Pyrazolopyrimidine compound containing piperazine or its medicinal salt and preparation method and application thereof

A technology for pyrazolopyrimidines and compounds is applied in the field of pyrazolopyrimidine compounds or their medicinal salts and their preparation, which can solve the problems such as slowing down the growth rate of tumors and achieve the effect of novel structure

Inactive Publication Date: 2018-11-06
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GSK690693 is the first AKT inhibitor to enter clinical research. Intraperitoneal injection of GK690693 in mice transplanted with BT474 breast cancer cells greatly slowed down the tumor growth rate. Intravenous injection of GSK690693 in cancer patients caused drug-related hyperglycemia and caused the disease The drug has been terminated in clinical phase I; other representative AKT inhibitors such as GSK2110183 have completed clinical phase II clinical research in blood cancer patients; AZD5363 has completed phase I clinical research in the treatment of metastatic prostate cancer; GDC0068 is being combined with paclitaxel to treat metastasis However, there are still some key issues that have not been fully resolved, such as toxic side effects, selectivity, etc.

Method used

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  • Pyrazolopyrimidine compound containing piperazine or its medicinal salt and preparation method and application thereof
  • Pyrazolopyrimidine compound containing piperazine or its medicinal salt and preparation method and application thereof
  • Pyrazolopyrimidine compound containing piperazine or its medicinal salt and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of Compound Y

[0050] 1) Preparation of Intermediate 2:

[0051] Dissolve 3-substituted-1H-pyrazolo[3,4-d]pyrimidine (10mmol) in DMF (15mL), add DIEA (15mmol, 2.5mL), 1-tert-butoxycarbonylpiperazine (10.5mmol ), microwave reaction at 90°C for 20-30min, after the reaction was completed, the reaction solution was quenched with ice water (150mL), extracted with ethyl acetate (3×30mL), the organic phases were combined, and saturated ammonium chloride (3 ×20mL), washed the organic phase with saturated brine (3×20mL), dried over anhydrous sodium sulfate, filtered, evaporated the solvent under reduced pressure, purified by column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain intermediate 2 .

[0052] The prepared intermediate 2 is the following compounds:

[0053] tert-butyl 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (2a)

[0054] White solid, 89% yield, 1 H NMR (400MHz, DMSO) δ8.94(s,1H), 8.60(s,1H), 4.32(s,4H), 3.35(s,4H)...

Embodiment 2

[0107] Determination of compound's inhibitory activity on AKT1 kinase and anti-proliferation activity of PC-3 cells

[0108] The biological activity of the target compounds Y1 to Y18 prepared in Example 1 was determined according to the following method, and the results are shown in Table 1.

[0109] The inhibitory activity of the compound on AKT1 kinase and the anti-proliferation activity of PC-3 cells were carried out using the methods reported in the literature. For details, see: LIu Y, Yin Y, Zhang J, NomIe K, Zhang L, Yang D, Wang ML, ZhaoG.2016. DIscovery of 4-(PIperazIn-1-yl)-7H-pyrrolo[2,3-d]pyrImIdIneDerIvatIves as Akt InhIbItors. Arch Pharm (WeInheIm) 349:356-362. LIu Y, Yin Y, Zhang Z, LI C.J, Zhang H, Zhang D, JIang C, NomIe K, Zhang L, Wang M.L, ZhaoG. 2017. Structural optImIzatIon elaborates novel potent Akt InhIbItors wIthpromIsIng antIcancer actIvIty. Eur J Med Chem 138:543-551.

[0110] Table 1. Target compounds Y1 to Y18 have inhibitory activity on AKT1 kina...

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PUM

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Abstract

The invention discloses a pyrazolopyrimidine compound containing piperazine or its medicinal salt. The pyrazolopyrimidine compound is characterized by comprising a following general formula Y shown asa specification, wherein R1 is hydrogen, single halogen substitute, double halogen substitute, a methoxy group or alkane; R2 is hydrogen, chlorine or bromine; and R3 is hydrogen, an amino group, a substituted amino group, substituted piperidine or a substitutedpiperazinyl group. The pyrazolopyrimidine compound containing piperazine or its medicinal salt have novel structures and are shown as thegeneral formula Y, and the introduction of a R3 group (the substituted amino group) is a necessary group for increasing the activity of the compound. Through the above design reconstruction mode, thepyrazolopyrimidine compound has AKT1 kinases inhibition activity, and prevents inhibition activity on prostate cancer cell lines (PC-3 cells).

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis and medicine, and specifically relates to a piperazine-containing pyrazolopyrimidine compound or a medicinal salt thereof, a preparation method and application thereof. Background technique [0002] Phosphatidylinositol 3-kinase (PI3K) / AKT / mTOR signaling pathway is currently a pathway that is actively studied and frequently mutated in tumor cells. It plays an important role in cell signal transduction, promotion of cell proliferation, survival, differentiation and apoptosis. The excessive activation of this signaling pathway is very common in acute and chronic leukemia, lymphoma, myeloma, ovarian cancer, prostate cancer and other tumors. This signal is usually activated by the binding of various ligands to multiple receptors (mainly receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs)); The combination of extracellular growth factors and RTKs activates RTKs;...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00
CPCA61P35/00C07D487/04Y02P20/55
Inventor 杨德志汪蓓蕾袁泽利令狐浪
Owner ZUNYI MEDICAL UNIVERSITY
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