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3-(2-amino-ethyl)-5-(3-cyclohexyl-propylidene)-thiazoline-2,4-diketone and derivatives thereof

An amino, C1-C4 technology, used in drug combinations, antipyretics, organic chemistry, etc., can solve problems such as undiscovered monomeric small molecular substances

Inactive Publication Date: 2011-05-25
SHANDONG QIDU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to the best of our knowledge, all combinatorial targeted therapies employ a cocktail of inhibitors targeting Raf / MEK / ERK and PI3K / Akt, respectively, and no monomeric small molecule that can simultaneously inhibit both pathways has been found substance

Method used

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  • 3-(2-amino-ethyl)-5-(3-cyclohexyl-propylidene)-thiazoline-2,4-diketone and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Embodiment 1.N-Boc-bromoethylamine

[0138] Di-tert-butyl dicarbonate (5.85g, 26.8mmol) and triethylamine (3.4mL, 24.4mmol) were dissolved in 25mL of dioxane, and added to 2-bromoethylamine hydrobromide (5.0 g, 24.4mmol) in 50mL dioxane solution. The mixture was stirred and reacted at room temperature for 48 hours, and the precipitate was filtered off. The filtrate was concentrated and dissolved in 100 mL of dichloromethane, washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate and brine, anhydrous Na 2 SO 4 dry. After distilling off the solvent, N-Boc-bromoethylamine was obtained as a colorless oil. Yield: 89%. 1 H-NMR (300MHz, CDCl 3 ): 3.55-3.52(t, 2H), 3.48-3.44(t, 2H), 1.45(s, 9H).

Embodiment 2

[0139] Example 2. tert-butyl 2-(2,4-dioxthiazol-3-yl)ethylcarbamate

[0140] In the 500mL flask, add 2,4-thiazolidinedione (2.0g, 17.1mmol), K 2 CO 3 (10.6 g, 1.2 e.q), tetrabutylammonium iodide (TBAI, 2.5 g, 0.1 e.q) and 300 mL acetone, and N-Boc-bromoethylamine (11.0 mL, 1.5 e.q) was added. The mixture was refluxed for 10 hours, filtered and evaporated to remove the solvent to obtain a yellow oil, which was dissolved in 100 mL of dichloromethane, washed with brine and washed with anhydrous Na 2 SO 4 dry. The crude product was purified by column chromatography (n-hexane / ethyl acetate=8 / 2) to obtain white crystals. Yield: 80%. 1 H-NMR (300MHz, CDCl 3 ): δ3.96(s, 2H), 3.76(t, 2H), 3.39(t, 2H), 1.43(s, 9H); 13 C-NMR (75MHz, CDCl 3 ): δ173.2, 171.3, 167.4 79.2, 41.6, 37.9, 33.3, 27.9.

Embodiment 3

[0141] Example 3. Cyclohexylpropanal

[0142] Oxalyl chloride (440uL, 5.0mmol) was dissolved in 20mL of dichloromethane, cooled to -78°C, N 2 Pure DMSO (1.0 mL, 14 mmol) was added dropwise at the same temperature under the atmosphere. After 15 minutes, cyclopropyl alcohol (610 μL, 4.0 mmol) was slowly added dropwise under temperature control at -78°C. The reaction was stirred for 1 hour, and the solution gradually became opaque. Add 5.0 mL of triethylamine and slowly warm to room temperature. 20 mL of water was added to separate the layers. The aqueous layer was extracted with 3x20 mL of dichloromethane. The crude product was purified by column chromatography (ethyl acetate / n-hexane=1 / 10). Yield: 89%. 1 H-NMR (400MHz, CDCl 3 ): δ9.77-9.76(t, 1H, J=1.92Hz), 2.45-2.41(dt, 2H, J=7.52, 1.92Hz), 1.71-1.55(m, 5H), 1.51-1.49(q, 2H ), 1.26-1.11(m, 4H), 0.93-0.86(m, 2H); 13 C-NMR (100MHz, CDCl 3 ): 203.1, 63.4, 41.5, 37.5, 37.2, 33.4, 33.0, 30.1, 29.3, 26.7, 26.4, 26.2.

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Abstract

The invention provides 3-(2-amino-ethyl)-5-(3-cyclohexyl-propylidene)-thiazoline-2,4-diketone and derivatives thereof. The compounds can be used as a dual inhibitor for Raf / MEK / ERK and PI3K / Akt signaling pathways, and can be used for treating cancer.

Description

field of invention [0001] The present invention relates to 5-alkylenethiazoline-2,4-dione analogs and their use as anticancer agents. Specifically, the present invention provides 3-(2-amino-ethyl)-5-(3-cyclohexyl-propylene)-thiazoline-2,4-dione and derivatives thereof, which can be used as Raf / Dual inhibitors of MEK / ERK and PI3K / Akt pathways, which can be used to treat cancer. Background of the invention [0002] Cancer has overtaken heart disease as the leading cause of death among Americans under the age of 85. In 2009, an estimated 1.53 million cancer cases were diagnosed in the United States, of which at least 569,490 died [1] . In addition to the massive labor costs, cancer treatment costs more than $72 billion annually, placing an enormous burden on the U.S. healthcare economy. In the past few decades, although some chemotherapy has been proposed and applied to the treatment of cancer, cancer is still a stubborn and fatal disease that endangers human health. Ther...

Claims

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Application Information

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IPC IPC(8): C07D277/34C07D277/36A61K31/426A61P35/00A61P29/00A61P35/02
Inventor 张世军贡肖巍张涛许超冯波崔美兰翟海民周海洋
Owner SHANDONG QIDU PHARMA
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