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Tetracycline compound with amino isonitroso

A compound and carbamoyl technology, applied in the field of tetracycline compounds with aminooxime group, can solve the problems of inconvenient medication, pain for patients, unsatisfactory activity of gram-negative bacteria and the like

Active Publication Date: 2010-06-30
HAINAN SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tigecycline has a broad antibacterial spectrum. It not only has the antibacterial activity of early tetracyclines, but also has antibacterial activity against pathogens resistant to tetracyclines due to the efflux mechanism and ribosome protection mechanism. However, it is not active against some Gram-negative bacteria. not ideal
Moreover, tigecycline can only be infused intravenously, and needs to be administered twice a day, which is inconvenient and brings pain to the patient

Method used

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  • Tetracycline compound with amino isonitroso
  • Tetracycline compound with amino isonitroso
  • Tetracycline compound with amino isonitroso

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1 [S-(4α, 12aα)]-9-[2-(tert-butylamino)-1-hydroxyimino-ethylamino]-4,7-bis(dimethylamino)- 1, 4, 4a, 5, 5a, 6, 11, 12a-eight Preparation of Hydrogen-3,10,12,12a-Tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide (Compound 1)

[0124] Step 1 [S-(4α,12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10 , Preparation of 12,12a-tetrahydroxyl-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride

[0125] Throw 5.3g (0.01mol) [S-(4α,12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11 into the reaction bottle , 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride, dissolved in 70ml of concentrated sulfuric acid, cooled in an ice bath under stirring , and then 1.3 g of sodium nitrate was added, and the mixture was stirred in an ice bath for 1 h. After the reaction was completed, the mixture was added dropwise to 800 ml of ether, and a solid was precipitated, which was washed with a small amount of ether and...

Embodiment 2

[0134] Example 2 [S-(4α, 12aα)]-9-[2-(N, N-dimethylamino)-1-hydroxyimino-ethylamino]-4,7-bis(dimethylamine base)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracenecarboxamide (compound 2) Preparation

[0135] Steps 1 and 2 are the same as in Example 1.

[0136] 3. Preparation method Referring to step 3 in Example 1, inject [S-(4α, 12aα)]-9-[(2-chloroacetyl)amino]-4,7-bis(dimethylamino)-1 , 4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide 2.7g (5mmol), 0.7 g (15 mmol) dimethylamine. [S-(4α, 12aα)]-9-[2-(N,N-dimethylamino)-acetamido]-4,7-bis(dimethylamino)-1,4,4a, 2.2 g of 5, 5a, 6, 11, 12a-octahydro-3, 10, 12, 12a-tetrahydroxy-1, 11-dioxo-2-tetracenecarboxamide, yield: 78.5%.

[0137] 4. Preparation method Referring to step 4 in Example 1, cast [S-(4α, 12aα)]-9-[2-(N,N-dimethylamino)-acetamido]-4,7-bis( Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene Amid...

Embodiment 3

[0141] Example 3 [S-(4α, 12aα)]-9-[2-(N, N-diethylamino)-1-hydroxyimino-ethylamino]-4,7-bis(dimethylamine base)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracenecarboxamide (compound 3) Preparation

[0142] Steps 1 and 2 are the same as in Example 1.

[0143] 3. Preparation method Referring to step 3 in Example 1, inject [S-(4α, 12aα)]-9-[(2-chloroacetyl)amino]-4,7-bis(dimethylamino)-1 , 4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide 2.7g (5mmol), 1.1 g (15 mmol) diethylamine. [S-(4α, 12aα)]-9-[2-(N,N-diethylamino)-acetamido]-4,7-bis(dimethylamino)-1,4,4a, Preparation of 5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracenecarboxamide 2.3g, yield: 79.3%.

[0144] 4. Preparation method Referring to step 4 in Example 1, cast [S-(4α, 12aα)]-9-[2-(N,N-diethylamino)-acetamido]-4,7-bis( Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene Amide...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a tetracycline compound with amino isonitroso as shown in a general formula (I), pharmaceutically acceptable salt, isomer or prodrug thereof. In the general formula, R2a, R2b, R4a, R4b, R5, R7, R8, R9a, R9b, X and n are as defined in the specification. The invention also relates to a preparation method of the compounds, a medicinal composition containing the compounds and an application of the compounds in the preparation of medicine for treating and / or preventing tetracycline-sensitive diseases, especially medicine for infectious diseases.

Description

1. Technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to tetracycline compounds having an aminoxime group, pharmaceutically acceptable salts thereof, isomers thereof or prodrugs thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, And the use of these compounds in the preparation of medicines for treating and / or preventing tetracycline-sensitive diseases, especially infectious diseases. 2. Background technology [0002] In 1948, chlortetraeycline, the first tetracycline drug with high efficiency, broad spectrum and oral activity, was extracted from Streptomyces aureofacients. In the following few years, oxytetracycline and tetracycline were also isolated from Streptomyces fermentation broth. These three antibiotics have similar broad antibacterial spectrum, and have strong antibacterial activity not only against Gram-positive but also Gram-negative bacteria. , ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/14C07D307/66C07D333/36C07D277/38C07D213/75C07D295/195A61K31/65A61P31/04
Inventor 黄振华
Owner HAINAN SIHUAN PHARMA