CN103382198B - Pyrazole amide compound, and preparation method thereof and application - Google Patents
Pyrazole amide compound, and preparation method thereof and application Download PDFInfo
- Publication number
- CN103382198B CN103382198B CN201310308096.3A CN201310308096A CN103382198B CN 103382198 B CN103382198 B CN 103382198B CN 201310308096 A CN201310308096 A CN 201310308096A CN 103382198 B CN103382198 B CN 103382198B
- Authority
- CN
- China
- Prior art keywords
- present
- preparation
- cell
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- VXARQHQREBHCKS-UHFFFAOYSA-N CCOC(c(c(C)n[nH]1)c1S(C)=O)=O Chemical compound CCOC(c(c(C)n[nH]1)c1S(C)=O)=O VXARQHQREBHCKS-UHFFFAOYSA-N 0.000 description 2
- NNWCYOLQUBFXQH-AWEZNQCLSA-N Cc(cc1)ccc1C(N(CCC1)C[C@H]1NC(CCBr)=O)=O Chemical compound Cc(cc1)ccc1C(N(CCC1)C[C@H]1NC(CCBr)=O)=O NNWCYOLQUBFXQH-AWEZNQCLSA-N 0.000 description 2
- CFCYEWSUKHUZLA-IZPSYREMSA-N CCOC(c(c(C)n[n]1CCC(N[C@@H](CCC2)CN2C(c2ccc(C)cc2)=O)=O)c1S(C)=O)=O Chemical compound CCOC(c(c(C)n[n]1CCC(N[C@@H](CCC2)CN2C(c2ccc(C)cc2)=O)=O)c1S(C)=O)=O CFCYEWSUKHUZLA-IZPSYREMSA-N 0.000 description 1
- 0 CCOC(c(c(C)n[n]1CCC(N[C@@](CCC2)CN2C(c2cc(CC[*-])c(C)cc2)=O)=O)c1S(C)=O)=O Chemical compound CCOC(c(c(C)n[n]1CCC(N[C@@](CCC2)CN2C(c2cc(CC[*-])c(C)cc2)=O)=O)c1S(C)=O)=O 0.000 description 1
Abstract
The invention relates to the field of medicines related with anti-cancer, in particular to a pyrazole amide derivative having anti-tumor performance of a general formula I, a preparation method thereof, a medicine compound and application. Definitions of every group are shown in an instruction book.
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, has become 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, new type anticancer disease drug development to the too many levels effect for machine-processed, in the novel targets of the antitumous effect of paying close attention at present both at home and abroad one of important be exactly protein tyrosine kinase (Huang Min, fourth is strong, antitumor drug novel targets, < < China prescription drugs > >, 2006,12 (57), 10-15).Protein tyrosine kinase has at present and surpasses 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 the compound that preparation has general formula I.
A further object of the present invention is to provide compound of Formula I in the purposes 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
1be selected from phenyl, the phenyl being replaced by the alkyl of C1-C5;
R
2be selected from the alkyl of H and C1-C5;
m＝0-5。
Preferred following compound of Formula I,
Wherein,
R
1be selected from phenyl, the phenyl being replaced by the alkyl of C1-C5;
R
2be selected from the alkyl of H and C1-C3;
m＝1-3。
It is as follows that preferred the present invention has the compound of general formula I:
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 effective constituent for the preparation of the medicine 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, the 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: ordinary method self-control
3.53g (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, faint yellow solid, mp221-223 ℃, MS, m/z=506 ([M+NH
4]
+).
Embodiment 2
3.53g (10mmol) compd A-1 and 2.16g (10mmol) compd B-1 are dissolved in the DMF that 20mL is dry, then add 4.15g (30mmol) salt of wormwood and 0.50g potassiumiodide, 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, faint yellow solid, mp221-223 ℃, MS, m/z=506 ([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 Jin Yao amino acid company limited.
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 ℃, 100% relative humidity, containing 5%CO
2incubator in, go down to posterity standby 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, with glass dropper, blow and beat into gently single cell suspension, 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 ℃, 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), and each group is all established 6 multiple holes.Cultured continuously 48h again, then every hole adds the MTT solution of 10 μ l5mg/ml, continues to cultivate after 4h, carefully suck supernatant liquor (suspension cell, need 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.The following method of usining is calculated inhibitory rate of cell growth as evaluation index.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average) 1 * 100%.
(3) result
Table 1. sample is to the inhibiting rate of cultured tumor cells in vitro (%)
(4) conclusion
From above-mentioned in vitro tests result, can find out, 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 when 10 μ g/ml concentration.
Claims (4)
1. the compound with general formula I:
Wherein,
R
1be selected from phenyl, the phenyl being replaced by the alkyl of C1-C5;
R
2be selected from the alkyl of H and C1-C5;
m＝0-5。
2. the defined compound with general formula I of claim 1:
Wherein,
R
1be selected from phenyl, the phenyl being replaced by the alkyl of C1-C5;
R
2be selected from the alkyl of H and C1-C3;
m＝1-3。
3. the defined compound of Formula I of claim 2, is selected from:
4. the defined compound of Formula I of claim 1 is in the purposes of preparing aspect antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310308096.3A CN103382198B (en) | 2013-07-16 | 2013-07-16 | Pyrazole amide compound, and preparation method thereof and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310308096.3A CN103382198B (en) | 2013-07-16 | 2013-07-16 | Pyrazole amide compound, and preparation method thereof and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103382198A CN103382198A (en) | 2013-11-06 |
| CN103382198B true CN103382198B (en) | 2014-11-19 |
Family
ID=49490149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310308096.3A Expired - Fee Related CN103382198B (en) | 2013-07-16 | 2013-07-16 | Pyrazole amide compound, and preparation method thereof and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103382198B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998042342A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
| CN101014595A (en) * | 2004-08-11 | 2007-08-08 | 杏林制药株式会社 | Novel cyclic aminobenzoic acid derivative |
| 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 |
| WO2013012723A1 (en) * | 2011-07-13 | 2013-01-24 | Novartis Ag | Novel 2-piperidin-1-yl-acetamide compounds for use as tankyrase inhibitors |
-
2013
- 2013-07-16 CN CN201310308096.3A patent/CN103382198B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998042342A1 (en) * | 1997-03-24 | 1998-10-01 | Merck & Co., Inc. | Thrombin inhibitors |
| CN101014595A (en) * | 2004-08-11 | 2007-08-08 | 杏林制药株式会社 | Novel cyclic aminobenzoic acid derivative |
| 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 |
| WO2013012723A1 (en) * | 2011-07-13 | 2013-01-24 | Novartis Ag | Novel 2-piperidin-1-yl-acetamide compounds for use as tankyrase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103382198A (en) | 2013-11-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9676749B2 (en) | Compositions and methods for cancer detection and treatment | |
| CN1950376B (en) | Curcumol derivatives, compositions comprising the same and use in manufacture of medicament | |
| Malpani et al. | Efficient synthesis of 3H, 3′ H-spiro [benzofuran-2, 1′-isobenzofuran]-3, 3′-dione as novel skeletons specifically for influenza virus type B inhibition | |
| CN101885731A (en) | Thiophene derivative | |
| ES2920888T3 (en) | Sulfonamide derivative and method of preparation and use thereof | |
| CN103450176A (en) | Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof | |
| CN103396400B (en) | Pyrazole amide compounds, and preparation method and application thereof | |
| CN102911118B (en) | Benzo-azepine type derivative and preparation method and purpose thereof | |
| CN104230912A (en) | Quinoline derivative as well as preparation method and application thereof | |
| CN103382198B (en) | Pyrazole amide compound, and preparation method thereof and application | |
| CN103387568B (en) | Compounds, preparation method thereof and applications thereof | |
| CN103420993B (en) | Thiophene substituent group-containing compound as well as preparation method and application thereof | |
| CN103382202B (en) | Compound containing furan substitute and preparation method and use thereof | |
| CN103387569B (en) | Antineoplastic compounds, preparation method thereof and applications thereof | |
| CN103408541B (en) | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof | |
| CN101974016A (en) | Amide compound and preparation method and applications thereof | |
| CN103382190B (en) | Thiazole-cyclohexane compound of same category and preparation method and purpose thereof | |
| CN103396414B (en) | Imidazolyl-substituted thiazocyclohexane compounds and antitumor application thereof | |
| CN103435572B (en) | Thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof | |
| CN103435573B (en) | Benzyl-substituted thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof | |
| CN103483414A (en) | 4-azasteroid purine nucleoside analog, and preparation and application thereof | |
| CN110028480B (en) | 4, 7-position split melphalan nitrogen mustard derivative of brefeldin A and preparation method and application thereof | |
| CN103467452B (en) | A kind of benzamide compound and application thereof | |
| CN103265535B (en) | Antitumor compounds, preparation method and application thereof | |
| CN103265537B (en) | Antitumor compounds, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141119 Termination date: 20170716 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |