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Crizotinib derivative as well as preparation method and application thereof

A technology of crizotinib and its derivatives, applied in the field of new anti-tumor drugs, to achieve the effect of improving anti-tumor activity

Inactive Publication Date: 2018-06-22
ZHEJIANG SHUREN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] After a single 250mg oral administration of crizotinib, the absolute bioavailability is 43%, but there is still a certain gap compared with imatinib, sunitinib, etc.

Method used

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  • Crizotinib derivative as well as preparation method and application thereof
  • Crizotinib derivative as well as preparation method and application thereof
  • Crizotinib derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023] Compound (II-a) (1.35g, 3mmol) was added into a 100mL flask and dissolved in 40mL of acetonitrile, phenylisothiocyanate (III-a) (0.446g, 3.3mmol) was added, and reacted at 25°C for 12h. The product (I-a) was obtained by filtration with a yield of 86%.

[0024] 1 H NMR (500MHz, CDCl 3 )δ13.40(s, 1H), 8.89(s, 1H), 7.90(d, J=1.8Hz, 1H), 7.71(d, J=7.6Hz, 2H), 7.64(s, 1H), 7.57( s, 1H), 7.41(t, J=7.9Hz, 2H), 7.18(d, J=7.4Hz, 1H), 7.14(d, J=7.6Hz, 2H), 7.10(d, J=1.8Hz, 1H), 6.18(m, J=6.7Hz, 1H), 4.64(d, J=7.5Hz, 2H), 4.46-4.37(m, 1H), 3.35-3.21(m, 2H), 2.29-2.18(m , 2H), 2.20-2.06(m, 2H), 1.93(d, J=6.7Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ184.02,178.19,142.40,140.02,139.77,138.81,136.33,135.74,133.15,129.37,128.72,126.17,125.33,124.71,123.50,123.37,122.53,118.99,117.30,117.10,116.18,73.37,58.60,51.13 , 48.47, 44.48, 31.73, 18.86.

Embodiment 2

[0026]

[0027] Add compound (II-a) (1.35g, 3mmol) in 100mL flask and dissolve in 40mL acetonitrile, add isothiocyanate plus p-methylphenylisothiocyanate (III-b) (0.439g, 3.3mmol ), reacted at 60°C for 8h. The product (I-b) was obtained by filtration with a yield of 87%.

Embodiment 3

[0029]

[0030] In a 100mL flask, compound (II-b) (1.39g, 3mmol) was added and dissolved in 40mL of dichloromethane, p-chlorophenylisothiocyanate (III-c) (0.560g, 3.3mmol) was added, and Reaction at 80°C for 6h. The product (I-c) was obtained by filtration with a yield of 78%.

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Abstract

The invention provides a novel crizotinib derivative as well as a preparation method and application thereof. The derivative provided by the invention has a structure shown as a formula (I), wherein R1 is one of the following groups: H and -CH3; R2 is one of the following groups: O, S and NH; R3 is one of the following groups: hydrogen, methyl, a chlorine group, a bromine group, an iodine group, nitryl and phenyl. The preparation method of the novel crizotinib derivative comprises the following steps: adding crizotinib or a homologous compound (II) thereof and phenyl isocyanate or an analogue(III) thereof into a certain solvent, and stirring at the temperature of 20 DEG C to 80 DEG C until components react completely; after reaction is finished, filtering and washing to obtain a product.The crizotinib derivative provided by the invention has an inhibition function in the aspect of resisting tumor cells and has a certain application prospect. (The formula (I) is shown in the description.).

Description

technical field [0001] The invention relates to a novel antitumor drug crizotinib derivative, a preparation method thereof, and an application thereof in the preparation of antitumor drugs. Background technique [0002] The chemical name of crizotinib is 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl) -1H-pyrazol-4-yl]-2-aminopyridine is a dual inhibitor of Alk and c-Met developed by Pfizer. It was approved by the US FDA on August 26, 2011 and marketed in the United States. The trade name is Xalkori. It was subsequently launched in South Korea, Japan and the European Union, and was approved by the CFDA to be launched in China in 2013. The Chinese product name is Seric. The chemical structure of crizotinib is shown in formula (II-a): [0003] [0004] The drug is clinically mainly used for the treatment of patients with anaplastic lymphoma (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Crizotinib, the first drug tar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61P35/00
CPCC07D401/14
Inventor 沈超郑凯金建忠
Owner ZHEJIANG SHUREN UNIV