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New sansanmycins, and their uses as anti-tuberculous medicines

A technology for drugs and uses, applied in the field of uridine peptide antibiotics and their preparation, can solve the problems of no anti-tuberculosis candidates with new structural skeletons, since the mid-1970s, etc.

Inactive Publication Date: 2015-01-28
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the mid-1970s, when the RNA polymerase inhibitor rifampicin was successfully used clinically, no drug specifically for TB treatment has been successfully developed in the past 40 years; no anti-tuberculosis candidate with a new structural skeleton has been seen things appear

Method used

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  • New sansanmycins, and their uses as anti-tuberculous medicines
  • New sansanmycins, and their uses as anti-tuberculous medicines
  • New sansanmycins, and their uses as anti-tuberculous medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Embodiment 1: the synthesis of SSA-1A

[0089] Dissolve 90 mg (0.104 mmol) of 50% SSA in 2 ml of distilled water, add 20 μl of acetic anhydride (0.208 mmol), add 1 mol / L NaOH solution to adjust the pH to about 6, and stir at room temperature for 3 hours. Purified by preparative liquid chromatography to obtain 11.2 mg of white powder, yield 23.73%, ESI (-) 946.4, 1 H NMR (600M HZ, DMSO-d 6 ):δ1.72(3H,S,H N-CO-CH3 ), 2.24(3H,S,H Ar-O-CO-CH3 ), 4.73 (1H,m,H m-Tyr-2 ), 6.92 (1H, S, H m-Tyr-2‘ ), 6.94 (1H, d, J=7.2HZ, H m-Tyr-4‘ ), 6.95 (1H, d, J=7.2HZ, H m-Tyr-6‘ ), 7.01 (1H, t, J=7.2HZ, H m-Tyr-5‘ ). The remaining signals are the same as those of Sansanmycin reported in the literature (Yunying Xie, et al. The Journal of Antibiotics. 2007, 60(2): 158-161). h m-Tyr-2 The chemical shift shifted from δ3.90 to δ4.73 downfield, indicating that the free amino group was acylated; H-2', 4', 6' on m-Tyr all shifted downfield, while 5' shifted upfield The displacement indi...

Embodiment 2

[0090]Embodiment 2: the synthesis of SSA-1B

[0091] Dissolve 90mg (0.104mmol) of 50% SSA in 2ml distilled water, add 40μl acetic anhydride (0.417mmol), add 1mol / L NaOH solution to adjust the pH to about 6, and stir at room temperature for 5 hours. Purified by preparative liquid chromatography to obtain 3.5 mg of white powder, yield 7.09%, ESI (-) 988.4, 1 H NMR (600M HZ, DMSO-d 6 ):δ1.72(3H,S,H N-CO-CH3 ), 1.98 (3H,S,H R-O-CO-CH3 ), 2.24(3H,S,H Ar-O-CO-CH3 ), 4.73 (1H,m,H m-Tyr-2 ), 5.37 (1H,m,H sugar-2 ), 6.95 (1H, S, H m-Tyr-2‘ ), 6.96 (1H, d, J=7.2HZ, H m-Tyr-4‘ ), 6.97 (1H, d, J=7.2HZ, H m-Tyr-6‘ ), 7.03 (1H, t, J=7.2HZ, H m-Tyr-5‘ ). The remaining signals are the same as Sansanmycin. Like SSA-1A, the free amino group and the 3’ phenolic hydroxyl group on m-Tyr can be judged to be acylated by the change of m-Tyr signal; H sugar-2 A downfield shift indicates that the hydroxyl group on sugar-2 is acylated.

Embodiment 3

[0092] Embodiment 3: the synthesis of SSA-2

[0093] Take 50% SSA 90mg (0.104mmol) dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 18ul bromoacetyl bromide (0.208mmol), stir at room temperature for 2 hours. Purified by preparative liquid chromatography to obtain 5.7 mg of white powder, yield 11.11%, ESI (-) 982.3, 984.3, 1H NMR (500M HZ, DMSO-d6): δ4.32 (2H, S, H-Br- CH2), 4.70 (1H,m,Hm-Tyr-2). The remaining signals are the same as Sansanmycin. The chemical shift of Hm-Tyr-2 shifted downfield to δ4.70, indicating that the free amino group was acylated.

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PUM

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Abstract

The invention relates to new sansanmycins, and their uses as anti-tuberculous medicines. The sansanmycins are compounds having a general formula represented by formula I, or their pharmaceutically acceptable salts or solvates, and all symbols in the formula I are shown in the specification. The invention also discloses a preparation method of the compounds of the formula I, medicinal compositions containing the compounds, and uses of the compounds as anti-infective medicines. The compounds have an effective antibacterial effect, and especially have a Mycobacterium tuberculosis infection resisting effect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a new class of compounds that can be used as bacteria inhibitors, in particular to a class of uridine peptide antibiotics with antibacterial activity and a preparation method thereof, and the use of such compounds as drugs, especially as antibacterial Drugs such as anti-tuberculosis drugs. Background technique [0002] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, and its prevalence has reemerged in recent years. my country is one of the 22 countries with a high burden of TB in the world, with a high prevalence rate and a high rate of drug resistance. According to the statistics of the World Health Organization (WHO), about 550 million people in my country are infected with tuberculosis, of which more than 400,000 are drug-resistant patients. It is one of the countries with the largest number of new tuberculosis cases and the highe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/09C07K1/113A61K38/06A61P31/04A61P31/06
Inventor 陈汝贤宋丹青李阳彪解云英许鸿章俞莹
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI