Naphthyl urea-piperazine compound as well as preparation method and application thereof

A compound, naphthylurea technology, applied in the field of tumor targeted therapy, can solve the problem of unmet demand for JAKs/STAT3 inhibitors

Pending Publication Date: 2022-07-05
HENAN RADIOMEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are currently three JAK inhibitors approved for marketing in immune diseases abroad, the research of multiple JAKs inhibitors for tumor treatment is in the late cli

Method used

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  • Naphthyl urea-piperazine compound as well as preparation method and application thereof
  • Naphthyl urea-piperazine compound as well as preparation method and application thereof
  • Naphthyl urea-piperazine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Synthesis of Compounds

[0049]

[0050] ID210916B-1:

[0051] ID210917B-1:

[0052] ID210918B-1:

[0053] ID210919B-1:

[0054] ID211130C-1:

[0055] ID211203B-1:

[0056] IY211214C-1:

[0057] IY211228B-1:

[0058] IY220302B-1:

[0059] IY220209A-1:

[0060] IY220313A-1:

[0061] IY220219A-1:

[0062] ID210928B-1:

[0063] ID210929B-1:

[0064] IY220319A-1:

[0065] ID211008B-1:

[0066] ID211009B-1: R 3 =H;

[0067] ID211010B-1: R 3 =CH 3 ;

[0068] ID211116B-1:

[0069] ID211012B-1:

[0070] The specific synthesis method, taking compound ID210916B-1 as an example, the structural formulas are as follows:

[0071]

[0072] Compound ID210916B-1 is named tert-butyl 4-(2-(4-(((4-(3-(pyridin-4-ylmethyl)ureido)naphthalen-1-yl)oxy)methyl)phenoxy)ethyl)piperazine -1-carboxylate,

[0073] Its synthetic route is as follows:

[0074]

[0075] Step 1. tert-butyl 4-(2-(4-formylphenoxy)ethyl)pipera...

Embodiment 2

[0121] Example 2: ID210916B-1, ID210917B-1, ID210918B-1, ID210919B-1, D211130C-1, ID211203B-1, IY211214C-1, IY211228B-1, IY220302B-1, IY220209A-1, IY22A-1, IY222031 1, ID210928B-1, ID210929B-1, IY220319A-1, ID211008B-1, ID211009B-1, ID211010B-1, ID211116B-1 and ID211012B-1, etc. on the proliferation inhibition of breast cancer and liver cancer cells

[0122] Collect tumor cells in logarithmic growth phase respectively, adjust the concentration of cell suspension to 5 × 10 4 cells / mL, added to a 96-well cell culture plate with a volume of 100ul per well. With DMSO as solvent control, WP1066 (Chinese name: (2E)-3-(6-bromo-2-pyridyl)-2-cyano-N-[(1S)-1-phenylethyl]-2- Acrylamide, CAS: 857064-38-1, the structure is ) as a positive control, the novel naphthalene urea-piperazine compounds ID210916B-1, ID210917B-1, ID210918B-1, etc. of the present invention were diluted with DMSO and added to the culture well, so that the final concentrations of the compounds in the system were 0.1...

Embodiment 3

[0124] Example 3: Effect of ID210916B-1 on induction of TNBC cell cycle arrest

[0125] MDA-MB-468 or 4T1 cells in logarithmic growth phase were taken, digested and centrifuged to make single cell suspension. After counting, cells were plated into a 12-well plate, and both cells were seeded at 2 × 10 per well. 5 Cells were plated in 3 wells for parallel control. 16h after plating, the cells were treated with compound. Using DMSO as the compound solvent, the final concentration of compound ID210916B-1 in 4T1 cell suspension was 0, 2.5, 5 and 10 μM, respectively, and the final concentration of compound ID210916B-1 in MDA-MB-468 cell suspension was 0, 0.025, respectively , 0.05 and 0.1 μM. 48h after dosing, each empty cell was digested with trypsin, resuspended and counted, and the cell concentration in each well was adjusted to 5×10 5 indivual. After digestion, centrifuge and discard the supernatant, then wash the cells twice with PBS (2000 rpm, centrifugation for 5 min), t...

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Abstract

The invention discloses naphthyl urea-piperazine compounds and a preparation method and application thereof.The naphthyl urea-piperazine compounds can remarkably inhibit activation of cell signal transduction JAKs/STATs signals under the low dosage, and the experimental results of a cell proliferation experiment, an immunoblotting experiment, a cell cycle experiment, a protein transfer membrane transport experiment, a cell invasion and migration experiment and the like show that the naphthyl urea-piperazine compounds have the advantages that the naphthyl urea-piperazine compounds can be used for remarkably inhibiting activation of cell signal transduction JAKs/STATs signals; the compound can specifically inhibit JAK2 signal activation and expression of downstream STAT3, CyclinD1, CyclinB1, MMP9 and other target genes, induce blocking of a cell cycle G1 phase and cell apoptosis, can significantly inhibit proliferation of breast cancer, liver cancer, lung cancer, colon cancer, leukemia, lymphoma, multiple myeloma, retinoblastoma and other tumor cell strains, and can be used for preparing drugs for treating breast cancer, liver cancer, lung cancer, colon cancer, leukemia, lymphoma, multiple myeloma, retinoblastoma and the like. Therefore, the compound has a prospect of being developed into a targeted anti-cancer drug of a related target spot of a JAKs/STATs cell regulation signal transduction pathway.

Description

technical field [0001] The invention belongs to the field of tumor targeted therapy, and particularly relates to a class of naphthylurea-piperazine compounds and a preparation method and application thereof. Background technique [0002] Numerous studies have demonstrated that abnormal activation of STATs (Signal transducer and activators of transcriptions) signaling is associated with many diseases, including cancer and immune-related diseases. Overexpression and constitutive activation of STAT3 are common in a variety of solid tumors and hematological cancers. STAT3 is a member of the STATs family and is a substrate protein of JAK2 (Janus kinase2), which has been confirmed to be closely related to the occurrence, development and malignant transformation of cancer. Under normal circumstances, STAT3 exists in the cytoplasm as an inactive monomer, and there is a strict negative feedback regulation mechanism. When the negative feedback regulation mechanism of JAK2 or STAT3 i...

Claims

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Application Information

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IPC IPC(8): C07D213/40C07D239/26C07D239/34C07D401/12C07D413/12C07D417/12A61P35/00A61P35/02A61K31/506A61K31/496A61K31/497
CPCC07D213/40C07D239/26C07D239/34C07D401/12C07D413/12C07D417/12A61P35/00A61P35/02Y02A50/30
Inventor 徐学军杨玉坡段超群杨争艳徐红运裴梦富
Owner HENAN RADIOMEDICAL SCI & TECH CO LTD
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