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Smo/bcr-abl dual target inhibitor and its synthesis method and application

A technology of bcr-abl and synthesis method, which is applied in the field of Smo/Bcr-Abl dual-targeted inhibitor and its synthesis, and can solve the problems of complex interaction pharmacokinetics and the like

Active Publication Date: 2020-12-11
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Hematological malignancies are highly complex and polygene-related diseases, and a single targeted drug is prone to drug resistance
Although the combination of anti-tumor drugs with different mechanisms of action can solve the problem of drug resistance to a certain extent, drug-drug interactions and complex pharmacokinetic problems may occur in combination

Method used

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  • Smo/bcr-abl dual target inhibitor and its synthesis method and application
  • Smo/bcr-abl dual target inhibitor and its synthesis method and application
  • Smo/bcr-abl dual target inhibitor and its synthesis method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048]

[0049] DMEDA: NN-isopropylethylamine; DCM: dichloromethane; DMF: N,N-dimethylformamide.

[0050] The synthesis of compound 8, its reaction process is as follows:

[0051] 1) Preparation of ethyl 3-bromo-4-methylbenzoate (compound 3):

[0052] Take the raw material 3-bromo-4-methylbenzoic acid (1.00g, 0.02mol), dissolve it in 25ml of absolute ethanol, slowly add 2.0ml of concentrated sulfuric acid with a concentration (mass fraction) of 98%, and react at reflux at 75°C for 5h . After the reaction was completed, the solvent was evaporated to dryness under reduced pressure, and the pH was adjusted to 7 with saturated aqueous sodium carbonate solution. A yellow oily substance was precipitated, extracted 3-4 times with dichloromethane, combined the organic phases, and washed with anhydrous NaSO 4 After drying, dichloromethane was distilled off under reduced pressure, and compound 3 (1.05 g, yield 93%) was obtained as a yellow oily liquid by column chromatography.

[...

Embodiment 2

[0072] Embodiment 2: Synthesis of A series of pyridazine derivatives, the reaction scheme is as follows:

[0073]

[0074] 1) Preparation of compound N-(6-chloropyridazin-3-yl)-4-methyl-3-[[4-(3-pyridyl)-2-pyrimidine]amino]benzamide (compound 11) :

[0075] The prepared 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidine]amino]benzoyl chloride was dissolved in 15ml of anhydrous dichloromethane, and the 3-amino-6-chloropyridazine (0.13g, 1.0mmol) was dissolved in 20ml of anhydrous dichloromethane, stirred at 0°C, and 2ml of N,N-diisopropylethylamine (DIPEA) and catalyst 4-dimethyl Pyridine (CAS number is 1122-58-3, the addition amount is 0.02g, 0.16mmol, DMAP), and then it is slowly added dropwise to 4-methyl-3-[[4-(3-pyridyl)-2- pyrimidine]amino]benzoyl chloride in dichloromethane. After the solution was added dropwise, it was placed at room temperature (25° C.) for overnight reaction. After the reaction, dilute with an appropriate amount of dichloromethane, wash with saturated bri...

Embodiment 3

[0096] Embodiment 3: Synthesis of B series pyridine derivatives:

[0097] 1) Compound N-(6-((2S,6R)-2,6-dimethylmorpholine)pyridin-3-yl)-4-methyl-3-((4-(pyridin-3-yl) The synthesis of pyrimidin-2-yl)amino)benzamide (compound B1) is shown below:

[0098]

[0099] Preparation of compound 14, namely (2S, 6R)-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine:

[0100] Take 2-chloro-5-nitropyridine (1.73g, 0.01mol) and cis-2,6-dimethylmorpholine (1.15g, 0.01mol) in a round bottom flask, add 10ml of DMF to dissolve, and then Add K to it 2 CO 3 (2.76g, 0.02mol), react at 55°C for 6h. Cool to room temperature after the reaction, extract 3-4 times with ethyl acetate, combine organic phases, wash 2-3 times with water, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain compound 14 as a yellow solid (2.20 g, yield 93%).

[0101] The detection data of compound 14 are as follows:

[0102] MS ca...

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PUM

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Abstract

The invention discloses an Smo inhibitor as well as a synthesis method and application thereof. A structural formula of the Smo inhibitor is shown by a formula (I) as shown in the specification. The invention also discloses the synthesis method and the application of the Smo inhibitor. According to the invention, nilotinib is optimized into the dual-targeted inhibitor being active against Smo andBcr-Abl, and the inhibitor can overcome the tolerance problem caused by single-targeted drugs, has the advantages of improving anti-tumor efficacy and reducing toxic or side effects, and provides a reference for future research on dual-targeted anti-hematologic malignant drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and relates to a Smo / Bcr-Abl dual-targeting inhibitor and its synthesis method and application. Background technique [0002] In recent years, the Hh signaling channel has also been widely studied in blood system diseases, and the channel is highly expressed in leukemia, lymphoma and multiple myeloma patients. It has been reported that the activation of Hh channels is associated with the course of chronic myeloid leukemia (CML) patients, and cyclopamine can inhibit the self-renewal of leukemia cells both in vivo and in vitro. In the study of leukemia multidrug resistance (MDR), it has been found that the activation of the Hh signaling channel is an important factor for the occurrence of MDR in leukemia cells. Blocking this channel can reverse drug resistance and reduce the expression of drug-resistant proteins. Glasdegib is a small molecule antagonist of Smo developed by P...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D401/04C07D413/14A61P35/00A61P35/02A61K31/506A61K31/5377
CPCA61P35/00A61P35/02C07D401/04C07D401/14C07D413/14
Inventor 蔡进宁瑶吉民王莹颖黄铭祺
Owner SOUTHEAST UNIV
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