CN106188030A - N (5 piperonyl thiazole 2 base) chlorinated amide derivant - Google Patents
N (5 piperonyl thiazole 2 base) chlorinated amide derivant Download PDFInfo
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- CN106188030A CN106188030A CN201610593801.2A CN201610593801A CN106188030A CN 106188030 A CN106188030 A CN 106188030A CN 201610593801 A CN201610593801 A CN 201610593801A CN 106188030 A CN106188030 A CN 106188030A
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- Prior art keywords
- piperonyl
- thiazol
- amide derivant
- chlorinated amide
- thiazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to shown in chemical constitution formula IN(5 piperonyl thiazole 2 base) chlorinated amide derivant and the application in preparing cancer therapy drug thereof:In I formula, R is selected from: C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；N is selected from: 0,1,2 or 3.
Description
Technical field
The present invention relates to a class noval chemical compound, its preparation method and application, specificallyN-(5-piperonyl thiazol-2-yl) two
Chloroamide derivant, its preparation method and preparing the application of anticarcinogen.
Background technology
Holla etc. [European Medical Chemistry, 2003,38:313-318] describe 2-virtue amino-4-
The preparation of (2,4-bis-chloro-5-fluorophenyl) thiazole and biological activity；Chinese invention patent (CN1018445026,
CN101781269) 5-(4-chlorophenylmethyl is described)-4-tertiary butyl thiazole derivatives and the 4-tert-butyl group-2-(nitrobenzyl imido
Base) thiazole preparation and as the application preparing antitumor drug.Chinese invention patent (CN101277692A,
2008.10.01 disclose) describe the preparation of 5-benzyl-4-methyl/trifluoromethyl-2-virtue aminothiazole.Chinese invention patent
(CN102070556A, 2011.5.25 are open；CN102067845A, 2011.5.25 are open) describe 5-benzyl-4-alkyl-2-
The preparation of virtue aminothiazole hydrobromate.
Summary of the invention
Present invention solves the technical problem that and be to provide a classN-(5-piperonyl thiazol-2-yl) chlorinated amide derivant, its
Preparation method, pharmaceutical composition and purposes.
For solving the technical problem of the present invention, the present invention provides following technical scheme:
The first aspect of technical solution of the present invention there is provided a class as shown in structural formula IN-(5-piperonyl thiazol-2-yl)
Chlorinated amide derivant and the most acceptable salt thereof:
I
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；N is selected from: 0,1,2 or 3.
The second aspect of technical solution of the present invention there is provided described in first aspect shown in formula IN-(5-piperonyl thiophene
Azoles-2-base) preparation method of chlorinated amide derivant, it is characterised in that its preparation reaction is as follows:
I
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；N is selected from: 0,1,2 or 3.
The third aspect of technical solution of the present invention is to provide containing compound described in first aspect and pharmaceutically acceptable
The pharmaceutical composition of salt, this pharmaceutical composition contains the present invention's of therapeutically effective amountN-(5-piperonyl thiazol-2-yl) two
Chloroamide derivant and pharmaceutically acceptable salt thereof, and optional containing pharmaceutical carrier.Wherein said pharmaceutical carrier refers to
The pharmaceutical carrier that pharmaceutical field is conventional；This pharmaceutical composition can be prepared according to method well known in the art.Can be by by the present invention
Compound and pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant
Combination, makes and is suitable to any dosage form that human or animal uses.The compounds of this invention and pharmaceutically acceptable salt thereof are at its medicine
Content in compositions is usually 0.1% ~ 95 % percentage by weight.
The compounds of this invention and pharmaceutically acceptable salt or the pharmaceutical composition containing it thereof can be in a unit
Being administered, route of administration can be intestinal or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral cavity are glued
Film, eye, lung and respiratory tract, skin, vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be that solution (includes
True solution and colloid solution), Emulsion (including o/w type, w/o type and emulsion), suspensoid, injection (include aqueous injection, injectable powder
And transfusion), eye drop, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (include ordinary tablet, enteric coatel tablets, buccal tablet,
Dispersible tablet, chewable tablet, effervescent tablet, oral cavity disintegration tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, dissipate
Agent, micropill, drop pill, suppository, membrane, paster, gas (powder) mist agent, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
The compounds of this invention and pharmaceutically acceptable salt thereof can make ordinary preparation, also to make be slow releasing preparation, control
Release formulation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention and pharmaceutically acceptable salt thereof are made tablet, can be widely used known in this field
Various excipient, including diluent, adhesive, wetting agent, disintegrating agent, lubricant, fluidizer.Diluent can be starch,
Dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate
Deng；Wetting agent can be water, ethanol, isopropanol etc.；Binding agent can be starch slurry, dextrin, syrup, Mel, glucose solution,
Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl
Cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, Polyethylene Glycol etc.；Disintegrating agent can be dried starch, crystallite fibre
Dimension element, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, carbon
Acid hydrogen sodium and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and fluidizer can be
Pulvis Talci, silicon dioxide, stearate, tartaric acid, liquid paraffin, Polyethylene Glycol etc..
Tablet can also be made coated tablet, such as sugar coated tablet, thin membrane coated tablet, ECT further, or double
Synusia and multilayer tablet.
In order to administration unit is made capsule, can be by effective ingredient the compounds of this invention and pharmaceutically acceptable
Salt mixes with diluent, fluidizer, is placed directly within by mixture in hard capsule or soft capsule.Also can be by effective ingredient of the present inventionization
Compound and pharmaceutically acceptable salt thereof first make granule or micropill with diluent, adhesive, disintegrating agent, then be placed in hard capsule or
In soft capsule.For preparing each diluent of the compounds of this invention and pharmaceutically acceptable salt tablet thereof, adhesive, moistening
Agent, disintegrating agent, fluidizer kind can also be used for preparing the capsule of the compounds of this invention and pharmaceutically acceptable salt thereof.
For the compounds of this invention and pharmaceutically acceptable salt thereof are made injection, can use water, ethanol, isopropanol,
Propylene glycol or their mixture as solvent and add solubilizing agent the most commonly used in the art, cosolvent, pH adjust agent, osmotic pressure
Regulator.Solubilizing agent or cosolvent can be poloxamer, lecithin, HP-β-CD etc.；PH adjustment agent can be phosphorus
Hydrochlorate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, vinegar
Hydrochlorate etc..As prepared lyophilized injectable powder, mannitol, glucose etc. also can be added as proppant.
Additionally, if desired, coloring agent, preservative, spice, correctives or other interpolation can also be added in pharmaceutical preparation
Agent.
For reaching medication purpose, strengthening therapeutic effect, the medicine of the present invention or pharmaceutical composition can be given known to any
Prescription method is administered.
The fourth aspect of technical solution of the present invention is to provide described in first aspect present inventionN-(5-piperonyl thiazol-2-yl)
Pharmaceutical composition described in chlorinated amide derivant and pharmaceutically acceptable salt thereof and the third aspect is preparing cancer therapy drug side
The application in face.
Further, described in first aspect present inventionN-(5-piperonyl thiazol-2-yl) chlorinated amide derivant and pharmacy thereof
Pharmaceutical composition application in terms of preparing medicament for resisting cervical cancer described in upper acceptable salt and the third aspect.
Further, described in first aspect present inventionN-(5-piperonyl thiazol-2-yl) chlorinated amide derivant and pharmacy thereof
Pharmaceutical composition application in terms of preparing anti-human adenocarcinoma of lung medicine described in upper acceptable salt and the third aspect.
Advantageous Effects: the present invention'sN-(5-piperonyl thiazol-2-yl) chlorinated amide derivant is a class new construction
The compound with active anticancer of type.
Detailed description of the invention
Following example are intended to illustrate rather than limitation of the invention further.
Embodiment 1
N-The synthesis of (5-piperonyl-4-tertiary butyl thiazole-2-base) dichloro acetamide
The 1.55 mmol5-piperonyl-4-tert-butyl groups-thiazolamine, 1.7 mmol triethylamines are dissolved in 15 mL dichloromethane,
Stirring is completely dissolved to solid, is slowly added dropwise 5 mL dichloromethane solutions of 1.7 mmol dichloroacetyl chlorides under ice bath；TLC with
Track reaction process, 0.5 h reaction is complete, and reactant liquor is washed 3 times, anhydrous Na2SO4Being dried, dichloromethane is steamed in rotation, uses column chromatography
(VPetroleum ether : VEthyl acetate=10: 1) separate, obtain white solidN-(5-piperonyl-4-tertiary butyl thiazole-2-base) two chloroethenes
Amide 0.24 g, yield 40%, m.p. 125 ~ 127 DEG C,1H NMR (400 MHz, CDCl3),δ: 1.40 (s, 9H, 3 ×
CH3), 4.15 (s, 2H, CH2), 5.95 (s, 2H, OCH2O), 6.09 (s, 1H, CH), 6.65 (d,J=7.9 Hz, H, C6H3
C6H36-H), 6.66 (s, 1H, C6H3 C6H32-H), 6.74 (d,J=7.9 Hz, 1H, C6H3 C6H3 5-H)。13C NMR
(101 MHz, CDCl3) δ: 30.66,32.68,35.41,66.08,100.96,108.26,108.76,121.29,
125.68,133.51,146.34,147.83,151.84,154.18,162.99.
Embodiment 2
N-(5-piperonyl thiazol-2-yl) chlorinated amide derivant and the anti-tumor activity of salt thereof
1. anti-tumor activity principle
Mtt assay biological activity test, also known as MTT colorimetry, is a kind of method detecting cell survival and growth.MTT analytic process with
Living cells metabolite reducing agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl bromination tetrazole;3-(4,5-
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] based on.MTT is a kind of energy
Accept the dyestuff of hydrogen atom.The MTT of yellow can be changed into by dehydrogenase relevant to NADP in living cells mitochondrion intracellular
Insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon), dead cell is then without this function.After dissolving formazon with DMSO, necessarily
Measure optical density value by microplate reader under wavelength, both can quantitatively measure the survival rate of cell.Sample is observed in change according to optical density value
The product inhibitory action to tumor cell.
2. anti-tumor activity experiment
Sample: embodiment compound.
Cell line: cervical cancer tumer lineHelaWith lung adenocarcinoma cell systemA549(Xiangya Medical College, Zhongnan Univ cell bank carries
For).
Reagent: tetrazolium bromide (MTT), RPMI RPMI-1640, new-born calf serum, antibiotic (U.S.'s hero's life technology
Company)；Pancreatin (AMRESCO company of the U.S.)；96 well culture plates (hero Life Technologies, Inc. of the U.S.)；Dimethyl sulfoxide (the U.S.
Sigma company).
Instrument: HFsafe-1500 type superclean bench, HF151UV type CO2(power Shen, Shanghai scientific instrument are limited for incubator
Company)；XSP-15C type inverted microscope (Shanghai rectangular optical instrument company limited)；Multiskan MK3 type microplate reader is (beautiful
Thermo company of state)；Ultra-pure water preparing instrument (Milli-Q company of the U.S.).
Experimental implementation: sample pairHelaCell,A549Cell andMCF-7The test of cell.The experimental implementation of every kind of cell
Process is identical, in an experimentation, per sample (p.s.) arrange 5 Concentraton gradient (10 μMs, 30 μMs, 100 μMs, 300 μMs and
1000 μMs), four parallel samples of each concentration, often parallel 3 times of group experiment, and reached a conclusion by the comparison of blank group.Microplate reader
Detect each hole OD value, detect wavelength 570 nm.
3. antitumor activity evaluation
1) cell inhibitory rate calculates:
2) IC50Value calculates
Sample solution concentration logarithm value and cell inhibitory rate linear regression, utilize the computed in software sample half-inhibition concentration to cell
IC50Value.N-(5-piperonyl-4-tertiary butyl thiazole-2-base) dichloro acetamide pairHelaCell andA549CellIC 50 Respectively
It it is 32.6 ± 5.7 μMs and 8.3 ± 1.8 μMs
Active testing result shows,N-(5-piperonyl thiazol-2-yl) chlorinated amide derivant or its salt are to cervical cancer cell
(HelaCell), human lung adenocarcinoma cell (A549Cell) there is good inhibitory activity, can be used for preparing antitumor drug.
Claims (4)
1. shown in a class chemical constitution Formulas IN-(5-piperonyl thiazol-2-yl) chlorinated amide derivant and pharmaceutically may be used
The salt accepted:
Ⅰ
In formula, R is selected from: C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；N is selected from: 0,1,2 or 3.
2. the preparation method of N-(5-piperonyl thiazol-2-yl) the chlorinated amide derivant described in claim 1, it is characterised in that
Its preparation reaction is as follows:
I
In formula, the definition of R and n is as claimed in claim 1.
3. N-(5-piperonyl thiazol-2-yl) the chlorinated amide derivant described in claim 1 is applied in preparing cancer therapy drug.
4. N-(5-piperonyl thiazol-2-yl) the chlorinated amide derivant described in claim 1 is at preparation anti-lung cancer cell drug
Middle application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610593801.2A CN106188030B (en) | 2016-07-26 | 2016-07-26 | N- (5- piperonyls thiazol-2-yl) chlorinated amide derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610593801.2A CN106188030B (en) | 2016-07-26 | 2016-07-26 | N- (5- piperonyls thiazol-2-yl) chlorinated amide derivative |
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| Publication Number | Publication Date |
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| CN106188030A true CN106188030A (en) | 2016-12-07 |
| CN106188030B CN106188030B (en) | 2018-08-21 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286149A (en) * | 2017-05-10 | 2017-10-24 | 南华大学 | N‑（The base of 5 piperonyl thiazole 2）Piperidyl amide and its application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012092471A2 (en) * | 2010-12-29 | 2012-07-05 | Development Center For Biotechnology | Novel tubulin inhibitors and methods of using the same |
| CN104530036A (en) * | 2015-01-07 | 2015-04-22 | 湖南大学 | 5-piperonyl-4-alkyl-2-benzyliminothiazole and preparing method and application thereof |
| CN104530035A (en) * | 2015-01-07 | 2015-04-22 | 湖南大学 | 5-piperonyl-4-alkyl-2-aromatic aminothiazole and preparing method and application thereof |
-
2016
- 2016-07-26 CN CN201610593801.2A patent/CN106188030B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012092471A2 (en) * | 2010-12-29 | 2012-07-05 | Development Center For Biotechnology | Novel tubulin inhibitors and methods of using the same |
| CN104530036A (en) * | 2015-01-07 | 2015-04-22 | 湖南大学 | 5-piperonyl-4-alkyl-2-benzyliminothiazole and preparing method and application thereof |
| CN104530035A (en) * | 2015-01-07 | 2015-04-22 | 湖南大学 | 5-piperonyl-4-alkyl-2-aromatic aminothiazole and preparing method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286149A (en) * | 2017-05-10 | 2017-10-24 | 南华大学 | N‑（The base of 5 piperonyl thiazole 2）Piperidyl amide and its application |
| CN107286149B (en) * | 2017-05-10 | 2021-02-12 | 南华大学 | N- (5-piperonyl thiazole-2-yl) piperidyl amide and application thereof |
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| CN106188030B (en) | 2018-08-21 |
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Granted publication date: 20180821 Termination date: 20190726 |