New sansanmycins, and their uses as anti-tuberculous medicines

A kind of drug, halogen technology, applied in the field of medicinal chemistry, can solve the problem of anti-tuberculosis candidates with no new structure skeleton, since the mid-1970s, etc.

Inactive Publication Date: 2012-12-19
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] Example 1: Synthesis of SSA-1A

[0089] Dissolve 90mg (0.104mmol) of 50% SSA in 2ml of distilled water, add 20μl of acetic anhydride (0.208mmol), add 1mol / L NaOH solution to adjust the pH to about 6, and stir at room temperature for 3 hours. Purified by preparative liquid chromatography, a white powder 11.2mg was obtained, the yield was 23.73%, and the ESI(-) was 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 the values ​​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 of m-Tyr shifted from δ3.90 to low-field to δ4.73, indicating that the free amino group was acylated; H-2', 4', and 6'on m-Tyr all shifted to low-field, and 5'to high-field The...

Embodiment 2

[0090] Example 2: Synthesis of SSA-1B

[0091] Dissolve 90mg (0.104mmol) of 50% SSA in 2ml of distilled water, add 40μl of 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, 3.5 mg of white powder was obtained, the yield was 7.09%, and the ESI (-) was 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‘ ). Other signals are the same as Sansanmycin. Like SSA-1A, the change of m-Tyr signal can judge that the free amino group and the 3'phenolic hydroxyl group on m-Tyr are acylated; H sugar-2 The shift to the lower field indicates that the hydroxyl group on sugar-2 is acylated.

Embodiment 3

[0092] Example 3: Synthesis of SSA-2

[0093] Dissolve 90mg (0.104mmol) of 50% SSA in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 18ul bromoacetyl bromide (0.208mmol), and stir at room temperature for 2 hours. Purified by preparative liquid chromatography to obtain white powder 5.7mg, yield 11.11%, ESI (-) is 982.3, 984.3, 1H NMR (500M HZ, DMSO-d6): δ 4.32 (2H, S, H-Br- CH2), 4.70 (1H, m, Hm-Tyr-2). Other signals are the same as Sansanmycin. The chemical shift of Hm-Tyr-2 shifted to δ4.70 to the low field, indicating that the free amino group was acylated.

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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 bacterial 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 medicines, especially as antibacterial The application of drugs such as anti-tuberculosis drugs. Background technique [0002] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, and its prevalence has increased 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 high drug resistance rate. According to statistics from the World Health Organization (WHO), about 550 million people in my country are infected with tuberculosis, among which more than 400,000 are drug-resistant patients. This is one of the countries with the highest number of new tuberculosis ca...

Claims

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Application Information

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Patent Type & Authority Applications(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
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