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Quinoline multi-target kinase inhibitor with antitumor activity and preparation method thereof

A technology of anti-tumor activity, quinolines, applied in the field of medicine

Inactive Publication Date: 2016-05-04
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But currently about N 1 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N 2 -substituted heterocycle-N 3 -Phenylmalonamide antitumor compounds have not been reported yet

Method used

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  • Quinoline multi-target kinase inhibitor with antitumor activity and preparation method thereof
  • Quinoline multi-target kinase inhibitor with antitumor activity and preparation method thereof
  • Quinoline multi-target kinase inhibitor with antitumor activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Embodiment 1: According to ROUTE1 synthetic intermediate quinoline aniline h

[0117] (1) Synthesis of compound 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline compound (h)

[0118] Add NaH (3.3g, 82.5mmol) and anhydrous DMSO into a 100ml round-bottomed flask, stir well, add p-aminophenol (6g, 55mmol), stir at room temperature for 10min, then add 4-chloro-6,7-di Methoxyquinoline (12.3g, 55.1mmol) was then stirred at 100°C for 3h and monitored by TLC. After the reaction was complete, water was added, extracted with chloroform, and the extract was evaporated to dryness to obtain 12.2g of a gray solid with a yield of 74.6%. Spectral data is: 1 HNMR (300MHz, CDCl 3 )δ8.50(d,J=5.5Hz,1H),7.64(d,J=7.0Hz,1H),7.48(s,1H),7.09–6.97(m,2H),6.86–6.76(m,2H ), 6.48 (d, J=5.3Hz, 1H), 4.09 (s, 6H), 3.7 (s, 2H).

Embodiment 2

[0119] Embodiment 2: Synthesize target compound 1 and m according to ROUTE1

[0120] (1) Synthesis of compound 1-tert-butyl-4-methylpiperidine-1,4-dicarboxylate (a)

[0121] Add 4-methyl piperidine formate (30g, 0.21mol) into a 1L round bottom flask, dissolve in 500ml of DCM, add (Boc) dropwise with a constant pressure dropping funnel 2 O (45.72g, 0.21mol), triethylamine (42.3g, 0.42mol), stirred at room temperature, and after 8 hours, after the reaction was complete, an equal volume of water was added to wash the DCM layer 3 times, and the colorless oil in the organic phase was evaporated to dryness 97.5 g, yield 95.5%. Spectral data is: 1 HNMR (300MHz, CDCl 3 )δ4.05–3.83(m,2H)3.68–3.56(m,3H),2.76(t,J=11.6Hz,2H),2.45–2.30(m,1H),1.80(dd,J=13.4,2.9 Hz, 2H), 1.64–1.47 (m, 2H), 1.38 (s, 9H).

[0122] (2) Synthesis of compound 1-tert-butyl-4,4-dimethylpiperidine-1,4,4-tricarboxylate (b)

[0123] Under nitrogen protection, add 90ml of dry THF and compound a (10g, 41mmol) into...

Embodiment 3

[0188] Embodiment 3: Synthesize target compound p according to ROUTE2

[0189] (1) Synthesis of compound dimethyl-2H-pyran-4,4(3H)-dicarboxylate (d)

[0190] Add absolute ethanol 400ml and sodium block (10.8g, 0.47mol) in 1L three-necked round bottom flask, stir in ice bath, after the sodium block dissolves completely, slowly add dimethyl malonate (30g, 0.23mol), stir After 20 minutes, dibromoethyl ether (57.9g, 0.25mol) was added dropwise and heated to reflux for 32 hours, monitored by TLC. After the reaction of the raw materials was completed, most of the ethanol was evaporated and water was added, and the pH of the aqueous phase was adjusted to 3 with dilute hydrochloric acid solution. Ethyl ester extraction, the organic phase was evaporated to dryness to a brownish-red oily substance, and a colorless oily substance was obtained by distillation under reduced pressure of an oil pump at 150°C, and then 21 g of a colorless oily substance was obtained by passing through a chrom...

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Abstract

The invention relates to a quinoline multi-target kinase inhibitor with antitumor activity and a preparation method thereof. A general structural formula of the compound is shown in a formula (I) described in the specification. In vitro cell experiments verify that the compound provided by the invention has strong in vitro inhibitory activity on five common tumor cell lines, namely human thyroid carcinoma SW579, human hepatic carcinoma HepG2, human lung adenocarcinoma A549, human colorectal adenocarcinoma HCT116 and human gastric carcinoma MKN45, antitumor activities of most of target compounds are better than or equivalent to that of a positive control drug Cabozantinib, and the in vitro cell experiments verify that the compound provided by the invention has strong inhibitory activity on two kinases KDR and MET, so that the compound provided by the invention has a broad application prospect in preparation of a new antitumor drug.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of N 1 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N 2 -substituted heterocycle-N 3 -Phenylmalonamide-type quinoline-type multi-target kinase inhibitor and its preparation method, and its use in the preparation of antitumor drugs. Background technique [0002] In recent years, with the improvement of people's living standards, and the increasingly serious problems of environmental pollution and food safety around humans, cancer has become one of the killers that endanger human health. Finding an ideal antineoplastic drug is of epoch-making significance. Traditional cytotoxic drugs such as cisplatin, cyclophosphamide, fluorouracil, etc. have disadvantages such as poor selectivity and large side effects, which also bring pain to patients while treating diseases. Therefore, a highly efficient, low toxicity, and high specificity drug was developed Anticancer drugs have b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D405/12A61P35/00
CPCC07D401/12C07D405/12
Inventor 周有骏周浩郑灿辉朱驹吕加国孙囡囡陈莎娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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