Mulin acetate comprising substituted squaric acid, and application thereof

A technology of mullinyl acetate and squarylium, applied in the field of medicine

Active Publication Date: 2013-07-17
BEIJING ABLEPHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of the proven strategies is to re-evaluate previously discovered drugs that have good activity against resistant strains but have not yet been used against humans

Method used

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  • Mulin acetate comprising substituted squaric acid, and application thereof
  • Mulin acetate comprising substituted squaric acid, and application thereof
  • Mulin acetate comprising substituted squaric acid, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: 2-(2-Amino-3,4-dioxocyclobuten-1-yl)thioglycolic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5 , 8-dihydroxy-4,6,9,10-tetramethyl-6-vinyl-3a,9-propane-3aH-cyclopentacyclooctene-1(4H)-one-8-ester is the compound AP-01

[0083] Step 1: 2-(Methanesulfonyloxy)acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxy-4,6,9,10-tetra Preparation of methyl-6-vinyl-3a, 9-propane-3aH-cyclopentene-1(4H)-one-8-ester

[0084] Pleuromutilin (37.8g, 0.1mol) was dissolved in 200ml of dichloromethane, triethylamine (12.1g, 0.12mol) was added, cooled to 0°C in an ice-water bath, 0.1mol of methanesulfonyl chloride was slowly added dropwise, and After the addition, the reaction was kept at 0°C and stirred for 6 hours until the disappearance of raw material-1, and 30 ml of saturated ammonium chloride aqueous solution was added dropwise at 0°C to quench the reaction. The dichloromethane layer was separated by a separatory funnel, the aqueous layer was ext...

Embodiment 2

[0093] Example 2: 2-(2-(2-Amino-2-oxoethylthio)-3,4-dioxocyclobuten-1-yl)thioglycolic acid (3aS, 4R, 5S, 6S, 8R , 9R, 9aR, 10R)-octahydro-5,8-dihydroxy-4,6,9,10-tetramethyl-6-vinyl-3a,9-propane-3aH-cyclopentacyclooctene-1 (4H)-Keto-8-ester is the form compound AP-02

[0094] Step 1: Preparation of 3-(2-amino-2-oxoethylthio)-4-ethoxy-3-cyclobutene-1,2-dione

[0095] Dissolve the diethyl squarylate (1.7g, 0.01mol) obtained in Example 1 in 20 ml of absolute ethanol, add 2-mercaptoacetamide (0.91g, 0.01mol), react at room temperature for 12 hours, and depressurize After concentration, 50 ml of ether was added, stirred, and a white solid was precipitated, filtered under reduced pressure, and dried to obtain 3-(2-amino-2-oxoethylthio)-4-ethoxy-3-cyclobutene-1, 2-Diketone (1.65 g, 77%). 1 H NMR (400MHz, CDCl 3 )δ8.83(br.s, 2H), 4.10(q, 2H), 3.85(s, 2H), 1.21(t, 3H); LC-MS m / z=215[M+H] + .

[0096] Step 2: 2-(2-(2-Amino-2-oxoethylthio)-3,4-dioxocyclobuten-1-yl)thioglycolic a...

Embodiment 3

[0098] Example 3: 2-(2-(piperazin-1-yl)-3,4-dioxocyclobuten-1-yl)thioglycolic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxy-4,6,9,10-tetramethyl-6-vinyl-3a,9-propane-3aH-cyclopentacyclooctene-1(4H)-one -8-ester is the form compound AP-05

[0099] Step 1: Preparation of 3-(piperazin-1-yl)-4-ethoxy-3-cyclobutene-1,2-dione

[0100]Dissolve the diethyl squarylate (1.7 g, 0.01 mol) obtained in Example 1 in 30 ml of absolute ethanol, add piperazine (0.86 g, 0.01 mol), heat to reflux for 12 hours, and concentrate under reduced pressure Add 50 milliliters of ether, stir, precipitate white solid, filter under reduced pressure, obtain 3-(piperazin-1-yl)-4-ethoxyl-3-cyclobutene-1,2-dione (1.49g , 71%). 1 H NMR (400MHz, CDCl 3 )δ4.06(q, 2H), 2.32(t, 4H), 2.18(t, 4H), 1.96(br.s, 1H), 1.21(t, 3H); LC-MSm / z=211[M+ H] + .

[0101] Step 2: 2-(2-(Piperazin-1-yl)-3,4-dioxocyclobuten-1-yl)thioglycolic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R )-octahydro-5,8-dihydroxy...

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Abstract

The invention relates to mulin acetate comprising substituted squaric acid, and an application thereof. The invention belongs to the field of chemical medicine. A mulin acetate compound comprising substituted squaric acid, a pharmaceutically acceptable salt thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a prodrug of salt thereof have a structural general formula represented by the formula (I). The MIC values of the compound against staphylococcus aureus and strepococcus equi are higher by 20-30 times than the antibacterial effect of a reference product of tiamulin in market. The mulin acetate comprising substituted squaric acid is a high-efficiency antibacterial medicine.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to muulin acetate substituted for squarylium, its pharmaceutically acceptable salt, its hydrate, and its isomer. The present invention also relates to the preparation method of these compounds, the pharmaceutical composition containing these compounds, and the application of these compounds in the preparation of therapeutic / or preventive antibacterial and antiviral drugs. Background technique [0002] Since the discovery of penicillin, human beings have been studying antibiotics for nearly a hundred years. During this period, research on new antibacterial drugs mainly focused on drugs such as β-lactams, macrolides and quinolones. The discovery of antibacterial drugs has greatly improved the healthy living standards of human beings, but the ensuing abuse of antibiotics has led to the emergence of drug resistance. It was not until the 1990s that the development and expansion of drug ...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C323/60C07D295/116C07D211/54C07C225/20C07C323/22C07C323/25C07C229/16C07F9/38A61K31/215A61K31/495A61K31/54A61K31/451A61K31/662A61P31/04A61P31/12C07C319/14C07C221/00C07C319/20C07C227/18
Inventor 陈剑
Owner BEIJING ABLEPHARMTECH CO LTD
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