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Berberine derivatives, their preparation method, pharmaceutical composition and anti-tumor application

A technology of berberine and its derivatives, which is applied in the field of berberine derivatives, its preparation, pharmaceutical composition and anti-tumor application, and can solve the problems of poor anti-tumor activity and specificity, influence on drugability, low bioavailability, etc. question

Active Publication Date: 2021-04-13
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, the discovered antitumor active berberine compounds still have some deficiencies in their druggability, such as poor antitumor activity and specificity, low bioavailability, etc. The solubility of most natural berberine quaternary ammonium compounds is very poor, which affects their druggability

Method used

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  • Berberine derivatives, their preparation method, pharmaceutical composition and anti-tumor application
  • Berberine derivatives, their preparation method, pharmaceutical composition and anti-tumor application
  • Berberine derivatives, their preparation method, pharmaceutical composition and anti-tumor application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment (1

[0050] The preparation of embodiment (1) compound 1

[0051] Weigh berberine chloride quaternary ammonium salt (20g, 53.84mmol) in reaction flask, add glacial acetic acid (250ml), be placed in ice-water bath, slowly add NaNO 2 (18.6g, 269.57mmol), dropwise into concentrated HNO 3 (30ml), after the dropwise addition was completed, the mixture was stirred in an ice-water bath for another 5 minutes, then heated to reflux at 50° C. for 1 hour, and the reaction was complete. Add water (200ml) to the reaction solution, extract with chloroform / methanol (v / v=10:1), the organic phase obtained is distilled under reduced pressure, removes the organic solvent, and the crude product obtained is subjected to silica gel column chromatography [with chloroform / methanol =20:1 (v / v) is the eluent] purified to obtain 12-nitroberberine chloride, 9.65 g of red solid, yield 43%. 1 H NMR: (400MHz, DMSO-d 6 )δ3.23(t, J=6Hz, 2H, Ar-CH 2 CH 2 N),4.16(s,3H,OCH 3 ),4.28(s,3H,OCH 3 ), 4.96(t, J=6Hz,...

Embodiment

[0052] The preparation of embodiment (2) compound 2

[0053] Weigh 12-aminotetrahydroberberine (250mg, 0.705mmol) in a reaction flask, add dichloromethane (10ml), then add 40% acetaldehyde aqueous solution (313μl, 3.1mmol), triacetoxy borohydrogenation Sodium (747 mg, 3.525 mmol), HOAc (18 drops), stirred at room temperature for 2 h, and the reaction was complete. Add saturated sodium bicarbonate to the reaction solution to adjust the pH to 8, stir at room temperature for 20 min, and then extract with dichloromethane; the dichloromethane extract was washed 3 times with water, once with saturated brine, and dried over anhydrous magnesium sulfate , filtered with suction, and the organic phase was evaporated under reduced pressure, and the crude residue was purified by silica gel column chromatography [with dichloromethane / methanol=80:1 (v / v) as eluent] to obtain compound 2, 277 mg of light brown solid, Yield 96%. 1 H NMR: (400MHz, CDCl 3 )δ0.98(t, J=7.2Hz, 6H, 2×NCH 2 CH 3 ...

Embodiment (7

[0062] The preparation of embodiment (7) compound 7

[0063] Weigh 12-aminotetrahydroberberine (200mg, 0.564mmol) in a reaction flask, add dichloromethane (8ml), then add n-heptanal (189 μl, 1.354mmol), sodium triacetoxyborohydride ( 358mg, 1.692mmol), HOAc (10 drops), the reaction was complete after stirring at room temperature for 2h. Add saturated sodium bicarbonate to the reaction solution to adjust the pH to 8, stir at room temperature for 20 min, and then extract with dichloromethane; the dichloromethane extract was washed 3 times with water, once with saturated brine, and dried over anhydrous magnesium sulfate , suction filtration, the organic phase was evaporated under reduced pressure, and the crude residue was purified by silica gel column chromatography [with dichloromethane / methanol=80:1 (v / v) as eluent] to obtain compound 7, light brown oil 272mg , yield 87.6%. 1 H NMR: (400MHz, CDCl 3 )δ0.85(t, J=6.8Hz, 6H, 2×NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ),1.23(m...

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Abstract

The invention discloses berberine derivatives, their synthesis method and their application in the preparation of products for preventing, alleviating and / or treating tumors. Described berberine derivatives are 12-aminotetrahydroberberine derivatives shown in general formula I or their physiologically acceptable salts and 12-N, N-disubstituted amino tetrahydro berberine derivatives Berberine derivatives or their physiologically acceptable salts and 12-aminoberberine quaternary ammonium salt derivatives or their physiologically acceptable salts and 12-N, N-disubstituted Amino berberine quaternary ammonium derivatives or physiologically acceptable salts thereof. Compared with the raw material berberine chloride quaternary ammonium compounds, the solubility of these berberine derivatives in organic solvents has been significantly improved. The berberine derivatives have inhibitory activity on the growth of tumor cell lines, and the intensity of action may be significantly higher than that of the raw material of berberine quaternary ammonium salt, or equivalent to or higher than that of the positive control drug, and can be used to prepare Products for the prevention, mitigation and / or treatment of tumors.

Description

technical field [0001] The invention aims at improving the solubility of berberine derivatives in organic solvents and enhancing their biological activity, and involves using common berberine quaternary ammonium salt compounds as substrates and adopting structural transformation derivatization reactions in organic chemistry The obtained 12-amino-tetrahydroberberine derivatives or their physiologically acceptable salts, 12-N,N-disubstituted amino-tetrahydroberberine derivatives or their physiologically acceptable salts , 12-amino-berberine quaternary ammonium salt derivatives and 12-N,N-disubstituted amino-berberine quaternary ammonium salt derivatives, their preparation methods and methods for preventing, alleviating and / or treating tumors application in the product. It belongs to the field of medical technology. Background technique [0002] All kinds of malignant tumors (cancer) are major diseases that seriously endanger human health, causing huge physical and mental pai...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/153C07D491/22A61K31/4375A61P35/00
CPCC07D491/153C07D491/22
Inventor 秦海林吴练秋王波张海婧张志辉王文杰邓安珺王楠李志宏李倩李想宋利
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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