CN102872017B - Use of 6-(4-difluoromethoxy)-3methoxyphenyl)pyridazine-3(2H)-one in preparation of antitumor drugs - Google Patents
Use of 6-(4-difluoromethoxy)-3methoxyphenyl)pyridazine-3(2H)-one in preparation of antitumor drugs Download PDFInfo
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- CN102872017B CN102872017B CN201110196266.4A CN201110196266A CN102872017B CN 102872017 B CN102872017 B CN 102872017B CN 201110196266 A CN201110196266 A CN 201110196266A CN 102872017 B CN102872017 B CN 102872017B
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Abstract
The invention relates to a use of 6-(4-difluoromethoxy)-3methoxyphenyl)pyridazine-3(2H)-one with the structure represented by formula I in preparation of antitumor drugs especially liver cancer resistant drugs.
Description
Technical field
The invention belongs to field of pharmacology, relate to the purposes of 6-(4-(difluoro-methoxy)-3-methoxyphenyl) pyridazine-3 (2H)-one, be specifically related to this compound and preparing antitumor drug, the purposes especially in medicines resistant to liver cancer.
Background technology
6-(4-(difluoro-methoxy)-3-methoxyphenyl) pyridazine-3 (2H)-one, trade name: zardaverine (Zardaverine) is the inhibitor of phosphodiesterase PDE III and PDE IV, clinical being used as anaesthetizes adjuvant (skeletal muscle relaxant).The patent (WO 2001094319, DE 4310051, DE4207822, EP 523513, EP 163965, US4665074) relevant to zardaverine relates generally to the purposes of its antiinflammatory or anti-immunology, and has no report to it in the application of anti-tumor aspect.
As everyone knows, hepatocarcinoma is the fifth-largest common male tumor disease, is the eighth-largest common female tumor disease.In 2007, the newly-increased liver cancer patient of estimation will have 80% to produce in developing country, and only China just account for 55% of sum.And in developing country, the hepatocarcinoma of 59% is attributable to HBV, the hepatocarcinoma of 33% is attributable to HCV.Especially in recent years, because Asia-Pacific nations hepatitis B virus infection is wreaked havoc, onset of liver cancer rate constantly rises, and has the huge market demand to Hepatoma therapy medicine.
Summary of the invention
An object of the present invention is 6-(4-(difluoro-methoxy)-3-methoxyphenyl) pyridazine-3 (2H)-one shown in open formula I and prepare antitumor drug, the purposes especially in medicines resistant to liver cancer.
The present inventor is by the pharmacological action of in vitro and in vivo experiment Late Cambrian 6-(4-(difluoro-methoxy)-3-methoxyphenyl) pyridazine-3 (2H)-one at anti-tumor aspect.Specifically, 6-(4-(difluoro-methoxy)-3-methoxyphenyl) pyridazine-3 (2H)-one shows very strong specificity at anti-liver cancer, it differs nearly 1000 times to the inhibit activities of sensitive cells strain BEL-7402 and SMMC-7721 with to the inhibit activities of insensitive cell strain (as HepG2, Hep3B or NCI-H460), and its antitumor action have also been obtained checking in Nude Mouse Model in hepatoma carcinoma cell BEL-7402 body simultaneously.
Accompanying drawing explanation
Fig. 1 is the activity of zardaverine to the dose-dependent inhibition tumor bulk-growth of Human hepatoma cell line Bel-7402 Nude Mice;
Fig. 2 is the impact of zardaverine on nude mouse body weight.
Detailed description of the invention
Further illustrate the present invention by embodiment below, but these embodiments do not limit the scope of the invention.
Embodiment 1: the anti tumor activity in vitro of zardaverine
RPMI 1640 culture medium, minimum essential medium (Minimum essential medium, MEM), Ham ' s F12 culture medium, Dole shellfish Kao Shi improve eagle culture medium (Dulbecco ' s modified Eagle ' s medium, DMEM) culture medium, M199 culture medium, hyclone (fetal bovine serum, FBS) all purchased from BRL (Gaithersburg, USA) company.Sulforhodamine B (sulforhodamine B, SRB) is purchased from Sigma-Aldrich (St Louis, Mo, USA) company.CO
2cell culture incubator is U.S.'s Thermo Forma Scientific (Marietta, OH, United States) Products; Inverted microscope is purchased from Olympus company; CA-1390-1 type superclean bench is Shanghai cleaning equipment company limited product; BT 124S type 100,000/balance is Sartorius Products; HF safe 1500 type continous sample adding apparatus is eppendorf Products; SPECTRA MAX 190 microplate reader is Molecular Devices (Sunnyvale CA, U.S.A.) Products.Human liver cancer cell BEL-7402 and SMMC-7721 is purchased from OEG cell institute of Shanghai Sheng Ke institute of Chinese Academy of Sciences cell bank.Other people tumor cell line HepG2, NCI-H460, Hep3B equal purchased from American Type Tissue Collection storehouse (American Type Culture Collection Manassas, VA).
Experimental technique: Compound ira vitro anti-tumor activity adopts Sulforhodamine B method.Tumor cell RPMI 1640 or DMEM culture medium (Gibco) are cultivated, and include 10% hyclone, condition of culture is 37 DEG C, 5%CO
2.BEL-7402, SMMC-7721, HepG2, Hep3B and NCI-H460 cell strain is inoculated in respectively 96 orifice plate (0.4-1.0 × 10
4cells/well), after 24 hours, add the target compound zardaverine of 10 times of dilutions; Target compound is at least containing 5 concentration.Compound treatment, after 72 hours, discards culture fluid, with 10% cold trichloroacetic acid fixed cell.Then with the dyeing of Sulforhodamine B solution.Wash away in conjunction with after SRB, dissolve and protein bound SRB with Tris, under 515nm wavelength, measure OD value by microplate reader, calculate inhibitory rate of cell growth as follows:
Suppression ratio=(OD value
control wells-OD is worth
dosing holes)/OD value
control wells× 100%
According to each control of the concentration rate, adopt Logit method calculation of half inhibitory concentration IC
50.The results are shown in Table 1.
The extracorporeal anti-tumor function of table 1. zardaverine
Embodiment 2: the Anticancer effect in vivo of zardaverine
Experimental technique: BALB/cA-nude nude mouse, in 6-7 week, ♀, purchased from Shanghai Slac Experimental Animal Co., Ltd..The quality certification number: SCXK (Shanghai) 2007-0005.Feeding environment: SPF level.Zardaverine and control drug Sorafenib (sorafenib) are all made into desired concn with the 0.5%CMC containing 0.1%Tween-80.Nude mouse subcutaneous vaccination Human hepatocarcinoma Bel-7402 cell, treats that tumor growth is to 100-200mm
3after, by animal random packet (d0), solvent control group: n=12; Zardaverine 60mg/kg group, zardaverine 200mg/kg group and positive controls: n=6, and start administration, every day 1 time, continuous gavage 14 days, then drug withdrawal, observe and continue 37 days, and measure tumor size.Survey 2-3 tumor volume weekly, claim Mus heavy, record data.
Gross tumor volume (V) computing formula is: V=1/2 × a × b
2(wherein a, b represent length and width respectively).
Relative tumour volume (RTV): gross tumor volume during gross tumor volume/beginning administration in last 1 day.
Experimental result: see Fig. 1.Fig. 1 shows the curative effect of zardaverine to Human hepatoma cell line Bel-7402 Nude Mice.As can be seen from Figure 1: zardaverine oral administration 200mg/kg, the antitumor action good to BEL-7402 transplanted tumor is shown.Meanwhile, as can be seen from Figure 2, little on the body weight impact of mouse during high dose, illustrate that toxicity is very little.
Zardaverine all shows effective antitumour activity in vivo and in vitro, especially has stronger specificity to hepatocarcinoma, and it can be used as antitumor drug and applies clinical.
Claims (2)
1. 6-(4-(difluoro-methoxy)-3-methoxyphenyl) pyridazine-3 (2H)-one shown in formula I is preparing the purposes in medicines resistant to liver cancer
2. purposes according to claim 1, wherein, described medicines resistant to liver cancer suppresses the activity of BEL-7402 and SMMC-7721 cell strain specifically.
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| CN201110196266.4A CN102872017B (en) | 2011-07-13 | 2011-07-13 | Use of 6-(4-difluoromethoxy)-3methoxyphenyl)pyridazine-3(2H)-one in preparation of antitumor drugs |
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| CN201110196266.4A CN102872017B (en) | 2011-07-13 | 2011-07-13 | Use of 6-(4-difluoromethoxy)-3methoxyphenyl)pyridazine-3(2H)-one in preparation of antitumor drugs |
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| CN102872017A CN102872017A (en) | 2013-01-16 |
| CN102872017B true CN102872017B (en) | 2015-02-04 |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2006508996A (en) * | 2002-11-27 | 2006-03-16 | アルタナ ファルマ アクチエンゲゼルシャフト | PDE4 and PDE3 / 4 inhibitors for use in the treatment of cachexia |
| DE10347994A1 (en) * | 2003-10-15 | 2005-06-16 | Pari GmbH Spezialisten für effektive Inhalation | Aqueous aerosol preparation |
| EP2188630A4 (en) * | 2007-10-02 | 2010-11-03 | Univ Rochester | Methods and compositions related to synergistic responses to oncogenic mutations |
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Non-Patent Citations (1)
| Title |
|---|
| Phosphodiesterase as a novel target in Cancer Chemotherapy;G Sandeep等;《The Internet Journal of Pharmacology》;20081231;第7卷(第1期);摘要 * |
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