts, and nucleosides conjugated to phosphorus oxides or their salts, can solve the problems of intracellular activation, high substrate specificity, etc.

Pending Publication Date: 2019-04-26
EMORY UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the intracellular activation of these compounds is often affected by the high substrate specificity of the host's endogenous kinases

Method used

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  • Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
  • Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
  • Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1814] Preparation of conjugates

[1815]Several groups of monophosphate and diphosphate prodrugs have been prepared. See Jessen et al., "Bioreversible Protection of Nucleoside Diphosphates", Angewandte Chemie - International Edition English, 2008, Vol. 47, No. 45, pp. 8719-8722, which is incorporated herein by reference. To prevent the breakage of the P-O-P anhydride bond, a rapidly cleavage side group (e.g., bis-(4-acyloxybenzyl)-nucleoside diphosphate (BAB-NDP) is deacylated by an endogenous esterase) is utilized in the A negative charge is created on the second phosphate. See also Routledge et al., "Synthesis, Bioactivation and Anti-HIV Activity of 4-Acyloxybenzyl-bis(nucleosid-5'-yl) Phosphates", Nucleosides & Nucleotides, 1995, Vol. 14, No. 7, pp. 1545-1558 , and Meier et al., "Comparative study of bis(benzyl) phosphate triesters of 2', 3'-dideoxy-2', 3'-didehydrothymidine(d4T) and cycloSal-d4TMP-hydrolysis, mechanistic insights and anti-HIV activity", Antiviral Chemi...

Embodiment 2

[1818] 2-fluoronucleoside activity

[1819] When activated to the corresponding triphosphate, ribonucleoside analogs inhibit RNA-dependent RNA viral replication by acting as competitive substrate inhibitors of virally encoded RdRp. Compounds in this therapeutic class are useful in the treatment of viruses found in, but not limited to, the Arenaviridae, Bunyanviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Togaviridae families. Certain compounds disclosed herein are expected to have advantages such as a high genetic barrier to antiviral resistance; broad spectrum activity within viral families; and high oral bioavailability for targeted delivery to the site of infection.

[1820] Nucleoside analogs are designed with 2'-α-fluoro substituents to mimic natural ribonucleosides. C-F bond length Similar to C-O bond length Fluorine is a hydrogen bond acceptor that makes the fluorine substituents heteropolar and replaces the hydroxyl groups. Unlike ribonucleoside an...

Embodiment 3

[1822] ZIKV NS5 RNA-dependent RNA polymerase assay results

[1823] The table below shows the activity of selected mock triphosphates against ZIKV NS5 RdRp.

[1824]

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PUM

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Abstract

This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, wherein the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.

Description

technical field [0001] The present disclosure relates to alkyne-containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the present disclosure relates to nucleosides optionally conjugated to phosphorus oxides or salts thereof. In certain embodiments, the present disclosure relates to conjugated compounds or salts thereof comprising amino acid esters, lipids, or sphingolipids or derivatives linked to nucleotides or nucleosides by phosphorus oxides. In certain embodiments, the present disclosure contemplates pharmaceutical compositions comprising these compounds for use in the treatment of infectious diseases, viral infections, and cancer. Background technique [0002] Nucleoside and nucleotide phosphates and phosphonates are clinically useful as antiviral agents. Two examples are tenofovir disoproxil fumarate used to treat human immunodeficiency virus and adefovir dipivoxil used to treat hepatitis B virus infection. C...

Claims

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Application Information

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IPC IPC(8): A61K31/70A61K31/7072A61K31/7076C07H19/02C07H19/04C07H19/056
CPCA61P31/14A61K31/706A61K31/7068A61K31/7072A61K31/7076A61K45/06C07H19/06C07H19/10C07H19/11C07H19/12C07H19/14C07H19/16C07H19/20C07H19/213A61P31/12A61P31/16A61P31/18Y02A50/30A61K2300/00A61K31/7064
Inventor 格雷戈里·布鲁姆林亚伯·德拉罗莎乔治·佩因特达米安·凯珀亚历山大·科雷哈洛夫
Owner EMORY UNIVERSITY
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