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Berberine benzimidazole compound or its pharmaceutically acceptable salt and its preparation method and application

A technology of benzimidazole and berberine, applied in the field of chemistry, can solve problems such as first-pass effect, poor solubility, poor tolerance and efficacy, and achieve the effect of solving drug resistance

Active Publication Date: 2017-01-11
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the disadvantages of such compounds, such as poor solubility, low bioavailability, frequent use of drugs, poor tolerance and efficacy, and first-pass effect, greatly limit their clinical application.

Method used

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  • Berberine benzimidazole compound or its pharmaceutically acceptable salt and its preparation method and application
  • Berberine benzimidazole compound or its pharmaceutically acceptable salt and its preparation method and application
  • Berberine benzimidazole compound or its pharmaceutically acceptable salt and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1, the preparation of compound I-1

[0033]

[0034] In a 50mL round-bottomed flask, add o-phenylenediamine (0.276g, 2.554mmol) and intermediate II (1.000g, 2.838mmol), use DMF-water (10mL) as solvent, stir the reaction at 80°C, thin-layer chromatography After tracking to the end of the reaction, 0.490 g was obtained by cooling, suction filtration, column chromatography and drying, with a yield of 40%.

[0035] Compound I-1: yellow-brown solid; melting point: 242–244°C; 1 H NMR (300MHz, DMSO-d 6 )δ: 12.34(s, 1H), 9.16(s, 1H), 7.63(d, J=7.3Hz, 1H), 7.49(d, J=7.3Hz, 1H), 7.30(s, 1H), 7.21– 7.14(m,2H),6.78(s,1H),6.69(s,1H),5.93(d,J=7.7Hz,2H),4.10(d,J=15.7Hz,1H),3.88(s,3H ),3.54(dd,J=16.5,2.8Hz,1H),3.39(t,J=11.5Hz,2H),3.16–3.11(m,1H),3.02(dd,J=16.4,11.3Hz,1H) , 2.97–2.91 (m, 1H), 2.63 (d, J=15.7Hz, 1H), 2.47 (d, J=11.2Hz, 1H) ppm.

Embodiment 2

[0036] Embodiment 2, the preparation of compound 1-2

[0037]

[0038] In a 50mL round bottom flask, add 4-fluoro-o-phenylenediamine (0.323g, 2.554mmol) and intermediate II (1.000g, 2.838mmol), use DMF-water (10mL) as solvent, and stir the reaction at 80°C, Thin-layer chromatography tracked to the end of the reaction, and then cooled, filtered, separated by column chromatography, and dried to obtain 0.560 g, with a yield of 45%.

[0039] Compound I-2: yellow-brown solid; melting point: 230–232°C; 1 H NMR (300MHz, DMSO-d 6 )δ: 12.52(d, J=17.6Hz, 1H), 9.23(s, 1H), 7.68(s, 0.5H), 7.64(d, J=8.4Hz, 0.5H), 7.50(d, J=8.5 Hz,1H),7.30(s,1H),7.19(dd,J=17.0,8.3Hz,1H),6.79(s,1H),6.69(s,1H),5.93(d,J=9.0Hz,2H ), 4.11(d, J=15.7Hz, 1H), 3.88(s, 3H), 3.52(d, J=16.0Hz, 1H), 3.40(d, J=14.9Hz, 2H), 3.13(s, 1H ), 3.03–2.91 (m, 2H), 2.63 (d, J=15.7Hz, 1H), 2.48 (s, 1H) ppm.

Embodiment 3

[0040] Embodiment 3, the preparation of compound 1-3

[0041]

[0042]In a 50mL round bottom flask, add 4-chloro-o-phenylenediamine (0.384g, 2.554mmol) and intermediate II (1.000g, 2.838mmol), use DMF-water (10mL) as solvent, and stir the reaction at 80°C, Thin-layer chromatography traced to the end of the reaction, and then cooled, filtered, separated by column chromatography, and dried to obtain 0.590 g, with a yield of 48%.

[0043] Compound I-3: yellow-brown solid; melting point: 222–224°C; 1 H NMR (600MHz, DMSO-d 6 )δ: 12.45(d, J=12.6Hz, 1H), 9.18(d, J=11.3Hz, 1H), 7.63(dd, J=8.7, 4.9Hz, 0.5H), 7.47(dd, J=8.6, 4.9Hz, 0.5H), 7.42(dd, J=9.9, 2.1Hz, 0.5H), 7.29(d, J=5.0Hz, 1H), 7.26(dd, J=9.0, 2.3Hz, 0.5H), 7.06 –6.98(m,1H),6.79(s,1H),6.69(s,1H),5.93(d,J=6.9Hz,2H),4.10(d,J=15.7Hz,1H),3.88(s, 3H), 3.51(dd, J=21.4, 8.0Hz, 1H), 3.39(t, J=12.0Hz, 2H), 3.13(dd, J=10.8, 3.0Hz, 1H), 3.04–2.91(m, 2H ), 2.63 (d, J=15.8Hz, 1H), 2.46 (dd, J=11.1, 2.9Hz, 1H) ppm.

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Abstract

The invention discloses berberine benzimidazole compounds represented as a general formula I or pharmaceutically acceptable salts of the berberine benzimidazole compounds, and further discloses preparation methods of the compounds. According to the preparation methods, berberine is taken as a starting material and has demethylation and reduction reaction, 9-demethylation tetrahydroberberine is obtained and reacts with hexamethylenetetramine in a trifluoroacetic acid solution, tetrahydroberberine aldehyde is obtained, tetrahydroberberine aldehyde reacts with multiple kinds of substituent o-phenylenediamine in a DMF (dimethyl formamide)-aqueous solution, and the compounds represented as the general formula I can be prepared. The berberine benzimidazole compounds or the pharmaceutically acceptable salts of the berberine benzimidazole compounds have certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi, and can be used for preparing antibacterial and / or antifungal drugs. R1, R2, R3 and R4 in the general molecular formula are defined in claims.

Description

technical field [0001] The invention belongs to the field of chemistry, and relates to a new class of organic compounds, berberine benzimidazoles or pharmaceutically acceptable salts thereof, and also relates to a preparation method of the compound and its medical application. Background technique [0002] Berberine is a class of quaternary ammonium isoquinoline alkaloids with a fused-ring aromatic hydrocarbon structure. Due to its own fused-ring aromatic hydrocarbon structure and positive and negative ion centers, it is easy to pass static electricity, hydrogen bonds, hydrophobic-hydrophobic, π-π, etc. This kind of non-covalent bond interacts with many enzymes and active sites in microorganisms, so it has a variety of biological activities and also shows potential medical research value. As a traditional natural medicine, berberine has a significant inhibitory effect on gram-positive bacteria and gram-negative bacteria. It is mainly used clinically to treat bacterial gastro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/03A61P31/04A61P31/10
CPCC07D455/03Y02A50/30
Inventor 周成合玛尼·杰克库玛彭莘媚
Owner SOUTHWEST UNIV
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