2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors and applications thereof

A technology of thiophene and pyrazole, applied in the field of medicinal chemistry, can solve the problems of safety, stability and off-target effects of RNA interference technology

Inactive Publication Date: 2013-11-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Inhibition of disease-related protein kinases can be achieved through a variety of methods, but because synthetic antisense oligonucleotides are vulnerable to ribozyme attack and degradation, RNA interference technology has problems such as safety, stability and off-target effects, so Researchers began to try chemical small molecule inhibitors from organically synthesized chemical small molecules or natural products

Method used

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  • 2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors and applications thereof
  • 2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors and applications thereof
  • 2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] 2-Acetyl-4-bromothiophene (M-1)

[0133] Add 3.00g (23.81mmol) of 2-acetylthiophene (23.81mmol), 9.53g (71.43mmol) of anhydrous aluminum chloride and 80ml of carbon tetrachloride into a 250ml single-necked flask, cool to -40℃, and slowly add liquid bromine after 10 minutes of stability. 3.81g (23.81mmol) of carbon tetrachloride solution (20ml), drip in 0.5h, and stir at room temperature. After 12h, TLC showed that there was no raw material left. The reaction system was poured into a mixture of saturated NaOH solution and crushed ice, extracted with ethyl acetate (75ml×3), combined the organic phases, washed twice with saturated brine, anhydrous MgSO 4 dry. After concentration under reduced pressure on the column layer (PE:EA=500:1), 2.74 g of light yellow oily liquid was obtained, with a yield of 72.6%.

[0134] 1 HNMR(300MHz DMSO-d 6 )δ: 7.65 (1H, d, ArH), 6.91 (1H, d, ArH), 2.57 (3H, s, -COC H 3 ).MS[M+H] + 205.2, 207.1.

Embodiment 2

[0136] 2-Acetyl-4-cyanothiophene (M-2)

[0137] Add M-10.5g (2.45mmol), cuprous cyanide 0.66g (3.68mmol), potassium iodide 0.04g (0.245mmol) and 10ml anhydrous DMF into a 100ml pressure tube. The temperature was raised to 190°C under inert gas protection, and TLC showed that there was no raw material remaining after 3h. The reaction system was poured into a mixture of ammonia water and crushed ice, extracted with ethyl acetate (20ml×3), combined the organic phases, washed twice with saturated brine, and anhydrous MgSO 4 After drying, concentration under reduced pressure and column chromatography (PE:EA=100:1), 0.23 g of light yellow solid was obtained, with a yield of 62.2%. mp.112~114℃ (document mp.111~113℃).

Embodiment 3

[0139] 1-methyl-4-(4-nitrobenzene)piperidine (M-3)

[0140] Add 1.41g (10.00mmol) of p-fluoronitrobenzene, 1.01g (10.00mmol) of 1-methylpiperazine, 1.01g (10.00mmol) of triethylamine and 25ml of anhydrous DMF into a 50ml single-necked flask, and react at room temperature for 24h Later TLC showed that there was no raw material left. Evaporate the solvent under reduced pressure, add ice water, adjust the pH to 8 with saturated sodium carbonate solution, extract with ethyl acetate (40ml×3), combine the organic phases, wash twice with saturated brine, anhydrous MgSO 4 dry. After concentration under reduced pressure and column chromatography (PE:EA=1:1), 1.38 g of orange-yellow needle-like crystals were obtained, with a yield of 85.3%, mp. 35-38°C.

[0141] MS[M+H] + 222.3.

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Abstract

The invention relates to the field of medicinal chemistry, and in particular relates to 2-imidazole ring-substituted thiophene PLK1 (Polo-like kinase 1) inhibitors, a preparation method for the inhibitors, a medicinal composition containing the compounds, and medical applications for the compounds, and in particular an application for the compounds as Polo-like kinase 1 (PLK1) inhibitors.

Description

Technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to 2-azole ring-substituted thiophene PLK1 inhibitors, their preparation methods, pharmaceutical compositions containing these compounds and their medical uses, especially as Polo-like kinase 1 (Polo-like kinase 1) Kinase1, PLK1) inhibitors. Background technique [0002] Tumor is a type of disease characterized by uncontrolled cell growth and proliferation. Abnormal cell proliferation, differentiation and apoptosis are all involved in the occurrence and development of tumors. Among them, cell cycle disorder is the main mechanism of tumor occurrence. In the entire regulatory network of the cell cycle, various molecular abnormalities may cause tumors. Tumor cells divide faster than normal cells, and various proteins that regulate microtubule polymerization, centrosome replication, spindle formation, and cytokinesis are often overexpressed and have increased activity. [0003] An ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14C07D409/04C07D413/04C07D413/14C07D417/14C07D417/04A61K31/454A61K31/4155A61K31/5377A61K31/496A61K31/422A61K31/4245A61K31/433A61P35/00A61P35/02
Inventor 卢帅张亮刘海春郭晓星孙善亮陈亚东陆涛
Owner CHINA PHARM UNIV
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