CN103387569B - Antineoplastic compounds, preparation method thereof and applications thereof - Google Patents
Antineoplastic compounds, preparation method thereof and applications thereof Download PDFInfo
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- CN103387569B CN103387569B CN201310308098.2A CN201310308098A CN103387569B CN 103387569 B CN103387569 B CN 103387569B CN 201310308098 A CN201310308098 A CN 201310308098A CN 103387569 B CN103387569 B CN 103387569B
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Abstract
The invention relates to the field of anticancer medicines, and particularly relates to antineoplastic compounds having a general formula I and having antineoplastic activity, a preparation method thereof, pharmaceutical compositions thereof and applications thereof, wherein definition of each group is described in the specification.
Description
Technical field
The present invention relates to antitumor relevant pharmaceutical field.Particularly, the present invention relates to pyrazole amide analog derivative having antitumor action and preparation method thereof, and the pharmaceutical composition that contains them.
Background technology
Cancer is the primary disease that threatens human life, and according to statistics, annual global cancer mortality sum reaches 7,000,000 people, and China dies from patient more than 100 ten thousand people of tumour every year, and increases gradually, and oneself becomes first cause of the death of urban population.At present China clinically the medicine of traditional treatment Cancerous disease have a lot, result for the treatment of is also more obvious clinically for they, but shortcoming is: specificity is low, and poor selectivity causes obvious toxic side effect, easily produces serious cancer multidrug resistance phenomenon.
Along with molecular biological development, current anticancer medicine is just from traditional cytotoxic drug, to the new type anticancer disease drug development of the too many levels effect for machine-processed, one of important in the novel targets of the antitumous effect of paying close attention at present is both at home and abroad exactly protein tyrosine kinase (Huang Min, Ding Jian, antitumor drug novel targets, " Chinese prescription drugs ", 2006,12 (57), 10-15).Protein tyrosine kinase has at present and exceedes 20 acceptors that adhere to different families separately and nonreceptor tyrosine kinase and be used as target and carry out screening anticancer medicine, its inhibitor has had several listings, in order to find active better medicine, molecular targeted anti-tumor agents treatment in recent years proposes again another challenge concept: many targets Tyrosylprotein kinase suppresses the strategy of (multiple targeted tyrosine kinase inhibition), is antineoplastic important direction.
The invention discloses the protein tyrosine kinase inhibitor that a class contains pyrazole amide structure, can be for the preparation of antitumor drug.
Summary of the invention
An object of the present invention is to provide a kind of protein tyrosine kinase inhibitor that contains pyrazole amide structure with general formula I.
Another object of the present invention is to provide prepares the compound with general formula I.
A further object of the present invention is to provide the purposes of compound of Formula I at anti-tumor aspect.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein,
R
1be selected from CN, NO
2;
R
2be selected from the alkyl of H, C1-C3.
The compound that preferred the present invention has general formula I is as follows:
Compound of Formula I of the present invention is synthesized by following steps:
Compd A and compd B react under alkali exists in suitable solvent, can obtain Compound I.Wherein said alkali is selected from triethylamine, diisopropyl ethyl amine, KOH, NaOH, salt of wormwood, sodium carbonate, sodium ethylate, sodium hydride, and solvent is selected from trichloromethane, methylene dichloride, acetonitrile, DMF etc.This reaction can be used salt compounded of iodine as catalyzer, as KI and NaI etc.
Compound of Formula I of the present invention has the restraining effect for cancer, can be used as the medicine of effective constituent for the preparation of cancer aspect.The activity of compound of Formula I of the present invention is by extracorporeal anti-tumor modelling verification.
Compound of Formula I of the present invention is effective in quite wide dosage range.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, individual reaction to medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
Reaction raw materials: laboratory self-control, ordinary method.
3.78g (10mmol) compd A-1 and 2.16g (10mmol) compd B-1 are dissolved in the MeCN that 20mL is dry, then add 4.15g (30mmol) salt of wormwood, and then in nitrogen atmosphere, reflux is spent the night.Reaction mixture is poured in frozen water, with the dichloromethane extraction of 50mL × 3, merge organic phase and wash with salt solution, anhydrous sodium sulfate drying, boil off solvent revolving to steam on instrument, obtain the crude product of I-1, column chromatography purification, obtains the sterling of I-1, white solid, mp173-177 DEG C, MS, m/z=531 ([M+NH
4]
+).
Embodiment 2
3.78g (10mmol) compd A-1 and 2.16g (10mmol) compd B-1 are dissolved in the DMF that 20mL is dry, add 4.15g (30mmol) salt of wormwood and 0.50g potassiumiodide, then in nitrogen atmosphere, reflux is spent the night again.Reaction mixture is poured in frozen water, with the dichloromethane extraction of 50mL × 3, merge organic phase and wash with salt solution, anhydrous sodium sulfate drying, boil off solvent revolving to steam on instrument, obtain the crude product of I-1, column chromatography purification, obtains the sterling of I-1, white solid, mp173-177 DEG C, MS, m/z=531 ([M+NH
4]
+).
Embodiment 3-7
With reference to the operation of embodiment 1 and 2, in synthetic following table, there is the compound of formula I.
Embodiment 8
(1) material
Cell strain: leukemia HL-60 cell, gastric cancer SGC-7901 cell line, MCF-7 Breast Cancer Cell, lung cancer cell A-549, all purchased from Shanghai cell research institute of the Chinese Academy of Sciences.
Reagent: MTT, Amresco packing; DMEM substratum, Gibco; Calf serum, Lanzhou people's marine life; Trypsinase, Amresco packing; Fluorouracil Injection, 0.25g/10ml (propping up), Tianjin KingYork Amino Acid Co., Ltd..
Instrument: Bechtop, Suzhou Decontamination Equipment Plant; CO
2incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
(2) method
Cell cultures: tumor cell inoculation is containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100ug/ml Vetstrep, puts 37 DEG C, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity for subsequent use after 3 times.
Mtt assay is measured: the cell in the vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in containing in the DMEM nutrient solution of 10% calf serum, blow and beat into gently single cell suspension with glass dropper, under microscope, use blood cell counts plate numeration viable cell.(cell concn is adjusted into 6～8 × 10 to the 96 every hole of well culture plate inoculating cell suspension 90 μ l
4individual/ml), at 37 DEG C, 100% relative humidity, containing 5%CO
2, 95% air incubator cultivate after 24h, every hole adds 5 μ l liquids (final concentration is 10 μ g/ml).In addition, each concentration is established negative control (isoconcentration DMSO) and blank background (not adding cell), all establishes 6 multiple holes for each group.Cultured continuously 48h again, then every hole adds the MTT solution of 10 μ l5mg/ml, continues to cultivate after 4h, carefully sucks supernatant liquor (suspension cell, need to be first centrifugal, then suck supernatant).Every hole adds 100 μ l DMSO, puts micro oscillator concussion so that crystallization is dissolved completely, and the mono-wavelength colorimetric of microplate reader 492nm, measures OD value.Calculate inhibitory rate of cell growth as evaluation index using following method.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] × 100%.
(3) result
The inhibiting rate (%) of table 1. sample to cultured tumor cells in vitro
(4) conclusion
Can find out from above-mentioned in vitro tests result, compound of Formula I of the present invention all has stronger restraining effect to these 4 kinds of human cancer cells after interaction in vitro 48h in the time of 10 μ g/ml concentration.
Claims (3)
1. there is the compound of general formula I:
Wherein,
R
1be selected from CN, NO
2;
R
2be selected from the alkyl of H, C1-C3.
2. the defined compound of Formula I of claim 1, is selected from:
3. the defined compound of Formula I of claim 1 or 2 is in the purposes of preparing aspect antitumor drug.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310308098.2A CN103387569B (en) | 2013-07-16 | 2013-07-16 | Antineoplastic compounds, preparation method thereof and applications thereof |
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| CN201310308098.2A CN103387569B (en) | 2013-07-16 | 2013-07-16 | Antineoplastic compounds, preparation method thereof and applications thereof |
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|---|---|
| CN103387569A CN103387569A (en) | 2013-11-13 |
| CN103387569B true CN103387569B (en) | 2014-09-24 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998042342A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
| CN102757422A (en) * | 2011-04-29 | 2012-10-31 | 赛诺菲 | Derivatives of N-[(1H-pyrazol-1-yl)aryl]-1H-indole or 1H- indazole-3-carboxamide and their therapeutic uses as p2y12 antagonists |
| CN102811619A (en) * | 2009-11-13 | 2012-12-05 | 金纳斯克公司 | Kinase inhibitors |
| CN102812022A (en) * | 2010-01-12 | 2012-12-05 | Ab科学有限公司 | Thiazole and oxazole kinase inhibitors |
-
2013
- 2013-07-16 CN CN201310308098.2A patent/CN103387569B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998042342A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
| CN102811619A (en) * | 2009-11-13 | 2012-12-05 | 金纳斯克公司 | Kinase inhibitors |
| CN102812022A (en) * | 2010-01-12 | 2012-12-05 | Ab科学有限公司 | Thiazole and oxazole kinase inhibitors |
| CN102757422A (en) * | 2011-04-29 | 2012-10-31 | 赛诺菲 | Derivatives of N-[(1H-pyrazol-1-yl)aryl]-1H-indole or 1H- indazole-3-carboxamide and their therapeutic uses as p2y12 antagonists |
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| CN103387569A (en) | 2013-11-13 |
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Granted publication date: 20140924 Termination date: 20170716 |