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Coptisine derivatives, preparation method, pharmaceutical composition and antitumor application thereof

A technology of coptisine and its derivatives, which is applied in the field of coptisine derivatives, its preparation, pharmaceutical composition and anti-tumor application, and can solve the problems of poor anti-tumor activity and specificity, low bioavailability, and high toxicity to human body

Active Publication Date: 2019-10-01
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 anti-tumor active coptisine compounds still have some deficiencies in their druggability, such as poor anti-tumor activity and specificity, low bioavailability, and high toxicity to humans.

Method used

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  • Coptisine derivatives, preparation method, pharmaceutical composition and antitumor application thereof
  • Coptisine derivatives, preparation method, pharmaceutical composition and antitumor application thereof
  • Coptisine derivatives, preparation method, pharmaceutical composition and antitumor application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment (1

[0052] Example (1) Preparation process and structural identification data of compound 1

[0053] Weigh KOH (5N, 200ml) in the reaction flask, add K at room temperature 3 [Fe(CN) 6 ] (46.27g, 140.54mmol), heated to 45°C and stirred to dissolve, added in batches the substrate coptisine chloride quaternary ammonium salt (10g, 28.10mmol), then heated to reflux for 8h, TLC monitored the reaction was complete, suction filtered, washed to neutral. A light yellow crude product was obtained, which was purified by silica gel column chromatography [v / v=100:1 (chloroform / methanol)] to obtain 5.75 g of a yellow solid with a yield of 61%, namely the intermediate 8-dihydrocoptisine oxide; 1 H NMR (DMSO-d 6 ,400MHz)δ 2.85(t,J=6.0Hz,2H,Ar CH 2 CH 2 N), 4.08(t, J=6.0Hz, 2H, ArCH 2 CH 2 N),6.06(s,2H,OCH 2 O),6.18(s,2H,OCH 2 O),6.91(s,1H,Ar- H ),7.11(s,1H,Ar- H ), 7.14 (d, J=8.4Hz, 1H, Ar- H ), 7.33 (d, J=8.4Hz, 1H, Ar- H ),7.46(s,1H,Ar- H ). 13 C NMR (DMSO-d 6 ,150MHz)δ 27.55...

Embodiment

[0054] Example (2) Preparation process and structural identification data of compound 7

[0055] Weigh 8-chlorocoptisine chloride quaternary ammonium salt (200mg, 0.51mmol) in a reaction flask, add toluene (20ml), slowly add methylamine (40.4μl, 1.02mmol) under the protection of argon, and react at room temperature for 2h, TLC monitored the completion of the reaction. Add 5ml of anhydrous diethyl ether, pass through dry HCl gas until no excessive precipitation occurs, filter with suction, add water (30ml) and a small amount of methanol to the filter cake, and use CHCl respectively 3 (50ml) extraction twice; take chloroform solution, extract once with saturated brine, anhydrous MgSO 4 Dry, filter with suction, and evaporate the solvent to dryness under reduced pressure to obtain a light yellow crude product, which is purified by silica gel column chromatography [v / v=20:1 (chloroform / methanol)] to obtain compound 7, a yellow solid of 73.76mg, with a yield of 37.4%; 1 H NMR (DM...

Embodiment (7

[0064] Example (7) preparation process and structural identification data of compound 12

[0065]Weigh 8-chlorocoptisine chloride quaternary ammonium salt (200mg, 0.51mmol) in a reaction flask, add toluene (20ml), slowly add hexylamine (134.7μl, 1.02mmol) under the protection of argon, and react at room temperature for 2h, TLC monitored the completion of the reaction. Add 5ml of anhydrous diethyl ether, pass through dry HCl gas until no excessive precipitation occurs, filter with suction, add water (30ml) and a small amount of methanol to the filter cake, and use CHCl respectively 3 (50ml) extracted twice; take chloroform solution, extract once with saturated brine, anhydrous MgSO 4 dry. Suction filtration and evaporation of the solvent under reduced pressure gave a light yellow crude product, which was purified by silica gel column chromatography [v / v=20:1 (chloroform / methanol)] to obtain 187 mg of compound 12 as a yellow solid with a yield of 80.2%; 1 H NMR (DMSO-d 6 ,40...

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PUM

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Abstract

The invention discloses coptisine derivatives, a synthesis method thereof, and application of the coptisine derivatives to preparation of products for preventing, relieving and / or treating tumor products. The coptisine derivatives are an 8-iminodihydrogen coptisine derivative and a N-dihydrogen coptisine-8-imino derivative which are as shown in a general formula I as well as an 8-N,N-disubstituted amino coptisine quaternary ammonium salt derivative and an 8-N,N-disubstituted amino-13-substituted coptisine quaternary ammonium salt derivative which are as shown in a general formula II. The coptisine derivatives have inhibitory activity on the growth of tumor cell strains, and the effect intensity of the coptisine derivatives is obviously higher than that of coptisine quaternary ammonium salt raw materials or equal to that of a positive control medicine or higher than that of a positive control medicine; part of the compounds does not show remarkable cytotoxicity on IEC-6 enterocyte; the coptisine derivatives can be applied to preparation of the products for preventing, relieving and / or treating tumor.

Description

technical field [0001] The present invention relates to the use of coptisine quaternary ammonium salt alkaloids as substrates to obtain 8-iminodihydrocoptisine derivatives and their physiologically acceptable salts, N-di Coptisine-8-ylidene amine derivatives and their physiologically acceptable salts, 8-N,N-disubstituted aminocoptisine quaternary ammonium derivatives and 8-N,N-disubstituted amino - 13-substituted coptisine quaternary ammonium salt derivatives, their preparation methods and their application in the preparation of products for the prevention, alleviation and / or treatment of tumors. 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 pain and economic pressure to patients and their families. Since there is no particularly effective method for treating cancer, clinically, patients are often forced to combine ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/03C07D491/22A61K31/4375A61P35/00
Inventor 秦海林吴练秋谢猛张海婧张志辉邓安珺李志宏王文杰
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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