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DNA toxic dimer compound

A hydrate and solvate technology, applied in the field of new cytotoxic compounds, can solve the problems of toxicity and high toxicity

Active Publication Date: 2019-01-11
バイリバイオ(チェンドゥ)ファーマスーティカル シーオーエルティーディー
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The benzodiazepine derivatives disclosed in the prior art are extremely toxic and are toxic at very low doses, therefore, improved less toxic and still therapeutically active benzodiazepines with a high therapeutic window Zodiac derivatives appear to be very necessary

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 Preparation of 3-(methoxyformyl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0076]

[0077] Add 1.48g methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate into a 50ml three-necked flask, dissolve it with 20ml methanol, slowly add NaOH (324mg) in methanol (5ml) solution dropwise at room temperature, add After completion, the temperature was raised to 80°C for 2 hours. After the reaction is completed, concentrate to dryness, add 40ml of water, extract with dichloromethane (50ml*3), adjust the pH of the aqueous layer to acidic with dilute hydrochloric acid, add dichloromethane for extraction (40ml*4), combine the organic layers, dry and concentrate 925mg of white solid, yield 68%. 1 H NMR (400MHz, CDCl3) δ3.71(s, 3H), 2.38(s, 6H); MS m / z 171(M+1).

Embodiment 2

[0078] Example 2 Preparation of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-methyl carboxylate

[0079]

[0080] Add 6.34g of 3-(methoxyformyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 30ml of tetrahydrofuran, and 4.89g of triethylamine to a 500ml three-necked flask successively, cool the reaction system to -10°C, and slowly add After adding 3.87g of methyl chloroformate, react at 0°C for 1 hour, add 2.54g of NaBH4 in batches, and continue to react at 0°C until the raw material is complete. The reaction was quenched by adding 400ml of water, extracted with ethyl acetate (600ml*3), the organic layers were combined, dried and concentrated, and the resulting residue was purified by column chromatography (DCM:MeOH=20:1) to obtain 3.83g of light yellow oil , yield 66%. 1 H NMR (400MHz, CDCl3) δ3.71(s,3H),2.38(s,6H); 3.48(s,2H); MS=157(M+1)

Embodiment 3

[0081] Example 3 Methyl 3-((p-toluenesulfonyloxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate

[0082]

[0083] Add 700mg of 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-methyl carboxylate to a 100ml flask, dissolve it with 10ml of dichloromethane, add 1.2ml of triethylamine and 0.55g of DMAP in sequence, Add a dichloromethane solution of p-toluenesulfonyl chloride dropwise, and then react at room temperature until the raw materials are completely reacted. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain 1.4 g of a yellow solid, which was directly used in the next reaction without further purification.

[0084]

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PUM

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Abstract

The invention discloses a DNA toxic dimer compound. Compared with a benzodiazepine conjugate disclosed in the prior art, a cytotoxic compound disclosed by the invention presents much higher in vivo treatment index (ratio of maximum tolerated dose and minimum effective dose).

Description

field of invention [0001] The present invention relates to novel cytotoxic compounds and medicaments comprising these cytotoxic compounds and cell-binding agents. More specifically, the present invention relates to novel benzodiazepine dimer compounds, their derivatives, their intermediates and their pharmaceutically acceptable salts, which are useful as medicines, especially as antiproliferative agents. Background of the invention [0002] Benzodiazepine derivatives have the ability to recognize and bind to specific DNA sequences. They are highly effective inter-strand cross-linking agents that can react with guanine in the DNA minor groove to form DNA adducts and interfere with DNA sequences. processing of DNA, thus making them useful as antineoplastic agents. (Rahman et al. (2009) Jour. Amer. Chem. Soc. 131 (38): 13756-13766; Thurston et al. (1994) Chem. Rev., 94: 433-46 5; Bose et al. (1992 ) J. Am. Chem. Soc. 114:4939-4941; Gregson et al. (2004) Jour. Med. Chem. 47(5)...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61P35/00A61P35/02A61P37/02A61P31/00A61K31/5517
CPCA61P31/00A61P35/00A61P35/02A61P37/02C07D487/04C07D519/00A61K31/395A61K31/5517A61P37/00C07D209/60
Inventor 朱义李杰刘威加万维李卓识
Owner バイリバイオ(チェンドゥ)ファーマスーティカル シーオーエルティーディー
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