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C-2 substituted Aldisin derivative and medicinal salt thereof, their pharmaceutical composition, and application in preparation of antitumor drug thereof

A derivative, C-2 technology, applied in the direction of drug combination, antineoplastic drugs, active ingredients of heterocyclic compounds, etc., can solve the problems of poor stability and high cytotoxicity, and achieve the effect of low cost and easy operation

Active Publication Date: 2011-12-14
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Since these compounds are all extracted from sponges, the amount is small, the stability is poor and the cytotoxicity is high, and there is no report on the C-2 substituted Aldisin derivatives as antitumor drugs. Oncology drugs have important application prospects

Method used

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  • C-2 substituted Aldisin derivative and medicinal salt thereof, their pharmaceutical composition, and application in preparation of antitumor drug thereof
  • C-2 substituted Aldisin derivative and medicinal salt thereof, their pharmaceutical composition, and application in preparation of antitumor drug thereof
  • C-2 substituted Aldisin derivative and medicinal salt thereof, their pharmaceutical composition, and application in preparation of antitumor drug thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0066] Preparation Example 1: Synthesis of 2-(4-bromobenzyl)-6,7-dihydropyrrole[2,3-c]azepine-4,8(1H,5H)-dione (Compound 5)

[0067] Pyrrole (100mmol, 6.7g), [bmim] + [BF 4 ] (20mL), K 2 CO 3 (16mmol, 2.208g) was added to 12mL of dry acetonitrile to obtain a mixed solution I, and p-bromobenzyl bromide (10mmol, 5.0g) was mixed with 25mL of dry acetonitrile to form II, and II was slowly added dropwise to I under reflux at 80°C , and vigorously stirred for 6.5h. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, extracted with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and filtered to remove Na 2 SO 4 , and the solvent was removed by rotary evaporation under reduced pressure, and the crude product was separated and purified by flash column chromatography (petroleum ether, then petroleum ether: ethyl acetate=20:1) to obtain light yellow oily liqui...

preparation Embodiment 2

[0073] Preparation Example 2: Synthesis of 2-(biphenyl-4-methylene)-6,7-dihydropyrrole[2,3-c]azepine-4,8(1H,5H)-dione

[0074] In a 10mL reaction tube, dissolve compound 5 (0.2mmol, 66.6mg) and phenylboronic acid (0.4mmol, 48.8mg) in degassed 2mL THF, mix well and then add Pd(PPh 3 ) 4 (0.015mmol, 17.0mg) and 2mol / L degassed K 2 CO 3 solution (1.0mL), filled with N 2 , quickly cover the reaction tube, and react at 90°C for 8 hours. After the reaction is completed and cooled, pour the reaction solution into 20 mL of distilled water, extract it with ethyl acetate several times, combine the organic phases, dry them with anhydrous sodium sulfate, and remove them by suction filtration. Sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate=1:1, 1% CH 3 COOH), to obtain 31 mg of white powdery solid, yield: 47%.

[0075] 1 H NMR (400MHz,...

preparation Embodiment 3

[0076] Preparation Example 3: 2-(4'-(methyl)biphenyl-4-methylene)-6,7-dihydropyrrole[2,3-c]azepine-4,8(1H,5H )-Diketone Synthesis

[0077] The synthesis method is the same as that of Preparation Example 2, except that 4-methylphenylboronic acid is used instead of phenylboronic acid. After purification, 34 mg of white powdery solid was obtained, with a yield of 49%.

[0078] 1 H NMR (300MHz, DMSO) δ: 12.13(s, 1H), 8.20(s, 1H), 7.53(dd, J=10.0, 8.1Hz, 4H), 7.33(d, J=7.9Hz, 2H), 7.23 (d, J=8.1Hz, 2H), 6.26(s, 1H), 3.93(s, 2H), 2.65(s, 2H), 2.33(s, 3H).EI-MS: m / z=344[M ] + .

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Abstract

The invention discloses a C-2 substituted Aldisin derivative and medicinal salts thereof, their pharmaceutical compositions, and an application in preparation of antitumor drugs thereof. The C-2 substituted Aldisin derivative has a structure as shown in formula (I), wherein R represents phenyl, or phenyl which is mono-substituted by C1-C6 alkyl, C1-C6 alkoxyl, keto-carbonyl, amino, hydroxyl, hydroxymethyl, halogen, trifluoromethyl, cyano, or nitro at the ortho position, the meta position, or the para position, or phenyl which is substituted by 1'3-dioxygen bridged ring. The C-2 substituted Aldisin derivative and medicinal salts, pharmaceutical compositions thereof of the invention have certain inhibition effect on various tumor cells, and can be used to prepare drugs for treating tumors. More drug selection is provided for clinical treatment of tumors.

Description

technical field [0001] The present invention relates to Aldisin derivatives and pharmaceutically acceptable salts thereof, in particular to a class of C-2 substituted Aldisin derivatives and pharmaceutically acceptable salts thereof, their pharmaceutical compositions and their application in the preparation of antitumor drugs. technical background [0002] Cancer is one of the most important diseases currently endangering human health and normal life. Due to the complexity and particularity of the pathogenesis of cancer, finding anticancer drugs with high efficiency and low toxicity is a research hotspot at present. [0003] Aldisin (6,7-dihydropyrrole [2,3-c] azepine-4,, 8 (1H, 5H)-diketone) compounds are a class of alkaloids containing a pyrrolo seven-membered ring, with multiple A biological activity, mainly manifested as anti-tumor activity and the treatment of cardiovascular diseases. The earliest report on Aldisin was in 1985. Schmitz, F.J. et al. isolated compounds ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/55A61P35/00
Inventor 万一千符立梧林晓琴朱新海王淑东梁永钜
Owner SUN YAT SEN UNIV