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Raf and HDAC small molecular double inhibitor, and preparation and use thereof

A technology for uses and compounds, applied in the field of medicinal chemistry, and can solve problems such as insufficient selectivity

Active Publication Date: 2013-02-27
深圳澳美制药技术开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the existing inhibitors all contain structures that can chelate with zinc ions, and HDAC has different subtypes and proteases in the body also contain metal ions such as zinc, the selectivity of HDAC inhibitors is not yet sufficient

Method used

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  • Raf and HDAC small molecular double inhibitor, and preparation and use thereof
  • Raf and HDAC small molecular double inhibitor, and preparation and use thereof
  • Raf and HDAC small molecular double inhibitor, and preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055]

[0056] 5-chloro-2-nitro-benzoic acid 100g (0.5mol), SOCl 2 200ml, N, N-dimethylformamide (DMF) 2ml were added to the reaction flask in turn, refluxed for 5 hours, the reaction solution became clear, cooled slightly, and the excess SOCl was evaporated under reduced pressure 2 , the remaining liquid was cooled and solidified to obtain 101 g of crude product with a yield of 98.3%, which was directly used in the next reaction without purification.

[0057] The crude compound 2 was dissolved in 500ml of dry dioxane, and methylamine gas was introduced at 0-5°C until the pH of the mixture was alkaline. React at room temperature for 1 hour. Concentrate to about 150ml, pour into ice water, filter with suction after the product precipitates, dry, and recrystallize with ethyl acetate to obtain 87g of light yellow crystals (compound 3), yield 82%, MP: 134-136°C.

[0058] In a 50ml three-necked flask, add 0.96g (8.8mmol) of p-aminophenol, 15ml of dried DMF (dried with molecu...

Embodiment 2

[0065] The final product of the present example, i.e. compound III, is prepared by a method similar to that of Example 1, and the partial detection data of compound III are as follows:

[0066] 1 HNMR [DMSO-d 6 ]: δ2.21(s, 6H, AR-CH 3 ), 2.69 (d, J=4.5, 3H, N-CH 3 ), 3.29 (s, 2H, NH 2 ), 6.59 (s, 1H, aromatic hydrogen), 6.72 (d, J=2.7Hz, 1H, aromatic hydrogen), 6.82, 7.37 (AA'BB', q, J=8.9Hz, 4H, aromatic hydrogen), 6.89 (m, 1H, aromatic hydrogen) 7.05 (s, 2H, aromatic hydrogen), 7.40 (s, 1H, aromatic hydrogen), 8.18 (q, 1H, NHCH 3 ), 8.40 (s, 1H, ureido hydrogen), 8.51 (s, 1H, ureido hydrogen).

[0067] IR (KBr, cm -1 ) data: 3469, 3386, 3311, 2916, 1641, 1558, 1502, 1417, 1294, 1224, 1155, 935, 842, 635, 516.

[0068] MS(m / z) data: 452[M+H] + .

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PUM

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Abstract

The invention provides compounds having a structure in a general formula I. As proved by a biological activity test result, the compounds have the activity of inhibiting Raf and HDAC, and have certain proliferation and inhibition function on tumor cell strains. The invention also provides a method for preparing the compounds, a medical composition containing an inhibitor or a pharmaceutically acceptable salt of the inhibitor, and medical application of the inhibitor or the pharmaceutically acceptable salt of the inhibitor and the medical composition, in particular application of the inhibitor or the pharmaceutically acceptable salt of the inhibitor and the medical composition in medicines for preventing, delaying or treating diseases which are mediate by the Raf or the HDAC or the Raf and the HDAC, particularly tumor.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a small molecule organic compound that can be used as a dual inhibitor of Raf and HDAC or a pharmaceutically acceptable salt thereof and a preparation method thereof, and also to a compound containing the inhibitor or a pharmaceutically acceptable salt thereof The pharmaceutical composition, and the medical use of the inhibitor or its pharmaceutically acceptable salt and the pharmaceutical composition thereof, especially relate to the prevention, delay or treatment of diseases mediated by Raf or HDAC alone or both, especially Use in medicine for tumors. Background technique [0002] The Ras / Raf / MAPKs (mitogen-activated protein kinases) signal transduction pathway exists in most cells, transducing extracellular stimulus signals to cells and their nuclei, causing cell biological responses (such as cell proliferation, differentiation, It plays a crucial role in the proces...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C275/36C07C273/18A61K31/17A61P43/00A61P35/00A61P35/02
Inventor 陆涛朱雍卢帅张陆勇陈亚东焦宇
Owner 深圳澳美制药技术开发有限公司