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13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs

A kind of berberine, 10-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: 2012-10-24
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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  • 13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs
  • 13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs
  • 13-substituted berberine derivatives and preparation method thereof, and uses of 13-substituted berberine derivatives as anti-tuberculosis drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1: Synthesis of 2,3-methylenedioxy-9,10-dimethoxy-13-n-octyl orthoberberine chloride (Y-191)

[0134] A solution of 5% sodium hydroxide (10 ml) dissolved in sodium borohydride (0.80 g, 21 mmol) was added dropwise to methanol (250 ml) containing berberine (7.43 g, 20 mmol) and potassium carbonate (8.3 g, 60 mmol). ) solution system, stirred at room temperature for two hours, collected the precipitated dark green solid by suction filtration, washed the filter cake several times with water, and recrystallized with 95% ethanol to obtain the intermediate dihydroberberine.

[0135] The intermediate dihydroberberine (5.0g, 15mmol) was dissolved in 80% ethanol (200ml), then 10ml of n-octanal and 50ml of acetic acid were added successively, heated to 85~95°C for reflux for 5 hours, and the reaction solution was reduced Concentrate under reduced pressure to obtain dark red oil, soak in ether for a period of time, filter with suction, collect the ether layer, add 2% hydroc...

Embodiment 2

[0139] Example 2: Synthesis of 2,3-methylenedioxy-9-hydroxyl-10-methoxy-13-n-octyl protoberberine chloride (A-18)

[0140]Put Y-191 (1.2g, 2.48mmol) in a 250ml flask, keep the vacuum at 30-40mmHg, heat to 195-210°C and react for 10-15min. It is found that the color of the solid changes from yellow to deep red quickly. After the reaction was completed, concentrated hydrochloric acid: ethanol (5:95) was acidified for recrystallization, but no solid crystallized out, and evaporated to dryness to obtain 1.14 g of solid, yield: 98%. mp 122-124°C.

[0141] MS-ESI(M / Z): 434.2【M-Cl】 +

[0142] 1 H-NMR (CD 3 OD, δppm): 0.85(t, J=7.2Hz, 3H), 1.23~1.41(m, 10H), 1.82(s, 2H), 3.04(t, J=6.0Hz, 2H), 3.33(t, J =8.4Hz, 2H), 4.03(s, 3H), 4.67((t, J=6.0Hz, 2H), 6.06(s, 2H), 6.96(s, 1H), 7.23(s, 1H), 7.79( d, J=9.2Hz, 1H), 7.96(d, J=9.2Hz, 1H), 9.72(s, 1H); 13 C NMR (DMSO-d6) δ: 148.8, 146.5, 145.2, 144.6, 144.4, 134.8, 133.9, 133.6, 131.6, 124.6, 120.5, 117.2, 115.9, 109.1, 108.3, 102.0, ...

Embodiment 3

[0144] Example 3: Synthesis of 2,3-methylenedioxy-9-ethoxy-10-methoxy-13-n-octyl protoberberine chloride (B-7)

[0145] Dissolve A-18 (200mg, 0.43mmol) in DMF (10ml), add finely ground KOH (78.4mg, 1.4mmol) and bromoethane (37.3μl, 0.5mmol), stir at room temperature for about one day, and concentrate under reduced pressure The solvent was removed, acidified with dilute hydrochloric acid, and finally analyzed and purified by vacuum silica gel column to obtain 82 mg of pure product, yield: 35.7%. mp 86-88°C.

[0146] MS-ESI(M / Z): 462.0【M-Cl】 +

[0147] 1 H-NMR (CD 3 OD, δppm): 0.84(t, J=7.2Hz, 3H), 1.24~1.48(m, 13H), 1.81(t, J=7.6Hz, 2H), 3.06(t, J=6.0Hz, 2H), 3.37(t, J=8.0Hz, 2H), 4.06(s, 3H), 4.43(q, J=6.8Hz, 2H), 4.74(t, J=6.0Hz, 2H), 6.07(s, 2H), 6.98(s, 1H), 7.24(s, 1H), 8.10(d, J=9.2Hz, 2H), 9.67(s, 1H); 13 C NMR (CD 3 OD)δ: 151.8, 151.3, 148.7, 145.3, 145.1, 137.7, 136.3, 135.1, 134.4, 127.0, 123.5, 122.1, 121.8, 110.4, 109.3, 103.7, 71.5, 58.9, 57.5, 32.3, 30.9, ...

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Abstract

The present invention discloses 13-substituted berberine derivatives, a preparation method and uses thereof. The berberine derivatives are compounds represented by a formula I or a pharmaceutically-acceptable salt or a solvate thereof, wherein each symbol is described in the instruction. The present invention further discloses a preparation method for the compounds represented by the formula I, drug compositions containing the compounds, and uses of the drug compositions as anti-infectious disease drugs. The compounds of the present invention have effective antimicrobial effects, and especially have anti-mycobacterium tuberculosis infection effects.

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 berberine derivatives with antibacterial activity and a preparation method thereof, and the use of such compounds as medicines, 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 highest...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/4375A61P31/04A61P31/06
Inventor 宋丹青蒋建东肖春玲刘延新李迎红汪燕翔杨延辉
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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