7-oxy, thio or imino substituted coumarin, and derivatives and applications thereof

A technology of coumarin and nitrogen substitution, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, medical preparations containing active ingredients, etc., can solve the problem of rare and few clinical drugs with anti-tumor activity

Inactive Publication Date: 2013-12-04
FUDAN UNIV
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The prior art discloses the presence of several natural coumarins and their derivatives in plant, animal and microbial metabolites, which play important roles 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-oxy, thio or imino substituted coumarin, and derivatives and applications thereof
  • 7-oxy, thio or imino substituted coumarin, and derivatives and applications thereof
  • 7-oxy, thio or imino substituted coumarin, and derivatives and applications thereof

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Experimental program
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Embodiment 1

[0027] 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,

[0028] 1. According to general formula 1, compound (6) is obtained by reflux reaction of commercially available 7-hydroxyl, mercapto or amino substituted coumarin (5) with N-oxide-2,6-dichloropyridine in pyridine; Phosphorous chloride and chloroform solvent reflux reduction to obtain 7-(6-chloropyridyl)-7-oxo, sulfur and azacoumarin compound (7); at the same time, compound (5) was treated with potassium carbonate and acetone at room temperature React with various alkyl, substituted aryl and substituted heterocyclic halides to obtain different substituted 7-oxo, sulfur and aza coumarin compounds (8),

[0029] General formula one:

[0030]

[0031] 2. According to the general formula 2, the starting material (9) was synthesized (refer to the reference (European Journal of Medicinal Chemistry, 2011, ...

Embodiment 2

[0035] According to the general formula 1, a compound 13 in compound type 6 was synthesized

[0036]

[0037] 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 a chromatographic column (eluent is chloroform / ethyl acetate=99 / 1) to obtain 240mg of 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,2Hof pyridine),7.62(1H,d,J=1.8Hz,8-H),7.73(1H,d,J=8.1Hz, 5-H). 13 C NMR δ18.83,58.42,116.76,120.27,122.30,124.00,125.77,126.45,131.11,133.28,141.80,151.75,154.05,154.91,159.97. ESI MS m / z 320(M + +1).

Embodiment 3

[0039] According to general formula 1, a compound 4 in compound type 7 is synthesized,

[0040]

[0041] Compound 13 (500mg, 1.56mmol) was dissolved in phosphorus trichloride (PCl 3 , 2mL) and chloroform (CHCl 3 , 20mL), after reflux reaction 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: chloroform / methanol=20 / 1) yielded 237 mg of product 4 with a yield of 50% and a melting point of 138-140°C. 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 ofpyridine),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 NMR δ18.94,116.55,121.00,122.05,122.26,122.31,126.24,129.81,136.78,140.25,152.41,152.80,154.75,160.35,161.25.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

technical field [0001] 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 [0002] 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 cancer and breast cancer. According to the World Health Organization (WHO), about 6.35 million people die of malignant tumors every year in the world, which is equivalent to 1 death every 5-6 seconds. Ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D311/16C07D311/22A61K31/4433A61K31/37A61K31/352A61P35/00
CPCC07D311/22C07D405/12
Inventor 陈瑛夏鹏刘洪瑞李国雄
Owner FUDAN UNIV
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