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Berberine-based derivative and preparation method thereof, pharmaceutical composition, and antitumor uses of berberine-based derivative and pharmaceutical composition

A technology of berberine and derivatives is applied in the fields of berberine derivatives, their preparation, pharmaceutical compositions and anti-tumor uses, and can solve the problems of poor anti-tumor activity and specificity, affecting druggability, and low bioavailability, etc. question

Active Publication Date: 2017-12-01
INST OF MATERIA MEDICA AN INST OF THE 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-based derivative and preparation method thereof, pharmaceutical composition, and antitumor uses of berberine-based derivative and pharmaceutical composition
  • Berberine-based derivative and preparation method thereof, pharmaceutical composition, and antitumor uses of berberine-based derivative and pharmaceutical composition
  • Berberine-based derivative and preparation method thereof, pharmaceutical composition, and antitumor uses of berberine-based derivative and pharmaceutical composition

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 a berberine-based derivative and a synthesis method thereof, and applications of the berberine-based derivative in preparation of products for prevention, alleviation and / or treatment of tumors, wherein the berberine-based derivative is a 12-aminotetrahydroberberine-based derivative represented by a general formula I or a physiologically acceptable salt thereof, a 12-N,N-disubstituted aminotetrahydroberberine-based derivative or a physiologically acceptable salt thereof, a 12-amino berberine quaternary ammonium salt derivative represented by a general formula II or a physiologically acceptable salt thereof, and a 12-N,N-disubstituted amino baterine quaternary ammonium salt derivative or a physiologically acceptable salt thereof. According to the present invention, the solubility of the berberine-based derivative is significantly improved compared to the raw material chlorinated berberine quaternary ammonium salt compound; and the obtained berberine-based derivative can provide inhibition activity on the growth of tumor cell lines, and can be used for preparing products for prevention, alleviation and / or treatment of tumors, wherein the action intensity of the berberine-based derivative is significantly higher than the berberine quaternary ammonium salt raw material, or is comparable to the positive control drug, or is higher than the positive control. The general formulas I and II are defined in the specification.

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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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 AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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