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Guanidinoalkanoylamino substituted tetracycline derivatives

A technology based on alkylamine and sulfonyl groups, applied in the field of medicine, can solve problems such as inconvenient medication, unsatisfactory activity of Gram-negative bacteria, and pain of patients

Active Publication Date: 2010-03-31
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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  • Guanidinoalkanoylamino substituted tetracycline derivatives
  • Guanidinoalkanoylamino substituted tetracycline derivatives
  • Guanidinoalkanoylamino substituted tetracycline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1 [S-(4α, 12aα)]-9-[2-[(N'-tert-butyl)guanidine]acetamido]-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 1) Preparation

[0105] Step 1 [S-(4α,12aα)]-9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10 , 12, 12a-4 Preparation of Hydroxy-1,11-dioxo-2-tetracenecarboxamide

[0106] Throw 11.4g (25mmol) [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-naphthacenecarboxamide dihydrochloride, dissolved in 80ml of concentrated sulfuric acid, stirred and cooled in an ice bath, then added 3.4g Sodium nitrate, and the mixture was stirred in an ice bath for 1 h. After the reaction was complete, the mixture was added dropwise to 1000 ml of ether, and a solid was precipitated, which was washed with a small amount of ether and dried. Add the solid to 50ml of ethanol, then add 1g of 10% pall...

Embodiment 2

[0115] Example 2 [S-(4α, 12aα)]-9-[2-[(N', N'-dimethyl)guanidino]acetamido]-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

[0116] The preparation method refers to Step 3 of Example 1, and puts [S-(4α, 12aα)]-9-[(chloroacetyl)amino]-4,7-bis(dimethylamino)-1,4,4a, 3.1g (5mmol) and 2.3 g (15 mmol) of N',N'-dimethylguanidine hydrochloride was reacted to obtain 2.4 g of the target compound, yield: 81.5%.

[0117] Molecular formula: C 28 h 37 N 7 o 8 Molecular weight: 599.64 Mass spectrum (m / e): 601 (M+1)

[0118] Elemental analysis: measured value: C, 55.84%; H, 6.48%; N, 16.11%;

[0119] Theoretical value: C, 56.08%; H, 6.22%; N, 16.35%;

[0120] 1 H-NMR (600MHz, CDCl 3 ): δ1.43(t, 1H), 1.75(t, 1H), 2.27(s, 1H), 2.31(s, 1H), 2.32(m, 1H), 2.35(t, 1H), 2.43(d, 1H), 2.44(s, 6H), 2.45(s, 6H), 2.66(d, 1H), 2.83(s, 6H), 3.16(d, 1H), 3.58(s, 2H), 5.16(s, 1H ), 5.41(s, 1H)...

Embodiment 3

[0121] Example 3 [S-(4α, 12aα)]-9-[2-[(N', N'-diethyl)guanidine]acetamido]-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

[0122] The preparation method refers to Step 3 of Example 1, and puts [S-(4α, 12aα)]-9-[(chloroacetyl)amino]-4,7-bis(dimethylamino)-1,4,4a, 3.1g (5mmol) and 2.3 g (15 mmol) of N',N'-diethylguanidine hydrochloride was reacted to obtain 2.4 g of the target compound, yield: 76.3%.

[0123] Molecular formula: C 30 h 41 N 7 o 8 Molecular weight: 627.69 Mass spectrum (m / e): 629 (M+1)

[0124] Elemental analysis: measured value: C, 57.12%; H, 6.85%; N, 15.87%;

[0125] Theoretical value: C, 57.40%; H, 6.58%; N, 15.62%;

[0126] 1 H-NMR (600MHz, CDCl 3 ): δ1.02(t, 6H), 1.44(t, 1H), 1.76(t, 1H), 2.28(s, 1H), 2.31(s, 1H), 2.34(m, 1H), 2.36(t, 1H), 2.45(d, 1H), 2.46(s, 6H), 2.60(q, 4H), 2.68(d, 1H), 2.87(s, 6H), 3.15(d, 1H), 3.58(s, 2H ), 5.16(s, 1H), ...

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Abstract

The invention belongs to the technical field of medicament, in particular to guanidinoalkanoylamino substituted tetracycline derivatives shown in a general formula (I), and pharmaceutically acceptablesalts or isomers thereof, wherein R<2>, R<2'>, R<3>, R<4>, R<4'>, R<5>, R<6>, R<6'>, R<7>, R<8>, R<9>, R<9'>, R<9'> and n are defined in the specification. The invention also relates to a method forpreparing 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 sensitivediseases, particularly in the preparation of medicaments for treating infectious diseases.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and in particular relates to tetracycline derivatives substituted by guanidinoalkanoyl amido groups, pharmaceutically acceptable salts and isomers thereof, preparation methods of these compounds, and the preparation of these compounds for the treatment and / or prevention of tetracycline derivatives. Application in drugs for sensitive diseases, especially 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 isolated from Streptomyces aureus in 1948, foll...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/14C07C279/16C07D307/66C07D333/36C07D277/48C07C279/18C07D213/75C07D213/40C07D205/04C07D295/32C07D265/02A61K31/65A61P43/00A61P31/00
Inventor 黄振华张蕙周广连
Owner HAINAN SIHUAN PHARMA
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