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Tetracycline compound with amino acid amidine

A compound, aminosulfonyl technology, applied in the field of medicine, can solve the problems of inconvenient medication, patient pain, less than ideal gram-negative bacteria activity, etc.

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 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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  • Tetracycline compound with amino acid amidine
  • Tetracycline compound with amino acid amidine
  • Tetracycline compound with amino acid amidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1 [S-(4α, 12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3, 10,12,12a-Tetrahydroxy Preparation of 1,11-dioxo-2-naphthalenamide dihydrochloride

[0099] 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 into 800 mL of diethyl ether, and a solid precipitated out, which was washed with a small amount of diethyl ether and dried. Add the solid to 20 mL of ethanol, then add 0.4 g of 10% palladium carbon, and stir at room temperature for 1 h under a hydrogen pressure of 2 MPa. After filtration and concentration under reduced pressure, 200 mL of di...

Embodiment 2

[0100] Example 2 [S-(4α, 12aα)]-9-[2-(tert-butylamino)acetamidoyl]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6 , 11, 12a-octahydro - Preparation of 3,10,12,12a-tetrahydroxyl-1,11-dioxo-2-naphthacenecarboxamide (compound 1)

[0101] Add 50mL of 10% HCl-ethanol, 8.5g (42mmol) of 2-(benzyl (tert-butyl)amino) acetonitrile into the reaction flask, stir at room temperature for 0.5h, distill off the solvent under reduced pressure, then add 100mL of ethanol to dissolve , and then slowly add [S-(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-naphthalene carboxamide dihydrochloride 18g (33mmol), reflux and stir for 5h, after the reaction is complete, add 0.4g 10 % palladium carbon, stirred at 45° C. for 2 h under 1 MPa hydrogen pressure. After filtration, the filtrate was concentrated under reduced pressure to 1 / 3 of the original volume, and was added dropwise to 100 mL of diethyl ether containing 6 mL of triethylamine under...

Embodiment 3

[0106] Example 3 [S-(4α, 12aα)]-9-[2-(N,N-dimethylamino)-acetamido]-4,7-bis(dimethylamino)-1,4, 4a, 5, 5a, 6, 11, 12a- Preparation of octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide (Compound 2)

[0107] Add 50mL of 10% HCl-ethanol and 3.4g (40mmol) of 2-(N,N-dimethylamino)acetonitrile into the reaction flask, stir at room temperature for 0.5h, distill off the solvent under reduced pressure, then add 100mL of ethanol to dissolve, Then slowly add [S-(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 dihydrochloride 18g (33mmol), reflux and stir for 5h, after reaction, concentrate the reaction solution under reduced pressure to the original volume 1 / 3 was added dropwise to 100 mL of diethyl ether containing 6 mL of triethylamine under ice-cooling, and a solid was precipitated, filtered and dried to obtain 13.4 g of the target compound, yield: 73.2%.

[0108] Molecular...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a tetracycline compound with amino acid amidine as shown in general formula (I), pharmaceutically acceptable salt or isomer thereof. In the general formula, R2a, R2b, R3, R4a, R4b, R5, R6a, R6b, R7, R8, R9a, R9b, R10, R11, R12 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 anti-infective medicine.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and in particular relates to tetracycline compounds with aminoalkylamidines, pharmaceutically acceptable salts or isomers thereof, methods for preparing these compounds, pharmaceutical compositions containing these compounds, and the preparation of these compounds The treatment and / or prevention of tetracycline-sensitive diseases, especially the application of anti-infective drugs. 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 isolated from Streptomyces aureus in 19...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C257/14C07D307/66C07D333/36C07D277/42C07D213/74C07D213/38C07D205/04C07D295/15A61K31/65A61P31/00A61P31/04
Inventor 黄振华张蕙周广连
Owner HAINAN SIHUAN PHARMA