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4-aminopyrrolopyrimidine derivative and preparation method and application thereof

A kind of use, alkyl technology, applied in the field of medicine, can solve the problems of complex tumor metastasis mechanism, tumor metastasis problem, and emergence of drug resistance in malignant tumor metastasis

Active Publication Date: 2020-05-05
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] In recent years, with the continuous improvement of medical conditions, although surgery and adjuvant therapy can quickly and effectively solve the problem of primary tumors, tumor metastasis is still a major medical problem
The reason lies in the complex mechanism of tumor metastasis and the emergence of drug resistance in malignant tumor metastasis

Method used

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  • 4-aminopyrrolopyrimidine derivative and preparation method and application thereof
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  • 4-aminopyrrolopyrimidine derivative and preparation method and application thereof

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Embodiment 1

[0137] Embodiment 1 Preparation of Compound 36b of the present invention

[0138]

[0139] 1 dichloromethane, N-iodosuccinimide, potassium hydroxide, normal temperature, 12 hours, 90%;

[0140] ii N, N-dimethylformamide, ethyl iodide, cesium carbonate, 80 degrees, 12 hours, 50%;

[0141] iii Acetonitrile, N,N-diisopropylethylamine, 4-dimethylaminopyridine, di-tert-butyl dicarbonate, 80 degrees, 3 hours, 90%;

[0142] iv Anhydrous dioxane, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, potassium acetate, pinacol diborate, 95 degrees, 24 hour, 60%;

[0143] v 1,4-dioxane / water=5:1, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, tricyclohexylphosphine, carbonic acid Cesium, 95 degrees, 18 hours, 58%;

[0144] vi 1,4-dioxane, ethanol hydrochloride, room temperature, 4 hours, 59%;

[0145] vii N,N-Dimethylformamide, N,N-Diisopropylethylamine, m-oxytrifluoromethylphenylacetic acid, 2-(7-azobenzotriazole)-N,N...

Embodiment 2

[0159] Embodiment 2 The in vitro kinase experiment of compound 36b of the present invention

[0160] In vitro kinase assays were performed using the Kinase Profiler service provided by Eurofins. The experimental method is as follows: the test small molecule compound 36b (0.001-10 μ M), the test protein kinase and the substrate, 10 mM magnesium acetate and [γ- 33 P-ATP] was incubated with the buffer, and the reaction was started by adding Mg\ATPmix. After incubation at room temperature for a period of time, 3% phosphate solution was added to the buffer to terminate the reaction. Then quantitatively pipette 10 μL of the reaction mixture onto the P30 filter paper, wash it three times with 75 mM phosphate solution, and wash it once with methanol, dry the P30 filter paper and add scintillation liquid for scintillation counting. The inhibitory activity of compound 36b was measured by half inhibitory concentration IC 50 to indicate that the IC 50 The values ​​were obtained by fitt...

Embodiment 3

[0172] Example 3 In vitro affinity test of compound 36b of the present invention and RIP family kinases

[0173] The in vitro kinase affinity analysis test of compound 36b for the RIP family was sent to DiscoverRx Company and completed by KINOMEscan service. KINOMEscan TM The experiment mainly includes: 1. DNA-labeled kinase; 2. Decoy molecules that can bind to the kinase; 3. Compounds to be tested. KINOMEscan TM The magnetic beads are attached with bait molecules, which can bind to the active site of the kinase. If the test compound also binds to the kinase, it competes with the bait. Or the compound to be tested cannot directly bind to the active site of the kinase, but can change the active site of the kinase and also reduce the amount of kinase bound to the magnetic beads. DNA is attached to the kinase, and the change of the number of kinase on the magnetic beads can be quantitatively reflected by qPCR. This system can be used to detect the binding of the kinase to th...

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Abstract

The invention relates to a 4-aminopyrrolopyrimidine derivative and a preparation method and application thereof, and belongs to the field of medicines. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The compound can significantly inhibit the activity of RIPK1 kinase, has high selectivity and good safety, and is a potential therapeutic drug for RIPK1 kinase related diseases. TNF alpha induced SIRS model and mouse melanoma lung metastasis model experiments prove that the compound disclosed by the invention can play a role in inhibiting RIPK1 kinase in vivo and has remarkable anti-inflammatory and anti-tumor metastasis activity. The invention provides a new strategy and means for comprehensively treating tumor metastasis.

Description

technical field [0001] The invention relates to 4-aminopyrrolopyrimidine derivatives, a preparation method and application thereof, and belongs to the field of medicine. Background technique [0002] In recent years, with the continuous improvement of medical conditions, although surgery and adjuvant therapy can quickly and effectively solve the problem of primary tumors, tumor metastasis is still a major medical problem. The reason lies in the complex mechanism of tumor metastasis and the emergence of drug resistance in malignant tumor metastasis. More than 90% of malignant tumor mortality is caused by tumor metastasis rather than primary tumor. Therefore, how to directly or indirectly inhibit tumor metastasis has become one of the key points and difficulties in the treatment of malignant tumors. [0003] Studies have shown (see: Nature, 536, 215-218) that amyloid precursor protein (APP, amyloid precursor protein) on the surface of tumor cells can interact with death rece...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P29/00
CPCC07D487/04A61P35/00A61P29/00Y02P20/55
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV
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