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Glycinamide alkyl oxanamide tetracycline derivants

An alkyl and amino technology, applied in the field of glycine alkoxyamide tetracycline derivatives, can solve problems such as less than ideal activity of gram-negative bacteria

Inactive Publication Date: 2009-05-13
黄振华 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Tigecycline is a new tetracycline antibiotic approved by the US FDA in 2005. The N-tert-butylglycylamide group is introduced at the 9th position. It has a wide antibacterial spectrum and is resistant to tetracyclines due to the efflux mechanism and ribosome protection mechanism. The pathogenic bacteria of the drug also have antibacterial activity, but the activity against some Gram-negative bacteria is not ideal

Method used

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  • Glycinamide alkyl oxanamide tetracycline derivants
  • Glycinamide alkyl oxanamide tetracycline derivants
  • Glycinamide alkyl oxanamide tetracycline derivants

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1 [4S-(4α, 12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3, 10, 12, 12a- Preparation of Tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

[0093] Throw 26.5g (50mmol) [4S-(4α, 12aα)]]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11 in the reaction bottle, 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthalene carboxamide dihydrochloride, dissolved in 150ml of concentrated sulfuric acid, cooled in an ice bath under stirring, Then 6.8g of sodium nitrate was added, the mixture was stirred in an ice bath for 1h, and the reaction was completed, the mixture was added dropwise to 2000ml of ether, a solid was precipitated, washed with a small amount of ether and dried, the solid was added to 100ml of ethanol, and then 2g of 10 % palladium carbon, stirred at room temperature under 2 MPa hydrogen pressure for 1.5 h, filtered, and concentrated under reduced pressure, and the residue was added with 800 ml of ether under vigorous stirring...

Embodiment 2

[0094] Example 2 [4S-(4α, 12aα)]-9-[(2-(tert-butylamino)-ethoxy)formamide]-4,7-bis(dimethylamine base)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracenecarboxamide

[0095] At 0°C, 4.7g (10mmol) [4S-(4α, 12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide, a mixed solution of 6ml of dimethylacetamide and 50ml of dichloromethane, and then Add 3ml of triethylamine, stir and mix evenly, slowly add 3.2g of 2-(benzyl(tert-butyl)amino)-ethoxycarbonyl chloride / 10ml of dichloromethane solution dropwise, reflux and stir for 2h, evaporate the solvent under reduced pressure Then add 100ml of ethanol to dissolve, add 1g of 10% palladium carbon, stir under 1.5MPa hydrogen pressure at 40°C for 4h, filter, concentrate the filtrate under reduced pressure, dropwise add 100ml of ether in ice bath, precipitate solid, filter and After drying, 4.1 g of the target compound was obtained, ...

Embodiment 3

[0100] Embodiment 3 The preparation of compound freeze-dried powder injection of the present invention

[0101] 1. Prescription:

[0102]

[0103] 2. Preparation process: clean, sterilize, and depyrogenate the vials, rubber stoppers, liquid-dosing containers, instruments and equipment used in production; weigh the raw material compound 1, vitamin C, and mannitol according to the prescription, add water, stir and dissolve , an appropriate amount of hydrochloric acid to adjust the pH, and then add activated carbon for needles with a dosing volume of 0.05%, stir for 15 minutes, filter, and decarbonize; add water for injection to the full amount, and constant volume; Clarity; inspection of semi-finished products; dispensing 2ml of liquid medicine into vials, half-tamped; put the sample in a freeze dryer, and freeze-dry using the following freeze-drying process: -40°C pre-freeze for 4 hours, -40~0°C Low-temperature vacuum drying for 18 hours, heating and drying at 0-30°C for ...

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Abstract

The invention belongs to the technical field of medicine, and in particular relates to a glycine alkane oxanamide tetracycline derivative shown in a general formula (I), as well as a pharmaceutically acceptable salt and an isomer thereof, wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and n are defined in instructions. The invention also relates to a method for preparing the compounds, a pharmaceutical composition containing the compounds, as well as application of the compounds for preparing medicine which treats and / or prevents tetracycline allergic diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to glycine alkoxyamide tetracycline derivatives, pharmaceutically acceptable salts thereof, and isomers thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and these compounds The use in the preparation of medicines for treating tetracycline-sensitive diseases, especially the use in the preparation of medicines for treating infectious diseases. 2. Background technology [0002] Tetracycline antibiotics are a class of broad-spectrum antibiotics produced by the fermentation of the actinomycete Streptomyces. Effective and can be used to treat various infectious diseases. Including aureomycin, oxytetracycline, tetracycline and semi-synthetic tetracycline antibiotics, which have a tetracyclic structure of hydrogenated tetracene. Chlortetracycline is only used for external use due to its high toxicity; oxytetracycline a...

Claims

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Application Information

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IPC IPC(8): C07C271/30C07C237/26A61K31/65A61P31/04
Inventor 黄振华赵红宇
Owner 黄振华
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