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Indole-2-ketone compound as well as preparation method and application thereof

A technology of ketone compounds and compounds, which is applied in the field of indole-2-one compounds and their preparation, can solve the problems of unavailable drugs and achieve important practical value

Pending Publication Date: 2022-03-22
深圳市乐土生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients will inevitably develop acquired drug resistance during the treatment process. In order to prevent patients from becoming drug-resistant, it is necessary to continuously develop new anti-tumor drugs

Method used

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  • Indole-2-ketone compound as well as preparation method and application thereof
  • Indole-2-ketone compound as well as preparation method and application thereof
  • Indole-2-ketone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Example 1 (Z)-3-((4-amino-1H-pyrrol-2-yl)methylene)-6-methyl-1-(4-(methylsulfonyl)phenyl)-2- Preparation of Oxoindoline-5-carbonitrile (Compound I-1)

[0118]

[0119] Adopt the following synthetic synthesis route:

[0120]

[0121] Step 1: Synthesis of (Z)-6-methyl-1-(4-(methylsulfonyl)phenyl)-3-((4-nitro-1H-pyrrol-2-yl)methylene)- 2-Oxoindoline-5-carbonitrile

[0122] Intermediate A-1 (163 mg, 0.5 mmol) and 4-nitro-1H-pyrrole-2-carbaldehyde (70 mg, 0.5 mmol) were dissolved in 20 mL of absolute ethanol with stirring, and two drops of piperidine were added dropwise, gradually turning yellow A solid precipitated out, and the reaction was continued overnight at room temperature. TLC detected that all the raw materials disappeared, filtered, the filter cake was rinsed with a small amount of cold ethanol, and dried to obtain 116 mg of a yellow solid, yield: 52%. TL C: Rf0.5 (petroleum ether: ethyl acetate = 1:1). ESI-MS: [M+1]=449.

[0123] Step 2: Synthesis of ...

Embodiment 2

[0126] Example 2 (Z)-3-((5-amino-6-chloropyridin-2-yl)methylene)-6-methyl-1-(4-(methylsulfonyl)phenyl)-2 - Preparation of oxoindoline-5-carbonitrile (compound 1-2)

[0127]

[0128] Adopt the following synthetic route:

[0129]

[0130] Step 1: Synthesis of (Z)-3-((6-chloro-5-nitropyridin-2-yl)methylene)-6-methyl-1-(4-(methylsulfonyl)phenyl) -2-Oxoindoline-5-carbonitrile

[0131] Intermediate A-1 (163 mg, 0.5 mmol) and 6-chloro-5-nitro-2-formylpyridine (92 mg, 0.5 mmol) were dissolved in 20 mL of absolute ethanol with stirring, and two drops of triethylamine were added dropwise, Raise the temperature to 80°C to react overnight. It was detected by TLC that all the raw materials disappeared, the reaction solution was concentrated, and purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain 160 mg of yellow solid, yield: 65%. ESI-MS: [M+1]=495.

[0132] Step 2: Synthesis of (Z)-3-((5-amino-6-chloropyridin-2-yl)methylene)-6-methyl-1-(4-(methylsulfonyl)phe...

Embodiment 3

[0135] Example 3 (Z)-3-((5-amino-6-(piperidin-1-yl)pyridin-2-yl)methylene)-1-(4-(methylsulfonyl)phenyl) - Preparation of 2-oxoindoline-5-carbonitrile (compound 1-3)

[0136]

[0137] Adopt the following synthetic route:

[0138]

[0139] Step 1: Synthesis of (Z)-1-(4-(methylsulfonyl)phenyl)-3-((5-nitro-6-(piperidin-1-yl)pyridin-2-yl)methylene Base) -2-oxoindoline-5-carbonitrile

[0140] Intermediate A-2 (156mg, 0.5mmol) and 6-chloro-5-nitro-2-formylpyridine (93mg, 0.5mmol) were dissolved in 20mL absolute ethanol with stirring, and piperidine (64mg, 0.75 mmol), the temperature was raised to 80°C for overnight reaction. It was detected by TLC that all the raw materials disappeared, the reaction solution was concentrated, and purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain 122 mg of a yellow solid, yield: 46%. ESI-MS: [M+1]=530;

[0141] Step 2: Synthesis of (Z)-3-((5-amino-6-(piperidin-1-yl)pyridin-2-yl)methylene)-1-(4-(methylsulfonyl)phenyl )-...

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Abstract

The invention relates to an indole-2-ketone compound as well as a preparation method and application thereof. The indole-2-ketone compound comprises a structure as shown in a general formula (I) or a tautomer, a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The indole-2-ketone compound provided by the invention has a remarkable inhibition effect on cancer cell proliferation, is suitable for being further developed into a cancer treatment medicine, and has an important practical value.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an indole-2-one compound and its preparation method and application. Background technique [0002] Lung cancer is a disease that seriously threatens human health and social development. Non-small cell lung cancer (NSCLC) accounts for about 80-85% of the total number of lung cancers, and most patients are diagnosed at an advanced stage. Patients with locally advanced NSCLC in good health can achieve a disease-free survival period of 8 months after a series of chemotherapy, radiotherapy and (or) surgery, and the 5-year survival rate is less than 15%. Therefore, it is necessary to find new effective drugs. There are currently some targeted drugs on the market for the treatment of non-small cell lung cancer, such as epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib, osimertinib, etc. However, patients will inevitably develop acquired dr...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D401/06C07D401/14C07D209/34C07D417/06A61P35/00A61P11/00A61K31/506A61K31/444A61K31/4439A61K31/4709A61K31/404
CPCC07D403/06C07D401/06C07D401/14C07D209/34C07D417/06A61P35/00A61P11/00
Inventor 邢青峰朱锡祯黄凯迪周彤宋侠侠吴焕娣何裕华姜孝明
Owner 深圳市乐土生物医药有限公司
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