CN106938989A - N- (5- benzyls thiazol-2-yl) acetamide derivative and preparation method and application - Google Patents

N- (5- benzyls thiazol-2-yl) acetamide derivative and preparation method and application Download PDF

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CN106938989A
CN106938989A CN201610003833.2A CN201610003833A CN106938989A CN 106938989 A CN106938989 A CN 106938989A CN 201610003833 A CN201610003833 A CN 201610003833A CN 106938989 A CN106938989 A CN 106938989A
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tert
thiazole
bases
acetamide
butyl groups
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CN106938989B (en
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胡艾希
丁娜
叶姣
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Hunan University
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Hunan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

The present invention relates to (the 5- benzyls thiazol-2-yl) acetamide derivatives of the N- shown in chemical structural formula I and its pharmaceutically acceptable salt, its preparation method and pharmaceutical composition and its application in cancer therapy drug is prepared.R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Y1、Y3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；R1、R2It is selected from：Hydrogen, C1~C6Straight chained alkyl；Or NR1R2It is selected from：Piperazinyl, 2- (C1~C4Alkyl) piperazinyl, 3- (C1~C4Alkyl) piperazinyl or 4- (C1~C4Alkyl) piperazinyl.

Description

N- (5- benzyls thiazol-2-yl) acetamide derivative and preparation method and application
Technical field
The present invention relates to a class noval chemical compound, its preparation method and application, specifically N- (5- benzyls thiazol-2-yl) acetamide spreads out Biological, its preparation method and its application in anticarcinogen is prepared.
Background technology
[the European Medical Chemistry, 2003,38 such as Holla：313-318] describe 2- fragrant aminos -4- (2, The chloro- 5- fluorophenyls of 4- bis-) thiazole preparation and bioactivity；Chinese invention patent describes the tertiary fourths of 5- (4- chlorophenylmethyls) -4- Base thiazole [ZL200910226774.5,2011.10.19 are authorized] and the 4- tert-butyl groups -2- (nitrobenzyl imino group) thiazole The preparation of [ZL201019060006.7,2011.10.19 authorize] and its it is used as the application for preparing antineoplastic.Chinese invention Patent (CN101277692A, 2008.10.01 are disclosed) describes 5- benzyls -4- methyl/trifluoromethyl -2- fragrant amino thiazoles Prepare；(ZL201010610300.3,2013.3.20 are authorized Chinese invention patent；ZL201110033057.8,2013.7.17 Authorize) describe the preparation of 5- benzyl -4- alkyl -2- fragrant amino thiazole hydrobromide salt；Chinese invention patent (ZL201310236629.1,2015.3.25 are authorized) describes the system of N- (the 4- tert-butyl group -5- benzyls thiazol-2-yl) acid amides Standby and its bioactivity.
The content of the invention
Present invention solves the technical problem that be to provide a class N- (5- benzyls thiazol-2-yl) acetamide derivative, its preparation method, Pharmaceutical 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 there is provided N- (the 5- benzyls thiazol-2-yl) second of a class as shown in structural formula I Amide derivatives：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Y1、Y3It is selected from：Hydrogen, C1~C2 Alkyl, hydroxyl, C1~C2Alkoxy, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2 Alkoxy；R1、R2It is selected from：Hydrogen, C1~C6Straight chained alkyl, NR1R2It is selected from：Piperazinyl, 2- (C1~C4Alkyl) piperazine Piperazine base, 3- (C1~C4Alkyl) piperazinyl or 4- (C1~C4Alkyl) piperazinyl.
Further, compound preferably is selected from：N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (N- methyl Piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (NEP base) acetamide, N- [4- The tert-butyl group -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- Base] -2- methylaminos acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- ethylaminos acetamide, N- [the 4- tert-butyl groups - 5- (4- chlorobenzyls thiazole) -2- bases] -2- fourths amino acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (N- methyl piperazines Piperazine base) acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (NEP base) acetamide, N- [the 4- tert-butyl groups - 5- (4- chlorobenzyls thiazole) -2- bases] -2- (piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- first Amino acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- ethylaminos acetamide, N- [the 4- tert-butyl group -5- (4- Methoxy-benzyl thiazole) -2- bases] -2- fourths amino acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (N- Methyl piperazine base) acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (NEP base) acetamides or N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (piperazinyl) acetamide；The structure of compound is as follows：
The second aspect of technical solution of the present invention there is provided the N- (5- benzyls thiazol-2-yl) described in first aspect shown in formula I The preparation method of acetamide derivative, it is characterised in that its preparation reaction is as follows：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；Y1、Y3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl Base, C1~C2Alkoxy；R1、R2It is selected from：Hydrogen, C1~C6Straight chained alkyl, NR1R2It is selected from：Piperazinyl, 2- (C1~C4 Alkyl) piperazinyl, 3- (C1~C4Alkyl) piperazinyl or 4- (C1~C4Alkyl) piperazinyl；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, N- (5- benzyls thiazol-2-yl) acetamide of the invention that the pharmaceutical composition contains therapeutically effective amount derives Thing and its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.It is normal that wherein described pharmaceutical carrier refers to pharmaceutical field Pharmaceutical carrier；The pharmaceutical composition can be prepared according to method well known in the art.Can by by the compounds of this invention and its Pharmaceutically acceptable salt is combined with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent, is made Any formulation used suitable for human or animal.The compounds of this invention and its pharmaceutically acceptable salt are in its pharmaceutical composition Content is 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, NaOH 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 N- described in first aspect present invention (5- benzyls thiazol-2-yl) acetamide The application of derivative and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition in terms of cancer therapy drug is prepared.
Advantageous Effects：N- (5- benzyls thiazol-2-yl) acetamide derivative of the present invention is having for a class new construction type The compound of active anticancer.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (N methyl piperazine base) acetamide
0.40g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazol-2-yls] chloroacetamide and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.20g N methyl piperazines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, plus petroleum ether separate out solid, and suction filtration, petroleum ether washes, dry faint yellow solid N- [4- The tert-butyl group -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (N methyl piperazine base) acetamide, yield 65.9%, M.p.168~170 DEG C；1H NMR (400MHz, CDCl3)δ：1.35 (s, 9H, 3 × CH3), 2.35 (s, 3H, CH3), 2.55 (s, 4H, CH2NCH2), 2.65 (s, 4H, CH2NCH2), 3.20 (s, 2H, COCH2), 4.26 (s, 2H, CH2), 7.02 (d, J=8.4Hz, 1H, C6H36-H), 7.16 (dd, J=8.4Hz, J=2.0 Hz, 1H, C6H35-H), 7.39 (d, J=2.0Hz, 1H, C6H33-H), 9.99 (s, 1H, NH).
Embodiment 2
The preparation of N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (NEP base) acetamide
0.20g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazol-2-yls] chloroacetamide and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.12g pyridines and 0.11g NEPs；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, plus petroleum ether separate out solid, and suction filtration, petroleum ether washes, dry buff white solid N- [4- The tert-butyl group -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (NEP base) acetamide, yield 77.9%, m.p.173~175 ℃；1H NMR (400MHz, CDCl3)δ：1.14 (t, J=6.8Hz, 3H, CH3), 1.34 (s, 9H, 3 × CH3), 2.52 (q, J=6.8Hz, 2H, CH2), 2.63 (s, 4H, CH2NCH2), 2.69 (s, 4H, CH2NCH2), 3.21 (s, 2H, COCH2), 4.26 (s, 2H, ArCH2), 7.02 (d, J=8.4Hz, 1H, C6H36-H), 7.16 (dd, J=8.4Hz, J=2.0Hz, 1H, C6H35-H), 7.39 (d, J=2.0Hz, 1H, C6H33-H), 9.97 (s, 1H, NH).
Embodiment 3
The preparation of N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (piperazinyl) acetamide
0.39g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazol-2-yls] chloroacetamide and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.37g 1-Boc- piperazines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, nothing Aqueous sodium persulfate is dried, precipitation, plus petroleum ether separates out solid, and suction filtration, petroleum ether washes, dry buff white solid N- [uncles 4- Butyl -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (N- tert-butoxycarbonyl-piperazines base) acetamide, take 0.15g to be dissolved in 5mL Dichloromethane, plus 1mL trifluoroacetic acids, stirring at normal temperature 2h, precipitation, plus ethyl acetate, saturated sodium bicarbonate solution are washed till Neutrality, anhydrous sodium sulfate drying, precipitation, dry faint yellow solid N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- Base] -2- (piperazinyl) acetamide, yield 94.1%, m.p.164~166 DEG C；1H NMR (400MHz, CDCl3)δ： 1.34 (s, 9H, 3 × CH3), 2.04 (s, 1H, piperazine 4-H), 2.67 (t, J=4.4Hz, 4H, CH2NCH2), 3.11 (t, J=4.4Hz, 4H, CH2NCH2), 3.22 (s, 2H, COCH2), 4.26 (s, 2H, CH2), 7.01 (d, J=8.4Hz, 1H, C6H36-H), 7.16 (dd, J=8.4Hz, J=2.0Hz, 1H, C6H35-H), 7.39 (d, J=2.0Hz, 1H, C6H33-H)。
Embodiment 4
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- chloroacetamides
7.02g 5- (4- the chlorobenzyls) -4- tert-butyl groups-thiazolamine, 3.04g triethylamines, the DMAP and 50mL of catalytic amount 3.39g chloracetyl chlorides are added dropwise under anhydrous methylene chloride, ice bath, 4h is reacted, saturated sodium bicarbonate solution is washed till neutrality, nothing Aqueous sodium persulfate dry, precipitation, column chromatography precipitation it is dry white solid N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- Chloroacetamide, yield 92.7%, m.p.153~155 DEG C；1H NMR (400MHz, CDCl3)δ：1.35 (s, 9H, 3 × CH3), 4.21 (s, 2H, COCH2), 4.22 (s, 2H, CH2), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H), 7.26 (d, J=8.4Hz, 2H, C6H43,5-H).
Embodiment 5
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- methylamino acetamides
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and the methylamine water solutions of 0.25g 25%；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, plus petroleum ether separates out solid, suction filtration, petroleum ether washes, dry faint yellow solid N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- methylamino acetamides, yield 68.2%, m.p.119~121 DEG C；1H NMR (400MHz, CDCl3)δ：1.34 (s, 9H, 3 × CH3), 2.51 (s, 3H, CH3), 3.45 (s, 2H, COCH2), 4.21 (s, 2H, CH2), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H), 7.25 (d, J=8.4Hz, 2H, C6H43,5-H).
Embodiment 6
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- ethylamino acetamides
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and the ethylamine solutions of 0.13g 70%；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, plus petroleum ether separates out solid, suction filtration, petroleum ether washes, dry faint yellow solid N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- ethylamino acetamides, yield 79.2%, m.p.118~120 DEG C；1H NMR (400MHz, CDCl3)δ：1.17 (t, J=7.2Hz, 3H, CH3), 1.35 (s, 9H, 3 × CH3), 2.74 (q, J=7.2Hz, 2H, CH2), 3.45 (s, 2H, COCH2), 4.21 (s, 2H, ArCH2), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H), 7.25 (d, J=8.4Hz, 2H, C6H43,5-H).
Embodiment 7
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- fourth amino acetamides
0.41g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.17g n-butylamines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, anhydrous Sodium sulphate is dried, precipitation, plus petroleum ether separates out solid, and suction filtration, petroleum ether washes, dry white solid N- [the 4- tert-butyl groups - 5- (4- chlorobenzyls thiazole) -2- bases] -2- fourth amino acetamides, yield 59.6%, m.p.109~111 DEG C；1H NMR(400 MHz, CDCl3)δ：0.94 (t, J=7.2Hz, 3H, CH3), 1.35 (s, 9H, 3 × CH3), 1.38 (m, 2H, CH2CH3), 1.52 (m, 2H, CH2), 2.68 (t, J=7.2Hz, 2H, NCH2), 3.45 (s, 2H, COCH2), 4.20 (s, 2H, ArCH2), 7.11 (d, J=8.0Hz, 2H, C6H42,6-H), 7.25 (d, J=8.0Hz, 2H, C6H43,5-H).
Embodiment 8
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (N methyl piperazine base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.20g N methyl piperazines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, plus petroleum ether separate out solid, and suction filtration, petroleum ether washes, dry light orange solid N- [4- The tert-butyl group -5- (4- chlorobenzyls thiazole) -2- bases] -2- (N methyl piperazine base) acetamide, yield 45.1%, m.p.117~119 DEG C；1H NMR (400MHz, CDCl3)δ：1.36 (s, 9H, 3 × CH3), 2.33 (s, 3H, CH3), 2.54 (s, 4H, CH2NCH2), 2.64 (s, 4H, CH2NCH2), 3.20 (s, 2H, COCH2), 4.21 (s, 2H, CH2), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H), 7.25 (d, J=8.4Hz, 2H, C6H43, 5-H)。
Embodiment 9
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (NEP base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.23g NEPs；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, plus petroleum ether separate out solid, and suction filtration, petroleum ether washes, dry faint yellow solid N- [4- The tert-butyl group -5- (4- chlorobenzyls thiazole) -2- bases] -2- (NEP base) acetamide, yield 71.3%, m.p.125~127 DEG C；1H NMR (400MHz, CDCl3)δ：1.11 (t, J=7.2Hz, 3H, CH3), 1.36 (s, 9H, 3 × CH3), 2.48 (q, J=7.2Hz, 2H, CH2), 2.58 (s, 4H, CH2NCH2), 2.66 (s, 4H, CH2NCH2), 3.20 (s, 2H, COCH2), 4.21 (s, 2H, ArCH2), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H), 7.25 (d, J=8.4Hz, 2H, C6H43,5-H).
Embodiment 10
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (piperazinyl) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazol-2-yl] chloroacetamide and 5mL tetrahydrofurans, stirring at normal temperature, plus Enter 0.24g pyridines and 0.37g 1-Boc- piperazines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, anhydrous Sodium sulphate is dried, precipitation, plus petroleum ether separates out solid, and suction filtration, petroleum ether washes, dry faint yellow solid N- [the tertiary fourths of 4- Base -5- (4- chlorobenzyls thiazole) -2- bases] -2- (N- tert-butoxycarbonyl-piperazines base) acetamide, take 0.20g to be dissolved in 5mL dichloromethane, Plus 1mL trifluoroacetic acids, stirring at normal temperature 2h, precipitation, plus ethyl acetate, saturated sodium bicarbonate solution is washed till neutrality, anhydrous Sodium sulphate is dried, precipitation, dry yellow solid N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (piperazinyl) acetyl Amine, yield 95.2%, m.p.105~107 DEG C；1H NMR (400MHz, CDCl3)δ：1.36 (s, 9H, 3 × CH3), 2.02 (s, 1H, piperazine 4-H), 2.62 (t, J=4.8Hz, 4H, CH2NCH2), 3.03 (t, J=4.8Hz, 4H, CH2NCH2), 3.19 (s, 2H, COCH2), 4.21 (s, 2H, CH2), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H), 7.25 (d, J=8.4Hz, 2H, C6H43,5-H).
Embodiment 11
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- chloroacetamides
6.75g 5- (4- the methoxy-benzyls) -4- tert-butyl groups-thiazolamine, 2.02g triethylamines, the DMAP of catalytic amount and 2.26g chloracetyl chlorides are added dropwise under 50mL anhydrous methylene chlorides, ice bath, 4h are reacted, during saturated sodium bicarbonate solution is washed till Property, anhydrous sodium sulfate drying, precipitation, column chromatography precipitation it is dry white solid N- [the 4- tert-butyl groups -5- (4- methoxy-benzyl thiophenes Azoles) -2- bases] -2- chloroacetamides, yield 44.6%, m.p.103~105 DEG C；1H NMR (400MHz, CDCl3)δ： 1.37 (s, 9H, 3 × CH3), 3.79 (s, 3H, OCH3), 4.18 (s, 2H, COCH2), 4.20 (s, 2H, CH2), 6.82 (d, J=8.4Hz, 2H, C6H43,5-H), 7.11 (d, J=8.4Hz, 2H, C6H42,6-H).
Embodiment 12
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- methylamino acetamides
0.36g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature are stirred Mix, add 0.24g pyridines and the methylamine water solutions of 0.25g 25%；Reaction is stayed overnight, precipitation, is added methylene chloride, saturation food Salt is washed, anhydrous sodium sulfate drying, precipitation, plus petroleum ether separates out solid, and suction filtration, petroleum ether is washed, dry that milky is consolidated Body N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- methylamino acetamides, yield 89.3%, m.p.145~147 ℃；1H NMR (400MHz, CDCl3)δ：1.36 (s, 9H, 3 × CH3), 2.50 (s, 3H, CH3), 3.43 (d, J=4.0Hz, 2H, COCH2), 3.78 (s, 3H, OCH3), 4.17 (s, 2H, CH2), 6.82 (d, J=8.8Hz, 2H, C6H43,5-H), 7.11 (d, J=8.8Hz, 2H, C6H42,6-H).
Embodiment 13
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- ethylamino acetamides
0.36g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature are stirred Mix, add 0.24g pyridines and the ethylamine solutions of 0.13g 70%；Reaction is stayed overnight, precipitation, is added methylene chloride, saturation food Salt is washed, anhydrous sodium sulfate drying, precipitation, plus petroleum ether separates out solid, and suction filtration, petroleum ether washes, dry pale yellow colored solid Body N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- ethylamino acetamides, yield 74.8%, m.p.125~127 ℃；1H NMR (400MHz, CDCl3)δ：1.16 (t, J=7.2Hz, 3H, CH3), 1.36 (s, 9H, 3 × CH3), 2.73 (q, J=7.2Hz, 2H, CH2), 3.44 (s, 2H, COCH2), 3.78 (s, 3H, OCH3), 4.17 (s, 2H, ArCH2), 6.82 (d, J=8.8Hz, 2H, C6H43,5-H), 7.11 (d, J=8.8Hz, 2H, C6H42,6-H).
Embodiment 14
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- fourth amino acetamides
0.43g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature are stirred Mix, add 0.24g pyridines and 0.18g n-butylamines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, plus petroleum ether separate out solid, and suction filtration, petroleum ether washes, dry white solid N- [uncles 4- Butyl -5- (4- methoxy-benzyls thiazole) -2- bases] -2- fourth amino acetamides, yield 21.4%, m.p.73~75 DEG C；1H NMR (400MHz, CDCl3)δ：0.93 (t, J=7.2Hz, 3H, CH3), 1.36 (s, 9H, 3 × CH3), 1.38 (m, 2H, CH2CH3), 1.52 (m, 2H, CH2), 2.68 (t, J=7.2Hz, NCH2), 3.45 (s, 2H, COCH2), 3.78 (s, 3H, OCH3), 4.17 (s, 2H, ArCH2), 6.82 (d, J=8.4Hz, 2H, C6H43,5-H), 7.10 (d, J=8.4Hz, 2H, C6H42,6-H).
Embodiment 15
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (N methyl piperazine base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature are stirred Mix, add 0.24g pyridines and 0.20gN- methyl piperazines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, plus petroleum ether separate out solid, and suction filtration, petroleum ether washes, dry faint yellow solid N- [4- The tert-butyl group -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (N methyl piperazine base) acetamide, yield 74.5%, m.p.135~136 ℃；1H NMR (400MHz, CDCl3)δ：1.38 (s, 9H, 3 × CH3), 2.33 (s, 3H, CH3), 2.54 (s, 4H, CH2NCH2), 2.63 (s, 4H, CH2NCH2), 3.18 (s, 2H, COCH2), 3.78 (s, 3H, OCH3), 4.18 (s, 2H, CH2), 6.82 (d, J=8.4Hz, 2H, C6H43,5-H), 7.10 (d, J=8.4Hz, 2H, C6H42,6-H).
Embodiment 16
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (NEP base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature are stirred Mix, add 0.24g pyridines and 0.23g NEPs；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, plus petroleum ether separates out solid, suction filtration, petroleum ether washes, dry faint yellow solid N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (NEP base) acetamide, yield 65.1%, m.p. 107~109 DEG C；1H NMR (400MHz, CDCl3)δ：1.11 (t, J=7.2Hz, 3H, CH3), 1.37 (s, 9H, 3 × CH3), 2.46 (q, J=7.2Hz, 2H, CH2), 2.58 (s, 4H, CH2NCH2), 2.65 (s, 4H, CH2NCH2), 3.18 (s, 2H, COCH2), 3.78 (s, 3H, OCH3), 4.18 (s, 2H, ArCH2), 6.82 (d, J=8.4Hz, 2H, C6H43,5-H), 7.10 (d, J=8.4Hz, 2H, C6H42,6-H).
Embodiment 17
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (piperazinyl) acetamide
0.28g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazol-2-yl] chloroacetamide and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.30g 1-Boc- piperazines；Reaction is stayed overnight, precipitation, is added methylene chloride, saturated common salt washing, nothing Aqueous sodium persulfate is dried, precipitation, plus petroleum ether separates out solid, and suction filtration, petroleum ether washes, dry faint yellow solid N- [uncles 4- Butyl -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (N- tert-butoxycarbonyl-piperazines base) acetamide, take 0.15g to be dissolved in 5mL bis- Chloromethanes, plus 1mL trifluoroacetic acids, stirring at normal temperature 2h, precipitation, plus ethyl acetate, during saturated sodium bicarbonate solution is washed till Property, anhydrous sodium sulfate drying, precipitation, dry faint yellow solid N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- Base] -2- (piperazinyl) acetamide, yield 94.2%, m.p.144~147 DEG C；1H NMR (400MHz, CDCl3)δ： 1.37 (s, 9H, 3 × CH3), 2.04 (s, 1H, piperazine 4-H), 2.66 (t, J=4.8Hz, 4H, CH2NCH2), 3.08 (t, J=4.8Hz, 4H, CH2NCH2), 3.20 (s, 2H, COCH2), 3.78 (s, 3H, OCH3), 4.18 (s, 2H, CH2), 6.82 (d, J=8.4Hz, 2H, C6H43,5-H), 7.10 (d, J=8.4Hz, 2H, C6H42,6-H).
Embodiment 18
The antitumor activity of N- (5- benzyls thiazol-2-yl) acetamide 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 one The dyestuff of hydrogen atom can be received by planting.The dehydrogenase related to NADP in the cell can be by yellow in living cells mitochondria MTT changes into the first a ceremonial jade-ladle, used in libation (formazon) of insoluble bluish violet, and dead cell is then without this function.Dissolved with DMSO After formazon, OD value is determined with ELIASA under certain wavelength, the survival rate for measuring cell can be both quantified.According to light Inhibitory action of the change observation sample of density value 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 1.000 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.
The antitumor activity test result of table 1
Active testing result shows that N- (5- benzyls thiazol-2-yl) acetamide derivative is to cervical cancer cell, human lung adenocarcinoma cell (A549 cells) and human breast cancer cell (MCF-7 cells) have good inhibitory activity, antitumor available for preparing Medicine.

Claims (4)

1. N- (5- benzyl thiazol-2-yl) acetamide derivative of the class as shown in structural formula I and its pharmaceutically acceptable Salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；
Y1、Y3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, fluorine, chlorine, bromine or iodine；Y2、Y4It is selected from： Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；
R1、R2It is selected from：Hydrogen, C1~C6Straight chained alkyl；
Or NR1R2It is selected from：Piperazinyl, 2- (C1~C4Alkyl) piperazinyl, 3- (C1~C4Alkyl) piperazinyl or 4- (C1~C4 Alkyl) piperazinyl.
2. N- (5- benzyls thiazol-2-yl) acetamide derivative described in claim 1 is selected from：
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (N methyl piperazine base) acetamide,
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (NEP base) acetamide,
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl thiazole) -2- bases] -2- (piperazinyl) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- methylaminos acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- ethylaminos acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- fourths amino acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (N methyl piperazine base) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (NEP base) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls thiazole) -2- bases] -2- (piperazinyl) acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- methylaminos acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- ethylaminos acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- fourths amino acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (N methyl piperazine base) acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (NEP base) acetamides or
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls thiazole) -2- bases] -2- (piperazinyl) acetamide.
3. the preparation method of N- (5- benzyls thiazol-2-yl) acetamide derivative shown in the formula I described in claim 1；Its It is characterised by that it prepares reaction as follows：
R, R in formula1、R2、Y1~Y4Definition it is as claimed in claim 1；X is selected from：Chlorine, bromine or iodine.
4. the answering in cancer therapy drug is prepared of N- (5- benzyls thiazol-2-yl) acetamide derivative described in claim 1 or 2 With.
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CN107286115A (en) * 2017-05-10 2017-10-24 南华大学 N‑（The base of 5 arylmethyl thiazole 2）Piperazinyl acid amides and its application as NA inhibitor
CN107365280A (en) * 2016-05-13 2017-11-21 湖南大学 N- (thiazol-2-yl) piperazine yl amide derivatives and its application as cancer therapy drug
CN112675170A (en) * 2021-02-03 2021-04-20 南华大学附属第一医院 Application of V027-0576 in preparation of antitumor drugs

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CN107365280A (en) * 2016-05-13 2017-11-21 湖南大学 N- (thiazol-2-yl) piperazine yl amide derivatives and its application as cancer therapy drug
CN107365280B (en) * 2016-05-13 2020-11-06 湖南大学 N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents
CN107286115A (en) * 2017-05-10 2017-10-24 南华大学 N‑（The base of 5 arylmethyl thiazole 2）Piperazinyl acid amides and its application as NA inhibitor
CN112675170A (en) * 2021-02-03 2021-04-20 南华大学附属第一医院 Application of V027-0576 in preparation of antitumor drugs
CN112675170B (en) * 2021-02-03 2022-02-01 南华大学附属第一医院 Application of V027-0576 in preparation of antitumor drugs

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