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Pleuromutilin antibiotic derivatives

A compound and prodrug technology, applied in the field of pleuromutilin antibiotic derivatives

Inactive Publication Date: 2014-04-09
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, few studies have found that only the veterinary drug tiamulin (Tiamulin), which is used to treat swine dysentery, porcine epidemic pneumonia and poultry chronic respiratory diseases, has been successfully applied to human skin pustular as an ointment. Retapamulin for dermatitis infections

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0240] The preparation of embodiment 14-O-(p-toluenesulfonylacetyl) tiamulin (intermediate M1)

[0241]

[0242] Tiamulin (SM1, 37.8g, 0.1mol) was dissolved in 60ml of dichloromethane, and triethylamine (15.15g, 0.15mol) was added under nitrogen protection. Stir for 30 minutes, cool down to -15°C, and add dropwise TosCl (13.75 g, 0.12 mol) into a dichloromethane solution. The mixture was stirred for 2 hours, and 1.15 L of water was added slowly. The organic phase was separated, dried, and spin-dried to obtain the product intermediate M1 (44g, 96%).

[0243] With reference to the above preparation method, the following compounds can also be prepared:

[0244]

Embodiment 114

[0245] Example 114-O-(4-Methylmorpholin-2-yl)methylthio)Tiamulin (Compound 1) Preparation

[0246]

[0247] (1) Preparation of 14-O-((N-Boc-4-methylmorpholin-2-yl)methylthio)tiamulin

[0248]

[0249] 22-O-methylsulfonyl tiamulin (3g, 6.369mmol), N-Boc-2-mercaptomethylmorpholine (3.0g, 12.2mmol), NaOH aqueous solution (1N, 1.12g) and triethyl Benzyl ammonium chloride (300mg, 1.4mmol) was dissolved in 100mL MTBE, reacted overnight at 90°C under nitrogen protection, concentrated, added water, extracted with ethyl acetate, dried, concentrated and separated by silica gel column (petroleum ether: ethyl acetate =5:1) 3.0 g of the product was obtained with a yield of 79%.

[0250] (2) Preparation of 14-O-((4-methylmorpholin-2-yl)methylthio)tiamulin trifluoroacetate

[0251]

[0252] Dissolve 14-O-((N-Boc-4-methylmorpholin-2-yl)thio)tiamulin (3.0 g, 5.0 mmol) in 100 mL of DCM, add 20 mL of trifluoroacetic acid, and After reacting for 3 h, it was concentrated to obtain an...

Embodiment 214

[0258] Example 214-O-(1-methyl-4-((2R)-2-amino-3-methylbutyryl)piperazin-2-yl)methylthio)tiamulin (compound 2 ) preparation

[0259]

[0260] (1) 14-O-((N-Boc-1-methyl-4-((2R)-2-amino-3-methylbutyryl)piperazin-2-yl)methylthio)tai Preparation of myocin

[0261]

[0262] 22-O-methylsulfonyl tiamulin (1.0g, 2.2mmol), N-Boc-3-mercaptomethyl-4-methylpiperazine (1.23g, 5mmol), 5mL1N NaOH aqueous solution and triethyl Benzyl ammonium chloride (0.1g, 0.44mmol) was dissolved in 000mL dioxane, reacted overnight at 90°C under nitrogen protection, concentrated, added water, extracted with ethyl acetate, dried, concentrated, and separated by silica gel column (petroleum ether : ethyl acetate=10:1) to obtain product 2g, productive rate 60%.

[0263] (2) 14-O-((1-methyl-4-((2R)-2-amino-3-methylbutyryl)piperazin-2-yl)methylthio)tiamulin tri Preparation of fluoroacetate

[0264]

[0265]14-O-((N-Boc-1-methyl-4-((2R)-2-amino-3-methylbutyryl)piperazin-2-yl)methylthio)Tiamulina T...

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PUM

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Abstract

The present invention relates to pleuromutilin antibiotic derivatives represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R<2>, Q<1>, Q<2>, m and X are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and / or prevention of diseases caused by microorganisms.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and relates to pleuromutilin antibiotic derivatives, pharmaceutically acceptable salts thereof, prodrugs thereof, solvates, deuteriums or stereoisomers thereof, and methods for preparing these compounds, including The pharmaceutical composition and pharmaceutical preparation of these compounds, and the application of these compounds in the preparation of medicines for treating and / or preventing diseases caused by microorganisms. 2. Background technology [0002] Pleuromutilin antibiotics are a kind of diterpene antibiotics, which are composed of five-membered, six-membered and eight-membered rings and three rings fused to form a 5-6-8 tricyclic diterpene structure. Basidiomycete species (basidiomycete species) Pleurotus mutilis (Pleurotus fungus) and P.passeckerianus isolated. [0003] Pleuromutilin antibiotics exhibit antibacterial activity by inhibiting bacterial protein synthesis. Based o...

Claims

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Application Information

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IPC IPC(8): C07D265/30C07D241/04C07D413/06A61K31/5375A61K31/495A61K31/5377A61P31/04A61P31/06A61P17/10
CPCC07D241/04C07D265/30C07D413/06
Inventor 罗浩贤王爱臣
Owner KBP BIOSCIENCES CO LTD
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