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Diarylurea PI3Kalpha/mTOR double-target inhibitor and pharmaceutical composition, and application of inhibitor and pharmaceutical composition

A diarylurea, dual-target technology, applied in the field of medicine, can solve problems such as drug resistance of single mTOR inhibitors, and achieve the effects of significant anti-tumor activity, novel structure and good development prospects

Active Publication Date: 2021-06-29
GUIZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the clinical treatment of single mTOR inhibitors is prone to drug resistance

Method used

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  • Diarylurea PI3Kalpha/mTOR double-target inhibitor and pharmaceutical composition, and application of inhibitor and pharmaceutical composition
  • Diarylurea PI3Kalpha/mTOR double-target inhibitor and pharmaceutical composition, and application of inhibitor and pharmaceutical composition
  • Diarylurea PI3Kalpha/mTOR double-target inhibitor and pharmaceutical composition, and application of inhibitor and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1: 6-(3-(4-(4,6-dimorpholine-1,3,5-triazin-2-yl)phenyl)ureido)-1-oxoisoindoline- tert-Butyl 2-carboxylate

[0144] Step 1: Synthesis of 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine

[0145] The structural formula of 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine:

[0146] Synthetic method: add cyanuric chloride (0.5g, 2.7mmol) in 50mL reaction flask, with anhydrous CH 2 Cl 2 Dissolve, cool to -10°C, slowly add a mixture of morpholine (0.47g, 5.4mmol) and triethylamine (0.5ml, 2.7mmol) dropwise, after the addition is complete, move the reaction to 0°C for 1h, then rise to room temperature Reaction 3h. A white solid precipitated out of the reaction solution. After TLC detection reaction finishes, reaction solution is poured in the ice water (50ml), separates CH 2 Cl 2 layer, the aqueous phase with CH 2 Cl 2 (100mL) was extracted once. The combined organic layers were washed once with saturated NaCl aqueous solution (50 mL), and the organic ...

Embodiment 2

[0153] Example 2: 1-(4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenyl)-3-(3-oxoisoindoline-5-yl ) urea

[0154] The structural formula of 1-(4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenyl)-3-(3-oxoisoindoline-5-yl)urea :

[0155] Synthesis method: 6-(3-(4-(4,6-dimorpholine-1,3,5-triazin-2-yl)phenyl)ureido)-1-oxo in Example 1 Dissolve tert-butyl isoindoline-2-carboxylate (0.05g, 0.08mmol) in redistilled DCM (2ml), cool to 0°C, slowly add trifluoroacetic acid (0.018ml) dropwise, move to room temperature and stir 2h. TLC monitored the completion of the reaction. The solvent was removed by evaporation to obtain a crude product, which was then purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain 30 mg of the target compound, yield: 72%. HRMS(ESI)calcd.for C26H29N8O4[M+H] + :517.2312,found:517.2308. The NMR data are 1 H NMR (400MHz, DMSO-d 6 )δ: 9.21(s, 2H), 8.55(s, 1H), 8.28(d, J=8.8Hz, 2H), 7.91(d, J=1.9Hz, 1H), 7.62–7.54(m, 3H), 7.47 (d, J = 8.2Hz, 1H), 4....

Embodiment 3

[0156] Example 3: 5-(3-(4-(4,6-dimorpholine-1,3,5-triazin-2-yl)phenyl)ureido)-1,3-dioxaindole tert-Butyl-line-2-carboxylate

[0157] 5-(3-(4-(4,6-Dimorpholine-1,3,5-triazin-2-yl)phenyl)ureido)-1,3-dioxaindoline-2- The structural formula of tert-butyl carboxylate:

[0158] Synthetic method: Change the condensed heterocyclic segment in Step 3 of Example 1 to tert-butyl 5-amino-1,3-dioxaindoline-2-carboxylate, and other steps and operations are similar to Example 1. Yield: 65.6%. HRMS(ESI)calcd.forC31H35N8O7[M+H] + :631.2629,found:631.2627. The NMR data are 1 H NMR (400MHz, DMSO-d 6 )δ: 9.64(s, 1H), 9.21(s, 1H), 7.92–7.88(m, 2H), 7.77(d, J=1.9Hz, 1H), 7.46(d, J=8.3Hz, 1H), 7.36(dd,J=8.3,1.9Hz,1H),7.21–7.17(m,2H),3.43(d,J=34.3Hz,8H),3.28–3.24(m,8H),1.15(s,9H) . 13 C NMR (100MHz, DMSO-d 6 )δ: 165.96, 165.71, 164.14, 164.06, 152.77, 148.11, 138.76, 138.70, 135.89, 131.14, 130.89, 129.77, 123.41, 121.02, 120.53, 114.90, 83.49, 456.89.

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Abstract

The invention discloses a diarylurea PI3Kalpha / mTOR double-target inhibitor as well as a pharmaceutical composition, and application of the diarylurea PI3K alpha / mTOR double-target inhibitor and the pharmaceutical composition. The diarylurea PI3Kalpha / mTOR double-target inhibitor comprises a substituted triazine compound with a general formula (I) described in the specification, and a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof. The diarylurea PI3Kalpha / mTOR double-target inhibitor provided by the invention and the pharmaceutical composition containing the diarylurea PI3K alpha / mTOR double-target inhibitor can be used for inhibiting PI3Kalpha / mTOR double kinase and proliferative diseases caused by the PI3Kalpha / mTOR double kinase, and an inhibitor with better effectiveness and selectivity can be provided for treatment of the PI3Kalpha / mTOR double-kinase-induced proliferative diseases.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of diaryl urea PI3Kα / mTOR dual-target inhibitors and its pharmaceutical composition and application. Background technique [0002] At present, cancer is one of the most common fatal diseases. Its essence is that the signal transduction regulation of tumor cells with gene mutations caused by carcinogenic factors is abnormal and malignant proliferation occurs. Common clinical treatments include surgical resection, radiotherapy, and chemotherapy. These traditional treatments have disadvantages such as low selectivity, high toxicity, and poor tolerance (Nature 2019, 575(7782), 299-309). In recent years, targeted therapy based on clinical needs has attracted more and more attention, and small molecule targeted antineoplastic drugs have become a research and development hotspot because they greatly reduce the harm to patients' bodies. So far, hundreds of targeted drugs have b...

Claims

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Application Information

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IPC IPC(8): C07D413/12C07D401/14C07D405/12C07D413/14C07D491/056C07D491/08A61P35/00A61P35/02A61K31/5377A61K31/553
CPCC07D413/12C07D401/14C07D405/12C07D413/14C07D491/056C07D491/08A61P35/00A61P35/02
Inventor 张吉泉吴春风王丽丽武婷婷汤磊
Owner GUIZHOU MEDICAL UNIV
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