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Ras and HDAC dual inhibitor as well as preparation method and application thereof

A dual inhibitor, CH2 technology, used in the preparation of thioethers, anti-inflammatory agents, pharmaceutical formulations, etc.

Active Publication Date: 2013-05-22
苏州圣典企业管理咨询有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention discloses a class of hydroxamic acid FTA derivatives with medicinal value and dual inhibitory activity of Ras and HDAC and pharmaceutically acceptable salts thereof. No reports on such compounds have been seen so far

Method used

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  • Ras and HDAC dual inhibitor as well as preparation method and application thereof
  • Ras and HDAC dual inhibitor as well as preparation method and application thereof
  • Ras and HDAC dual inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Embodiment 1N-(2-(hydroxylamino)-2-oxaethyl)-farnesyl thiosalicylic acid amide (Ⅰ 1 ) Preparation of farnesylthiosalicylic acid chloride (1)

[0102] Dissolve 0.36 g (1.00 mmol) FTA in 10 mL anhydrous CH 2 Cl 2 0.40 mL (5.51 mmol) of thionyl chloride was added thereto, stirred at 55°C for 1 hour, and concentrated to obtain farnesylthiosalicylic acid chloride (1) as a yellow oil.

[0103] Preparation of N-(2-(methoxy)-2-oxaethyl)-farnesylthiosalicylic acid amide (2a)

[0104] Dissolve 0.09 g (1.00 mmol) of glycine methyl ester and 0.2 mL (1.50 mmol) of triethylamine in 5 mL of anhydrous CH 2 Cl 2 , add dropwise 10 mL of anhydrous CH prepared in 1 under ice bath 2 Cl 2 solution, then stirred at room temperature for 1.5h, the reaction solution was washed with 10mL water and saturated NaCl solution, CH 2 Cl 2 Dry with anhydrous sodium sulfate, filter, and spin dry to obtain 0.37g of yellow oil, with a yield of 86%.

[0105] N-(2-(hydroxyamino)-2-oxaethyl)-farnesylt...

Embodiment 2

[0108] Embodiment 2N-(3-(hydroxylamino)-3-oxapropyl group)-farnesyl thiosalicylic acid amide (Ⅰ 2 ) preparation

[0109] Preparation of N-(3-(methoxy)-3-oxapropyl)-farnesylthiosalicylic acid amide (2b)

[0110] With reference to the preparation method of N-(2-(methoxy)-2-oxaethyl)-farnesylthiosalicylic acid amide (2a) in Example 1, the method is replaced by methyl 3-alanine Glycine methyl ester in (1) was reacted with (1) to obtain yellow oily substance (2b) with a yield of 85%.

[0111] N-(3-(hydroxyamino)-3-oxapropyl)-farnesylthiosalicylic acid amide (Ⅰ 2 ) preparation

[0112] Referring to I in Example 1 1 The preparation method, by 2a in the alternative method of 2b, reacts with hydroxylamine hydrochloride to obtain oil (Ⅰ 2 ), with a yield of 73%.

[0113] 1 H NMR (CDCl 3 ,300MHz):δ8.24(m,1H,NH),8.09(m,1H,NH),7.65(m,2H,ArH),7.37(m,2H,ArH),5.41(m,1H,SCH 2 C H ),5.18(m,2H,2×CH 2 C H =CCH 3 ), 3.76(d, 2H, J=7.2Hz, SC H 2 ),3.18(m,4H,2×CH 2 ),2.05-1.83(m,8H,2×...

Embodiment 3

[0114] Embodiment 3N-(4-(hydroxylamino)-4-oxabutyl)-farnesyl thiosalicylic acid amide (Ⅰ 3 ) preparation

[0115] Preparation of N-(4-(methoxy)-4-oxabutyl)-farnesylthiosalicylic acid amide (2c)

[0116] With reference to the preparation method of N-(2-(methoxy)-2-oxaethyl)-farnesylthiosalicylic acid amide (2a) in Example 1, the method is replaced by methyl 4-aminobutyrate Glycine methyl ester in (1) was reacted with (1) to obtain yellow oil (2c), the yield was 83%.

[0117] N-(4-(hydroxyamino)-4-oxabutyl)-farnesylthiosalicylic acid amide (Ⅰ 3 ) preparation

[0118] Referring to I in Example 1 1 The preparation method, by 2a in the alternative method of 2c, reacts with hydroxylamine hydrochloride to obtain oil (Ⅰ 3 ), the yield is 70%.

[0119] 1 H NMR (CDCl 3 ,300MHz):δ7.98(d,1H,J=7.8Hz,Ar-H),7.60-7.57(m,2H,Ar-H),7.39(m,1H,Ar-H),5.46(m, 1H,SCH 2 C H ),5.20(m,2H,2×CH 2 C H =CCH 3 ),3.78(d,2H,J=7.2Hz,SC H 2 ),3.52(m,2H,NHC H 2 ),2.34(m,2H,C H 2 CONH),2.21(m,2...

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Abstract

The invention discloses a Ras and HDAC dual inhibitor as well as a preparation method and an application thereof. The Ras and HDAC dual inhibitor has a structure of general formulas I and II and can be used for preparing a medicine for treating chronic inflammation and treating tumors of liver cancer, pancreatic cancer, lung cancer, breast cancer, cerebral cancer, colon cancer and stomach cancer.

Description

technical field [0001] The pharmaceutical field of the present invention, specifically relates to hydroxamic acid farnesyl thiosalicylic acid derivatives and pharmaceutically acceptable salts thereof that can be used as dual inhibitors of Ras and HDAC, their preparation methods, and pharmaceuticals containing these derivatives The compositions and their medical applications especially relate to the prevention, delay or treatment of diseases mediated by Ras or HDAC alone or both, especially in tumor drugs. Background technique [0002] All-trans farnesylthiosalicylic acid (abbreviation: FTA, trade name: Salirasib), as a new farnesyl transferase-based Ras protein inhibitor, is similar to farnesyl cysteine ​​on the cell membrane in vivo, and can Competitive substitution of F-Ras and F-Ras muteins for galectin binding, inhibition of Ras-initiated downstream signaling pathway Z (including Raf and PI3K signaling pathways) and mTOR (stimulator of tumorigenesis, which can rely on or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/62C07C319/20A61K31/166A61K31/167A61P29/00A61P35/00
Inventor 凌勇杨宇民王新杨肖幼安王志强丰楠楠颜森森惠易
Owner 苏州圣典企业管理咨询有限公司
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