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Otobain compound, preparation method therefor and application thereof

A technology of myristin and ottoman, applied in drug combination, organic chemistry, pharmaceutical formula, etc., can solve the problems of high cost, difficulty in the total synthesis of podophyllotoxin, and many steps, and achieve low toxicity and good anti-tumor Active, less side effects

Inactive Publication Date: 2015-08-19
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] On the other hand, because the total synthesis of podophyllotoxin is difficult, there are many steps, low yield and high cost, it is difficult to realize industrialization

Method used

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  • Otobain compound, preparation method therefor and application thereof
  • Otobain compound, preparation method therefor and application thereof
  • Otobain compound, preparation method therefor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of Compound 2

[0036] Add 15.00g of piperonal into 150mL of dichloromethane, stir until dissolved, then add 1.90g of p-toluenesulfonic acid and 11.02mL of 1,3-propanedithiol, under nitrogen protection, and stir at room temperature for 24 hours. Add saturated sodium carbonate and stir for 2 hours, separate the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, filter with suction, spin off the solvent to obtain a yellow solid, recrystallize from absolute ethanol to obtain a white needle-like solid, the yield is 90% .

Embodiment 2

[0038] Preparation of compound 3

[0039] 4.00 g of compound 2 was added to 30 mL of anhydrous tetrahydrofuran and stirred until dissolved, then the system was lowered to -78°C, and 6.96 mL of butyllithium was added dropwise, and the reaction was continued for 1 hour. A solution of 1.44 g of 2(5H)-furanone and 12 mL of tetrahydrofuran was added dropwise, and the reaction was continued for 2 hours. After adding 12 mL of acetic acid dropwise, it was slowly raised to room temperature and reacted for another 3 hours. The tetrahydrofuran was removed by rotary evaporation, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spun off to obtain a brown-yellow oil, which was recrystallized from ethyl acetate to obtain a white solid with a yield of 80%. Melting point: 162-163°C; 1 H NMR (500MHz, CDCl 3 ):δ1.85-1.99(m,2H),2.40-2.46(m,1H),2.66-2.76(m,4H),2.82-2.87(m,1H),2.98-3.04(m,1H),4.18 -4.22 (m, 1H), 4.39-4.43 (m, ...

Embodiment 3

[0041] Preparation of Compound 4

[0042] Add 1.20mL of diisopropylamine to 5.00mL of anhydrous tetrahydrofuran and stir well, lower the system to -30°C, add 3.20mL of butyllithium dropwise, continue the reaction for 30 minutes, then raise to room temperature for 60 minutes. The system was lowered to -78°C again, and a solution of 2.00 g of compound 3 and 15 mL of tetrahydrofuran was added dropwise, and the reaction was continued for 2 hours. A solution of 1.11 g of piperonal and 5 mL of anhydrous tetrahydrofuran was added dropwise, reacted for 1 hour, and slowly rose to room temperature for reaction for another 3 hours. After adding dropwise 1 mL of acetic acid, tetrahydrofuran was removed by rotary evaporation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and spinned to remove the solvent, followed by column chromatography (ethyl acetate / petroleum ether, 3:7) to obtain compound 4(42 %), white solid, melting point: 181-182°C...

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Abstract

The invention discloses an otobain compound, a preparation method therefor and application thereof. The compound has a structure shown in formula I. The preparation method is that piperonal is protected by 1,3-propanedithiol, reacts with 2-(5H)-furanone, and is subjected to cyclizing, deprotection, reduction and acylation reaction synthesis to obtain the otobain compound. The otobain compound adopts the piperonal which is cheap and easy to get as the raw material, is obtained through a simple and easy method, has good anti-neoplasm activity, is lower toxicity to normal cells compared to podophyllotoxin medicine, and has less side effects.The otobain compound can be clinically applied in manners of oral taking, intravenous injection, intramuscular injection and the like. Formula I:(img file='DDA0000691317640000011.TIF' wi='431' he='627' / )

Description

technical field [0001] The present invention relates to a class of inhibitors acting on topoisomerase II, as well as methods and uses of these compounds. More specifically, it relates to novel ottomyristin derivatives (I) having the following structures, their preparation methods and the application of these compounds in the antitumor field. [0002] Background technique [0003] DNA topoisomerase is an important class of anti-tumor targets. Podophyllotoxin (1) is a representative anti-tumor compound that acts on topoisomerase II. It was first isolated from Podophyllum scutellaria and has significant Antitumor and antiviral activity, but its application is limited due to strong toxicity and side effects (K. Kobayashi, M.J. Ratain, Cancer Chemother. Pharmacol. 34 (1994) 64-68.). [0004] Etoposide (VP-16) (2) and its phosphate (etoposide phosphate, or etopophos) and teniposide (VM-26) (3) derived from podophyllotoxin structural modification It has become a representative...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/365A61K31/381A61K31/443A61K31/497A61K31/4709A61P35/00A61P35/02
CPCC07D493/04
Inventor 邹新琢李忠洲刘明耀逄秀凤于薇薇程浩苏慧李新军韩冰冰周斌
Owner EAST CHINA NORMAL UNIV
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