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Pleuromutilin derivatives having alkaline parahelium side chains, and preparation method and application thereof

A technology for pleuromutilin and derivatives, which is applied in the field of pleuromutilin derivatives and their preparation, can solve the problems of unsuitability for systemic and oral administration, low bioavailability, reduced activity and the like, and achieves good in vitro antibacterial properties. Active, easy to popularize and apply, simple structure

Inactive Publication Date: 2017-10-03
SOUTH CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the active center of tiamulin and warnimulin, which are already on the market, has a thioether group, which is a strong hydrophobic group, has low solubility, and has a large ester-water distribution coefficient, which has been metabolized and decomposed in the body. Azamyulin, which was terminated in clinical phase I in the 1960s, was highly toxic due to its irreversible inhibitory effect on liver microsomes, and pleuromutilin containing a thioether side chain would cause in vivo activity due to its strong hydrophobicity. Low, easy to produce first-pass effect, low bioavailability, short half-life, fast metabolism, not suitable for systemic and oral administration
The carboxylate group is usually chosen as the side chain, although the water solubility is greatly improved, but the activity is reduced

Method used

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  • Pleuromutilin derivatives having alkaline parahelium side chains, and preparation method and application thereof
  • Pleuromutilin derivatives having alkaline parahelium side chains, and preparation method and application thereof
  • Pleuromutilin derivatives having alkaline parahelium side chains, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The preparation of embodiment 1 intermediate A

[0060] Take 5.4g (14.27mmol) of pleuromutilin and dissolve it in 30ml of pyridine, cool it in ice to about 0°C, and add 8.6g (45.11mmol) of p-toluenesulfonyl chloride. The reaction was stirred in an ice bath for 3 h, and then 50 ml of ice water was added to quench the reaction. Pour the reaction solution into a separatory funnel, first add 50ml of chloroform to separate layers, remove the water phase, then wash the organic phase twice with 100ml of sulfuric acid solution with a concentration of 2mol / L, and then wash the organic phase twice with 50ml of saturated sodium bicarbonate solution , and finally the organic phase was washed twice with 100 ml of deionized water and dried with anhydrous sodium sulfate. Dry the organic phase by rotary evaporation, add 10ml of isopropanol to the residual solid and heat to dissolve. After cooling, a large amount of white powder is precipitated, filtered under reduced pressure, and the...

Embodiment 2

[0061] The preparation of embodiment 2 intermediate B

[0062] Dissolve 1 g (1.88 mmol) of intermediate A obtained in Example 1 in 35 ml of ethyl acetate, add 0.31 g (2.07 mmol) of anhydrous sodium iodide, and heat and stir at 70°C for 1 h. Pour the reaction solution into a separatory funnel, add 50ml of 15% brine, and then extract with 30ml of chloroform, take the organic phase, repeat three times, dry over anhydrous sodium sulfate, filter the obtained organic phase and rotate to dryness to obtain the mixture after the subsequent reaction solvent Redissolved to obtain intermediate B, such as figure 1 As shown, the yield was 90%.

Embodiment 3

[0063] Example 3 Synthesis of 14-O-(phenylpropyl)aminoacetyl muulin (compound 1)

[0064] Dissolve intermediate B in 5ml of acetonitrile, add 5ml of acetonitrile solution containing amphetamine (2.07mmol) dropwise, then add potassium carbonate powder (4.14mmol), heat and stir at 75±1°C for 4h, pour the reaction solution into a separatory funnel, add 50ml of 15% brine and 30ml of chloroform were added for extraction, and the organic phase was taken, repeated three times, dried over anhydrous sodium sulfate, and filtered to obtain a mixture. The obtained mixed solution was rotary evaporated to dryness, and the mixture was redissolved in dichloromethane, and 1 g of 100-200 mesh silica gel was added to mix thoroughly. After the solvent evaporated, the above-mentioned crude product-silica gel powder mixture was purified by column chromatography (200-300 Mesh silica gel powder is the stationary phase, petroleum ether: ethyl acetate=2:1 is mobile phase), obtains the pure product of p...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses pleuromutilin derivatives having alkaline side chains and a preparation method thereof. The structural formula of the pleuromutilin derivatives having alkaline side chains is shown in Formula (I), wherein R is phenylpropylamine, phenylethylamine, 4-hydroxyl-phenylethylamine, 4-methylphenylethylamine, 2-methylphenylethylamine, 4-(2-aminoethyl)pyridine, di-iso-butylmanice, thiophene-2-ethylamine, octylamine, laurylamine, cetylamine, 2-(mesyl)ethylamine or 2-(methylthio)ethylamine. The derivatives have favorable activity of inhibiting drug-resistant Staphylococcus aureus and mycoplasma, and are especially suitable to serve as a novel antibacterial drug for preventing and treating human or animal infectious diseases caused by methicillin-resistant Staphylococcus aureus or multi-drug resistant bacteria.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a pleuromutilin derivative with a basic side chain and a preparation method and application thereof. Background technique [0002] Kavanagh reported for the first time in 1951 that the substance pleuromutilin isolated from basidiomycetes Pleurotus and P. passeckerianus with antibacterial activity is shown in formula 1: [0003] [0004] The compound has been confirmed by X-crystal diffraction technology to be a compound with a 5-6-8 tricyclic diterpene structure. Studies have shown that it can selectively inhibit the synthesis of prokaryotic proteins, thereby inhibiting the growth of various Gram-positive bacteria and mycoplasma. Growth without affecting the synthesis of eukaryotic proteins, and the specificity of its action site is not easy to produce joint resistance with other antibiotics. With the continuous emergence of drug-resistant bacteria, pleuromu...

Claims

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Application Information

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IPC IPC(8): C07C229/14C07C229/12C07C227/06C07C51/41C07C57/15C07C315/04C07C317/28C07D333/20C07D213/36C07C319/20C07C323/25A61K31/216A61K31/381A61K31/4409A61P31/04
CPCC07C229/14C07C57/15C07C229/12C07C317/28C07C323/25C07D213/36C07D333/20
Inventor 刘雅红曾杰汤有志廖晓萍孙坚
Owner SOUTH CHINA AGRI UNIV
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