CN107098895A - Phenylamino thiazole methyl qualone derivative and preparation method and application - Google Patents
Phenylamino thiazole methyl qualone derivative and preparation method and application Download PDFInfo
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- CN107098895A CN107098895A CN201610091620.XA CN201610091620A CN107098895A CN 107098895 A CN107098895 A CN 107098895A CN 201610091620 A CN201610091620 A CN 201610091620A CN 107098895 A CN107098895 A CN 107098895A
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- 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 invention discloses the phenylamino thiazole methyl qualone derivative shown in a class chemical structural formula I and its pharmaceutically acceptable salt：Wherein, R is selected from：C1~C2Alkyl；C3~C4Straight chained alkyl or C3~C4Branched alkyl；X1、X2It is selected from：Hydrogen, deuterium, C1~C2Alkyl；X3、X7It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine；X4、X6It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine or trifluoromethyl；X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine, nitro or trifluoromethyl；The application of phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt and pharmaceutical composition in anticarcinogen is prepared.
Description
Technical field
The present invention relates to class noval chemical compound and preparation method and application, specifically phenylamino thiazole methyl qualone derivative
And its application in cancer therapy drug is prepared.
Background technology
[the Eur Med Chem, 2003,38 such as Holla:313-318] describe 2- fragrant aminos -4- (the chloro- 5- fluorophenyls of 2,4- bis-) thiophene
The preparation of azole compounds and active anticancer.Hu Aixi etc. describes 5- benzyl -4- alkyl -2- fragrant amino thiazole hydrobromide salt
Active anticancer [SCI, 2013,34 (7)：1646~1652]；Chinese invention patent (CN102070556B；
CN102319244B；CN101277692A the preparation and antitumor work of 5- benzyl -4- alkyl -2- fragrant amino thiazoles) are described
Property.
The content of the invention
Present invention solves the technical problem that being to provide a class phenylamino thiazole methyl qualone derivative, its preparation method, medicine
Composition and purposes.
To solve 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 phenylamino thiazole methyl quinolinone shown in a class chemical structural formula I
Derivative and its pharmaceutically acceptable salt：
Wherein, R is selected from：C1~C2Alkyl；C3~C4Straight chained alkyl or C3~C4Branched alkyl；X1、X2It is selected from：Hydrogen,
Deuterium, C1~C2Alkyl；X3、X7It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine；X4、X6It is selected from：Hydrogen, deuterium,
C1~C2Alkyl, fluorine, chlorine, bromine or trifluoromethyl；X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine, nitro
Or trifluoromethyl.
Further, compound preferably is selected from：
3- ((the 4- tert-butyl groups -2- (phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (2- methylphenylaminos)
Thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (3- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -
Ketone, 3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (2- fluorobenzene
Amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (4- fluoroanilinos) thiazole -5- bases) methyl) quinoline
- 2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (2- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl group -2- (3-
Chloroanilino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (4- chloroanilinos) thiazole -5- bases) methyl) quinoline
- 2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (4- bromoanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl group -2- (3-
Trifluoromethyl phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (4- trifluoromethyls phenylamino) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (2,6- dimethyl benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -
Ketone, 3- ((the 4- tert-butyl groups -2- (the trifluoromethyl phenylaminos of 3,5- bis-) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups
- 2- (the fluoro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (the fluoro- 4- chloroanilinos of 3-)
Thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (the fluoro- 3- chloroanilinos of 4-) thiazole -5- bases) methyl) quinoline
- 2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (2,3- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups
- 2- (3,4- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (3,5- dichloro-benzenes amino) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, 3- ((the 4- tert-butyl groups -2- (the chloro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -
Ketone.
The second aspect of technical solution of the present invention there is provided the phenylamino thiazole methyl qualone derivative described in first aspect
Preparation method, it is characterised in that it preparation reaction it is as follows：
R is selected from：C1~C2Alkyl；C3~C4Straight chained alkyl or C3~C4Branched alkyl；X1、X2It is selected from：Hydrogen, deuterium, C1~C2
Alkyl；X3、X7It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine；X4、X6It is selected from：Hydrogen, deuterium, C1~C2Alkane
Base, fluorine, chlorine, bromine or trifluoromethyl；X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine, nitro or fluoroform
Base；X is selected from：Chlorine, bromine or iodine.
The third aspect of technical solution of the present invention is to provide containing compound described in first aspect and its pharmaceutically acceptable salt
Pharmaceutical composition, the pharmaceutical composition contain therapeutically effective amount phenylamino thiazole methyl qualone derivative of the invention and
Its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein described pharmaceutical carrier refers to what pharmaceutical field was commonly used
Pharmaceutical carrier；The pharmaceutical composition can be prepared according to method well known in the art.Can be by by the compounds of this invention and its pharmacy
Upper acceptable salt is combined with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent, is made and is suitable to
Any formulation that human or animal uses.The content of the compounds of this invention and its pharmaceutically acceptable salt in its pharmaceutical composition
Usually 0.1%~95% percentage by weight.
The compounds of this invention and its pharmaceutically acceptable salt or pharmaceutical composition containing it can be administered in a unit,
Method of administration can be enteron aisle or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic 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 that solution is (including true
Solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection,
Powder-injection and transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet,
Enteric coatel tablets, lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule,
Capsulae enterosolubilis), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；
Semisolid dosage form can be ointment, gel, paste etc..
It is sustained release preparation, controlled release system that the compounds of this invention and its pharmaceutically acceptable salt, which can be made ordinary preparation, also be made,
Agent, targeting preparation and various particulate delivery systems.
In order to which the compounds of this invention and its pharmaceutically acceptable salt are made into tablet, it can widely use well known in the art each
Plant excipient, including diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch,
Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate,
Calcium carbonate etc.；Wetting agent can be water, ethanol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey,
Glucose solution, microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
Methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant
Can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, PVPP, cross-linked carboxymethyl fibre
The plain sodium of dimension, sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfonate
Sodium etc.；Lubricant and glidant can be talcum powder, silica, stearate, tartaric acid, atoleine, poly- second two
Alcohol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or it is double-deck
Piece and multilayer tablet.
In order to which administration unit is made into capsule, can by active ingredient the compounds of this invention and its pharmaceutically acceptable salt with
Diluent, glidant mixing, mixture is placed directly within hard shell capsules or soft capsule.Also can be by active ingredient chemical combination of the present invention
Thing and its pharmaceutically acceptable salt are first made particle or micropill with diluent, binder, disintegrant, then be placed in hard shell capsules or
In soft capsule.Each diluent, binder, wetting for preparing the compounds of this invention and its pharmaceutically acceptable salt tablet
Agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.
For the compounds of this invention and its pharmaceutically acceptable salt are made into injection, water, ethanol, isopropanol, third can be used
Glycol or their mixture as solvent simultaneously add appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, infiltration
Press conditioning agent.Solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjusts agent can
To be phosphate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose,
Phosphate, acetate etc..Freeze drying powder injection is such as prepared, mannitol, glucose etc. can be also added as proppant.
In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition can be with any known to prescription
Method is administered.
The fourth aspect of technical solution of the present invention is to provide phenylamino thiazole methyl quinolinone described in first aspect present invention and derived
The application of thing and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition in terms of anticarcinogen is prepared.
Further, phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in first aspect present invention
And third aspect described pharmaceutical composition is preparing the application in anti-human cervical carcinoma prescription face.
Further, phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in first aspect present invention
And third aspect described pharmaceutical composition is preparing the application in anti-human adenocarcinoma of lung prescription face.
Further, phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in first aspect present invention
And application of the third aspect described pharmaceutical composition in terms of anti-human breast cancer drug is prepared.
Advantageous effects：
The phenylamino thiazole methyl qualone derivative of the present invention is the compound with active anticancer of a class new construction type.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of 3- ((the 4- tert-butyl groups -2- (phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol phenylthioureas are added afterwards, flow back 1.5h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation is molten except part
Agent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (phenylamino) thiazole -5- bases) first
Base) quinoline -2 (1H) -one, yield 72.0%, 229~232 DEG C of fusing point；1H NMR (400MHz, DMSO-d6)δ：11.92
(s, 1H, NH), 9.92 (s, 1H, NH), 7.66 (d, J=7.8Hz, 1H), 7.60 (d, J=8.3Hz, 2H),
7.56 (s, 1H), 7.46 (s, 1H), 7.34~7.25 (m, 3H), 7.14 (s, 1H), 6.89 (s, 1H), 4.00 (s, 2H,
CH2), 1.35 (s, 9H, 3 × CH3)。
Embodiment 2
The preparation of 3- ((the 4- tert-butyl groups -2- (2- toluidinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 2- aminomethyl phenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation is removed
Partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (2- methylphenylaminos)
Thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 80.0%, 218~222 DEG C of fusing point；1H NMR (400MHz, CDCl3)
δ：12.22 (s, 1H, NH), 7.69 (d, J=8.2Hz, 1H), 7.54 (s, 1H), 7.50 (d, J=8.3Hz, 1H),
7.46 (d, J=7.6Hz, 1H), 7.40 (d, J=8.1Hz, 1H), 7.23~7.14 (m, 3H), 6.96 (t, J=7.4Hz,
1H), 4.21 (s, 2H, CH2), 2.31 (s, 3H), 1.42 (s, 9H, 3 × CH3)；13C NMR (100MHz,
CDCl3)δ：158.86,156.31,134.16,132.51,127.84,125.94,124.97,122.58,122.19,
118.36,117.71,116.59,115.19,113.67,112.53,110.79,110.39,31.17,26.00,22.61,
12.94。
Embodiment 3
The preparation of 3- ((the 4- tert-butyl groups -2- (3- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 3- aminomethyl phenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation is removed
Partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (3- methylphenylaminos)
Thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 70%, 161~165 DEG C of fusing point；1H NMR (400MHz, CDCl3)
δ：12.23 (s, 1H), 7.54 (s, 1H), 7.51 (d, J=7.7Hz, 1H), 7.47 (d, J=7.3Hz, 1H), 7.41
(d, J=8.1Hz, 1H), 7.19 (dd, J=18.7,7.5Hz, 2H), 7.13 (s, 2H), 6.85 (d, J=7.2Hz,
1H), 4.21 (s, 2H), 2.31 (s, 3H), 1.44 (s, 9H, 3 × CH3).13C NMR (100MHz, CDCl3)δ：
158.76,156.30,134.94,134.58,132.67,132.57,127.28,125.16,124.37,122.65,119.21,
117.90,115.10,114.03,110.78,110.21,109.86,31.06,25.88,22.53,16.61.
Embodiment 4
The preparation of 3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 4- aminomethyl phenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation is removed
Partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos)
Thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 71.8%, 210~212 DEG C of fusing point.1H NMR(400MHz,CDCl3)
δ：12.03 (s, 1H, NH), 7.53 (s, 1H), 7.50~7.45 (m, 2H), 7.40 (d, J=8.1Hz, 1H), 7.22~7.17 (m,
3H), 7.09 (d, J=8.4Hz, 2H), 4.21 (s, 2H, CH2),2.28(s,3H,CH3),1.41(s,9H,3×CH3)；13C
NMR(100MHz,CDCl3)δ：163.63,160.89,155.73,138.11,137.35,132.76,132.27,129.85,
127.49,122.59,120.08,118.13,115.59,114.73,36.03,30.85,27.40,20.71。
Embodiment 5
The preparation of 3- ((the 4- tert-butyl groups -2- (2- fluoroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 2- fluorophenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation removes portion
Point solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (2- fluoroanilinos) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, yield 84.5%, 226~230 DEG C of fusing point.1H NMR (400MHz, CDCl3)δ：
11.77 (s, 1H, NH), 8.11 (t, J=8.1Hz, 1H), 7.66 (s, 1H), 7.54~7.43 (m, 3H), 7.38 (d,
J=8.1Hz, 1H), 7.20 (t, J=7.5Hz, 1H), 7.10 (dd, J=18.3,10.0Hz, 2H), 6.93 (dd,
J=13.1,7.2Hz, 1H), 4.23 (s, 2H, CH2), 1.43 (s, 9H, 3 × CH3)；13C NMR (100MHz,
CDCl3)δ：δ 163.42,137.41,137.30,136.13,132.75,129.96,129.73,127.55,124.64,
122.70,121.89,120.03,118.03,117.23,116.18,115.49,114.96,114.77,36.09,30.85,
27.35。
Embodiment 6
3- ((the 4- tert-butyl groups -2- (4- fluoroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 4- fluorophenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation removes portion
Point solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (4- fluoroanilinos) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, yield 45%, 170~173 DEG C of fusing point.1H NMR (400MHz, CDCl3)δ：
12.06 (s, 1H, NH), 7.63 (s, 1H), 7.56~7.43 (m, 3H), 7.34 (dd, J=8.5,4.2Hz, 2H),
7.19 (t, J=7.5Hz, 1H), 6.98 (dd, J=11.9,5.2Hz, 2H), 4.19 (s, 2H, CH2), 1.41 (s,
9H, 3 × CH3)；13C NMR (100MHz, CDCl3)δ：166.34,149.23,144.00,138.37,137.52,
132.18,131.17,130.94,129.01,127.94,125.83,123.26,119.53,116.80,115.96,115.31,
35.20,30.27,27.70.
Embodiment 7
The preparation of 3- ((the 4- tert-butyl groups -2- (2- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, after dissolving
10mmol 2- chlorphenyl thiocarbamides are added, flow back 2.5h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation removes part
Solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (2- chloroanilinos) thiazole -5-
Base) methyl) quinoline -2 (1H) -one, yield 64.3%, 223~225 DEG C of fusing point.1H NMR (400MHz, DMSO-d6)δ：
11.92 (s, 1H, NH), 9.31 (s, 1H, NH), 8.46 (d, J=8.2Hz, 1H, N=CH), 7.64 (t, J=8.1
Hz, 1H), 7.59 (s, 1H), 7.50~7.39 (m, 2H), 7.35~7.25 (m, 2H), 7.15 (t, J=7.5Hz, 1H),
6.97 (t, J=7.6Hz, 1H), 4.02 (s, 2H, CH2), 1.35 (s, 9H, 3 × CH3)；13C NMR (100MHz,
DMSO-d6)δ：161.82,158.89,154.30,138.13,136.46,135.37,133.40,129.98,129.73,
127.90,127.83,122.69,122.07,121.56,120.21,119.46,117.29,115.11,36.08,30.92,
27.08。
Embodiment 8
The preparation of 3- ((the 4- tert-butyl groups -2- (3- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 3- chlorphenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation removes portion
Point solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (3- chloroanilinos) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, yield 75.4%, 271~272 DEG C of fusing point；1H NMR (400MHz, DMSO-d6)
δ：11.93 (s, 1H, NH), 10.21 (s, 1H, NH), 7.98 (t, J=2.0Hz, 1H), 7.66 (d, J=7.3Hz,
1H), 7.58 (s, 1H), 7.46 (t, J=8.4Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 7.34~7.27 (m, 2H),
7.14 (t, J=8.0Hz, 1H, 2-H), 6.95 (d, J=6.7Hz, 1H), 4.02 (s, 2H, CH2), 1.36 (s, 9H,
3×CH3)。
Embodiment 9
The preparation of 3- ((the 4- tert-butyl groups -2- (4- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 4- chlorphenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation removes portion
Point solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (4- chloroanilinos) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, yield 70.7%, 227~229 DEG C of fusing point；1H NMR (400MHz, DMSO-d6)
δ：11.92 (s, 1H, NH), 10.08 (s, 1H, NH), 7.65 (t, J=7.9Hz, 3H), 7.56 (s, 1H), 7.46
(t, J=7.7Hz, 1H), 7.32 (dd, J=8.2,4.8Hz, 3H), 7.14 (t, J=7.5Hz, 1H), 4.00 (s, 2H,
CH2), 1.35 (s, 9H, 3 × CH3)；
Embodiment 10
The preparation of 3- ((the 4- tert-butyl groups -2- (4- bromoanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 4- bromophenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation removes portion
Point solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (4- bromoanilinos) thiazoles
- 5- bases) methyl) quinoline -2 (1H) -one, yield 70.2%, 150~153 DEG C of fusing point.1H NMR (400MHz, CDCl3)δ：
12.16 (s, 1H, NH), 7.65 (s, 1H), 7.55~7.48 (m, 2H), 7.44 (d, J=8.1Hz, 1H), 7.39 (dd,
J=8.6,1.8Hz, 3H), 7.28 (s, 2H), 4.19 (s, 2H, CH2), 1.41 (s, 9H, 3 × CH3)；13C NMR
(100MHz, CDCl3)δ：163.31,139.46,137.58,136.25,132.83,132.21,130.08,129.76,
127.60,122.81,121.41,120.00,119.16,117.23,115.52,115.31,36.10,30.82,27.47.
Embodiment 11
The preparation of 3- ((the 4- tert-butyl groups -2- (3- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 3- trifluoromethyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back,
Rotation removes partial solvent, and cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (3- fluoroforms
Base phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 43.7%, 225~228 DEG C of fusing point；1H NMR (400MHz,
DMSO-d6)δ：11.93 (s, 1H, NH), 10.32 (s, 1H, NH), 7.66 (d, J=7.7Hz, 1H), 7.58 (d,
J=5.7Hz, 2H), 7.50 (t, J=7.8Hz, 1H, 5-H), 7.45 (d, J=8.1Hz, 1H, 4-H), 7.32 (m,
J=8.2Hz, 3H, 3-H, 4-H, 5-H), 7.22 (d, J=7.6Hz, 1H, 2-H), 7.14 (t, J=7.6Hz, 1H,
6-H), 4.02 (s, 2H, CH2), 1.36 (s, 9H, 3 × CH3)。
Embodiment 12
The preparation of 3- ((the 4- tert-butyl groups -2- (4- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 4- trifluoromethyl thiocarbamides are added afterwards, flow back 3.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back,
Rotation removes partial solvent, and cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (4- fluoroforms
Base phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 71.8%, 210~212 DEG C of fusing point.1H NMR (400MHz,
CDCl3)δ：11.73 (s, 1H, NH), 7.93 (s, 1H), 7.53~7.44 (m, 4H), 7.39 (t, J=8.0Hz, 2H),
7.25~7.17 (m, 2H), 4.22 (s, 2H, CH2), 1.43 (s, 9H, 3 × CH3).13C NMR (100MHz, CDCl3)
δ：158.56,154.00,136.11,132.59,132.40,127.62,125.11,124.78,122.66,117.85,
115.13,113.63,111.33,110.63,109.10,31.31,25.91,22.45.
Embodiment 13
The preparation of 3- ((the 4- tert-butyl groups -2- (2,6- dimethyl benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, after dissolving
10mmol 2 is added, 6- fenthiurons, backflow 2.0h is added dropwise ammoniacal liquor and adjusts pH=8~9, then the 0.5h that flows back, rotation
Except partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (2,6- dimethyl
Phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 71.6%, 203~205 DEG C of fusing point.1H NMR (400MHz,
DMSO-d6)δ：11.85 (s, 1H, NH), 8.81 (s, 1H, NH), 7.57 (d, J=7.6Hz, 1H), 7.48 (s,
1H), 7.44 (d, J=8.0Hz, 1H), 7.30 (d, J=8.2Hz, 1H), 7.14 (t, J=7.5Hz, 1H), 7.10~7.04
(m, 3H), 3.91 (s, 2H, CH2), 2.22 (s, 6H, 3 × CH3), 1.30 (s, 9H, 3 × CH3)；13C NMR(100
MHz, DMSO-d6)δ：164.09,161.82,154.77,138.74,138.05,136.29,136.04,133.61,
129.91,128.67,127.68,126.79,122.13,119.39,115.13,114.11,36.01,31.00,27.36,
18.46。
Embodiment 14
The preparation of 3- ((the 4- tert-butyl groups -2- (the trifluoromethyl phenylaminos of 3,5- bis-) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
Add 10mmol 3 afterwards, the trifluoromethyl thiocarbamides of 5- bis-, flow back 2.5h, and ammoniacal liquor is added dropwise and adjusts pH=8~9, then flows back 0.5
H, rotation removes partial solvent, and cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (3,5-
Two trifluoromethyl phenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 51.9%, 215~218 DEG C of fusing point.1H NMR
(400MHz, CDCl3)δ：11.15 (s, 1H, NH), 8.08 (s, 2H), 7.52 (s, 1H), 7.47 (t, J=9.5Hz,
3H), 7.32 (d, J=7.7Hz, 1H), 7.20 (t, J=7.2Hz, 1H), 4.22 (s, 2H, CH2), 1.45 (s, 9H,
3×CH3)；13C NMR (100MHz, CDCl3)δ：162.85,150.29,137.62,137.20,132.82,132.50,
131.89,130.25,127.66,124.44,122.88,121.73,119.79,117.41,117.34,117.06,115.28,
36.02,30.74,27.37.
Embodiment 15
The preparation of 3- ((the 4- tert-butyl groups -2- (the fluoro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
The fluoro- 4- nitrobenzophenones thiocarbamides of 10mmol 2- are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back,
Rotation removes partial solvent, and cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- (the fluoro- 4- of 2-
Nitrobenzene amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 64.4%, 270~275 DEG C of fusing point.1H NMR(400
MHz, DMSO-d6)δ：11.92 (s, 1H, NH), 10.03 (s, 1H, NH), 8.83 (d, J=9.2Hz, 1H),
8.28 (d, J=2.3Hz, 1H), 8.22 (dd, J=9.4,2.3Hz, 1H), 7.65 (d, J=10.2Hz, 2H), 7.47 (t,
J=7.6Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 7.15 (t, J=7.5Hz, 1H), 4.08 (s, 2H, CH2),
1.39 (s, 9H, 3 × CH3)；13C NMR (100MHz, DMSO-d6)δ：158.72,157.79,132.55,132.45,
127.84,127.16,125.01,122.63,120.53,117.69,116.63,116.53,115.13,114.06,112.37,
110.67,30.73,25.63,22.90.
Embodiment 16
The preparation of 3- ((the 4- tert-butyl groups -2- (the fluoro- 3- chloroanilinos of 4-) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
The fluoro- 3- chlorphenyls thiocarbamides of 10mmol 4- are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back, rotation
Except partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- ((the fluoro- 3- chlorine of 4-
Phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 63.6%, 196~199 DEG C of fusing point.1H NMR (400MHz,
DMSO-d6)δ：11.92 (s, 1H, NH), 10.16 (s, 1H, NH), 8.13 (dd, J=6.7,2.6Hz, 1H),
7.66 (d, J=7.8Hz, 1H), 7.58 (s, 1H), 7.47 (t, J=7.7Hz, 1H), 7.44~7.39 (m, 1H), 7.36~7.30 (m,
2H), 7.15 (t, J=7.5Hz, 1H), 4.02 (s, 2H, CH2), 1.37 (s, 9H, 3 × CH3)；13C NMR (100MHz,
DMSO-d6)δ：161.82,158.48,154.81,139.00,138.10,136.38,133.29,129.97,127.84,
122.12,119.46,117.81,117.36,117.15,116.79,116.73,116.23,115.11,36.10,30.88,
27.02。
Same operation preparation 3- ((the 4- tert-butyl groups -2- (the fluoro- 4- chloroanilinos of 3-) thiazole -5- bases) methyl) quinoline -2 (1H) -one.
Embodiment 17
The preparation of 3- ((the 4- tert-butyl groups -2- (2,3- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 2 is added afterwards, and 3- dichlorophenyl thiocarbamides, backflow 3.0h is added dropwise ammoniacal liquor and adjusts pH=8~9, then the 0.5h that flows back, rotation
Except partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- ((2,3- dichloro-benzenes
Amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 63.6%, yield 71.7%, 228~231 DEG C of fusing point.1H NMR
(400MHz, CDCl3)δ：12.13 (s, 1H, NH), 8.20 (d, J=8.0Hz, 1H), 7.51 (dd, J=15.7,
7.9Hz, 3H), 7.45~7.40 (m, 1H), 7.19 (dd, J=16.1,8.0Hz, 2H), 7.07 (d, J=8.0Hz,
1H), 4.25 (s, 2H, CH2), 1.44 (s, 9H, 3 × CH3)；13C NMR (100MHz, CDCl3)δ：158.41,
152.83,133.90,132.57,128.04,127.90,127.67,125.10,124.79,122.90,122.62,117.81,
117.68,115.12,112.65,110.77,110.32,31.41,25.99,22.54.
Embodiment 18
The preparation of 3- ((the 4- tert-butyl groups -2- (3,4- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 3 is added afterwards, and 4- dichlorophenyl thiocarbamides, backflow 2.5h is added dropwise ammoniacal liquor and adjusts pH=8~9, then the 0.5h that flows back, rotation
Except partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- ((3,4- dichloro-benzenes
Amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 71.8%, 210~212 DEG C of fusing point.1H NMR (400MHz,
DMSO-d6)δ：11.92 (s, 1H, NH), 10.28 (s, 1H, NH), 8.22 (d, J=2.5Hz, 1H), 7.66 (d,
J=7.8Hz, 1H), 7.58 (s, 1H), 7.51 (d, J=8.8Hz, 1H), 7.47 (t, J=7.2Hz, 1H), 7.39 (dd,
J=8.9,2.4Hz, 1H), 7.33 (d, J=8.2Hz, 1H), 7.15 (t, J=7.5Hz, 1H), 4.03 (s, 2H,
CH2), 1.37 (s, 9H, 3 × CH3)；13C NMR (101MHz, DMSO-d6)δ：161.81,158.12,154.94,
141.62,138.10,136.42,133.25,131.38,130.87,130.00,127.86,122.14,121.75,119.46,
117.88,116.92,116.80,115.11,36.11,30.88,27.02.
Embodiment 19
The preparation of 3- ((the 4- tert-butyl groups -2- (3,5- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 3 is added afterwards, and 5- dichlorophenyl thiocarbamides, backflow 2.5h is added dropwise ammoniacal liquor and adjusts pH=8~9, then the 0.5h that flows back, rotation
Except partial solvent, cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- ((3,5- dichloro-benzenes
Amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 82.9%, 223~226 DEG C of fusing point.1H NMR (400MHz,
CDCl3)δ：11.94 (s, 1H, NH), 7.50 (s, 1H), 7.48~7.41 (m, 4H), 7.38 (d, J=8.2Hz, 1H),
7.18 (t, J=7.5Hz, 1H), 6.92 (s, 1H), 4.22 (s, 2H, CH2), 1.41 (s, 9H, 3 × CH3)；13C NMR
(100MHz, CDCl3)δ：158.71,153.34,151.27,137.64,132.75,132.37,130.41,127.50,
125.14,122.64,117.92,116.52,115.16,111.84,110.74,110.35,31.36,25.94,22.48.
Embodiment 20
The preparation of 3- ((the 4- tert-butyl groups -2- (the chloro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one
10mmol 3- (2- bromo -4,4- dimethyl -3- oxopentyls) quinoline -2 (1H) -one, 15ml absolute ethyl alcohols, dissolving
10mmol 2- chloro-4 nitrophenyl thiocarbamides are added afterwards, flow back 2.0h, ammoniacal liquor is added dropwise and adjusts pH=8~9, then the 0.5h that flows back,
Rotation removes partial solvent, and cooling separates out solid, filtering, the washing of 95% ethanol, dry 3- ((the 4- tert-butyl groups -2- ((the chloro- 4- of 2-
Nitrobenzene amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one, yield 65.9%, 273~277 DEG C of fusing point.1H NMR(400
MHz, DMSO-d6)δ：11.92 (s, 1H, NH), 10.22 (s, 1H, NH), 8.36 (d, J=8.4Hz, 1H),
8.06 (d, J=7.6Hz, 1H), 7.70 (t, J=4.0Hz, 1H), 7.65 (d, 1H, 5-H), 7.61 (s, 1H),
7.45 (t, J=7.6Hz, 1H, 7.32 (d, J=8.4Hz, 1H), 7.15 (t, J=7.2Hz, 1H), 4.05 (s, 2H,
CH2), 1.33 (s, 9H, 3 × CH3)。
Embodiment 21
The antitumor cytolytic activity of phenylamino thiazole methyl qualone derivative
1. antitumor activity principle
Mtt assay biological activity test is also known as MTT colorimetric methods, is a kind of method for detecting cell survival and growth.MTT
Analytic approach is with living cells metabolin reducing agent tetrazolium bromide [3- (4,5- dimethyl -2- thiazoles) -2,5- diphenyl bromination tetrazoles；3-
(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, MTT] based on.MTT is a kind of energy
Receive the dyestuff of hydrogen atom.The dehydrogenase related to NADP in the cell can turn the MTT of yellow in living cells mitochondria
The first a ceremonial jade-ladle, used in libation (formazon) of insoluble bluish violet is melted into, and dead cell is then without this function.Formazon is dissolved with DMSO
Afterwards, OD value is determined with ELIASA under certain wavelength, can both quantifies the survival rate for measuring cell.According to OD value
Inhibitory action of the change observation sample to tumour cell.
2. antitumor activity is tested
Sample：Embodiment compound
Cell line：Cervical cancer tumer line HeLa, lung adenocarcinoma cell line A549 and breast cancer cell line MCF-7 are (Central-South big
Xue Xiangya medical colleges cell bank is provided).
Reagent：Tetrazolium bromide (MTT), RPMI 1640 culture mediums, NBCS, antibiotic (U.S.'s hero's life
Technology company)；Pancreatin (AMRESCO companies of the U.S.)；96 well culture plates (hero Life Technologies, Inc. of the U.S.)；Diformazan
Base sulfoxide (Sigma Co., USA).
Instrument：HFsafe-1500 types superclean bench, HF151UV types CO2(Shanghai power Shen scientific instrument have incubator
Limit company)；XSP-15C types inverted microscope (the rectangular optical instrument Co., Ltd in Shanghai)；Multiskan MK3 type enzyme marks
Instrument (Thermo companies of the U.S.)；Ultra-pure water preparing instrument (Milli-Q companies of the U.S.).
Experimental implementation：Test of the sample to Hela cells, A549 cells and MCF-7 cells.The experiment behaviour of every kind of cell
Make process identical, in an experimentation, per sample (p.s.) sets 5 concentration gradients (0.010 μm of ol/mL, 0.030
μm ol/mL, 0.100 μm of ol/mL, 0.300 μm of ol/mL and 0.500 μm of ol/mL), each four parallel samples of concentration,
Every group of experiment is parallel 3 times, and is drawn a conclusion by blank group control.ELIASA detects each hole OD values, Detection wavelength 570nm.
3. antitumor activity evaluation
(1) cell inhibitory rate is calculated：
(2)IC50Value is calculated
Sample solution concentration logarithm value and cell inhibitory rate linear regression, half-inhibition concentration of the sample to cell is calculated using software
IC50Value.IC of the preferred compound to A549 cells, HeLa cells and MCF-7 cells50It is shown in Table 1~3.
Inhibitory activity of the phenylamino thiazole methyl qualone derivative of table 1 to A549 cells
| Phenylamino thiazole methyl qualone derivative | IC50, μM |
| 3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 20.2±0.3 |
| 3- ((the 4- tert-butyl groups -2- (the fluoro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 3.0±0.8 |
| 3- ((the 4- tert-butyl groups -2- (the fluoro- 3- chloroanilinos of 4-) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 19.3±2.2 |
Inhibitory activity of the phenylamino thiazole methyl qualone derivative of table 2 to Hela cells
| Phenylamino thiazole methyl qualone derivative | IC50, μM |
| 3- ((the 4- tert-butyl groups -2- (phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 6.4±0.5 |
| 3- ((the 4- tert-butyl groups -2- (2- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 18.5±2.2 |
| 3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 19.6±3.2 |
| 3- ((the 4- tert-butyl groups -2- (4- fluoroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 4.4±0.7 |
| 3- ((the 4- tert-butyl groups -2- (4- bromoanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 11.6±0.2 |
| 3- ((the 4- tert-butyl groups -2- (3- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 8.9±0.5 |
| 3- ((the 4- tert-butyl groups -2- (4- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 4.6±0.4 |
| 3- ((the 4- tert-butyl groups -2- (the fluoro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 8.6±0.4 |
| 3- ((the 4- tert-butyl groups -2- (the fluoro- 3- chloroanilinos of 4-) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 19.5±0.6 |
| 3- ((the 4- tert-butyl groups -2- (3,4- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 4.5±0.6 |
| 3- ((the 4- tert-butyl groups -2- (3,5- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 20.7±0.4 |
Inhibitory activity of the phenylamino thiazole methyl qualone derivative of table 3 to MCF-7 cells
| Phenylamino thiazole methyl qualone derivative | IC50, μM |
| 3- ((the 4- tert-butyl groups -2- (3- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 0.4±0.1 |
| 3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 4.2±1.2 |
| 3- ((the 4- tert-butyl groups -2- (4- fluoroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 1.8±0.6 |
| 3- ((the 4- tert-butyl groups -2- (2- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 13.2±2.6 |
| 3- ((the 4- tert-butyl groups -2- (3- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 17.3±1.2 |
| 3- ((the 4- tert-butyl groups -2- (4- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 5.6±2.6 |
| 3- ((the 4- tert-butyl groups -2- (4- bromoanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 13.1±2.5 |
| 3- ((the 4- tert-butyl groups -2- (3- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 10.0±0.3 |
| 3- ((the 4- tert-butyl groups -2- (3,4- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 11.7±1.0 |
| 3- ((the 4- tert-butyl groups -2- (3,5- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one | 16.6±0.7 |
Active testing result shows that phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt are to people's lung gland
Cancer cell (A549 cells), human cervical carcinoma cell (Hela cells) and human breast cancer cell (MCF-7 cells) have
Good inhibitory activity, available for preparing antineoplastic.
Claims (8)
1. phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt shown in a class chemical structural formula I：
Wherein, R is selected from：C1~C2Alkyl；C3~C4Straight chained alkyl or C3~C4Branched alkyl；
X1、X2It is selected from：Hydrogen, deuterium, C1~C2Alkyl；
X3、X7It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine；
X4、X6It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine or trifluoromethyl；
X5It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine, nitro or trifluoromethyl.
2. phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in claim 1, its feature
It is, described compound is selected from：
3- ((the 4- tert-butyl groups -2- (phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (2- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (3- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (4- methylphenylaminos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (2- fluoroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (4- fluoroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (2- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (3- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (4- chloroanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (4- bromoanilinos) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (3- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (4- trifluoromethyls phenylamino) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (2,6- dimethyl benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (the trifluoromethyl phenylaminos of 3,5- bis-) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (the fluoro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (the fluoro- 4- chloroanilinos of 3-) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (the fluoro- 3- chloroanilinos of 4-) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (2,3- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (3,4- dichloro-benzenes amino) thiazole -5- bases) methyl) quinoline -2 (1H) -one,
3- ((the 4- tert-butyl groups -2- (3,5- dichloro-benzenes amino) thiazole -5- bases) methyl) (1H) -one of quinoline -2 or
3- ((the 4- tert-butyl groups -2- (the chloro- 4- nitrobenzene amino of 2-) thiazole -5- bases) methyl) quinoline -2 (1H) -one.
3. the preparation method of the phenylamino thiazole methyl qualone derivative described in claim 1, it is characterised in that its system
It is standby to react as follows：
Wherein, R, X1~X7Definition it is as claimed in claim 1；X is selected from：Chlorine, bromine or iodine.
4. phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in any one of claim 1~2
And application of the pharmaceutical composition in anticarcinogen is prepared.
5. phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in any one of claim 1~2
And application of the pharmaceutical composition in anti-human cervical carcinoma medicine is prepared.
6. phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in any one of claim 1~2
And application of the pharmaceutical composition in anti-human adenocarcinoma of lung medicine is prepared.
7. phenylamino thiazole methyl qualone derivative and its pharmaceutically acceptable salt described in any one of claim 1~2
And application of the pharmaceutical composition in anti-human breast cancer drug is prepared.
8. available carrier in a kind of pharmaceutical composition, including at least one compound of claim 1~2 and pharmaceutics.
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| US6822097B1 (en) * | 2002-02-07 | 2004-11-23 | Amgen, Inc. | Compounds and methods of uses |
| 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 |
| CN103755697A (en) * | 2014-01-14 | 2014-04-30 | 湖南大学 | 3-[[2-(2-benzylamino) thiazole-5-yl]-methyl] quinolone-2(1H)-ketone as well as preparation and application thereof |
| CN105246887A (en) * | 2013-03-15 | 2016-01-13 | 发现生物医药公司 | Coumarin derivatives and methods of use in treating hyperproliferative diseases |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6822097B1 (en) * | 2002-02-07 | 2004-11-23 | Amgen, Inc. | Compounds and methods of uses |
| 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 |
| CN105246887A (en) * | 2013-03-15 | 2016-01-13 | 发现生物医药公司 | Coumarin derivatives and methods of use in treating hyperproliferative diseases |
| CN103755697A (en) * | 2014-01-14 | 2014-04-30 | 湖南大学 | 3-[[2-(2-benzylamino) thiazole-5-yl]-methyl] quinolone-2(1H)-ketone as well as preparation and application thereof |
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