Pleuromutilin antibiotics

A technology of alkyl and compound, applied in anti-inflammatory agent, antibacterial drug, sulfide preparation, etc.

Active 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

[0279] The preparation of embodiment 14-O-(p-toluenesulfonylacetyl) tiamulin (intermediate M1)

[0280]

[0281] 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%).

[0282] With reference to the above preparation method, the following compounds can also be prepared:

[0283]

Embodiment 1

[0284] The preparation of embodiment 1 compound 1

[0285]

[0286] (1) Preparation of intermediate 664602

[0287]

[0288] Dissolve SM2 (10.9g, 0.1mol) in 200mL MeOH, stir and react at -10°C for 30mins, then add TEA (30.3g, 0.3mol). After reacting for 2h, add (Boc) 2 O (21.8 g, 0.1 mol). The reaction was stirred overnight at -10°C. After completion of the reaction, concentrate in vacuo. Add water and DCM (200ml), stir for 10min. Separate the organic phase, wash with saturated brine, anhydrous Na 2 SO 4 Dry, filter, and concentrate to give crude intermediate 664602 (17 g, 98%).

[0289] (2) Preparation of intermediate 664603

[0290]

[0291] A solution of oxalyl chloride (6.36mmol) in DCM (25ml) was cooled to -78°C, and DMSO (12.7mmol), intermediate 664602 (1g, 5.78mmol) and TEA (3.25ml) were added sequentially. After rising to room temperature, stir the reaction for 15h. Dilute with water, stir and separate the layers, separate the organic phase, wash twice...

Embodiment 2

[0321] The preparation of embodiment 2 compound 2

[0322]

[0323] With reference to the method of Example 1, the synthetic route is as follows:

[0324]

[0325] The preparation of compound 2 was 0.8g, and the yield was 60%.

[0326] Mass Spectrum (m / e): 518(M+H) +

[0327] 1 H NMR (400MHz, MeOD, δ ppm )δ:6.34(m,1H),5.75(m,1H),5.15-5.19(m,2H),4.66(m,1H),4.43(m,1H),4.06-4.22(m,1H),3.84 -4.01(m,2H),3.78(m,1H),3.51(m,1H),3.33(m,3H),2.07-2.42(m,6H),1.83(m,1H),1.53-1.75(m ,3H),1.45(s,4H),1.34(m,3H),1.17(m,4H),1.07(m,6H),0.95(m,3H),0.73(m,3H).

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Abstract

The present invention relates to pleuromutilin antibiotics represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R<1>, R<2>, R<2a>, R<2b>, m, X and Y 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 antibiotics containing spirocycles, pharmaceutically acceptable salts thereof, prodrugs thereof, solvates, deuterated substances or stereoisomers thereof, and methods for preparing these compounds , pharmaceutical compositions and pharmaceutical preparations containing 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 protei...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/04C07C323/52C07C319/14C07D333/24C07D277/40A61K31/397A61K31/215A61K31/381A61K31/426A61P11/00A61P17/00A61P31/04A61P29/00
CPCC07C323/52C07D205/04C07D277/40C07D333/24
Inventor 张蕙孙亮
Owner KBP BIOSCIENCES CO LTD
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