Pleuromulin derivative with acyl piperazine side chain and preparing method and application of pleuromulin derivative

A technology of pleuromutilin and piperazine group, which is applied in the field of pleuromutilin derivatives and their preparation, and can solve the problems of rare bacteria resistant to pleuromutilin antibacterial drugs and the like

Active Publication Date: 2017-05-24
SOUTH CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Due to the unique mechanism of action of pleuromutilin antibiotics, there will be no cross-resistance between this type of drug and other drugs, so drug-resistant bacteria against pleuromutilin antibiotics are still rare

Method used

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  • Pleuromulin derivative with acyl piperazine side chain and preparing method and application of pleuromulin derivative
  • Pleuromulin derivative with acyl piperazine side chain and preparing method and application of pleuromulin derivative
  • Pleuromulin derivative with acyl piperazine side chain and preparing method and application of pleuromulin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Synthesis of 14-O-1-(4-(2-N-methylpiperazinylacetyl)) piperazinyl muulin (compound 1a)

[0084] 1g (1.91mmol) of intermediate III was dissolved in 10mL of acetonitrile, 0.53g (3.82mmol) of potassium carbonate and 0.233mL (2.1mmol) of 1-methylpiperazine were added, and heated and stirred at 70°C for 3h to obtain the target product. 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 crude product-silica gel powder mixture was purified by column chromatography (200-300 The mesh silica gel powder is the stationary phase, and ethyl acetate:methanol=20:1 is the mobile phase), to obtain the product 14-O-1-(4-(2-N-methylpiperazinylacetyl))piperazinyl The pure product of Lin (compound 1a). Yield 40.78%. HR-MS(ESI): Calcd.for C 33 h 55 N 4 o 5 (M+H + ):587.4167; Found: 665.41803.

Embodiment 2

[0085] Example 2: Synthesis of 14-O-1-(4-(2-methylphenylpiperazinylacetyl)) piperazinyl muulin (compound 2a)

[0086] 1g (1.91mmol) of intermediate III was dissolved in 10mL of acetonitrile, 0.53g (3.82mmol) of potassium carbonate and 0.37g (2.1mmol) of 2-methylphenylpiperazine were added, and heated and stirred at 70°C for 3h to obtain the target product. 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 crude product-silica gel powder mixture was purified by column chromatography (200-300 Mesh silica gel powder is stationary phase, and ethyl acetate:methanol=20:1 is mobile phase), obtains product 14-O-1-(4-(2-methylphenylpiperazinylacetyl))piperazinyl The pure product of Lin (compound 2a). Yield 46.74%. HR-MS(ESI): Calcd.for C 39 h 59 N 4 o 5 (M+H + ): 663.4480; Found: 663.4485.

Embodiment 3

[0087] Example 3: Synthesis of 14-O-1-(4-(3-methylphenylpiperazinylacetyl)) piperazinyl muulin (compound 3a)

[0088] 1g (1.91mmol) of intermediate III was dissolved in 10mL of acetonitrile, 0.53g (3.82mmol) of potassium carbonate and 0.36mL (2.1mmol) of 3-methylphenylpiperazine were added, and heated and stirred at 70°C for 3h to obtain the target product. 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 crude product-silica gel powder mixture was purified by column chromatography (200-300 Mesh silica gel powder is stationary phase, and ethyl acetate:methanol=20:1 is mobile phase), obtains product 14-O-1-(4-(3-methylphenylpiperazinylacetyl))piperazinyl The pure product of Lin (compound 3a). Yield 60.56%. HR-MS(ESI): Calcd.for C 39 h 59 N 4 o 5 (M+H + ): 663.4480; Found: 663.4470.

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses a pleuromulin-like compound and with an acyl piperazine side chain and a preparing method and application of the pleuromulin-like compound. The pleuromulin derivative is a compound and an officinal salt of which the structure can be shown in the formula 3, formula 4 or formula 5, wherein R1, R2, and R3 are independently chosen from one of hydrogen atom, hydroxide radical, amidogen, sulfydryl, hydroxymethyl, amine methyl, nitro, halogen, trihalogenated methyl, methyl, natural amino acid acylamino, and alkoxy of which the number of carbon atoms is 1-6. The pleuromulin-like compound and with the acyl piperazine side chain has good property of inhibiting staphylococcus aureus and mycoplasma activities, and is particularly suitable for being used as a novel anti-microbial agent to prevent infectious diseases of human or animal caused by infection of mycoplasma or multidrug resistant microorganisms.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a pleuromutilin derivative with an acylpiperazinyl side chain, a preparation method and application thereof. Background technique [0002] Pleuromutilin (Formula 1) is a compound with a 5-6-8 tricyclic diterpene structure produced by higher fungi Pleurotusmutiliz (Fr.) Sacc. and Pleurotus Passeckeranius Pilat, which only selectively inhibit prokaryotic cells The synthesis of protein has no effect on eukaryotic cells, nor does it interact with mammalian ribosomes, and it is not easy to produce combined resistance with other antibiotics. Since its discovery, researchers have obtained tens of thousands of pleuromutilin derivatives through structural modification of pleuromutilin, among which other pleuromutilin substituted at the hydroxyl group have been developed, and many of them have high antibacterial activity , less toxic alternatives such as antimicrobials. Up ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185C07D295/192C07D295/15A61K31/495A61K31/496A61P31/04
Inventor 汤有志高美玲刘雅红
Owner SOUTH CHINA AGRI UNIV
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