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 singl

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
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Example Embodiment

[0143] Example 1: 6- (3- (4- (4- (4,6-diimorino-1,3,5-triazine-2-yl) phenyl) urea group) -1-oxo-isoindenpropine- 2-carboxylic acid tert butyl

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

[0145] 4,4 '- (6-chloro-1,3,5-triazine-2,4-dika) stomatal formula:

[0146] Synthesis: Add tri chloride (0.5 g, 2.7 mmol) in a 50 ml reaction bottle, with anhydrous CH 2 CL 2 Dissolved, cooled to -10 ° C, slowly dropped with Morpholine (0.47 g, 5.7 mmol) mixture of triethylamine (0.5 ml, 2.7 mmol), and the reaction was added to 0 ° C reaction for 1 h, and then raised to room temperature Reaction 3H. The reaction liquid has a white solid precipitation. After the TLC detection reaction, the reaction solution was poured into ice water (50ml), separated from CH. 2 CL 2 Layer, water phase with CH 2 CL 2 (100ml) extraction once. The organic layer was combined, washed once with a saturated NaCl (50ml), and the organic layer re-use water Na. 2 SO 4 dry. The solvent was ...

Example Embodiment

[0153] Example 2: 1- (4- (4,6-diimorin-1,3,5-triazine-2-yl) phenyl) -3- (3-oxine isoindenin-5-yl) Urea

[0154] 1- (4- (4- (4,6-diimorino-1,3,5-triazine-2-yl) phenyl) -3- (3-oxine isoindenin-5-yl) urea :

[0155] Synthetic method: 6- (3- (4- (4- (4- (4,6-diimorino-1,3,5-triazine-2-yl) phenyl) ureide group) -1-oxide) -1-oxide Isoindopulin-2-carboxylic acid tert-butyl (0.05 g, 0.08 mmol) is dissolved in a vapor DCM (2 mL), cooled to 0 ° C, slowly dropped with trifluoroacetic acid (0.018 mL), and stirred at room temperature 2h. The TLC monitoring reaction is complete. The solvent was evaporated, and the crude product was purified, then purified by silica gel column chromatography (DCM / MeOH = 10 / 1), the target compound was 30 mg, yield: 72%. HRMS (ESI) Calcd.for C26H29N8O4 [M + H] + : 517.2312, Found: 517.2308. Nuclear magnetic data is 1 H NMR (400MHz, DMSO-D 6 Δ: 9.21 (S, 2H), 8.55 (S, 1H), 8.28 (D, J = 8.8 Hz, 2H), 7.91 (D, J = 1.9 Hz, 1H), 7.62-7.54 (M, 3H), 7.47 (D, J = 8.2Hz, ...

Example Embodiment

[0156] Example 3: 5- (3- (4- (4,6-diimorino-1,3,5-triazine-2-yl) phenyl) urea group) -1,3-dioxane Porroline-2-carboxylic acid tert-butyl

[0157] 5- (3- (4- (4- (4,6-diimorino-1,3,5-triazine-2-yl) phenyl) urea group) -1,3-dioxane-2- Structural formula of t-butyl carboxylate:

[0158] Synthetic method: The condensed heterocyclic fragment in Example 1 was changed to 5-amino-1,3-dioxylindolin-2-carboxylic acid tert butyl, other steps and operations similar to Example 1. Yield: 65.6%. HRMS (ESI) Calcd.FORC31H35N8O7 [M + H] + : 631.2629, Found: 631.2627. Nuclear magnetic data is 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 = 1.9 Hz, 1H), 7.46 (D, J = 8.3 Hz, 1H), 7.36 (DD, J = 8.3, 1.9 Hz, 1H), 7.21-7.17 (m, 2H), 3.43 (D, J = 34.3 Hz, 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, 12.53, 114.90, 83.49, 66.20, ...

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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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