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N,N-bis(2-chloroethyl)-2-(benzoisoselenazole-3-one)-amide compound with anti-tumor activity

An amide compound, benzisoselenazole technology, applied in antitumor drugs, organic chemistry, drug combination and other directions, can solve the problems affecting clinical use, poor selectivity of antitumor drugs, etc., to reduce drug resistance, improve Sensitivity, the effect of a simple synthesis method

Active Publication Date: 2018-09-07
济源希健生物医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, as a non-specific drug for the cell cycle, nitrogen mustard has poor selectivity in the application of anti-tumor drugs, and has serious side effects of chemotherapy, which affects the clinical use.

Method used

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  • N,N-bis(2-chloroethyl)-2-(benzoisoselenazole-3-one)-amide compound with anti-tumor activity
  • N,N-bis(2-chloroethyl)-2-(benzoisoselenazole-3-one)-amide compound with anti-tumor activity
  • N,N-bis(2-chloroethyl)-2-(benzoisoselenazole-3-one)-amide compound with anti-tumor activity

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preparation example Construction

[0038] A method for preparing N,N-bis(2-chloroethyl)-2-(benzisoselazol-3-one)-amide compounds with antitumor activity, the preparation method specifically includes the following steps:

[0039] Step 1. Weigh 1.0 molar equivalent of benzisoselazol-3-one-2-aminocarboxylic acid, dissolve it in 200-1000 mL of organic solvent, and add 1.0~ 1.2 molar equivalent of condensation reagent, after stirring for 5-20min, add 1.0~3.0 molar equivalent of catalyst or / and 0.2~1.2 molar equivalent of additive, then add 0.8~5.0 molar equivalent of di(2-chloroethyl)amine Hydrochloride, stirred at room temperature for 12-36h to obtain the stirred product A;

[0040] Step 2, filter the product A stirred in step 1, then wash the filter cake with an organic solvent for 2-5 times, combine the organic phase after washing, remove the solvent under reduced pressure, use petroleum ether and ethyl acetate as the eluent, and use Separation on a silica gel column and evaporation of the solvent under reduced ...

Embodiment 1

[0048] Example 1: Preparation of N,N-bis(2-chloroethyl)-2-(benzisoselazol-3-one)-formamide

[0049]

[0050] Weigh 1.0 molar equivalent of benzisoselazol-3-one-2-carboxylic acid, dissolve in 200mL dimethylformamide (DMF) solution, add 1.0 molar equivalent of dicyclohexylcarbodiimide ( After DCC) was added, stir for 5 min, then respectively add 1.0 molar equivalent of potassium carbonate and 0.8 molar equivalent of di(2-chloroethyl)amine hydrochloride and stir at room temperature for 12 h, filter, and wash the filter cake with DMF (20 mL washing 3 times) , combined the organic phases, removed the solvent under reduced pressure, petroleum ether:ethyl acetate (V:V=3:1~8:1) was used as the eluent, separated on a silica gel column, and evaporated the solvent under reduced pressure to obtain the target compound. Yield 60%. HR-MS: 366.9514 (C12H12Cl2N2O2Se, [M+H]+).

Embodiment 2

[0051] Example 2: Preparation of N,N-bis(2-chloroethyl)-2-(benzisoselazol-3-one)-acetamide

[0052]

[0053] Weigh 1.0 molar equivalent of benzisoselazol-3-one-2-acetic acid, dissolve it in 500 mL of dimethylformamide (DMF) solution, add 1.1 molar equivalent of N,N'-diisopropyl After adding carbodiimide (DIC), stir for 20 min, then add 2.0 molar equivalents of potassium carbonate, 0.4 molar equivalents of 1-hydroxybenzotriazole (HOBt) and 1.0 molar equivalents of bis(2-chloroethyl ) amine hydrochloride, stirred at room temperature for 24h, filtered, washed the filter cake with DMF (20mL washed 3 times), combined the organic phases, removed the solvent under reduced pressure, petroleum ether:ethyl acetate (V:V=3:1~8:1) As the eluent, it was separated on a silica gel column, and the solvent was evaporated under reduced pressure to obtain the target compound. Yield 85%. HR-MS: 380.9670 (C13H14Cl2N2O2Se, [M+H]+).

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Abstract

The invention relates to an N,N-bis(2-chloroethyl)-2-(benzoisoselenazole-3-one)-amide compound with anti-tumor activity. The amide compound is obtained by taking benzoisoselenazole-3-one-2-amino carboxylic acid and di(2-chloroethyl) amine hydrochloride as raw materials and carrying out condensation reaction in an organic solvent under the actions of a condensation reagent and a catalyst. The amidecompound molecule contains a benzoisoselenazole active group with cancer inhibition, anticancer and attenuation activities and also contains a nitrogen mustard active group with obvious anticancer activity and relatively high biocompatibility, amino acid is taken as a carrier, multiple active groups are bridged and spliced into one chemical molecular structure by virtue of a chemical synthesis means, on the one hand, the combined effect of benzoisoselenazole and a nitrogen mustard anticancer structural unit is played, and toxicity and side effect of a nitrogen mustard bio-alkylating agent arereduced due to introduction of a selenium element; and on the other hand, the aim of efficiently conveying an organic selenium compound to tumor tissues is achieved by virtue of non-selective combining capability of a nitrogen mustard compound.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to N,N-bis(2-chloroethyl)-2-(benzisoselazol-3-one)-amide compounds with antitumor activity. Background technique [0002] Selenium is one of the essential trace elements for the human body. Selenium is closely related to the occurrence of cancer. Studies have shown that the blood selenium level of cancer patients is 3-6 times lower than that of normal people; the incidence of cancer in selenium-deficient people is as high as 50%. Selenium supplementation can inhibit the expression of oncogenes, eliminate free radicals in the body by enhancing the activity of glutathione peroxidase, protect the cell membrane structure, and prevent gene mutation; supplementation of selenium can enhance human immune function and prevent cancer; The level of cyclic adenosine monophosphate (cAMP) inhibits the synthesis of DNA and RNA proteins, and inhibits the division and proliferation of cancer cell...

Claims

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Application Information

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IPC IPC(8): C07D293/10A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D293/10
Inventor 姚永强姚一冯书晓田瑞昌范江伟贾朋君
Owner 济源希健生物医药科技发展有限公司
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