CN105777739A - Naphthoic aminothiazole methyl quinolinone derivative and medical application thereof - Google Patents
Naphthoic aminothiazole methyl quinolinone derivative and medical application thereof Download PDFInfo
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- CN105777739A CN105777739A CN201610099044.3A CN201610099044A CN105777739A CN 105777739 A CN105777739 A CN 105777739A CN 201610099044 A CN201610099044 A CN 201610099044A CN 105777739 A CN105777739 A CN 105777739A
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- 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
- C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a naphthoic aminothiazole methyl quinolinone derivative shown in the chemical formula I and medical acceptable salts thereof, wherein R is selected from C1-C2 alkyl or C3-C4 linear alkayl or C3-C4 branched alkayl; X1-X8 are selected from hydrogen, deuterium and C1-C2 alkayl.The naphthoic aminothiazole methyl quinolinone derivative, the medically acceptable salts thereof and application of the medical composition for preparing anticancer drugs are included.
Description
Technical field
The present invention relates to class noval chemical compound and preparation method thereof and application, specifically naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide and the application in preparing cancer therapy drug thereof.
Background technology
Holla etc. [EurMedChem, 2003,38:313-318] describe preparation and the active anticancer of 2-virtue amino-4-(the chloro-5-fluorophenyl of 2,4-bis-) thiazole compound.Hu Aixi etc. describe the active anticancer [SCI, 2013,34 (7): 1646～1652] of 5-benzyl-4-alkyl-2-virtue aminothiazole hydrobromate；Chinese invention patent (CN102070556B；CN102319244B；CN101277692A) preparation and the anti-tumor activity of 5-benzyl-4-alkyl-2-virtue aminothiazole are described.
Summary of the invention
Present invention solves the technical problem that and be to provide a class naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide, its preparation method, pharmaceutical composition and medical usage.
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 is to provide the naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide shown in a class chemical constitution formula I and pharmaceutically acceptable salt thereof:
Wherein, R is selected from: C1～C2Alkyl；C3～C4Straight chained alkyl or C3～C4Branched alkyl；X1～X8It is selected from: hydrogen, deuterium, C1～C2Alkyl；X1～X8Identical, or differ.
Further, it is preferred that compound is selected from: 3-((the 4-tert-butyl group-2-(1-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one.
The preparation method that the second aspect of technical solution of the present invention there is provided the naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in first aspect, it is characterised in that its preparation reaction is as follows:
Wherein, R is selected from: C1～C2Alkyl；C3～C4Straight chained alkyl or C3～C4Branched alkyl；X1～X8It is selected from: hydrogen, deuterium, C1～C2Alkyl；X1～X8Identical, or differ；X is selected from: chlorine, bromine or iodine.
The third aspect of technical solution of the present invention is to provide the pharmaceutical composition containing compound described in first aspect and pharmaceutically acceptable salt thereof, this pharmaceutical composition contains naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide and the pharmaceutically acceptable salt thereof of the present invention of therapeutically effective amount, 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 pass through, by the compounds of this invention and pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solids or liquid excipient and/or adjuvant combination, to make any dosage form being suitable to human or animal's use.The compounds of this invention and pharmaceutically acceptable salt content in its pharmaceutical composition thereof are generally 0.1%～95% percentage by weight.
The compounds of this invention and pharmaceutically acceptable salt or the pharmaceutical composition containing it thereof can be administered in a unit, route of administration can be intestinal or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, 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 solution (including true solution and colloid solution), Emulsion (including o/w type, w/o type and emulsion), suspensoid, injection (including aqueous injection, injectable powder and transfusion), eye drop, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including 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, powder, micropill, drop pill, suppository, membrane, paster, gas (powder) mist agent, spray etc.；Semisolid dosage form can be ointment, gel, paste etc..
The compounds of this invention and pharmaceutically acceptable salt thereof can be made ordinary preparation, also make is slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention and pharmaceutically acceptable salt thereof are made tablet, it is possible to widely use various excipient well known in the art, 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 etc.；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, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium bicarbonate 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 further, for instance sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
In order to administration unit is made capsule, it is possible to effective ingredient the compounds of this invention and pharmaceutically acceptable salt thereof are mixed with diluent, fluidizer, mixture is placed directly within hard capsule or soft capsule.Also effective ingredient the compounds of this invention and pharmaceutically acceptable salt thereof first can be made granule or micropill with diluent, adhesive, disintegrating agent, then be placed in hard capsule or soft capsule.For preparing each diluent of the compounds of this invention and pharmaceutically acceptable salt tablet thereof, adhesive, wetting 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, it is possible to adjust agent, osmotic pressure regulator with water, ethanol, isopropanol, propylene glycol or their mixture as solvent addition solubilizing agent commonly used in the art in right amount, cosolvent, pH.Solubilizing agent or cosolvent can be poloxamer, lecithin, HP-β-CD etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate 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 additive can also be added in pharmaceutical preparation.
For reaching medication purpose, strengthening therapeutic effect, the medicine of the present invention or pharmaceutical composition can be administered by any known medication.
The fourth aspect of technical solution of the present invention is to provide pharmaceutical composition application in preparing anticarcinogen described in naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in first aspect present invention and pharmaceutically acceptable salt thereof and the third aspect.
Further, pharmaceutical composition described in naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in first aspect present invention and pharmaceutically acceptable salt thereof and the third aspect is in the application preparing anti-human adenocarcinoma of lung prescription face.
Further, pharmaceutical composition application in preparing anti-human breast cancer drug described in naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in first aspect present invention and pharmaceutically acceptable salt thereof and the third aspect.
Advantageous Effects:
The naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide of the present invention is the compound with active anticancer of a class new construction type.
Detailed description of the invention
Following example are intended to illustrate the present invention rather than limitation of the invention further.
Embodiment 1
The preparation of 3-((the 4-tert-butyl group-2-(1-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one
10mmol3-(2-bromo-4,4-dimethyl-3-oxopentyl) quinoline-2 (1H)-one and 15ml anhydrous alcohol solution, add 10mmol1-naphthylamino thiourea, and reflux 2.0h, and ammonia adjusts pH=8～9；Reflux 0.5h again, and rotation is except partial solvent, cooling, precipitate out solid, filter, 95% washing with alcohol, dry to obtain 3-((the 4-tert-butyl group-2-(1-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one, yield 56.8%, fusing point 165～168 DEG C.1HNMR (400MHz, CDCl3) δ: 11.96 (s, 1H, NH), 8.08 (d, J=8.9Hz, 1H), 7.84 (dd, J=6.1,3.1Hz, 1H), 7.75 (d, J=7.4Hz, 1H), 7.58 (d, J=8.2Hz, 1H), 7.52～7.47 (m, 4H), 7.42 (d, J=9.4Hz, 1H), 7.40～7.33 (m, 2H), 7.17 (t, J=7.4Hz, 1H), 4.19 (s, 2H, CH2), 1.43 (s, 9H, 3 × CH3)；13CNMR (101MHz, CDCl3) δ: 161.85,158.23,157.04,138.16,137.03,136.77,136.55,136.42,133.40,129.99,127.84,126.55,126.36,123.00,122.13,119.49,118.99,117.10,115.13,112.71,36.10,31.00,27.16,25.03.
Embodiment 2
The preparation of 3-((the 4-tert-butyl group-2-(2-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one
3-((the 4-tert-butyl group-2-(2-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one is prepared by embodiment 1 method.
Embodiment 3
The antitumor cytolytic activity of naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide
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 is with living cells metabolite reducing agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl bromination tetrazoles；3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, MTT] based on.MTT is a kind of dyestuff that can accept hydrogen atom.The MTT of yellow can be changed into insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) by dehydrogenase relevant to NADP in living cells mitochondrion in cell, and dead cell is then without this function.After dissolving formazon with DMSO, under certain wavelength, measure optical density value by microplate reader, both can quantitatively measure the survival rate of cell.The sample inhibitory action to tumor cell is observed in change according to optical density value.
2. anti-tumor activity experiment
Sample: embodiment compound
Cell line: lung adenocarcinoma cell line A549 and breast cancer cell line MCF-7 (offer of Xiangya Medical College, Zhongnan Univ cell bank).
Reagent: tetrazolium bromide (MTT), RPMI1640 culture fluid, new-born calf serum, antibiotic (hero Life Technologies, Inc. of the U.S.)；Pancreatin (AMRESCO company of the U.S.)；96 well culture plates (hero Life Technologies, Inc. of the U.S.)；Dimethyl sulfoxide (Sigma Co., USA).
Instrument: HFsafe-1500 type superclean bench, HF151UV type CO2Incubator (Shanghai Lishen Scientific Equipment Co., Ltd.)；XSP-15C type inverted microscope (the rectangular optical instrument company limited in Shanghai)；MultiskanMK3 type microplate reader (Thermo company of the U.S.)；Ultra-pure water preparing instrument (Milli-Q company of the U.S.).
Experimental implementation: the sample test to A549 cell and MCF-7 cell.The experimental implementation process of every kind of cell is identical, in experimentation, per sample (p.s.) arranges 5 Concentraton gradient (0.010 μm of ol/mL, 0.030 μm of ol/mL, 0.100 μm of ol/mL, 0.300 μm of ol/mL and 1.000 μm of ol/mL), 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 detects each hole OD value, detects wavelength 570nm.
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 IC to cell50Value.3-((the 4-tert-butyl group-2-(1-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one IC to A549 cell and MCF-7 cell50Respectively 15.6 ± 4.6 μMs and 1.1 ± 0.1 μMs.
Active testing result shows, human lung adenocarcinoma cell (A549 cell) and human breast cancer cell (MCF-7 cell) are had good inhibitory activity by naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide and pharmaceutically acceptable salt thereof, can be used for preparing antitumor drug.
Claims (7)
1. the naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide shown in a class chemical constitution formula I and pharmaceutically acceptable salt thereof:
Wherein, R is selected from: C1～C2Alkyl；C3～C4Straight chained alkyl or C3～C4Branched alkyl；
X1～X8It is selected from: hydrogen, deuterium, C1～C2Alkyl；X1～X8Identical, or differ.
2. naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in claim 1 and pharmaceutically acceptable salt thereof, it is characterized in that, described compound is selected from: 3-((the 4-tert-butyl group-2-(1-naphthylamino) thiazole-5-base) methyl) quinoline-2 (1H)-one.
3. the preparation method of the naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in claim 1, it is characterised in that its preparation reaction is as follows:
Wherein, R, X1～X8Definition as claimed in claim 1；X is selected from: chlorine, bromine or iodine.
4. naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in any one of claim 1～2 and pharmaceutically acceptable salt thereof and pharmaceutical composition application in preparing anticarcinogen.
5. naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in any one of claim 1～2 and pharmaceutically acceptable salt thereof and pharmaceutical composition application in preparing anti-human adenocarcinoma of lung medicine.
6. naphthylamino thiazole methyl (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide described in any one of claim 1～2 and pharmaceutically acceptable salt thereof and pharmaceutical composition application in preparing anti-human breast cancer drug.
7. a pharmaceutical composition, including carrier available at least one compound of claim 1～2 and pharmacopedics.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108003152A (en) * | 2017-09-14 | 2018-05-08 | 南华大学 | 4- phenyl -5- (1,2,4- triazolyls) -2- pridylaminos thiazoles and its medical usage |
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| CN102319244A (en) * | 2011-07-22 | 2012-01-18 | 湖南大学 | Application of 5-benzyl-4-alkyl-2-aryl aminothiazole serving as anti-cervical cancer medicaments |
| CN102675303A (en) * | 2011-10-19 | 2012-09-19 | 湖南大学 | 4-alkyl-2-arylamino-5-(1,2,4-triazole-1-group) thiazole and application thereof to preparation of medicaments for resisting cancer |
| CN103058949A (en) * | 2011-10-18 | 2013-04-24 | 华东理工大学 | Thiazole derivative acting as DHODH inhibitor and its application |
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- 2016-02-23 CN CN201610099044.3A patent/CN105777739B/en not_active Expired - Fee Related
Patent Citations (5)
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| WO2003051878A1 (en) * | 2001-12-14 | 2003-06-26 | Merck Frosst Canada & Co. | Quinolinones as prostaglandin receptor ligands |
| CN102070556A (en) * | 2010-12-29 | 2011-05-25 | 湖南大学 | 5-benzyl-4-alkyl-2-aminothiazole as well as preparation and application of 5-benzyl-4-alkyl-2-aminothiazole |
| CN102319244A (en) * | 2011-07-22 | 2012-01-18 | 湖南大学 | Application of 5-benzyl-4-alkyl-2-aryl aminothiazole serving as anti-cervical cancer medicaments |
| CN103058949A (en) * | 2011-10-18 | 2013-04-24 | 华东理工大学 | Thiazole derivative acting as DHODH inhibitor and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108003152A (en) * | 2017-09-14 | 2018-05-08 | 南华大学 | 4- phenyl -5- (1,2,4- triazolyls) -2- pridylaminos thiazoles and its medical usage |
| CN108003152B (en) * | 2017-09-14 | 2020-10-02 | 南华大学 | 4-phenyl-5- (1,2, 4-triazolyl) -2-pyridylaminothiazole derivatives and medical application thereof |
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