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XPO1 inhibitor

A protein inhibitor, 1.XPO1 technology, applied in anti-inflammatory agents, antiviral agents, non-central analgesics and other directions, can solve the problems of toxic side effects, limited relief of inflammatory bowel disease, etc., to achieve small side effects, biological The effect of good safety and bioavailability, huge market space and economic benefits

Active Publication Date: 2015-06-24
ONCOCURE BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, these clinical treatment options often have limited remission for inflammatory bowel disease, and may produce more obvious toxic side effects, including liver toxicity and myelosuppressive toxicity, etc.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1. Preparation of compound F-01

[0075]

[0076] Step 1. Preparation of (2-ethyl)-1-propylthiophenol-ethyl methyl phosphate

[0077]

[0078] Dissolve 0.76 g of 1-propylthiophenol and 1.38 g of potassium carbonate in 50 ml of DMF solution, slowly add 1.50 g of diethyl methyl methanesulfonate phosphate dropwise at room temperature, stir at room temperature, detect by TLC, for 2 hours After the raw material is no longer reduced, the reaction is complete. The combined organic layers were extracted and dried, and 0.71 g of yellow oily liquid (yield rate was 72%) was obtained by column chromatography. The mass spectrum MS of the compound: [M+H] + 226.1.

[0079] Step 2. Preparation of (2-Ethyl)-1-Propylthiophenol Sulphinyl-Methyl Phosphate Ethyl Ester

[0080]

[0081]2.26 g of the product from step 1 was dissolved in 15 ml of chloroform solution, and then 0.25 g of m-CPBA solution was slowly added dropwise. Stir at room temperature and detect by TLC...

Embodiment 2

[0085] Embodiment 2. Preparation of compound F-03

[0086]

[0087] Step 1. Preparation of (2-ethyl)-1-cyclopropylthiophenol-ethyl methyl phosphate

[0088]

[0089] Dissolve 0.74 g of 1-cyclopropylthiophenol and 1.38 g of potassium carbonate in 50 ml of DMF solution, slowly add 1.50 g of diethyl methyl methanesulfonate phosphate dropwise at room temperature, stir at room temperature, and detect with TLC, 2 After 1 hour, the raw materials no longer decrease, and the reaction is completed. The combined organic layers were extracted and dried, and 1.81 grams of yellow oily liquid (yield rate 85%) were obtained by column chromatography. The mass spectrum MS of the compound: [M+H] + 224.2.

[0090] Step 2. Preparation of (2-Ethyl)-1-Propylthiophenol Sulphinyl-Methyl Phosphate Ethyl Ester

[0091]

[0092] 2.24 g of the product from step 1 was dissolved in 20 ml of chloroform solution, and then 0.25 g of m-CPBA solution was slowly added dropwise. Stir at room temperatu...

Embodiment 3

[0096] Embodiment 3. Preparation of compound F-05

[0097]

[0098] Step 1. Preparation of (2-ethyl)-methylthiophenol-ethyl methyl phosphate

[0099]

[0100] Dissolve 0.50 g of methylthiophenol and 1.38 g of potassium carbonate in 50 ml of DMF solution, slowly add 1.50 g of diethyl methyl methanesulfonate phosphate dropwise at room temperature, stir at room temperature, and detect by TLC. After 2 hours, the raw material no longer decrease, the reaction is complete. The combined organic layers were extracted and dried, and 1.32 grams of yellow oily liquid (yield rate 72%) were obtained by column chromatography. The mass spectrum MS of the compound: [M+H] + 198.2.

[0101] Step 2. Preparation of (2-ethyl)-1-methylthiophenol sulfinyl-methylphosphonate

[0102]

[0103] 1.99 g of the product from step 1 was dissolved in 25 ml of chloroform solution, and then 0.80 g of m-CPBA solution was slowly added dropwise. Stir at room temperature and detect by TLC. After 2 hours...

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PUM

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Abstract

The invention discloses an XPO1 (Exportin 1) inhibitor of which the structural formula F is as shown in the specification. The XPO1 inhibitor has very good solubility in water; by taking sulforaphene as a representative, the compounds have extremely high inhibitory activity to XPO1, tiny side effect, and good biosafety and bioavailability, and are very suitable for clinical application, so that the XPO1 inhibitor has a huge potential market space and economic benefits.

Description

technical field [0001] The invention relates to a class of XPO1 protein inhibitors, which is a class of isothiocyanate compounds, and also relates to the application of the compounds in new fields. Background technique [0002] Some specific proteins of organisms are transported into or out of the nucleus by specific transport proteins, which are divided into import proteins and export proteins (transport molecules out of the nucleus). Proteins that are transported into or out of the nucleus contain nuclear import localization sequence (NLS) or nuclear export localization (NES) sequences that allow them to interact with specific transporters. XPO1 (also known as CRM1 protein), is one of the most important nuclear export proteins. [0003] The cargo proteins of XPO1 include some specific tumor suppressor proteins such as P53, P21, BRCA1, FOXOs, BCR-Abl, and NPM. A large number of studies have shown that XPO1 protein is highly expressed in various tumor types such as ovarian...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C331/22C07D307/38C07D333/18C07D277/26A61K31/26A61K31/341A61K31/381A61K31/426A61P29/00A61P35/00A61P35/04A61P35/02A61P31/12
Inventor 杨永亮
Owner ONCOCURE BIOTECH INC
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