Piperazinone substituted tetracycline derivatives

A compound, cyclopentyl technology, applied in sensitive fields, can solve problems such as unsatisfactory activity of Gram-negative bacteria, inconvenient medication, and pain of patients

Active Publication Date: 2011-11-09
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 pathogenic bacteria resistant to tetracyclines due to the efflux mechanism and ribosome protection mechanism. However, it has antibacterial activity against some Gram-negative bacteria. Activity is 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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  • Piperazinone substituted tetracycline derivatives
  • Piperazinone substituted tetracycline derivatives
  • Piperazinone substituted tetracycline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] Example 1 [S-(4α, 12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3, Preparation of 10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

[0114] Throw 22.8g (50mmol) [S-(4α,12aα)]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro in the reaction bottle -3,10,12,12a-Tetrahydroxy-1,11-dioxo-2-naphthalene carboxamide dihydrochloride, dissolved in 150ml of concentrated sulfuric acid, stirred and cooled in an ice bath, then added 6.8g sodium nitrate, and the mixture was stirred in an ice bath for 1 h. After the reaction was completed, the mixture was added dropwise to 2000ml of ether, and a solid was precipitated, which was washed with a small amount of ether and dried. Add the solid to 100ml of ethanol, then add 2g of 10% palladium carbon, and stir at room temperature under 2MPa hydrogen pressure for 1.5h. After filtration and concentration under reduced pressure, 800ml of ether was added to the residue under vigorous stirring. Filter a...

Embodiment 2

[0115] Example 2 Preparation of 4-tert-butylmorpholine-2,6-dione

[0116] 1. Preparation of 2,2'-[(tert-butyl)amino]diacetic acid

[0117] Add 4.7g (50mmol) of chloroacetic acid, 40ml of water, 5.6g (100mmol) of KOH, and 1.8g (25mmol) of tert-butylamine to the reaction flask, heat it in a water bath to 70°C, react for 4h and then cool it to room temperature. Neutralize, distill under reduced pressure, filter, adjust the pH value of the filtrate to about 3, and cool to obtain 3.5 g of the product, yield: 75.0%.

[0118] 2, Preparation of 4-tert-butylmorpholine-2,6-dione

[0119] Add 9.5g (50mmol) of 2,2'-[(tert-butyl)amino]diacetic acid and 20ml of acetic anhydride to the reaction flask, heat it in a water bath to 70°C, react for 24h and distill under reduced pressure to obtain 5.3g of the product, yield: 62%.

Embodiment 3

[0120] Example 3 [S-(4α, 12aα)]-9-[N-4-tert-butylpiperazine-2,6-dione-1-yl]-4,7-bis(dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracenecarboxamide (Compound 9) preparation

[0121] Add 100ml of toluene and 8.9g (52mmol) of 4-tert-butylmorpholine-2,6-dione into the dry reaction flask, stir and raise the temperature to above 80°C, slowly add [S-(4α, 12aα)] in batches -9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11 -Dioxo-2-tetracenecarboxamide 14.2g (30mmol), stirred at reflux for 4h. After the reaction is complete, cool to 60°C. Poured into crushed ice with vigorous stirring, a solid precipitated. After filtration, the filter cake was recrystallized with ethanol to obtain 12.7 g of the target compound, yield: 67.8%.

[0122] Molecular formula: C 31 h 39 N 5 o 9 Molecular weight: 625.67 Mass spectrum: (m / e): 626 (M+1)

[0123] Elemental analysis: Theoretical value: C, 59.51%; H, ...

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Abstract

The invention belongs to the technical field of medicament, and particularly relates to piperazinone substituted tetracycline derivatives shown in a general formula (I), and pharmaceutically acceptable salts or isomers thereof, wherein R<1a>, R<1b>, R<2>, R<3a>, R<3b>, R<4>, R<5a>, R<5b>, R<6>, R<7>, R<8>, R<9>, R<10>, R<11>, R<12>, R<13>, X and Y are defined in the specification. The invention also relates to a method for preparing the compounds, medicinal composition containing the compounds, as well as application of the compounds in the preparation of medicaments for treating and / or preventing tetracycline sensitive diseases, particularly in the preparation of medicaments for treating infectious diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to tetracycline derivatives substituted by piperazinone, pharmaceutically acceptable salts or isomers thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and preparation of these compounds Use in medicines for treating and / or preventing tetracycline-sensitive diseases, especially in preparing medicines for treating infectious diseases. 2. Background technology [0002] Tetracycline antibiotics are a class of oral broad-spectrum antibiotics and semi-synthetic derivatives produced by the fermentation of the actinomycete Streptomyces, against Rickettsia, many Gram-positive bacteria and Gram-negative bacteria, lymphogranuloma venereum The pathogen, the inclusion body conjunctivitis pathogen and the psittacosis pathogen have good pharmacological effects. [0003] The first tetracycline antibiotic was aureomycin isolate...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/08C07D487/04C07D471/04C07D403/04C07D403/06A61K31/65A61P31/04
Inventor 黄振华张蕙周岩周广连
Owner HAINAN SIHUAN PHARMA
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