CN103382190B - Thiazole-cyclohexane compound of same category and preparation method and purpose thereof - Google Patents
Thiazole-cyclohexane compound of same category and preparation method and purpose thereof Download PDFInfo
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- CN103382190B CN103382190B CN201310308090.6A CN201310308090A CN103382190B CN 103382190 B CN103382190 B CN 103382190B CN 201310308090 A CN201310308090 A CN 201310308090A CN 103382190 B CN103382190 B CN 103382190B
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Abstract
The invention relates to the field of anticancer medicine, in particular to a thiazole-cyclohexane derivative with anticancer performance and with a general formula I and a preparation method, a medicine composition and a purpose thereof. Definitions of groups are described in an instruction book.
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, 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 class and contain thiazole and the protein tyrosine kinase inhibitor of cyclohexane structure, may be used for preparing antitumor drug.
Summary of the invention
An object of the present invention is to provide a kind of have general 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 general formula I and the method for pharmaceutically acceptable salt thereof.
Another object of the present invention be to provide compound containing general 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 general formula I has following structural formula:
Wherein,
R is selected from the alkyl of H, C1-C5.
Preferred following compound of Formula I, wherein,
R is selected from H, methyl, ethyl, sec.-propyl, isobutyl-, sec-butyl.
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 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.
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 taking compound of Formula I of the present invention 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: self-control.
0.75g (10mmol) compd A-1 and 2.75g (10mmol) compd B-1 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-1, column chromatography purification, obtain the sterling of I-1, white solid, mp.243-245 DEG C; MS, m/z=270 ([M+H]
+).
Embodiment 2
0.75g (10mmol) compd A-1 and 2.75g (10mmol) compd B-1 are dissolved in the THF of 20mL drying, then add 3.88g (30mmol) Et
3n, 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, boils off solvent revolving to steam on instrument, obtains the crude product of I-1, column chromatography purification, obtain the sterling of I-1, mp.243-245 DEG C; MS, m/z=270 ([M+H]
+).
Embodiment 3-7
With reference to the operation of embodiment 1 and 2, there is in synthesis following table the compound of formula I.
Embodiment 8
Be dissolved in 15mL dehydrated alcohol by 2.69g (10mmol) Compound I-1, ice-water bath slowly drips the HCl ethanolic soln of 5mL20% under stirring, continue stirring 30 minutes, then suction filtration, gained solid drying at room temperature under vacuo, obtains the hydrochloride of I-1.
Embodiment 9
(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, compound of 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. following compounds or its pharmacy acceptable salt:
2. arbitrary compound described in claim 1 is preparing the purposes in antitumor drug.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310308090.6A CN103382190B (en) | 2013-07-16 | 2013-07-16 | Thiazole-cyclohexane compound of same category and preparation method and purpose thereof |
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| CN103382190B true CN103382190B (en) | 2015-01-14 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101671329A (en) * | 2009-06-17 | 2010-03-17 | 东华大学 | Indolylmaleimide compound substituted with 3-amino alcohol, preparation method and application thereof |
| WO2010064722A1 (en) * | 2008-12-02 | 2010-06-10 | Takeda Pharmaceutical Company Limited | 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 |
| CN103006645A (en) * | 2011-09-27 | 2013-04-03 | 华东理工大学 | Application of 2-aminobenzothiazole derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor |
-
2013
- 2013-07-16 CN CN201310308090.6A patent/CN103382190B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2010064722A1 (en) * | 2008-12-02 | 2010-06-10 | Takeda Pharmaceutical Company Limited | Benzothiazole derivatives as anticancer agents |
| CN101671329A (en) * | 2009-06-17 | 2010-03-17 | 东华大学 | Indolylmaleimide compound substituted with 3-amino alcohol, preparation method and application thereof |
| CN102351854A (en) * | 2011-07-29 | 2012-02-15 | 华中科技大学 | Amino thiazole derivative and preparation method and medical purpose thereof |
| CN103006645A (en) * | 2011-09-27 | 2013-04-03 | 华东理工大学 | Application of 2-aminobenzothiazole derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| 5-取代-2-(吡啶基)苯并噻唑类化合物的合成及抗肿瘤活性;刘文虎 等;《药学学报》;20130131;第48卷(第1期);83-88 * |
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