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Compounds and use thereof in anti-AML drugs

A compound, independent technology, applied in the field of ITD mutant selective inhibitor of FMS-like tyrosine kinase 3, azole ring substituted thiophene compounds, can solve the problem of expression level as an indicator and the like

Active Publication Date: 2018-10-23
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the PLK1 inhibitors, Volasertib (BI6727) has the fastest progress in clinical trials. The results of its clinical trials have shown that it can produce therapeutic effects on human AML, but the selection of clinical research subjects does not take the expression level of FLT3 or FLT-ITD as an important factor. indicator (Leukemia, 2015, 29(1): 11-19), which also shows that its mechanism of action is different from that of FLT3 inhibitors

Method used

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  • Compounds and use thereof in anti-AML drugs
  • Compounds and use thereof in anti-AML drugs
  • Compounds and use thereof in anti-AML drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] 2-Acetyl-5-bromothiophene (M-1)

[0193] Add 2-bromothiophene (2.00g, 12.3mmol) and acetic anhydride (2.51g, 24.6mmol) into a 100ml eggplant-shaped bottle, slowly add perchloric acid (3.71g, 36.9mmol) dropwise under ice-bath conditions, add 0.5h After that, remove the ice bath and stir at room temperature. After 6h TLC showed no starting material remained. Add ice water, adjust the pH to neutral with sodium carbonate, extract with ethyl acetate (25ml×3), combine the organic phases, wash twice with saturated brine, anhydrous MgSO 4 dry. The solvent was distilled off under reduced pressure, and the crude product was subjected to column chromatography (PE: EA = 50: 1) to obtain 2.03 g of light yellow oil, with a yield of 80.6%.

[0194] MS (m / z): [M+H] + 204.9, 206.9.

Embodiment 2

[0196] 2-Acetyl-5-cyanothiophene (M-2)

[0197]Add M-1 (2.00g, 9.75mmol), cuprous cyanide (2.62g, 29.3mmol), potassium iodide (0.02g, 0.1mmol) and 6ml of anhydrous DMF into a 50ml pressure tube. The temperature was raised to 150° C. under the protection of argon, and after 12 hours, TLC showed that there was no remaining raw material. The reaction solution was poured into a mixture of ammonia water and crushed ice (1:3), stirred to quench the reaction, filtered with suction, and the solid was dried and extracted with ethyl acetate. The mother liquor was extracted with ethyl acetate (20ml×3), the organic phases were combined, washed twice with saturated brine, anhydrous MgSO 4 After drying and concentration under reduced pressure, the crude product was subjected to column chromatography (PE:EA=50:1) to obtain 0.95 g of a yellow oil with a yield of 64.2%.

[0198] 1 H-NMR (300MHz DMSO-d 6 )δ: 2.62 (3H, s, -COC H 3 ), 8.05 (1H, d, J=4.0Hz, -CH-, Thiophene), 8.08 (1H, d, J=4...

Embodiment 3

[0201] 1-Methyl-4-(4-nitrophenyl)piperidine (M-3)

[0202] Add p-fluoronitrobenzene (2.00g, 14.2mmol), 1-methylpiperazine (1.42g, 14.2mmol), potassium carbonate (1.96g, 14.2mmol) and DMSO 25ml in a 100ml single-necked bottle, react at room temperature, After 6h, TLC showed that no starting material remained. The reaction solution was poured into 200ml of water, a brown solid was precipitated, suction filtered, the solid was dried, the mother liquor was extracted with ethyl acetate (40ml×3), the organic phases were combined, washed twice with saturated brine, and anhydrous MgSO 4 dry. After concentration under reduced pressure, it was combined with the dried solid, and the crude product was subjected to column chromatography (PE:EA=6:1) to obtain 2.73 g of yellow needle-like crystals, with a yield of 87.2%.

[0203] 1 H-NMR (300MHz CDCl 3 )δ: 2.36 (3H, s, C H 3 -N-), 2.57 (4H, t, J=5.1Hz, -N-C H 2 -×2), 3.45 (4H, t, J=5.1Hz, CH 3 -N-C H 2 -×2), 6.82-6.85 (2H, m, Ar-H...

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Abstract

The present invention relates to the field of medicinal chemistry, discloses compounds and use thereof in anti-AML drugs, and specifically relates to imidazole ring-substituted thiophenic compounds, preparation method thereof, pharmaceutical compositions containing the compounds, and medical use of the compounds, particularly use of the compounds as an ITD mutant selective inhibitor of FMS-like tyrosine kinase 3.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to azole ring-substituted thiophene compounds, their preparation methods, pharmaceutical compositions containing these compounds and their medical use, especially as an ITD mutant selection for FMS-like tyrosine kinase 3 The use of sex inhibitors. Background technique [0002] Cell signal transduction plays a key role in regulating cell growth, proliferation, differentiation, apoptosis and other processes. The imbalance of cell proliferation and apoptosis leads to major diseases such as cancer, and the essence of cell canceration is the imbalance of cell signal transduction. When the cell signal transduction pathway that regulates the normal physiological activities of cells is changed under the action of carcinogens, the normal biological effects of regulating cell growth, division and differentiation will be abnormal, which will cause abnormal cell growth, division and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/04A61K31/496A61K31/454A61K31/5377A61K31/4155A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D409/04
Inventor 卢帅衡浩向黎王志杰蔡炅桁秦天人支燕乐田洁怡陈亚东陆涛
Owner CHINA PHARM UNIV
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