Novel pleuromutilin derivate, preparation method and medical use thereof

A technology of pleuromutilin and derivatives, which is used in pharmaceutical formulations, antibacterial drugs, drug combinations, etc.

Active Publication Date: 2011-11-02
南通药享科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Referring to the structure-activity relationship and the latest research progress of pleuromutilin derivatives, we analyzed the structural characteristics of typical anti-drug-resistant bacteria drugs, and designed thiazole pleuromutilin derivatives to o

Method used

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  • Novel pleuromutilin derivate, preparation method and medical use thereof
  • Novel pleuromutilin derivate, preparation method and medical use thereof
  • Novel pleuromutilin derivate, preparation method and medical use thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0092] 14-Deoxy-[(2-(p-toluenesulfonyloxy)acetoxy]-mutriptyline (2) Preparation

[0093] Dissolve 20 g (52.9 mmol) of pleuromutilin in 160 mL of 1,2-dichloroethane, and then add 12 mL (86.6 mmol) of triethylamine to obtain a yellow clear liquid. Add 14 g (73.7 mmol) of p-toluenesulfonyl chloride and react at room temperature (20°C). As the reaction progresses, the solution gradually turns yellow and turbid. After 17 h, the reaction was complete. After stopping the stirring, let it stand still, remove the solid by filtration, wash the filtrate twice with water until pH = 7, and dry it with anhydrous sodium sulfate. The solution was vortexed until dry, and a large amount of white matter was produced. The resulting solid was recrystallized from ethyl acetate, and filtered with suction to obtain 14.2 g of a white solid. Yield: 50.4% Melting point 141-144°C.

[0094] Preparation of deoxy-(2-iodoacetoxy)-mutriptyline (3)

[0095] Dissolve 1.08 g (6.54 mmol) of potassium iodid...

Embodiment 2

[0104] 14-Deoxy-[2-[2-[2-(piperidinyl)acetamido]-thiazole-4-methylthio]acetoxy]-mutriptyline (II 2 ) preparation

[0105] Refer to I I 1 The preparation method, by ( 5 ) reacted with hexahydropyridine, a white foamy solid with a yield of 65%. 1 HNMR (CDCl 3, 400 MHz): δ 10.42 (1H, br, NH), 6.79 (1H, s, H25), 6.51 ( 1H, dd, J 1 =10.8, J 2=17.2, H19), 5.79 (1H, d, J =8.4, C14), 5.39 (1H, d, J =10.8, C20), 5.24 (1H, d, J =17.6, C20), 3.83 (2H, s, H23), 3.38 (1H, m, H11), 3.18 (2H, s, H22), 3.06 (2H, s, H28), 2.52 (4H, br, 2× NCH 2 ), 2.39~2.05 (5H, m, H2, H4, H10, H13), 1.80~1.19 (20H, m, H1, H6, H7, H8, H15, H13,11-OH, H18, 3×CH 2 ), 0.89 (3H, d, J =6.8, H17), 0.75 (3H, d, J =6.8, H16); 13 CNMR (CDCl 3, 400 MHz): δ 217.10 (C3), 168.64 (C21), 157.83 (C27), 146.17 (C26), 139.08 (C24), 117.30 (C19), 111.32 (C20), 107.03 (C25), 74.61 (C11), 69.19 (C14), 61.89 (CH 2 NCH 2 ), 58.17 (C4), 56.68 (C28), 45.44 (C22), 45.38 (C9), 43.89 (C13), 41.72 (C12), 36.78 ...

Embodiment 3

[0107] 14-Deoxy-[2-[2-[2-(morpholinyl)acetamido]-thiazole-4-methylthio]acetoxy]-mutriptyline (II 3 ）

[0108] Refer to I I 1 The preparation method, by ( 5 ) reacted with morpholine, white foamy solid, yield 61%. 1 HNMR (CDCl 3, 400 MHz): δ 7.27 (CHCl 3 ), 6.81 (1H, s, H25), 6.50 (1H, dd, J 1 =11.2, J 2 =17.6, H19), 5.79 (1H, d, J =8.4, H14), 5.38 (1H, d, J =11.2, H20), 5.24 (1H, d, J =17.6, H20), 3.83 (2H, s, H23), 3.79 (4H, t, C H 2 OC H 2 , 3.38 (1H, m, H11), 3.27 (2H, s, H22), 3.05 (2H, s, H28), 2.64 (4H, br, CH 2 NCH 2 ), 2.39~2.05 (5H, m, H2, H4, H10, H13), 1.80~1.14 (16H, m, H1, H6, H7, H8, H15, H13, 11-OH, H18), 0.89 (3H, d, J =7.2, H17), 0.75 (3H, d, J =6.8, H16); 13 CNMR (CDCl 3, 400 MHz): δ 217.06 (C3), 168.61 (C21), 157.68 (C27), 146.27 (C26), 139.13 (C24), 117.25 (C19), 111.46 (C20), 107.04 (C25), 74.62 (C11), 69.28 (C14), 61.00 (CH 2 OCH 2 ), 59.18 (C4), 57.63 (C28), 53.52 (CH 2 NCH 2 ), 45.46 (C22), 44.84 (C9), 43.92 (C13), 41.7...

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Abstract

The invention discloses a pleuromutilin derivate, a preparation method and medical use thereof. The pleuromutilin derivate is a compound, which is obtained by coupling pleuromutilin to alkyl acylamino-thiazole-4-methyl merecaptan with 2-different substitutional amino. Pharmacological experimental results show that: compared with the pleuromutilin, the pleuromutilin derivate disclosed by the invention has better antimicrobial and antibiotic resistant bacteria activities; and therefore, the compound is possibly applicable for curing a plurality of infection and inflammatory diseases on clinic.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a class of pleuromutilin derivatives and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their pharmaceutical applications, especially in the preparation of antibacterial and applications in anti-drug-resistant bacteria. [0002] Background technique [0003] Pleuromutilin is a broad-spectrum diterpene antibiotic produced by submerged cultures of the higher fungi Basidiomycetes Pleurotus mutilus and Pleurotas passeck-rianus, mainly active against Gram-positive bacteria and mycoplasma . In 1951, Kavanagh et al first discovered, defined and isolated this crystalline antibacterial substance, and named it Pleuromutilin (Compound 1). [0004] In 1974, on the basis of pleuromutilin, the Sandoz Institute obtained a highly active animal-specific antibiotic tiamulin (compound 2, Tiamulin) through semi-syn...

Claims

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Application Information

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IPC IPC(8): C07D277/46C07D277/40C07D417/12A61K31/5377A61K31/496A61K31/4439A61K31/427A61K31/426A61P31/04A61P11/00A61P1/00A61P13/02A61P15/00A61P17/00A61P25/00A61P19/08
Inventor 王新杨凌勇张丽颖高琦汪东庚陈广通赵育仇文倩陶金华赵喜
Owner 南通药享科技有限公司
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