CN103408541B - Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof - Google Patents
Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof Download PDFInfo
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- CN103408541B CN103408541B CN201310308086.XA CN201310308086A CN103408541B CN 103408541 B CN103408541 B CN 103408541B CN 201310308086 A CN201310308086 A CN 201310308086A CN 103408541 B CN103408541 B CN 103408541B
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Abstract
The invention relates to the field of anticancer related medicines, and particularly relates to an indole-substituted thiazolo cyclohexanea compound having antineoplastic activity and having a structure shown as the formula I, a preparation method thereof, pharmaceutical compositions thereof and applications thereof.
Description
Technical field
The present invention relates to antitumor relevant pharmaceutical field.Specifically, the present invention relates to the thiazole with antitumor action and cyclohexane derivant, its preparation method, containing their pharmaceutical composition and the application at anti-tumor aspect.
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, and oneself becomes 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 containing indyl replace thiazole and the protein tyrosine kinase inhibitor of cyclohexane structure, have obvious restraining effect to tumour cell.
Summary of the invention
An object of the present invention is to provide a kind of have formula I containing thiazole the protein tyrosine kinase inhibitor of cyclohexane structure and pharmaceutically acceptable salt.
Another object of the present invention is to provide preparation and has the compound of formula I and the method for pharmaceutically acceptable salt thereof.
Another object of the present invention be to provide compound containing formula I and pharmaceutically acceptable salt 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, salt of wormwood, sodium carbonate, and temperature of reaction is the temperature of room temperature to solvent refluxing used.
The pharmacy acceptable salt of formula I of the present invention comprises, but be not limited to and various mineral acid, such as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, the pharmacy acceptable salt that such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc. generate.
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 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.
Embodiment 1
Reaction raw materials: commercially available or self-control.
1.90g (10mmol) compd A and 2.75g (10mmol) compd B are dissolved in the THF of 20mL drying, then add 3.04g (30mmol) Et
3n, then at room temperature stirs until reacted (24-48 hour).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, white solid, mp.157-159 DEG C; MS, m/z=385 ([M+H]
+).
Embodiment 2
1.90 (10mmol) compd As and 2.75g (10mmol) compd B are dissolved in the THF of 20mL drying, add 3.88g (30mmol) DIPEA again, then under agitation backflow is until reacted (in 10 hours).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, white solid, mp.157-159 DEG C; MS, m/z=385 ([M+H]
+).
Embodiment 3
(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 (2)
1. there is compound and the pharmaceutically acceptable salt thereof of formula I structure:
2. the formula I that claim 1 defines is preparing the purposes in antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310308086.XA CN103408541B (en) | 2013-07-16 | 2013-07-16 | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof |
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| CN201310308086.XA CN103408541B (en) | 2013-07-16 | 2013-07-16 | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof |
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| CN103408541A CN103408541A (en) | 2013-11-27 |
| CN103408541B true CN103408541B (en) | 2015-04-01 |
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| CN112574192B (en) * | 2020-12-24 | 2021-10-01 | 烟台大学 | Amino acid derivative bithiazole-tryptamine anticancer compound and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002047762A1 (en) * | 2000-12-13 | 2002-06-20 | Tularik Limited | Serine protease inhibitors |
| WO2005033102A2 (en) * | 2003-10-03 | 2005-04-14 | Amphora Discovery Corporation | Thiophene-based compounds exhibiting atp-utilizing enzyme inhibitory activity, and compositions, and uses thereof |
| CN1688557A (en) * | 2002-10-09 | 2005-10-26 | 辉瑞产品公司 | Thiazole compounds for treatment of neurodegenerative disorders |
| CN102300854A (en) * | 2008-12-02 | 2011-12-28 | 武田药品工业株式会社 | Benzothiazole derivatives as anticancer agents |
| CN102351854A (en) * | 2011-07-29 | 2012-02-15 | 华中科技大学 | Amino thiazole derivative and preparation method and medical purpose thereof |
-
2013
- 2013-07-16 CN CN201310308086.XA patent/CN103408541B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002047762A1 (en) * | 2000-12-13 | 2002-06-20 | Tularik Limited | Serine protease inhibitors |
| CN1688557A (en) * | 2002-10-09 | 2005-10-26 | 辉瑞产品公司 | Thiazole compounds for treatment of neurodegenerative disorders |
| WO2005033102A2 (en) * | 2003-10-03 | 2005-04-14 | Amphora Discovery Corporation | Thiophene-based compounds exhibiting atp-utilizing enzyme inhibitory activity, and compositions, and uses thereof |
| CN102300854A (en) * | 2008-12-02 | 2011-12-28 | 武田药品工业株式会社 | Benzothiazole derivatives as anticancer agents |
| CN102351854A (en) * | 2011-07-29 | 2012-02-15 | 华中科技大学 | Amino thiazole derivative and preparation method and medical purpose thereof |
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