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Dual-channel inhibitor using Raf/MEK/ERK and PI3K/Akt as targets

An inhibitor and dual-channel technology, applied in the field of dual-channel inhibitors targeting Raf/MEK/ERK and PI3K/Akt, can solve the problem of undiscovered monomer small molecules, increased human toxicity, and increased drug dosage and other issues, to achieve the effect of reducing the probability of drug resistance, reducing toxicity, and improving potency

Active Publication Date: 2014-07-30
北京太洋药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as far as we know, all current combined target therapies are combined drugs that use inhibitors targeting Raf / MEK / ERK and PI3K / Akt respectively, and combined drugs will increase the dosage of drugs, which has a negative effect on the human body. Increased toxicity and increased probability of drug resistance
However, no monomeric small molecule substances that can simultaneously inhibit these two pathways have been found

Method used

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  • Dual-channel inhibitor using Raf/MEK/ERK and PI3K/Akt as targets
  • Dual-channel inhibitor using Raf/MEK/ERK and PI3K/Akt as targets
  • Dual-channel inhibitor using Raf/MEK/ERK and PI3K/Akt as targets

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1). The synthesis of N-phenylethylenediamine (2):

[0037] 2-Bromoethylamine hydrobromide (0.1 mmol) and aniline (1) (0.2 mmol) were added to 40 ml of toluene, heated to reflux for 16 hours, and cooled. Add 60ml of water and 20ml of 50% KOH aqueous solution, and let stand to separate layers. The aqueous phase was washed with saturated NaCl and extracted three times with dichloromethane. Combined organic phases were washed with saturated NaCl, anhydrous Na 2 SO 4 Dry, filter and evaporate to dryness. The pure compound (2) was obtained by column chromatography with a yield of 60%. 1 H(400MHz,MeOH):δ7.10-7.08(t,J=3.4Hz,2H),6.67-6.60(m,3H),3.23-3.20(t,J=6.08Hz,2H),2.90-2.87( t, J=6.24Hz, 2H).

[0038] 2). Synthesis of N-tert-butoxycarbonyl-N'-phenylethylenediamine (3):

[0039] N-phenylethylenediamine (2) (1.0 mmol) and di-tert-butyl carbonate (1.2 mmol) were dissolved in 15 ml of methanol, stirred for 4 hours, and concentrated under reduced pressure to obtain a brown ...

Embodiment 2

[0054] 1). The synthesis of N-phenylethylenediamine (2):

[0055] 2-Bromoethylamine hydrobromide (0.1 mmol) and aniline (1) (0.25 mmol) were added to 40 ml of toluene, heated to reflux for 18 hours, and cooled. Add 60ml of water and 20ml of 50% KOH aqueous solution, and let stand to separate layers. The aqueous phase was washed with saturated NaCl and extracted three times with dichloromethane. Combined organic phases were washed with saturated NaCl, anhydrous Na 2 SO 4 Dry, filter and evaporate to dryness. The pure compound (2) was obtained by column chromatography with a yield of 62%.

[0056] 2). Synthesis of N-tert-butoxycarbonyl-N'-phenylethylenediamine (3):

[0057] N-phenylethylenediamine (2) (1.0 mmol) and di-tert-butyl carbonate (1.5 mmol) were dissolved in 15 ml of methanol, stirred for 5 hours, and concentrated under reduced pressure to obtain a brown oil. The pure white solid compound (3) was obtained by column chromatography with a yield of 90%.

[0058] 3)...

Embodiment 3

[0070] 1). The synthesis of N-phenylethylenediamine (2):

[0071] Add 2-bromoethylamine hydrobromide (0.1 mmol) and aniline (1) (0.15 mmol) into 40 ml of toluene, heat to reflux for 14 hours, and cool. Add 60ml of water and 20ml of 50% KOH aqueous solution, and let stand to separate layers. The aqueous phase was washed with saturated NaCl and extracted three times with dichloromethane. Combined organic phases were washed with saturated NaCl, anhydrous Na 2 SO 4 Dry, filter and evaporate to dryness. The pure compound (2) was obtained by column chromatography with a yield of 58%.

[0072] 2). Synthesis of N-tert-butoxycarbonyl-N'-phenylethylenediamine (3):

[0073] N-phenylethylenediamine (2) (1.0 mmol) and di-tert-butyl carbonate (1.0 mmol) were dissolved in 15 ml of methanol, stirred for 3 hours, and concentrated under reduced pressure to obtain a brown oil. The pure white solid compound (3) was obtained by column chromatography with a yield of 86%.

[0074] 3). Synthes...

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PUM

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Abstract

The invention discloses a dual-channel inhibitor using Raf / MEK / ERK and PI3K / Akt as targets. The chemical name of the composition is 1-(2-amido) ethyl-3-(3-(4-methoxyl) phenyl) allyl indole-2-ketone hydrochloride, and the structural formula (I) of the composition is as shown in the specification. The invention also discloses a preparation method of the composition and an application of the composition for preparing an anti-tumor drug. The dual-channel inhibitor disclosed by the invention has the advantages of improving titer and reducing the occurrence probability of drug resistance as well as reducing toxicity and improving the compliance of patients. Thus, the design and development of the dual-channel inhibitor provide a new chemical tool for cancer research groups, and the dual-channel inhibitor is possible to be developed as a new anti-cancer agent.

Description

technical field [0001] The present invention relates to a dual-channel inhibitor targeting Raf / MEK / ERK and PI3K / Akt, specifically, the present invention provides 1-(2-amino)ethyl-3-(3-(4-methyl Oxygen)phenyl)propenylindol-2-one hydrochloride and preparation method thereof, can be used as a dual-channel inhibitor with Raf / MEK / ERK and PI3K / Akt as dual targets, can be used for treating cancer, Belongs to the field of medicinal chemistry technology Background technique [0002] Malignant tumor is a major disease that seriously endangers human health. Infiltration and metastasis are one of its basic characteristics, and they are also the main reason for the death of patients caused by clinical treatment failure. At present, there is a lack of effective anti-tumor metastasis drugs in clinic. However, most of the existing drugs have poor tumor selectivity, low curative effect, and large toxic and side effects. The study of effective anti-cancer and anti-metastasis drugs has beco...

Claims

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Application Information

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IPC IPC(8): A61K31/4045C07D209/34A61P35/00
Inventor 吴敬德王雪林曲颖江余祺李晓杨
Owner 北京太洋药业股份有限公司
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