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Guanidyl substitutional tetracycline derivative

An alkyl and amino technology, which is used in the field of anti-infective drugs, preparation, treatment and/or prevention of tetracycline-sensitive diseases, and can solve problems such as unsatisfactory activity of Gram-negative bacteria, pain of patients, inconvenient medication, etc.

Inactive Publication Date: 2010-06-30
SHANDONG XUANZHU PHARMA TECH CO LTD
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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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  • Guanidyl substitutional tetracycline derivative
  • Guanidyl substitutional tetracycline derivative
  • Guanidyl substitutional tetracycline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1 [S-(4α, 12aα)]-9-[N'-tert-butylguanidino]methyl-4,7-bis(dimethylamino)-1,4,4a,5,5a, 6, 11, 12a-octahydro -3,10,12,12a-tetrahydroxyl-1,11-dioxo 2-naphthacene carboxamide (compound 1) preparation

[0100] Step 1 [S-(4α,12aα)]-9-aminomethyl-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

[0101] Put [S-(4α,12aα)]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10 into the reaction flask, 12,12a-Tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide 4.6g (10mmol), add 100ml of trifluoroacetic acid, stir to dissolve, then add 3.6g (20mmol) hydroxymethyl-benzyl carbamate ester (HMBC), stirred at room temperature for 2 d, after the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove trifluoroacetic acid. Can be purified by preparative HPLC. 2.0 g of solid compound was obtained, yield: 41%.

[010...

Embodiment 2

[0108] Example 2 [S-(4α, 12aα)]-9-[N'-(N,N-dimethyl)guanidino]methyl-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)

[0109] Referring to Step 2 of Example 1, cast [S-(4α, 12aα)]-9-aminomethyl-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide 12.2g (25mmol), N,N-dimethylcyanamide 3.5g (50mmol ). 6.9 g of the target compound was obtained, yield: 50.0%.

[0110] Molecular formula: C 27 h 36 N 6 o 7 Molecular weight: 556.61 Mass spectrum (m / e): 557 (M+1)

[0111] Elemental analysis: theoretical value: C, 58.26%; H, 6.52%; N, 15.10%

[0112] Found: C, 58.15%; H, 6.65%; N, 15.01%

[0113] 1 H-NMR (600MHz, CDCl 3 ): δ1.45(t, 1H), 1.77(t, 1H), 2.12(s, 1H), 2.28(s, 1H), 2.32(t, 1H), 2.34(s, 6H), 2.38(m, 1H), 2.45(s, 6H), 2.48(d, 1H), 2.71(d, 1H), 2.83(s, 6H), 3.27(d, 1H), 4.03(s, 2H), 5.14(s...

Embodiment 3

[0114] Example 3 [S-(4α, 12aα)]-9-[N'-(N,N-diethyl)guanidino]methyl-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 3)

[0115] Referring to Step 2 of Example 1, cast [S-(4α, 12aα)]-9-aminomethyl-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracenecarboxamide 12.2g (25mmol), N,N-diethylcyanamide 4.9g (50mmol ). 7.4 g of the target compound was obtained, yield: 50.5%.

[0116] Molecular formula: C 29 h 40 N 6 o 7 Molecular weight: 584.66 Mass spectrum (m / e): 585 (M+1)

[0117] Elemental analysis: theoretical value: C, 59.57%; H, 6.90%; N, 14.37%

[0118] Found: C, 59.47%; H, 7.00%; N, 14.25%

[0119] 1 H-NMR (600MHz, CDCl 3 ): δ1.03(t, 6H), 1.46(t, 1H), 1.75(t, 1H), 2.08(s, 1H), 2.26(s, 1H), 2.29(s, 6H), 2.31(t, 1H), 2.36(m, 1H), 2.46(d, 1H), 2.57(q, 4H), 2.70(d, 1H), 2.83(s, 6H), 3.25(d, 1H), 4.02(s, ...

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Abstract

The invention belongs to the field of medical technology, in particular to a guanidyl substitutional tetracycline derivative shown by a general formula (I), wherein R2, R2', R3, R4, R4', R5, R6, R6', R7, R8, R9, r9', R10, R11 and R12 are defined in an instruction book; the invention further relates to a preparation method of compounds, and medicine composites containing the compounds and the application of the compounds to treating and / or preventing tetracyclines sensitive diseases, particular for the application of anti-infective drugs.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and in particular relates to tetracycline derivatives substituted by guanidinium groups, pharmaceutically acceptable salts and isomers thereof, preparation methods of these compounds, and the use of these compounds in the preparation of tetracyclines for the treatment and / or prevention of Sensitive diseases, especially the use 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 1948, followed by the development...

Claims

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Application Information

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IPC IPC(8): C07C279/14C07D307/66C07D333/36C07D277/48C07C279/18C07D213/75C07D213/40C07C279/16C07D205/04C07D295/215A61K31/65A61P31/00A61P31/04
Inventor 黄振华张蕙周岩周广连
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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