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Pyrimido [5, 4-b] methotrexate compound and optical isomer, preparation method and application thereof

A technology for optical isomers and compounds, which is applied in the fields of pyrimido[5,4-b]pyrine compounds, optical isomers, preparations and uses thereof, can solve the problems of large toxic and side effects, unsatisfactory oral bioavailability, Lack of irreversible activity of off-target kinases

Active Publication Date: 2020-10-30
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since ibrutinib also has a good inhibitory effect on kinases such as Tec and EGFR, the drug has relatively large toxic and side effects.
The second-generation BTK inhibitor Acalabrutinib (ACP-96), which was launched in 2017, has high selectivity for BTK and lacks irreversible activity against off-target kinases. It is effective in relapsed / refractory chronic lymphocytic leukemia (CLL ) in phase I / II clinical trials in patients with higher overall response rates
However, further studies have found that the compounds S1, S10, S18s and S19s are unstable in the metabolic process, and the 4-position of the terminal phenyl group is easily oxidized; and the oral bioavailability of the compound S20s is not ideal

Method used

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  • Pyrimido [5, 4-b] methotrexate compound and optical isomer, preparation method and application thereof
  • Pyrimido [5, 4-b] methotrexate compound and optical isomer, preparation method and application thereof
  • Pyrimido [5, 4-b] methotrexate compound and optical isomer, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0122] Synthesis of Preparation Example 1 S17016

[0123] 1. Synthesis of Intermediate 3

[0124]

[0125] Add 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (raw material 2, 17.28g, 1eq) and anhydrous potassium carbonate (2eq) into a 250mL round bottom flask, and dry in vacuo to remove water. Add dry DMF as solvent, crushed (S)-methanesulfonic acid 2-((tert-butoxycarbonyl)amino)-but-3-en-1-yl ester (raw material 1, 24.6g, 1.5eq), Replace nitrogen. Heat and stir at 55° C. for 12 hours, and the time may be extended appropriately to ensure the completion of the reaction.

[0126] After the reaction was completed, water and ethyl acetate were added to extract three times, and the ester layers were combined, back-extracted once with water, and washed with saturated brine. Dry over anhydrous sodium sulfate. Dry column (eluent: CHCl 3 : MeOH=100:1) to get product (S)-(1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-ene-2- base) tert-butyl carbamate (Intermediate 3, 19...

experiment Embodiment 1

[0150] Experimental Example 1: Evaluation of Bruton Kinase (BTK) Molecular Level Enzyme Activity Inhibitory Activity

[0151] The enzyme reaction substrate Poly(Glu,Tyr) 4:1 Dilute with PBS without potassium ions (10mM sodium phosphate buffer, 150 mMNaCl, pH 7.2-7.4) to 20μg / mL to coat the microtiter plate, react at 37℃ for 12-16 hours, then use 200μL / well T- Wash the plate three times with PBS (PBS containing 0.1% Tween-20), and dry the microplate in an oven at 37°C for 1-2 hours. In the above substrate-coated ELISA plate, first add the reaction buffer (50mM HEPES pH 7.4, 50mM MgCl 2 , 0.5mM MnCl 2 , 0.2mM Na 3 VO 4 , 1 mM DTT) diluted ATP solution 49 μL / well (final concentration 5 μM). Add 1 μL of the compound to be tested (compound well) or DMSO containing the corresponding concentration (negative control well) to each well, and set no enzyme control well for each experiment. Add 50 μL of BTK tyrosine kinase protein diluted in reaction buffer to start the reaction.

...

experiment Embodiment 2

[0160] Experimental Example 2: Detection of in vitro proliferation inhibitory activity of compounds on human B lymphoma cells Ramos (Burkitt lymphoma) and human diffuse large B lymphoma cells TMD8

[0161] The cell suspension (Ramos: 10,000 cells / well; TMD8: 12,000 cells / well) was inoculated in a 96-well plate, and left in a 37°C incubator for 2 hours until the cell state was stable, and each well was added with different concentrations of the test compound (Three replicate wells are set for each concentration), and a blank control (well containing only culture medium, no cells), a negative control (wells only added cells, no compound) and a positive compound control are set at the same time. After 72 hours of drug treatment, add 20 μL of MTT (5 mg / mL) to each well and incubate at 37°C for 4 hours, add 100 μL of triple solution (10% SDS, 5% isobutanol, 0.01M HCl), and place overnight at 37°C. The OD value was measured at a wavelength of 570nm with an adjustable wavelength micr...

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Abstract

The invention relates to a pyrimido [5, 4-b] methotrexate compound as shown in a general formula I, an optical isomer, a preparation method, a pharmaceutical composition containing the pyrimido [5, 4-b] methotrexate compound and application. The compound has good inhibitory activity on kinase BTK at a molecular level and a cellular level, and also has good in-vivo antitumor activity and pharmacokinetic properties.

Description

technical field [0001] The present invention relates to a pyrimido[5,4-b]pyrrolizin compound, its optical isomer, preparation method, pharmaceutical composition and application, specifically, to a A pyrimido[5,4-b]pyrine compound used as a small molecule inhibitor targeting BTK kinase, its preparation method, pharmaceutical composition and its preparation for treating diseases related to BTK kinase signal transduction pathway Uses in medicine. Background technique [0002] Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase belonging to the TEC tyrosine kinase family. TEC family members include Tec, Bmx, BTK, Itk and Txk. BTK is the most widely studied member of the TEC family. It is a key regulator in the B cell receptor (BCR) signaling pathway. It is widely expressed in various types of malignant hematological tumors and participates in the proliferation, differentiation and apoptosis of B cells. Therefore, BTK has become an important molecular target for d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14A61P35/00A61P35/02A61K31/519
CPCC07D487/14A61P35/00A61P35/02A61P29/00A61P37/02Y02P20/55
Inventor 张翱丁健谢华宋子兰薛宇邢莉童林江耿美玉
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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