CN103265537B - Antitumor compounds, preparation method and application thereof - Google Patents
Antitumor compounds, preparation method and application thereof Download PDFInfo
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- CN103265537B CN103265537B CN201310192271.7A CN201310192271A CN103265537B CN 103265537 B CN103265537 B CN 103265537B CN 201310192271 A CN201310192271 A CN 201310192271A CN 103265537 B CN103265537 B CN 103265537B
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- MHXXQLNCMLFSTN-UHFFFAOYSA-N CCOC(c(c(C)n[n]1CC(NCc2ccc[s]2)=O)c1SC)=O Chemical compound CCOC(c(c(C)n[n]1CC(NCc2ccc[s]2)=O)c1SC)=O MHXXQLNCMLFSTN-UHFFFAOYSA-N 0.000 description 3
- XIOMMLQTVVTLJU-UHFFFAOYSA-N CCOC(c(c(C)n[nH]1)c1SC)=O Chemical compound CCOC(c(c(C)n[nH]1)c1SC)=O XIOMMLQTVVTLJU-UHFFFAOYSA-N 0.000 description 2
- UZEHBSOAOVRKKB-UHFFFAOYSA-N O=C(CBr)NCC1S=CC=C1 Chemical compound O=C(CBr)NCC1S=CC=C1 UZEHBSOAOVRKKB-UHFFFAOYSA-N 0.000 description 2
Abstract
The invention relates to the field of anticancer related medicines, particularly antitumor-activity compounds disclosed as Formula I, and a preparation method, pharmaceutical composition and application thereof.
Description
Technical field
The present invention relates to antitumor relevant pharmaceutical field.Specifically, the present invention relates to a kind of compound with antitumor action and preparation method thereof, and contain their pharmaceutical composition.
Background technology
Cancer is the primary disease threatening 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, has become first cause of the death of urban population.The medicine of the current Therapeutic cancer disease traditional clinically in China has a lot, and result for the treatment of is also comparatively obvious clinically for they, but shortcoming is: specificity is low, poor selectivity, causes obvious toxic side effect, easily produces serious cancer multi-drug resistance phenomenon.
Along with molecular biological development, current anticancer medicine is just from traditional cytotoxic drug, new type anticancer disease drug to the too many levels effect for mechanism develops, one of important in the novel targets of the antitumous effect paid 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 the acceptor that adheres to different family more than 20 separately and nonreceptor tyrosine kinase to be carried out screening anticancer medicine by as target at present, its inhibitor has had several listing, in order to find active better medicine, molecular targeted anti-tumor agents treatment in recent years proposes again another challenge concept: the strategy of many targets tyrosine-kinase enzyme level (multiple targeted tyrosine kinase inhibition) is antineoplastic important direction.
The invention discloses a kind of protein tyrosine kinase inhibitor, may be used for preparing antitumor drug.
Summary of the invention
An object of the present invention is to provide a kind of protein tyrosine kinase inhibitor with formula I structure.
Another object of the present invention is to provide the method that preparation has the compound of formula I structure.
Another object of the present invention is to provide compound containing formula I as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and in the application of 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 formula I has following structural formula:
Formula I of the present invention is synthesized by following steps:
Compd A and compd B react in the presence of a base in a 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 use salt compounded of iodine as catalyzer, as KI and NaI etc.
Formula I of the present invention, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carrier, vehicle or thinner.This pharmaceutical composition can make the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution punishment.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle.
Composition of the present invention, described pharmacy or bromatology can accept auxiliary material.Weighting agent comprises the composition of one or more of lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises the composition of one or more of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises the composition of one or more of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Formula I of the present invention has the restraining effect to cancer, can be used as the medicine of effective constituent for the preparation of cancer aspect.The activity of formula I of the present invention is by extracorporeal anti-tumor modelling verification.
Formula I of the present invention is effective in quite wide dosage range.The actual dosage taking formula I can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
First, be the effect of checking the compounds of this invention in inhibition tumor cell, introducing is invented by applicant equally and is had comparative example 1 compound (I-1) of anti-tumor activity, and Compound I-1 is the compound of brand new, there is no bibliographical information.
Comparative example 1
1.66g (10mmol) compd A-1 and 2.00g (10mmol) compd B-1 are dissolved in the MeCN of 15mL drying, then add 4.15g (30mmol) salt of wormwood, then heated overnight at reflux in nitrogen atmosphere.Reaction mixture is poured in frozen water, with the dichloromethane extraction of 50mL × 3, merges organic phase brine It, anhydrous sodium sulfate drying, boil off solvent revolving to steam on instrument, obtain the crude product of I-1, column chromatography purification, obtain the sterling of I-1, MS, m/z=286 ([M+H]
+).
Embodiment 1
2.34g (10mmol) compd A and 2.00g (10mmol) compd B are dissolved in the MeCN of 20mL drying, then add 4.15g (30mmol) salt of wormwood, then heated overnight at reflux in nitrogen atmosphere.Reaction mixture is poured in frozen water, with the dichloromethane extraction of 50mL × 3, merges organic phase brine It, anhydrous sodium sulfate drying, boil off solvent revolving to steam on instrument, obtain the crude product of I, column chromatography purification, obtain the sterling of I, MS, m/z=354 ([M+H]
+).
Embodiment 2
2.34g (10mmol) compd A and 2.00g (10mmol) compd B are dissolved in the DMF of 20mL drying, then add 4.15g (30mmol) salt of wormwood and 0.2g KI, then in nitrogen atmosphere 120 DEG C spend the night.Reaction mixture is poured in frozen water, with the dichloromethane extraction of 50mL × 3, merges organic phase brine It, anhydrous sodium sulfate drying, boil off solvent revolving to steam on instrument, obtain the crude product of I, column chromatography purification, obtain the sterling of I, MS, m/z=354 ([M+H]
+).
Embodiment 3
Preparation technology: activeconstituents and auxiliary material are pulverized and sieved in advance 100 orders, takes main ingredient and adds auxiliary material lactose, pregelatinized Starch carboxymethylstach sodium and Microcrystalline Cellulose and fully mix, cross 60 mesh sieve three times, add povidone solution, mixing, softwood processed, crosses 20 mesh sieves, wet granular processed, after 50-60 DEG C of drying, add Magnesium Stearate and talcum powder sieves in advance, after then joining in above-mentioned particle fully mixing, measure midbody particle, compressing tablet.
Embodiment 4
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, fully mixes, then take recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood again, 14 mesh sieves are granulated, 55 DEG C of dryings, the whole grain of 12 mesh sieve, measure bag and heavily pack.
Embodiment 5
Small injection
Preparation technology: get water for injection 100ml, add main ingredient, after Sodium Pyrosulfite, sodium bicarbonate be stirred to dissolve, adding appropriate sodium hydroxide regulates PH to be 7.0-9.0, benefit injects water to 200ml, add 2.5g gac, whip attachment 30 minutes, carbon removal, essence are filtered, often to prop up 2ml embedding, sterilizing, to be obtained final product.
Embodiment 6
(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 containing 10% calf serum, in the DMEM nutrient solution of 100IU/ml penicillin G sodium salt and 100ug/ml Vetstrep, put 37 DEG C, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity for subsequent use after 3 times.
Mtt assay measures: the cell in vegetative period of taking the logarithm, after 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution containing 10% calf serum, single cell suspension is blown and beaten into gently, with blood cell counts plate numeration viable cell under microscope with glass dropper.(cell concn is adjusted to 6 ~ 8 × 10 to 96 well culture plate every hole inoculating cell suspension 90 μ l
4individual/ml), 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 establishes 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, after continuing to cultivate 4h, carefully sucks supernatant liquor (suspension cell needs first centrifugal, then sucks supernatant).Every hole adds 100 μ l DMSO, and put micro oscillator concussion to make crystallization dissolve completely, microplate reader 492nm Single wavelength colorimetric, measures OD value.Inhibitory rate of cell growth is calculated 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
Table 1. sample is to the inhibiting rate (%) of cultured tumor cells in vitro
(4) conclusion
As can be seen from above-mentioned in vitro tests result, formula I of the present invention all has stronger restraining effect to these 4 kinds of human cancer cells when 10 μ g/ml concentration after interaction in vitro 48h.
Claims (5)
1. the compound of formula I structure or its pharmacy acceptable salt:
2. formula I according to claim 1 is preparing the application in antitumor drug.
3. a pharmaceutical composition, containing formula I according to claim 1 and pharmaceutically acceptable auxiliary material.
4. pharmaceutical composition according to claim 3, wherein, described composition is solid orally ingestible, injection.
5. solid orally ingestible comprises according to claim 4: tablet, granule.
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|---|---|---|---|
| CN201310192271.7A CN103265537B (en) | 2013-05-14 | 2013-05-14 | Antitumor compounds, preparation method and application thereof |
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|---|---|---|---|
| CN201310192271.7A CN103265537B (en) | 2013-05-14 | 2013-05-14 | Antitumor compounds, preparation method and application thereof |
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| Publication Number | Publication Date |
|---|---|
| CN103265537A CN103265537A (en) | 2013-08-28 |
| CN103265537B true CN103265537B (en) | 2015-05-27 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072498A (en) * | 1974-11-15 | 1978-02-07 | The Upjohn Company | Pyrazole amides |
| CN1050382A (en) * | 1989-09-22 | 1991-04-03 | 藤泽药品工业株式会社 | Pyrazole derivatives and preparation method thereof and medicinal compositions |
| WO1998042342A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
| WO2011094708A2 (en) * | 2010-01-29 | 2011-08-04 | Dana-Farber Cancer Institute, Inc | Small molecules for the modulation of mcl-1 and methods of modulatiing cell death, cell division, cell differentiation and methods of treating disorders |
| CN102884051A (en) * | 2010-01-27 | 2013-01-16 | 贝林格尔.英格海姆国际有限公司 | Pyrazole compounds as CRTH2 antagonists |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7432271B2 (en) * | 2003-09-02 | 2008-10-07 | Bristol-Myers Squibb Company | Pyrazolyl inhibitors of 15-lipoxygenase |
-
2013
- 2013-05-14 CN CN201310192271.7A patent/CN103265537B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072498A (en) * | 1974-11-15 | 1978-02-07 | The Upjohn Company | Pyrazole amides |
| CN1050382A (en) * | 1989-09-22 | 1991-04-03 | 藤泽药品工业株式会社 | Pyrazole derivatives and preparation method thereof and medicinal compositions |
| WO1998042342A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
| CN102884051A (en) * | 2010-01-27 | 2013-01-16 | 贝林格尔.英格海姆国际有限公司 | Pyrazole compounds as CRTH2 antagonists |
| WO2011094708A2 (en) * | 2010-01-29 | 2011-08-04 | Dana-Farber Cancer Institute, Inc | Small molecules for the modulation of mcl-1 and methods of modulatiing cell death, cell division, cell differentiation and methods of treating disorders |
Non-Patent Citations (3)
| Title |
|---|
| Identification of a Novel Family of BRAFV600E Inhibitors;Qin Jie 等;《Journal of Medicinal Chemistry》;20121231;第55卷(第11期);第5220-5230页 * |
| 蛋白酪氨酸激酶小分子抑制剂的研究新进展;王勇 等;《有机化学》;20111231;第31卷(第10期);第1595-1606页 * |
| 酪氨酸酶抑制剂的研究进展;陈清西 等;《厦门大学学报(自然科学版)》;20070331;第46卷(第2期);第274-282页 * |
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