7-oxygen, sulphur or aza-substituent coumarin and derivative and application thereof

A technology of coumarin derivatives and nitrogen substitution, applied in drug combination, organic chemistry, anti-tumor drugs, etc., can solve the problems of rare and few anti-tumor active clinical drugs

Inactive Publication Date: 2015-10-21
FUDAN UNIV
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The prior art discloses the presence of several natural coumarins and their derivatives in plant, animal and microbial metabolites, which play an important role in agriculture and medicine (John Wiley&Sons Ltd, New York, 1982, p.21.), For example, the coumarin core derivatives have various biological activities such as antibacterial, antiviral, antiosteoporosis and antitumor (J.Enz.Inhib.Med.Chem.2004,19,373-379; PCT Int.Appl .Wo 9747634,1997; Chem.Abstr.128(1999)75634; Anticancer Res 21(2001)917-923; Med.Res.Rev.2003,23,322-345.); Among them, warfarin (1) and its derivative Tecarfarin (2) substituted by benzyl at the 3-position of coumarin are currently used drugs that produce anticoagulant effects by inhibiting the activity of vitamin K epoxide reductase ; And there are few clinical drugs with the corresponding structure of coumarin on anti-tumor activity

Method used

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  • 7-oxygen, sulphur or aza-substituent coumarin and derivative and application thereof
  • 7-oxygen, sulphur or aza-substituent coumarin and derivative and application thereof
  • 7-oxygen, sulphur or aza-substituent coumarin and derivative and application thereof

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Experimental program
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Embodiment 1

[0028] Synthesize compound 7-oxygen, sulfur or nitrogen substituted coumarin and derivatives thereof of formula 8 or 12 according to general formula one or general formula two,

[0029] 1. according to general formula one, with commercially available 7-hydroxyl, mercapto or amino-substituted coumarin (5) and N-oxidation-2,6-dichloropyridine obtains compound (6) by reflux reaction in pyridine; Then in three Reflux reduction in phosphorus chloride and chloroform solvent obtains 7-(6-chloropyridyl)-7-oxygen, sulfur and azacoumarin compound (7); simultaneously compound (5) is passed through potassium carbonate and acetone room temperature condition React with various alkyl, substituted aryl and substituted heterocyclic halides to obtain differently substituted 7-oxo, sulfur and aza coumarin compounds (8),

[0030] General formula one:

[0031]

[0032] 2. According to general formula two, synthetic starting material (9) (referring to reference (European Journal of Medicinal Ch...

Embodiment 2

[0036] According to the general formula 1, a compound 13 in compound type 6 was synthesized

[0037]

[0038]7-mercapto-4-methyl-chromen-2-one (5,300mg, 1.56mmol) and 2,6-dichloropyridine N-oxide (256mg, 1.56mmol) were refluxed in pyridine (6mL) solvent for 2 hour; Then add 2 equivalents of hydrochloric acid (50mL), filter and distill off the solvent under reduced pressure, separate with chromatographic column (eluent is chloroform / ethyl acetate=99 / 1) to obtain 240mg product 13, yield 48%, melting point It is 236-237°C. 1 H NMR (CDCl 3 ):δ2.50(3H,s,4-CH 3 ),6.41(1H,s,3-H),6.55(1H,dd,J1=8.1Hz,J2=1.8Hz,6-H),7.01(1H,t,J=8.4Hz,H of pyridine), 7.28, 7.54 (each 1H, dd, J1 = 8.4Hz, J2 = 1.8Hz, 2H of pyridine), 7.62 (1H, d, J = 1.8Hz, 8-H), 7.73 (1H, d, J = 8.1Hz ,5-H). 13 C NMRδ18.83,58.42,116.76,120.27,122.30,124.00,125.77,126.45,131.11,133.28,141.80,151.75,154.05,154.91,159.97. ESI MS m / z 320(M + +1).

Embodiment 3

[0040] According to general formula 1, a compound 4 in compound type 7 is synthesized,

[0041]

[0042] Compound 13 (500mg, 1.56mmol) was dissolved in phosphorus trichloride (PCl 3 , 2mL) and chloroform (CHCl 3 , 20mL), after reflux for 1.5 hours, add ice water (200mL) to dilute the reaction solution, extract with dichloromethane (30mL×4), combine the organic phases and dry with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure and then chromatograph Column separation (eluent is chloroform / methanol=20 / 1) to obtain 237mg product 4, yield 50%, melting point is 138-140 ℃. 1 H NMR (CDCl 3 )δ2.46(3H,s,4-CH 3 ),6.33(1H,s,3-H),7.01,7.13,7.52(each 1H,d,J=7.8Hz,3H of pyridine),7.45(1H,d,J=8.4Hz,6-H), 7.48(1H,s,8-H),7.62(1H,d,J=8.4Hz,5-H). 13 C NMRδ18.94,116.55,121.00,122.05,122.26,122.31,126.24,129.81,136.78,140.25,152.41,152.80,154.75,160.35,161.25.ESI MS m / z 304(M + +1).

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Abstract

The invention belongs to the field of chemical pharmaceuticals, and more specifically relates to 7-oxy, thio or imino substituted coumarin with a structure represented by formula 8 or 12, and derivatives and antineoplastic activity thereof. The results of antineoplastic activity and pharmacological target experiments show that 7-oxy, thio or imino substituted coumarin derivatives possess inhibitory activity on the growth of nasopharyngeal carcinoma cells and drug-resistant tumor strains of nasopharyngeal carcinoma cells, lung cancer cells and prostatic cancer cells; and the results of pharmacological research show that 7-oxy, thio or imino substituted coumarin is capable of promoting cell apoptosis and influencing cell division cycle G2 / M. 7-oxygen, sulfur or nitrogen substituted coumarin is novel in structure, and is capable of providing basis for intensive study on target sports and related pharmacological mechanisms such as reversing drug-resistance mechanism. X is selected from oxygen, sulfur or nitrogen atoms; R2 is selected from alkyl, alkoxy, halogenated alkyl groups or ester group; and R3 is selected from alkyl, and substituted aromatic heterocyclic compounds including 6-chloropyridine and substituted aralkyl.

Description

[0001] This application is the divisional case of invention name: 7-oxo, sulfur or aza substituted coumarin and its derivatives and uses, application number: 2012101653595, filing date: May 23, 2012. technical field [0002] The invention belongs to the field of chemical pharmacy, and specifically relates to 7-oxo, sulfur or aza substituted coumarin and derivatives thereof and antitumor activity. Background technique [0003] According to reports, tumors, especially malignant tumors, have become common and frequently-occurring diseases that seriously threaten human health and life, and are also one of the major diseases that cause global human deaths. Cancer has surpassed cardiovascular and cerebrovascular diseases to become the "number one killer" of human health and one of the largest public health problems in the world. Among them, lung cancer ranked first in both new cancer cases and death cases, followed by gastric cancer, liver cancer, esophageal cancer, colorectal can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D311/22A61P35/00
CPCC07D311/22C07D405/12
Inventor 陈瑛夏鹏刘洪瑞李国雄
Owner FUDAN UNIV
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