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A class of pleuromytilin derivatives, drug composition, synthesis methods and uses thereof

A technology for pleuromutilin and compounds, applied in the fields of pharmacy, drug synthesis and pharmacology, can solve the problem of low activity

Inactive Publication Date: 2014-03-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The currently known pleuromutilin compounds are mainly C14 thioether side chains and carbamate side chains. Although carbamate series have better metabolic stability than thioether series, they are more active than thioether-substituted The derivatives of pleuromutilins currently on the market and in clinical research are all C14 thioether side chains

Method used

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  • A class of pleuromytilin derivatives, drug composition, synthesis methods and uses thereof
  • A class of pleuromytilin derivatives, drug composition, synthesis methods and uses thereof
  • A class of pleuromytilin derivatives, drug composition, synthesis methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1 14-O-[(5-aminomethylpyridine)-3-thioacetyl]-mutriptyline

[0089] (a) Methyl 5-bromonicotinate

[0090]

[0091]Dissolve 5-bromonicotinic acid (3.0g, 15mmol) in anhydrous methanol (20ml), add 98% concentrated sulfuric acid (4ml) dropwise at room temperature, stir for 10min after addition, heat up to reflux for 15h, distill methanol off, add water to dilute , add saturated aqueous sodium bicarbonate solution, adjust the pH to neutral, extract with ethyl acetate, wash with water, dry over anhydrous sodium sulfate, filter, evaporate the solvent, and the residue is subjected to silica gel column chromatography to obtain white flaky crystals (2.6g, 80%).

[0092] 1 H NMR (300MHz, CDCl 3 )δ9.13(s,1H),8.85(s,1H),8.45(s,1H),3.97(s,3H)MS(EI)m / z:216(M+H) + .

[0093] (b) 3-bromo-5-hydroxymethylpyridine

[0094]

[0095] Dissolve 5-bromo-nicotinic acid methyl ester (3g, 13.1mmol) in absolute ethanol (50ml), add sodium borohydride (1.48g, 39.1mmol) in batches ...

Embodiment 2

[0121] Example 2 14-O-[(5-aminopyridine)-3-thioacetyl]-mutriptyline

[0122] (a) 3-bromo-5-(tert-butoxycarbonyl)aminopyridine

[0123]

[0124] Dissolve 5-bromonicotinic acid (2g, 9.9mmol) in dry toluene (20ml), add tert-butanol (20ml), diphenylphosphoryl azide (3.2ml, 14.9mmol), triethylamine (4.1ml , 29.6mmol), under the protection of argon, reacted at 60°C for 40min, then raised the temperature to 100°C, and refluxed for 4h. Cool to room temperature, evaporate the solvent under reduced pressure, add water and ethyl acetate to the residue, shake, separate the ethyl acetate layer, dry over anhydrous sodium sulfate, filter off the desiccant, evaporate ethyl acetate, and Silica gel column chromatography gave the target compound (1.7 g, 63%).

[0125]1 H NMR (300MHz, CDCl 3 )δppm 8.33-8.32 (m, 3H), 6.77 (br, 1H), 1.53 (s, 9H) MS (EI) m / z: 272 (M) + .

[0126] (b) 14-O-[(5-aminopyridine)-3-thioacetyl]-mutriptyline

[0127]

[0128] Using 3-bromo-5-(tert-butoxycarbonyl...

Embodiment 3

[0130] Example 3 14-O-[(5-hydroxypyridine)-3-thioacetyl]-mutriptyline

[0131] (a) 3-bromo-5-(dimethyltert-butylsilyloxy)pyridine

[0132]

[0133] Dissolve 3-bromo-5-hydroxypyridine (150mg, 0.87mmol) in DMF (5ml), add TBDMSCl (170mg, 1.13mmol), imidazole (89mg, 1.31mmol), DMAP (5.2mg, 0.04mmol), Ar Under gas protection, the reaction was stirred at room temperature for 12 h. Dilute with ethyl acetate, add water, shake to separate the liquid, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate to dryness to give a yellow oil (210mg, 84%).

[0134] 1 H NMR (300MHz, CDCl 3 )δ8.29(d,J=2.2Hz,1H),8.14(d,2.3Hz,1H),7.33(t,J=2.1Hz,1H)H),1.00(s,9H),0.25(s, 6H) MS (EI) m / z: 287 (M) + .

[0135] (b) 14-O-[[5-(Dimethyltert-butylsilyloxy)pyridine]-3-thioacetyl]-mutriptyline

[0136]

[0137] Using 3-bromo-5-(dimethyltert-butylsilyloxy)pyridine as raw material, the target compound can be obtained according to steps f and g in Example 1.

[0138] 1 H NMR ...

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Abstract

The present invention relates to a class of pleuromytilin compounds represented by the following general formula (I), pharmaceutically acceptable salts and preparation methods thereof, and compositions comprising the compound represented by the general formula (I) as an active component. The compounds have excellent antibacterial activities and can be adopted as the active substance for infectious disease treatment.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to the fields of drug synthesis and pharmacology. More specifically, the present invention relates to a class of pyridinesulfide pleuromutilin derivatives, their pharmaceutical composition, their synthesis method and their use in the preparation of medicines for treating bacterial infectious diseases. Background technique [0002] Pleuromutilin is a tricyclic diterpenoid isolated from the fermentation broth of Basidiomycetes strains Pleurotus mutilus (Fr.) Sacc. and P. passeckerianus Pil. in 1951. It has moderate in vitro activity and weak in vivo activity. In the 1960s, Arigoni and Birch elucidated the chemical structure and biosynthetic pathway of pleuromutilin. In the 1970s, on the basis of pleuromutilin, Sandoz developed a highly active animal-specific antibiotic, Tiamulin, which is more active against Gram-positive bacteria and mycoplasma than pleuromutilin by 10- 50 times, is recommend...

Claims

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Application Information

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IPC IPC(8): C07D213/70C07D213/73C07D213/84C07D213/85C07D213/80C07D213/803C07D213/76A61K31/44A61P31/04
CPCC07D213/70C07D213/73C07D213/76C07D213/80C07D213/803C07D213/84C07D213/85
Inventor 杨玉社凌晨雨付利强李战
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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