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Indazole hydrazide compound and application thereof

A technology of indazole hydrazide and compound, applied in the field of drug synthesis, can solve problems such as failure and weak anti-tumor activity

Active Publication Date: 2021-06-11
PEKING UNIV FIRST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although cilengitide monotherapy is well tolerated, the antitumor activity is relatively weak, and the phase 3 clinical trial of cilengitide ended in failure

Method used

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  • Indazole hydrazide compound and application thereof
  • Indazole hydrazide compound and application thereof
  • Indazole hydrazide compound and application thereof

Examples

Experimental program
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preparation example Construction

[0072] The present invention also provides a method for preparing the above-mentioned indazole hydrazide compound, comprising: reacting the compound represented by formula (II) with RCOR' to obtain the compound represented by formula (I).

[0073]

[0074] The compound represented by the formula (II) and RCOR' are preferably reacted in a solvent; the solvent is preferably an alcohol solvent, more preferably ethanol; the reaction is preferably a reflux reaction; the compound represented by the formula (II) The molar ratio to RCOR' is preferably 1:(1-1.2); in the examples provided by the present invention, it is specifically 1:1.1.

[0075] The compound represented by the formula (II) is preferably carried out according to the following steps: the compound represented by the formula (III) is reacted with hydrazine to obtain the compound represented by the formula (II).

[0076]

[0077] Among them, R″ is a C1-C5 alkyl group, more preferably a C1-C4 alkyl group, and still m...

Embodiment 1

[0091] Compounds represented by formula (1), formula (2) to formula (10) were prepared according to the following steps:

[0092]

[0093] A sodium ethoxide solution was prepared by adding sodium (1.5 g, 65 mmol) to absolute ethanol (20 mL) at 0°C; then a mixture of cyclohexanone (4.41 g, 44 mmol) and diethyl oxalate (7.3 g, 50 mmol) was added slowly , and stirred the solution at room temperature for 12 h, and then decomposed the reaction mixture with 2N sulfuric acid solution, then extracted the mixture with ethyl acetate, dried and concentrated the organic solvent, and the obtained crude product was purified by n-hexane:ethyl acetate (12:1) column Further purification by chromatography gave product 2 as a yellow oil (5.87 g, 67%).

[0094] Hydrazine (448 mg, 14 mmol) was slowly added to a cooled suspension of product 2 (2.38 g, 12 mmol) in acetic acid (5 mL), the mixture was heated to reflux for 1 h, poured into ice water, washed with NaHCO 3 Neutralized and extracted wi...

Embodiment 3

[0135] Example 3: Detection of antitumor activity

[0136] 3.1 Experimental method

[0137] 3.1.1 Tumor cell recovery culture

[0138] Take out cryopreserved tumor cells (prostate cancer, ovarian cancer and other cells) from liquid nitrogen, dissolve quickly at 37°C, add 5ml of the corresponding medium containing FBS, centrifuge at 300g for 5 minutes, collect the precipitate, and resuspend in the corresponding medium Then, after thorough mixing, it was added to a 24-well cell culture dish, supplemented with medium to a total volume of 2 mL per well, incubated at 37°C to about 90% confluence, passaged, expanded or counted for plating.

[0139] 3.1.2 Tumor cell inoculation

[0140] After the tumor cells were cultured enough to be passaged, they were digested with trypsin and a single cell suspension was prepared. After counting the cells, adjust the cell concentration to 1.2×10 with the corresponding medium 4 cells / ml, add 90 μl of the mixture to a 96-well plate, incubate at...

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Abstract

The invention provides an indazole hydrazide compound as shown in a formula (I), wherein R is selected from substituted alkyl, substituted alkenyl or substituted phenyl; substituent groups in the substituted alkyl group and the substituted alkenyl group comprise phenyl and / or substituted phenyl; and R' is selected from H or alkyl. Compared with the prior art, the indole hydrazide compound provided by the invention can be used as an integrin avbeta3 receptor antagonist, has obvious anti-prostatic cancer activity, and has a significant inhibition effect on enzalutamide drug-resistant cell lines.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to an indazole hydrazide compound and an application thereof. Background technique [0002] Prostate cancer is one of the most common malignant tumors among men in my country and Western countries, and with the aging of the population in my country and changes in living habits, the incidence of prostate cancer is rising rapidly, and two-thirds of prostate cancer patients are diagnosed. It is too late, and the opportunity for radical treatment is lost. Endocrine therapy based on anti-androgen drugs is the preferred treatment for advanced prostate cancer, with satisfactory initial results, but after 12 to 18 months, most patients will gradually develop into highly metastatic castration-resistant prostate. Cancer (castration resistant prostate cancer, CRPC), of which 90% metastatic CRPC occurs in the bone. [0003] For CRPC patients with resistance to first-generation anti-andr...

Claims

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Application Information

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IPC IPC(8): C07D231/56A61P35/00
CPCC07D231/56A61P35/00
Inventor 崔一民庞晓丛张智何旭张峻岭谷延伦
Owner PEKING UNIV FIRST HOSPITAL
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