Crystal form, preparation and application of 4'-substituted nucleoside

A crystal form and crystal technology, applied in the field of medicinal chemistry, can solve the problems of no synthetic method and biological activity, unpredictable effect on HIV inhibitory activity, and reduced anti-HIV activity of tenofovir didronate diamide

Active Publication Date: 2019-06-18
HENAN GENUINE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The anti-HIV activity of 2-fluoro-substituted tenofovir didronate was reduced by 183-1377 times (EC 50 =5.51uM)
Therefore, the effect of 2-fluoro substitution on the HIV-inhibitory activity of the product is unpredictable
U.S. Patent (J.Chang US8835615,2014) discloses the chemical structure of compound Ia, but there is no relevant report on its synthetic method and biological activity

Method used

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  • Crystal form, preparation and application of 4'-substituted nucleoside
  • Crystal form, preparation and application of 4'-substituted nucleoside
  • Crystal form, preparation and application of 4'-substituted nucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1, the preparation of compound 1:

[0044] Compound 1 was prepared according to literature method (K. Fukuyama et al Org. Lett. 2015, 17, 828-831).

Embodiment 2

[0045] Embodiment 2, the preparation of compound Ia:

[0046]

[0047] Starting material 1 (9.64g, 15.97mmol, 1.0eq), pyridine (7.7mL, 95.8mmol, 6.0eq) was added to 100mL of dry toluene, and DAST (15.4g, 95.8mmol, 6.0eq) was dissolved in 40mL of dry In toluene, under nitrogen protection, add dropwise to the reaction solution at 0°C, after the dropwise addition is completed, rise to 50°C for reflux reaction for 6h, LC-MS detects that the reaction is complete, stop the reaction, cool down, add dropwise saturated sodium bicarbonate solution at low temperature to quench extinguished, adjusted the pH to 7-8, added EA for extraction, washed the organic phase with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, PE beating, filtered to obtain 7.44g of crude compound 2, which was directly used in the following step. 1 H NMR (400MHz, CDCl 3 )δ8.01(d,J=2.0Hz,1H),7.44–7.28(m,10H),6.53(dd,J=11.4,5.1Hz,1H),5.86(s,2H),5...

Embodiment 3

[0054] The assay material and method of embodiment 3, compound Ia and Ib antiviral activity

[0055] 3.1. Compounds:

[0056] Dissolve compound Ia or Ib in DMSO, store at -20°C, stock 10mg / ml;

[0057] 3.2. HIV-1 virus:

[0058] The plasmid used to package pseudotyped single-cycle infectious HIV-1 (HIV-luc / JRFL) is as follows: pLAI-Δenv-Luc contains the backbone gene sequence of HIV-1, but the env and vpr genes are deleted, and the nef gene locus is inserted Luciferase reporter gene; pJRFL contains the env gene of CCR5 tropism HIV-1; plasmid co-transfection into HEK293T cells. Cell supernatants were collected and aliquoted by filtration. p24 gag capture ELISA for quantification.

[0059] 3.3. HIV-1 infection detection:

[0060] CD4 + T cells (Hut / CCR5) were cultured in complete 1640 medium (Gibco) containing 10% fetal bovine serum (Gibco), 100 U / ml penicillin (Invitrogen) and 100 U / ml streptomycin (Invitrogen) . 1×10 5 Hut / CCR5 cells were added with test compound Ia...

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Abstract

The invention discloses a crystal form, preparation and application of a 4'-substituted nucleoside compound I with the structure shown in the description, as well as salts, prodrugs and composition ofthe compound. An animal pharmacokinetic study result proves that effective drug concentrations of compounds Ia and Ig in HIV (human immunodeficiency virus) target cells and PBMC (peripheral blood monouclear cells) can still effectively inhibit HIV replication after 7 days and 5 days respectively. Therefore, the compound I can serve as a long-acting drug for preventing and treating AIDS (acquiredimmune deficiency syndrome). R is selected from acetenyl, azide and cyanogroup; X is selected from hydrogen and fluorine; B is selected from B1 and B2.

Description

technical field [0001] The invention relates to the crystal form, preparation and application of 4'-substituted nucleosides, and belongs to the field of medicinal chemistry. Background technique [0002] HIV infection causes the onset of AIDS. From the discovery of the first AIDS patient in the United States in 1981, there are currently about 39 million AIDS patients in the world. AIDS has become a major threat to human health. HIV replication is completed through adsorption, invasion and uncoating, reverse transcription, synthesis of integrated viral RNA and protein, assembly, release and maturation. Each of these links can be used as a target for HIV-inhibiting drugs. After more than 30 years of research, including drug combinations, 40 AIDS treatment drugs have been approved by the US FDA for clinical use. According to the mechanism of action of these drugs, they can be mainly divided into several categories: nucleoside and non-nucleoside reverse transcriptase inhibito...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7076A61K31/7068A61P31/18C07H1/00C07H19/173C07H19/073
CPCA61K31/7068A61K31/7076A61P31/18C07H1/00C07H19/073C07H19/173A61P31/12C07H19/04C07H19/16C07H19/06A61K31/7064Y02P20/55A61K38/162A61K31/553A61K31/683A61K31/675A61K31/5383A61K31/505A61K31/513C07B2200/13
Inventor 常俊标杜锦发朱凯凯王凯李建永张春霞
Owner HENAN GENUINE BIOTECH CO LTD
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