CN107365280A - N- (thiazol-2-yl) piperazine yl amide derivatives and its application as cancer therapy drug - Google Patents

N- (thiazol-2-yl) piperazine yl amide derivatives and its application as cancer therapy drug Download PDF

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CN107365280A
CN107365280A CN201610317454.0A CN201610317454A CN107365280A CN 107365280 A CN107365280 A CN 107365280A CN 201610317454 A CN201610317454 A CN 201610317454A CN 107365280 A CN107365280 A CN 107365280A
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thiazol
tert
alkyl
acetamide
butyl groups
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CN107365280B (en
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胡艾希
伍智林
丁娜
叶姣
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses (base of thiazole 2) the piperazine yl amide derivatives of the N shown in structural formula I and II 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；R1It is selected from：Hydrogen, C1~C4Alkyl or C1~C5Alkoxy carbonyl group；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2Alkylene oxide group, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O；X5、X9It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；X6、X8It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；X7It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；N is selected from：1st, 2 or 3.

Description

N- (thiazol-2-yl) piperazine yl amide derivatives and its application as cancer therapy drug
Technical field
The present invention relates to a kind of noval chemical compound, its preparation method and application, specifically N- (thiazol-2-yl) piperazinyl acid amides spreads out Biology, its preparation method and its preparing the application of anticarcinogen.
Background technology
Gurdal etc. describes compound 1 to human colon cancer cell HCT-116, human breast cancer cell line Bcap-37 and people liver Cancer cell HUH-7 inhibitory activity, its GI50Respectively 7.9 μM, 9.2 μM and 3.1 μM, wherein, to HCT-116 With HUH-7 inhibitory activity better than positive control 5 FU 5 fluorouracil [J Enzyme Inhibition and Med Chem, 2015,30(4):649-654].Abou-Seri et al. describes compound 2 to vascular endothelial growth factor receptor -2 (VEGFR-2) inhibitory activity of kinases, its IC50For 0.40 ± 0.04 μM, with positive control PTK787 (IC50 =0.18 ± 0.02 μM) it is close；Cytoactive test display, GI of the compound to a variety of cancer cells50Less than the positive Tester Sorafenib [Eur J Med Chem, 2016,107:165-179].
World inventions patent [WO 2014145642A2,2014-9-18 disclose] describes a series of with nuclear factor Nrf2 For the anticancer compound of target spot, wherein inhibitory activity of the compound 3a and 3c to human lung cancer cell A549 and H1437 Score as B levels (5 μM of ＜ IC5025 μM of ＜)；Compound 3b is commented the inhibitory activity of A549 and H1437 cells It is divided into A levels (IC50≤5μM)。
El-Messery and Hassan etc. describes a series of thiazolamine derivatives 4 under the conditions of concentration is 10 μM To the external inhibitory activity of a variety of cancer cells [Eur J Med Chem, 2012,54:615-625；Bioorg&Med Chem Lett,2012,22(20):6318-6323]：Wherein suppression of the compound 4a to leukaemia CCRF-CEM and SR Rate is respectively 75.5% and 51.8%；Compound 4b is 69.3% to leukaemia CCRF-CEM inhibiting rate； Compound 4c is respectively 54.6% and 51.4% to colon cancer cell HCT-15 and kidney cancer cell UO-31 inhibiting rate； Compound is 60.2% to non-small cell lung cancer cell HOP-92 inhibiting rate to 4d；Compound 4e is thin to leukaemia Born of the same parents K562, kidney cancer cell UO-31 and breast cancer cell MDA-MB-468 inhibiting rate are respectively 70.7%, 54.6% With 55.6%.In propionamide (i.e. n=2) derivative, suppressions of the compound 4f to leukaemia CCRF-CEM Rate processed is 96.2%, and compound 4g is 54.0% to kidney cancer cell UO-31 inhibiting rate, and compound 4h is to non-small thin Born of the same parents' lung carcinoma cell HOP-92, the suppression to melanoma cells SK-MEL-5, kidney cancer cell A498 and UO-31 Rate is respectively 59.6%, 52.5%, 67.5% and 68.9%；Suppression of the compound 4i to leukaemia MOLT-4 Rate is 51.8%, and the inhibiting rate to breast cancer cell MDA-MB-468 is 62.8%；Compound 4j is thin to colon cancer Born of the same parents HT29 inhibiting rate is 80.4%, and melanoma cells SK-MEL-5 and UACC-62 inhibiting rate are distinguished For 76.2% and 71.6%.
Choi et al. describes compound 5 to wild type (wild-type) oncogenic kinase (oncogenic kinase) Bcr-Abl Inhibitory activity, its EC50For 5.21 μM of [Bioorg＆Med Chem Lett, 2012,22 (16):5297-5302].
Chinese invention patent [CN 103524535A, 2014-1-22 disclose] describes a series of compound hedgehog signalling channels The IC of antagonist 6, wherein compound 6a and 6b to the NIH3T3 cells of expression GRE- fluoresceins50Respectively 134.3 NM and 150.9nM, it is close with positive control vismodegib (Vismodegib).
The content of the invention
Present invention solves the technical problem that it is to provide a kind of N- (thiazol-2-yl) piperazines yl amide derivatives, its preparation method, medicine Compositions 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 a kind of N- (thiazol-2-yl) piperazinyl acyl as shown in structural formula I Amine derivative and its pharmaceutically acceptable salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C4 Alkyl or C1~C5Alkoxy carbonyl group；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2It is sub- Alkoxy, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2 Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O；N is selected from：1st, 2 or 3.
The first aspect of technical solution of the present invention additionally provides a kind of N- (thiazol-2-yl) piperazinyl acyl as shown in formula II Amine derivative and its pharmaceutically acceptable salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2Alkylene oxide group, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O； X5、X9It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；X6、X8It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl Base, C1~C2Alkoxy；X7It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；N is selected from：1st, 2 or 3.
Further, preferable compound is selected from：N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- methyl piperazines Piperazine base) acetamide, N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide, N- [4- The tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazole -2- Base] -2- (4- methyl piperazines base) acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetyl Amine, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) Thiazol-2-yl] -2- (4- methyl piperazines base) acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- ethyls Piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (piperazinyl) acetamide, N- [the 4- tert-butyl groups - 5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide, N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiophenes Azoles -2- bases] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- phenyl Piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamides or N- [the 4- tert-butyl groups -5- (4- methoxies Base benzyl) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide.
The second aspect of technical solution of the present invention there is provided N- (thiazol-2-yl) piperazinyl described in first aspect shown in formula I The preparation method of amide derivatives, 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；R1It is selected from：C1~C4Alkyl Or C1~C5Alkoxy carbonyl group；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2Alkylene oxide Base, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2Alkylene Epoxide；X2X3It is selected from：OCH2O or OCH2CH2O；N is selected from：1st, 2 or 3；X is selected from：Chlorine, bromine or iodine.
Or
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；X1、X3It is selected from：Hydrogen, C1~C2 Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2Alkylene oxide group, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2 Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O；N is selected from： 1st, 2 or 3；X is selected from：Chlorine, bromine or iodine.
The second aspect of technical solution of the present invention is to additionally provide N- (thiazol-2-yl) piperazine described in first aspect shown in formula II The preparation method of piperazine yl amide derivatives, 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；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2Alkylene oxide group, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O； X5、X9It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；X6、X8It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl Base, C1~C2Alkoxy；X7It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；N is selected from：1st, 2 or 3； 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 contains N- (thiazol-2-yl) piperazine yl amide derivatives of the invention of therapeutically effective amount And its pharmaceutically acceptable salt, and optional contain pharmaceutical carrier.Wherein described pharmaceutical carrier refers to pharmaceutical field and 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 medicine Acceptable salt combines with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent on, is made suitable In any formulation that human or animal uses.The compounds of this invention and its pharmaceutically acceptable salt containing in its pharmaceutical composition Amount is usually 0.1%~95% percentage by weight.
The compounds of this invention and its pharmaceutically acceptable salt can be administered in a unit containing its pharmaceutical composition, 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, can widely use well known in the art each Kind 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 Tie up plain sodium, 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 First particle or micropill is made with diluent, binder, disintegrant in thing and its pharmaceutically acceptable salt, then be placed in hard shell capsules or In soft capsule.For preparing each diluent, binder, wetting of 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 and be used 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 give prescription known to any Method is administered.
The fourth aspect of technical solution of the present invention is to provide N- described in first aspect present invention (thiazol-2-yl) piperazinyl acid amides and spread out The application of biology and its pharmaceutically acceptable salt and third aspect described pharmaceutical composition in terms of cancer therapy drug is prepared.
Further, (thiazol-2-yl) the piperazine yl amide derivatives of N- described in first aspect present invention and its pharmaceutically acceptable salt And application of the third aspect described pharmaceutical composition in terms of medicament for resisting cervical cancer is prepared.
Further, (thiazol-2-yl) the piperazine yl amide derivatives of N- described in first aspect present invention and its pharmaceutically acceptable salt And application of the third aspect described pharmaceutical composition in terms of anti-human adenocarcinoma of lung medicine is prepared.
Further, (thiazol-2-yl) the piperazine yl amide derivatives of N- described in first aspect present invention and its pharmaceutically acceptable salt And application of the third aspect described pharmaceutical composition in terms of anti-human breast cancer medicines are prepared.
Advantageous effects：N- (thiazol-2-yl) piperazine yl amide derivatives of the present invention are that having for a kind of new construction type is anti- The compound of cancer activity.
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) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide
0.40g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] chloroacetamides and 5mL tetrahydrofurans, normal temperature stir Mix, add 0.24g pyridines and 0.20g N methyl piperazines；Reaction overnight, precipitation, adds methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry faint yellow solid N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- methyl piperazines 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) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide
0.20g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] chloroacetamides and 5mL tetrahydrofurans, normal temperature stir Mix, add 0.12g pyridines and 0.11g NEPs；Reaction overnight, precipitation, adds methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry buff white solid N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide, yield 77.9%, m.p. 173~175 DEG C；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) thiazol-2-yl] -2- (piperazinyl) acetamide
0.39g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] chloroacetamides and 5mL tetrahydrofurans, normal temperature stir Mix, add 0.24g pyridines and 0.37g 1-Boc- piperazines；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry buff white solid N- [4- The tert-butyl group -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- tert-butoxycarbonyl-piperazines base) acetamide, take 0.15g to be dissolved in 5mL Dichloromethane, add 1mL trifluoroacetic acids, stirring at normal temperature 2h, precipitation adds ethyl acetate, and saturated sodium bicarbonate solution is 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, CH2NHCH2), 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) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide
(1) preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- chloroacetamides
7.02g 5- (4- the chlorobenzyls) -4- tert-butyl groups-thiazolamine, 3.04g triethylamines, the DMAP and 50mL of catalytic amount Anhydrous methylene chloride, 3.39g chloracetyl chlorides are added dropwise under ice bath, react 4h, 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) thiazol-2-yl] -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).
(2) preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.20g N methyl piperazines；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry light orange solid N- [4- The tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- methyl piperazines 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 5
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.23g NEPs；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry faint yellow solid N- [4- The tert-butyl group -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- ethyl piperazidines 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 6
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (piperazinyl) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, add Enter 0.24g pyridines and 0.37g 1-Boc- piperazines；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, anhydrous Sodium sulphate is dried, precipitation, adds petroleum ether to separate out solid, is filtered, and petroleum ether washes, dry faint yellow solid N- [the tertiary fourths of 4- Base -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- tert-butoxycarbonyl-piperazines base) acetamide, take 0.20g to be dissolved in 5mL dichloromethane, Add 1mL trifluoroacetic acids, stirring at normal temperature 2h, precipitation, add 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) thiazol-2-yl] -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, CH2NHCH2), 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 7
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide
(1) preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- chloroacetamides
6.75g 5- (4- the methoxy-benzyls) -4- tert-butyl groups-thiazolamine, 2.02g triethylamines, the DMAP of catalytic amount and 50mL anhydrous methylene chlorides, 2.26g chloracetyl chlorides are added dropwise under 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-benzyls) Thiazol-2-yl] -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).
(2) preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature stir Mix, add 0.24g pyridines and 0.20gN- methyl piperazines；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry faint yellow solid N- [4- The tert-butyl group -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- methyl piperazines 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 8
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.24g pyridines and 0.23g NEPs；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, Anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, filter, petroleum ether washes, dry faint yellow solid N- [4- The tert-butyl group -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide, yield 65.1%, m.p.107~109 ℃；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=8.4 Hz, 2H, C6H43,5-H), 7.10 (d, J=8.4Hz, 2H, C6H42,6-H).
Embodiment 9
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -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 overnight, precipitation, adds methylene chloride, saturated common salt washing, nothing Aqueous sodium persulfate is dried, precipitation, adds petroleum ether to separate out solid, is filtered, and petroleum ether washes, dry faint yellow solid N- [uncles 4- Butyl -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- tert-butoxycarbonyl-piperazines base) acetamide, take 0.15g to be dissolved in 5mL bis- Chloromethanes, adds 1mL trifluoroacetic acids, stirring at normal temperature 2h, precipitation, adds during ethyl acetate, 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, CH2NHCH2), 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 10
The preparation of N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide
0.39g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature Stirring, add 0.12g pyridines and 0.32g 1-phps；Reaction overnight, precipitation, adds methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, ethyl alcohol recrystallization, filter, ethanol is washed, dry in vain Color solid N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide, yield 72.3%, M.p.170~172 DEG C；1H NMR (400MHz, CDCl3)δ：1.33 (s, 9H, 3 × CH3), 2.78 (t, J= 4.8Hz, 4H, CH2NCH2), 3.27 (s, 2H, COCH2), 3.30 (t, J=4.8Hz, 4H, CH2NCH2), 4.26 (s, 2H, CH2), 6.90 (t, J=7.2Hz, 1H, C6H54-H), 6.96 (d, J=8.0Hz, 2H, C6H52,6-H), 7.02 (d, J=8.4Hz, 1H, C6H36-H), 7.16 (dd, J=8.4Hz, J=2.4Hz, 1H, C6H35-H), 7.27~7.31 (m, 2H, C6H53,5-H), 7.40 (d, J=2.4Hz, 1H, C6H33-H)。
Embodiment 11
The preparation of N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide
0.20g N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature Stirring, add 2.5mL 1%NaOH solution and 0.18g 1- (4- hydroxy phenyls) piperazine；Reaction overnight, precipitation, adds dichloro Methane, watery hydrochloric acid are washed, saturated common salt washing, anhydrous sodium sulfate drying, and precipitation adds petroleum ether to separate out solid, and ethanol is tied again Crystalline substance, filter, ethanol washes, dry white solid N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- [4- (4- hydroxyls Base phenyl) piperazinyl] acetamide, yield 64.1%, m.p.206~208 DEG C；1H NMR (400MHz, CDCl3)δ： 1.36 (s, 9H, 3 × CH3), 2.63 (s, 8H, piperazine rings), 3.22 (s, 2H, COCH2), 4.29 (s, 2H, CH2), 6.72 (d, J=8.0Hz, 2H, C6H42,6-H), 6.87 (d, J=8.0Hz, 2H, C6H43,5-H), 7.04 (d, J=8.4Hz, 1H, C6H36-H), 7.19 (dd, J=8.4Hz, J=2.0Hz, 1H, C6H35-H), 7.42 (d, J=2.0Hz, 1H, C6H33-H)。
Embodiment 12
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide
0.36g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 0.12g pyridines and 0.32g 1-phps；Reaction overnight, precipitation, adds methylene chloride, saturated common salt washing, nothing Aqueous sodium persulfate is dried, precipitation, is added petroleum ether to separate out solid, ethyl alcohol recrystallization, is filtered, and ethanol washes, dry white solid N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide, yield 85.5%, m.p.179~180 ℃；1H NMR (400MHz, CDCl3)δ：1.35 (s, 9H, 3 × CH3), 2.78 (t, J=4.8Hz, 4H, CH2NCH2), 3.27 (s, 2H, COCH2), 3.30 (t, J=4.8Hz, 4H, CH2NCH2), 4.22 (s, 2H, CH2), 6.90 (t, J=7.2Hz, 1H, C6H54-H), 6.96 (d, J=8.0Hz, 2H, C6H52,6-H), 7.12 (d, J=8.0Hz, 2H, C6H42,6-H), 7.25 (d, J=8.0Hz, 2H, C6H43,5-H), 7.27~7.31 (m, 2H, C6H53,5-H)。
Embodiment 13
The preparation of N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide
0.18g N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, stirring at normal temperature, Add 2.5mL1%NaOH solution and 0.18g 1- (4- hydroxy phenyls) piperazine；Reaction overnight, precipitation, adds methylene chloride, Watery hydrochloric acid is washed, and saturated common salt washing, anhydrous sodium sulfate drying, precipitation, is added petroleum ether to separate out solid, ethyl alcohol recrystallization, is taken out Filter, ethanol washes, dry faint yellow solid N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazines Piperazine base] acetamide, yield 60.9%, m.p.175~177 DEG C；1H NMR (400MHz, CDCl3)δ：
1.36 (s, 9H, 3 × CH3), 2.60 (s, 8H, piperazine rings), 3.22 (s, 2H, COCH2), 4.23 (s, 2H, CH2), 6.70 (d, J=8.0Hz, 2H, 4-HOC6H42,6-H), 6.87 (d, J=8.0Hz, 2H, 4-HOC6H4 3,5-H), 7.13 (d, J=8.0Hz, 2H, C6H42,6-H), 7.27 (d, J=8.0Hz, 2H, C6H43,5-H)。
Embodiment 14
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide
0.15g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature Stirring, add 0.05g pyridines and 0.13g 1-phps；Reaction overnight, precipitation, adds methylene chloride, saturated aqueous common salt Wash, anhydrous sodium sulfate drying, precipitation, add petroleum ether to separate out solid, ethyl alcohol recrystallization, filter, ethanol is washed, dry in vain Color solid N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide, yield 90.6%, M.p.179~180 DEG C；1H NMR (400MHz, CDCl3)δ：1.37 (s, 9H, 3 × CH3), 2.76 (t, J= 4.8Hz, 4H, CH2NCH2), 3.25 (s, 2H, COCH2), 3.29 (t, J=4.8Hz, 4H, CH2NCH2), 3.79 (s, 3H, OCH3), 4.19 (s, 2H, CH2), 6.83 (d, J=8.8Hz, 2H, C6H43,5-H), 6.90 (t, J=7.2Hz, 1H, C6H54-H), 6.95 (d, J=8.0Hz, 2H, C6H52,6-H), 7.11 (d, J=8.8Hz, 2H, C6H42,6-H), 7.27~7.31 (m, 2H, C6H53,5-H)。
Embodiment 15
The preparation of N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide
0.06g N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- chloroacetamides and 5mL tetrahydrofurans, normal temperature Stirring, add 2.5mL1%NaOH solution and 0.06g 1- (4- hydroxy phenyls) piperazine；Reaction overnight, precipitation, adds dichloro Methane, watery hydrochloric acid are washed, saturated common salt washing, anhydrous sodium sulfate drying, and precipitation adds petroleum ether to separate out solid, and ethanol is tied again Crystalline substance, filter, ethanol washes, dry Off-white solid N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- [4- (4- Hydroxy phenyl) piperazinyl] acetamide, yield 59.5%, m.p.212~214 DEG C；1H NMR (400MHz, CDCl3)δ： 1.38 (s, 9H, 3 × CH3), 2.60 (s, 8H, piperazine rings), 3.21 (s, 2H, COCH2), 3.80 (s, 3H, OCH3), 4.20 (s, 2H, CH2), 6.72 (d, J=8.0Hz, 2H, 4-HOC6H42,6-H), 6.85 (d, J=8.4Hz, 2H, C6H43,5-H), 6.87 (d, J=8.0Hz, 2H, 4-HOC6H43,5-H), 7.13 (d, J=8.4Hz, 2H, C6H42,6-H), 9.65 (s, 1H, NH), 10.53 (s, 1H, HO).
Embodiment 16
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide
1.55mmol5- piperonyls -4- the tert-butyl groups-thiazolamine, 1.7mmol triethylamines are dissolved in 15mL dichloromethane, Stirring and dissolving, the 5mL dichloromethane solutions of 1.7mmol chloracetyl chlorides are slowly added dropwise under ice bath；TLC tracking react into Journey, 0.5h reactions are finished, and reaction solution is washed 3 times, anhydrous Na2SO4Dry, rotate dichloromethane, add a small amount of oil Ether and ethyl acetate mixtures, white solid is slowly separated out, collect white solid, dried, obtaining white solid N-, (5- is recklessly Green pepper base -4- tertiary butyl thiazole -2- bases) chloroacetamide 0.45g, yield 82%, m.p.127~129 DEG C,1H NMR (400MHz, CDCl3), δ：1.38 (s, 9H, 3 × CH3), 4.15 (s, 2H, CH2), 4.22 (s, 2H, ClCH2), 5.94 (s, 2H, OCH2O), 6.64 (d, J=8.0Hz, 1H, C6H36-H), 6.66 (s, 1H, C6H32-H), 6.74 (d, J=8.0Hz, 1H, C6H35-H)。13C NMR (101MHz, CDCl3)δ：30.80,32.54,35.65,41.91,100.89, 108.18,108.75,121.20,125.27,134.03,146.17,147.74,151.86,153.48,163.58.
Embodiment 17
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- chlorine propionamides
The 1.55mmol 5- piperonyls -4- tert-butyl groups-thiazolamine, 1.7mmol triethylamines are dissolved in 15mL dichloromethane, Stirring and dissolving, the 5mL dichloromethane solutions of 1.7mmol3- chlorpromazine chlorides are slowly added dropwise under ice bath；TLC tracking reactions Process, 0.5h reactions are finished, and reaction solution is washed 3 times, anhydrous Na2SO4Dry, rotate dichloromethane, add a small amount of stone Oily ether and ethyl acetate mixtures, white solid is slowly separated out, collect white solid, dried, obtain white solid N- (5- Piperonyl -4- tertiary butyl thiazole -2- bases) -3- chlorine propionamide 0.50g, yield 85%, m.p.143~145 DEG C,1H NMR(400 MHz, CDCl3), 1.38 (s, 9H, 3 × CH3), 2.85 (t, J=6.3Hz, CH2), 3.84 (t, J=6.3Hz, CH2), 4.15 (s, 2H, CH2), 5.94 (s, 2H, OCH2O), 6.65 (d, J=8.0Hz, 1H, C6H3), 6.66 (s, 1H, C6H3), 6.73 (d, J=8.0Hz, 1H, C6H3)。13C NMR (101MHz, CDCl3)δ：30.78, 32.30,35.57,37.40,39.87,100.90,108.18,108.76,121.21,125.25,134.02,146.19, 147.75,151.88,153.49,167.04.
Embodiment 18
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -4- chlorobutamides
The 1.55mmol 5- piperonyls -4- tert-butyl groups-thiazolamine, 1.7mmol triethylamines are dissolved in 15mL dichloromethane, Stirring and dissolving, the 5mL dichloromethane solutions of 1.7mmol3- chlorpromazine chlorides are slowly added dropwise under ice bath；TLC tracking reactions Process, 0.5h reactions are finished, and reaction solution is washed 3 times, anhydrous Na2SO4Dry, rotate dichloromethane, post processing uses Column chromatography (VPetroleum ether:VEthyl acetate=15:1) separate, obtain faint yellow sticky semi-solid N- (5- piperonyl -4- tertiary butyl thiazoles - 2- bases) -4- chlorobutamide 0.29g, yield 74%,1H NMR (400MHz, CDCl3), δ:1.39 (s, 9H, 3 × CH3), 2.17 (m, 2H, CH2), 2.64 (t, J=7.1Hz, 2H, CH2), 3.62 (t, J=6.2Hz, 2H, CH2), 4.14 (s, 2H, OCH2), 5.94 (s, 2H, CH2), 6.64 (d, J=8.0Hz, 1H, C6H36-H), 6.66 (s, 1H, C6H3C6H32-H), 6.74 (d, J=8.0Hz, 1H, C6H35-H)。
Embodiment 19
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (4- methyl piperazines base) acetamide
0.55mmol N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide, 0.83mmol1- methyl piperazines, 0.8mmol Triethylamine, it is dissolved in 10mL tetrahydrofurans, 12h is stirred at room temperature, reaction solution is diluted with 50mL ethyl acetate, washing Once, saturated common salt is washed once, anhydrous Na2SO4Dry, be evaporated under reduced pressure precipitation, add few drops of petroleum ethers, separate out solid Body, filter, dry, obtain white solid N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (4- methyl piperazines base) acetamide 0.21g, yield 89%, m.p.171~173 DEG C,1H NMR (400MHz, CDCl3) (s, 9H, 3 × CH of δ 1.373), 2.35 (s, 3H, CH3), 2.57~2.65 (m, 8H, piperazine rings), 3.19 (s, 2H, COCH2), 4.15 (s, 2H, CH2), 5.93 (s, 2H, OCH2O), 6.62~6.68 (m, 2H, C6H3), 6.72 (d, J=8.0Hz, 1H, C6H3), 9.94 (s, 1H, NH).13C NMR (101MHz, CDCl3) δ 30.91,32.55,35.65,45.82,53.39,54.76, 61.03,100.89,108.17,108.80,121.20,124.28,134.33,146.09,147.72,152.49,153.29, 168.04。
Embodiment 20
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (4- ethyl piperazidines base) acetamide
0.55mmol N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide, 0.83mmol 1- ethyl piperazidines, 0.8mmol Triethylamine, it is dissolved in 10mL tetrahydrofurans, 12h is stirred at room temperature, reaction solution is diluted with 50mL ethyl acetate, washing Once, saturated common salt is washed once, anhydrous Na2SO4Dry, be evaporated under reduced pressure precipitation, add few drops of petroleum ethers, separate out solid Body, filter, dry, obtain white solid N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (4- ethyl piperazidines base) acetamide 0.22g, yield 90%, m.p.153~156 DEG C,1H NMR (400MHz, CDCl3) δ 1.17 (t, J=6.8Hz, 3H, CH3), 1.37 (s, 9H, 3 × CH3), 2.57~2.72 (m, 8H, piperazine rings), 3.21 (s, 2H, COCH2), 4.15 (s, 2H, CH2), 5.93 (s, 2H, OCH2O), 6.63~6.67 (m, 2H, C6H3), 6.72 (d, J=8.0Hz, 1H, C6H3), 9.91 (s, 1H, NH).13C NMR (101MHz, CDCl3) δ 11.66,30.87,32.49,35.59, 52.12,52.31,53.14,60.95,100.85,108.13,108.75,121.15,124.26,134.25,146.05, 147.67,152.46,153.21,167.94.
Embodiment 21
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (4- ethoxycarbonylpiperazines base) acetamide
0.55mmol N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) chloroacetamide, 0.83mmol1- ethoxycarbonylpiperazines, 0.8 Mmol triethylamines, it is dissolved in 10mL tetrahydrofurans, 14h is stirred at room temperature, reaction solution is diluted with 50mL ethyl acetate, Once, saturated common salt is washed once, anhydrous Na for washing2SO4Dry, be evaporated under reduced pressure precipitation, add few drops of petroleum ethers, analysis Go out solid, filter, dry, obtain white solid N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -2- (4- ethoxycarbonylpiperazines Base) acetamide 0.23g, yield 85%, m.p.88~90 DEG C,1H NMR (400MHz, CDCl3) δ 1.27 (t, J=7.1 Hz, 3H, CH3), 1.39 (s, 9H, 3 × CH3), 2.56 (s, 4H, piperazine rings 2,6-H), 3.22 (s, 2H, COCH2), 3.61 (s, 4H, piperazine rings 3,5-H), 4.11-4.18 (m, 4H, OCH2, CH2), 5.94 (s, 2H, OCH2O), 6.64~6.66 (m, 2H, C6H3), 6.73 (d, J=8.0Hz, 1H, C6H3), 9.93 (s, 1H, NH).13C NMR (101MHz, CDCl3) δ 14.59., 30.84,32.49,35.59,43.41,53.20,61.16,61.48,100.87, 108.16,108.74,121.17,124.43,134.09,146.11,147.71,152.63,155.31,167.68.
Embodiment 22
The preparation of N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- (4- ethyl piperazidines base) propionamide
0.55mmol N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- chlorine propionamides, 0.83mmol1- ethyl piperazidines, 0.8 Mmol triethylamines, it is dissolved in 10mL tetrahydrofurans, 24h is stirred at room temperature, reaction solution is diluted with 50mL ethyl acetate, Once, saturated common salt is washed once, anhydrous Na for washing2SO4Dry, be evaporated under reduced pressure precipitation, add few drops of petroleum ethers, analysis Go out solid, filter, dry, obtain white solid N- (5- piperonyl -4- tertiary butyl thiazole -2- bases) -3- (4- ethyl piperazidines base) third Acid amides 0.20g, yield 89%, m.p.148~150 DEG C,1H NMR (400MHz, CDCl3) δ 1.16 (t, J=6.8Hz, 3H, CH3), 1.35 (s, 9H, 3 × CH3), 1.68 (s, 4H, piperazine rings 2,6-H), 2.52~2.55 (m, 4H, COCH2, CH2), 2.75~2.77 (m, 6H, piperazine ring 3,5-H, CH2), 4.14 (s, 2H, CH2), 5.92 (s, 2H, OCH2O), 6.62~6.68 (m, 2H, C6H3), 6.71 (d, J=8.0Hz, 1H, C6H3), 12.45 (s, 1H, NH).13C NMR (101MHz,CDCl3) δ 11.79,30.92,31.15,32.55,35.64,51.98,52.29,52.59,52.78,100.90, 108.16,108.89,121.22,123.61,134.70,146.06,147.74,152.86,153.47,169.42.
Embodiment 23
The antitumor activity of N- (thiazol-2-yl) piperazine yl amide derivatives and its salt
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 Kind can receive the dyestuff of hydrogen atom.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, can both quantify the survival rate for measuring cell.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 provides).
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 It is identical to make process, in an experimentation, per sample (p.s.) set 5 concentration gradients (10 μM, 30 μM, 100 μM, 300 μM and 1000 μM), each four parallel samples of concentration, every group of experiment is parallel 3 times, and is compareed by blank group Go out conclusion.ELIASA detects each hole OD values, Detection 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, half-inhibition concentration of the sample to cell is calculated using software IC50Value.IC of the preferred compound to MCF-7 cells, Hela cells and A549 cells50It is shown in Table 1~2.
The anti-MCF-7 cytoactives result of the preferred compound of table 1
N- (thiazol-2-yl) piperazine yl amide derivatives IC50/μM
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide 36.3±3.7
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide 15.3±0.5
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (piperazinyl) acetamide 14.8±0.4
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide 12.5±1.4
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (piperazinyl) acetamide 13.7±1.7
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide 23.4±0.1
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide 24.8±2.0
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (piperazinyl) acetamide 24.4±3.9
The anti-A549 cells of the preferred compound of table 2 and Hela cytoactive results
Active testing result shows that N- (thiazol-2-yl) piperazine yl amide derivatives are to cervical cancer cell (Hela cells), people Lung adenocarcinoma cell (A549 cells) and human breast cancer cell (MCF-7 cells) have good inhibitory activity, can be used for Prepare antineoplastic.

Claims (9)

1. N- (thiazol-2-yl) piperazine yl amide derivatives shown in a kind of chemical structural formula I and its pharmaceutically acceptable Salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C4 Alkyl or C1~C5Alkoxy carbonyl group；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2It is sub- Alkoxy, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2 Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O；N is selected from：1st, 2 or 3.
2. N- (thiazol-2-yl) piperazine yl amide derivatives shown in a kind of chemical constitution Formula II and its pharmaceutically acceptable Salt：
R is selected from formula：C1~C2Alkyl, C3~C4Straight chained alkyl or C3~C4Branched alkyl；X1、X3It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy, C1~C2Alkylene oxide group, fluorine, chlorine, bromine or iodine；X2、X4It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy or C1~C2Alkylene oxide group；X2X3It is selected from：OCH2O or OCH2CH2O； X5、X9It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；X6、X8It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl Base, C1~C2Alkoxy；X7It is selected from：Hydrogen, C1~C2Alkyl, hydroxyl, C1~C2Alkoxy；N is selected from：1st, 2 or 3.
3. N- (thiazol-2-yl) piperazine yl amide derivatives and its pharmaceutically acceptable salt described in claim 1 and 2, Characterized in that, described compound is selected from：
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide,
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide,
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (piperazinyl) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- methyl piperazines base) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (piperazinyl) acetamide, N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) Thiazol-2-yl] -2- (4- methyl piperazines base) acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- ethyl piperazidines base) acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (piperazinyl) acetamide,
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide,
N- [the 4- tert-butyl groups -5- (2,4- dichloro benzyl) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamide,
N- [the 4- tert-butyl groups -5- (4- chlorobenzyls) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide,
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- (4- Phenylpiperazinyls) acetamides or
N- [the 4- tert-butyl groups -5- (4- methoxy-benzyls) thiazol-2-yl] -2- [4- (4- hydroxy phenyls) piperazinyl] acetamide.
4. the preparation method of N- (thiazol-2-yl) piperazine yl amide derivatives described in claim 1, it is characterised in that it It is as follows to prepare reaction：
R in formula1It is selected from：C1~C4Alkyl or C1~C5Alkoxy carbonyl group；R、X1~X4、X2X3With n such as claim 1 institutes State；X is selected from：Chlorine, bromine or iodine.
5. the preparation method of N- (thiazol-2-yl) piperazine yl amide derivatives described in claim 2, it is characterised in that it It is as follows to prepare reaction：
R, X in formula1~X9、X2X3It is as claimed in claim 1 with n；X is selected from：Chlorine, bromine or iodine.
6. N- (thiazol-2-yl) the piperazine yl amide derivatives in claims 1 to 3 described in any one are preparing cancer therapy drug In application.
7. N- (thiazol-2-yl) the piperazine yl amide derivatives in claims 1 to 3 described in any one are preparing anti-cervical cancer Application in medicine.
8. N- (thiazol-2-yl) the piperazine yl amide derivatives in claims 1 to 3 described in any one are preparing anti-human lung gland Application in cancer drug.
9. N- (thiazol-2-yl) the piperazine yl amide derivatives in claims 1 to 3 described in any one are preparing anti-human mammary gland Application in cancer drug.
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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

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CN1325389A (en) * 1998-10-30 2001-12-05 法玛西雅厄普约翰公司 2-amino-thiazole derivatives, process for their preparation, and their use as antitumor agents
CN106938989A (en) * 2016-01-04 2017-07-11 湖南大学 N- (5- benzyls thiazol-2-yl) acetamide derivative and preparation method and application

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CN1325389A (en) * 1998-10-30 2001-12-05 法玛西雅厄普约翰公司 2-amino-thiazole derivatives, process for their preparation, and their use as antitumor agents
CN106938989A (en) * 2016-01-04 2017-07-11 湖南大学 N- (5- benzyls thiazol-2-yl) acetamide derivative and preparation method and application

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Publication number Priority date Publication date Assignee Title
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

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