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Use of sulfur-containing fused heterotetracyclic azasugar derivatives

A technology of tetracyclic azasaccharides and derivatives, applied in the field of anti-HIV virus drugs, can solve the problems of no relevant reports on biological activity, etc., to alleviate the trouble of drug resistance of HIV virus drug resistance, facilitate large-scale production, Effect of Good HIV Reverse Transcriptase Inhibitory Activity

Inactive Publication Date: 2017-03-01
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of the existing modification sites are concentrated on heterocycles such as pyrrole, pyridine, imidazole, triazole, tetrazole, oxazole (oxazine) containing oxygen atom, and sulfur-containing Atomic thiazolidinones, however, there are no relevant reports on the synthesis and biological activity of polyvalent (more than three) fused azasaccharides

Method used

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  • Use of sulfur-containing fused heterotetracyclic azasugar derivatives
  • Use of sulfur-containing fused heterotetracyclic azasugar derivatives
  • Use of sulfur-containing fused heterotetracyclic azasugar derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of raw material five-membered aza-urethane compound 1a((3aS,4R,6aR)-tert-butyl-2,2-dimethyl-4-formyldihydro-3aH-[1,3]dioxolane[ 4,5-c)pyrrole-5(4H)-carboxylate)

[0041] The preparation method is as follows:

[0042] (1) Synthesis of compound II-b((3aS,6R,6aS)-6-[(R)-2,2-dimethyl-1,3-dioxolane-4-yl]-2,2- Dimethyltetrahydrofuran [3,4-d][1,3]dioxolane-4-ol):

[0043] Add 20g anhydrous D-mannose (compound Ia, 0.11mol, a commercially available product) and 600mL acetone into a 1000mL round-bottom flask, add 14.0mL concentrated sulfuric acid (content 98%) while stirring, and stir at room temperature under the protection of nitrogen About 5h (TLC monitoring reaction), after the reaction is complete, add anhydrous sodium carbonate powder, neutralize the reaction solution to colorless, remove unreacted sodium carbonate by suction, wash the filter cake with a small amount of acetone (20-30mL), and reduce pressure Evaporate the acetone, add 200mL of dichloromethane to dis...

Embodiment 2

[0059] Synthesis of (4R)-tert-butyl 4-[(S)-3-(2-ethoxy-2-oxoethyl)-4-carbonyl-3,4-dihydro-2H-benzo[e] [1,3]thiazin-2-yl]-2,2-dimethyldihydro-3aH-[1,3]dioxazole [4,5-c]pyrrole-5(4H)-carboxylate (Abbreviated as compound 2a) and (4R)-tert-butyl 4-((R)-3-(2-ethoxy-2-oxoethyl)-4-carbonyl-3,4-dihydro-2H- Benzo[e][1,3]thiazin-2-yl]-2,2-dimethyldihydro-3aH-[1,3]dioxazole[4,5-c]pyrrole-5(4H )-Carboxylate (abbreviated as compound 2b)

[0060] The chemical reaction process is as follows:

[0061]

[0062] The specific method is:

[0063] In a 25mL eggplant-shaped flask, add five-membered aza-urethane 1a (127mg, 0.47mmol, 1.2 equivalent), glycine ethyl ester hydrochloride (54mg, 1 equivalent), NaHCO 3 Powder (34mg, 1 equivalent), dissolved in freshly distilled toluene, N 2 After stirring for 30 minutes under protection at 40°C, TLC monitoring showed that the reaction of five-membered aza-urethane 1a was completely added mercaptosalicylic acid (120mg, 2eq), and N,N'-dicyclohexylcarbodiimide (D...

Embodiment 3

[0067] Synthesis of (3aS, 4R, 6aR)-tert-butyl 4-{(S)-3-[(S)-1-ethoxy-1-oxopropyl-2-yl]-4-carbonyl-3, 4-Dihydro-2H-benzo[e][1,3]thiazin-2-yl}-2,2-dimethyldihydro-3aH-[1,3]dioxazole[4,5- c]pyrrole-5(4H)-carboxylate (compound 2c for short) and (3aS,4R,6aR)-tert-butyl 4-{(R)-3-[(S)-1-ethoxy-1 -Oxopropyl-2-yl]-4-carbonyl-3,4-dihydro-2H-benzo[e][1,3]thiazin-2-yl}-2,2-dimethyldi Hydrogen-3aH-[1,3]dioxazole[4,5-c]pyrrole-5(4H)-carboxylate (abbreviated as compound 2d)

[0068] The chemical reaction process is as follows:

[0069]

[0070] The specific method is:

[0071] In a 25mL eggplant-shaped flask, add five-membered aza-urethane 1a (164mg, 0.60mmol) and L-alanine methyl ester hydrochloride (93mg, 1.0 equivalent), NaHCO 3 Powder (1.2 equivalent), dissolved with freshly steamed toluene, N 2 After stirring for 1 hour under protection at 55°C, TLC monitoring showed that the reaction of compound 1a was completely added mercaptosalicylic acid (188mg, 2.0 equivalent), N,N'-dicyclohexylcarbod...

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Abstract

The invention discloses sulfur-containing fused heterotetracyclic azasugar derivatives shown in a general chemical formula I. A preparation method of the sulfur-containing fused heterotetracyclic azasugar derivatives provided by the invention is simple, is easy to operate and is easy to produce in large scale. A test proves that the prepared compound I has strong HIV inhibition activity and can be promoted and used in an anti-HIV virus drug preparation.

Description

[0001] This divisional application is a divisional application for a sulfur-containing fused heterotetracyclic azasaccharide derivative and its preparation method and application submitted by application number: 201510315468.4 and application date: 2015-06-10. Technical field [0002] The invention relates to anti-HIV virus drugs, in particular to the application of sulfur-containing fused heterotetracyclic azasaccharide derivatives. Background technique [0003] AIDS is Acquired Immunodeficiency Syndrome (AIDS), which is caused by the infection of Human Immunodeficiency Virus (HIV). Currently, there are three main types of drugs used to treat AIDS: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Because HIV has a strong ability to rapidly mutate, patients will develop resistance soon after taking a certain anti-HIV virus drug. For this reason, clinicians often combine more than three different anti-HIV drugs. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/542A61P31/18
CPCY02P20/55A61K31/542
Inventor 陈华李小六魏思楠朱墨邵洁张平竹王克让
Owner HEBEI UNIVERSITY