CN107365280B - N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents - Google Patents
N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents Download PDFInfo
- Publication number
- CN107365280B CN107365280B CN201610317454.0A CN201610317454A CN107365280B CN 107365280 B CN107365280 B CN 107365280B CN 201610317454 A CN201610317454 A CN 201610317454A CN 107365280 B CN107365280 B CN 107365280B
- Authority
- CN
- China
- Prior art keywords
- tert
- thiazol
- acetamide
- butyl
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Abstract
The invention discloses N- (thiazole-2-yl) piperazinylamide derivatives shown in structural formulas I and II, pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition thereof and application thereof in preparing anticancer drugs, wherein the N- (thiazole-2-yl) piperazinylamide derivatives are as follows:
wherein R is selected from: c1～C2Alkyl radical, C3～C4Straight chain alkyl or C3～C4A branched alkyl group; r1Selected from: hydrogen, C1～C4Alkyl or C1～C5An alkoxycarbonyl group; x1、X3Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy radical, C1～C2Alkyleneoxy, fluoro, chloro, bromo or iodo; x2、X4Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy or C1～C2An alkyleneoxy group; x2X3Selected from: OCH (OCH)2O or OCH2CH2O；X5、X9Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; x6、X8Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; x7Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; n is selected from: 1. 2 or 3.
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to an N- (thiazole-2-yl) piperazinyl amide derivative, a preparation method and application thereof in preparing an anticancer drug.
Background
Gurdal et al describe the inhibitory activity of Compound 1 on human colon cancer cell HCT-116, human breast cancer cell MCF-7 and human liver cancer cell HUH-7, their GI507.9. mu.M, 9.2. mu.M and 3.1. mu.M, respectively, wherein the inhibitory activities on HCT-116 and HUH-7 were superior to those of the positive control 5-fluorouracil [ J Enzyme Inhibition and Med Chem,2015,30(4):649-]. Abou-Seri et al describe the inhibitory activity of Compound 2 on vascular endothelial growth factor receptor-2 (VEGFR-2) kinase, its IC500.40 + -0.04 μ M, and positive control vartanib (IC)50＝0.18±0.02 μ M) approach; the cell activity test shows that the compound has GI (gastrointestinal tract) of various cancer cells50Sorafenib [ Eur J Med Chem,2016,107:165-]。
World invention patent [ WO 2014145642A2, 2014-9-18 disclosure]A series of anti-cancer compounds targeting nuclear transcription factor Nrf2 are described, in which the inhibitory activity of compounds 3a and 3c on human lung cancer cells A549 and H1437 was scored as class B (5. mu.M < IC)50< 25 μ M); the inhibitory activity of compound 3b on a549 and H1437 cells was scored as a grade a (IC)50≤5μM)。
El-Messery and Hassan et al describe the in vitro inhibitory activity of a series of 2-aminothiazole derivatives 4 at a concentration of 10 μ M on a variety of cancer cells [ Eur J Med Chem,2012,54: 615-625; bioorg & Med Chem Lett,2012,22(20): 6318-6323): wherein the inhibition rate of the compound 4a on leukemia cells CCRF-CEM and SR is 75.5 percent and 51.8 percent respectively; the compound 4b has 69.3 percent of inhibition rate on leukemia cell CCRF-CEM; the inhibition rates of the compound 4c on colon cancer cells HCT-15 and renal cancer cells UO-31 are 54.6% and 51.4% respectively; the compound has an inhibition rate of 60.2% on the non-small cell lung cancer cell HOP-92 by 4 d; the inhibition rates of the compound 4e on leukemia cells K562, renal cancer cells UO-31 and breast cancer cells MDA-MB-468 are 70.7%, 54.6% and 55.6%, respectively. Among propionamide (i.e., n ═ 2) derivatives, the inhibition rate of compound 4f on leukemia cell CCRF-CEM was 96.2%, the inhibition rate of compound 4g on renal cancer cell UO-31 was 54.0%, and the inhibition rates of compound 4h on non-small cell lung cancer cell HOP-92, melanoma cell SK-MEL-5, renal cancer cell a498 and UO-31 were 59.6%, 52.5%, 67.5% and 68.9%, respectively; the compound 4i has an inhibition rate of 51.8% on leukemia cell MOLT-4 and 62.8% on breast cancer cell MDA-MB-468; the inhibition rate of the compound 4j on colon cancer cells HT29 is 80.4%, and the inhibition rate on melanoma cells SK-MEL-5 and UACC-62 is 76.2% and 71.6%, respectively.
Choi et al describe the inhibitory activity of Compound 5 on the wild-type oncogenic kinase (oncogenic kinase) Bcr-Abl, its EC50At 5.21. mu.M [ Bioorg ]&Med Chem Lett,2012,22(16):5297-5302]。
Chinese invention patent publication [ CN 103524535A,2014-1-22]A series of compounds hedgehog signaling channel antagonists 6 are described, in which the IC of compounds 6a and 6b on GRE-fluorescein expressing NIH3T3 cells50134.3nM and 150.9nM, respectively, close to the positive control Vismodegib (Vismodegib).
Disclosure of Invention
The invention aims to provide N- (thiazole-2-yl) piperazinyl amide derivatives, a preparation method, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides N- (thiazole-2-yl) piperazinylamide derivatives shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: c1～C2Alkyl radical, C3～C4Straight chain alkyl or C3～C4A branched alkyl group; r1Selected from: hydrogen, C1～C4Alkyl or C1～C5An alkoxycarbonyl group; x1、X3Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy radical, C1～C2Alkyleneoxy, fluoro, chloro, bromo or iodo; x2、X4Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy or C1～C2An alkyleneoxy group; x2X3Selected from: OCH (OCH)2O or OCH2CH2O; n is selected from: 1. 2 or 3.
The first aspect of the technical scheme of the invention also provides N- (thiazole-2-yl) piperazinylamide derivatives shown as a structural formula II and pharmaceutically acceptable salts thereof:
wherein R is selected from: c1～C2Alkyl radical, C3～C4Straight chain alkyl or C3～C4A branched alkyl group; x1、X3Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy radical, C1～C2Alkyleneoxy, fluoro, chloro, bromo or iodo; x2、X4Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy or C1～C2An alkyleneoxy group; x2X3Selected from: OCH (OCH)2O or OCH2CH2O；X5、X9Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; x6、X8Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; x7Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; n is selected from: 1. 2 or 3.
Further, preferred compounds are selected from: n- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (4-ethylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (piperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] alkanoic acid 2- (4-ethylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (piperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-ethylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (piperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-, N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide, and mixtures thereof, N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide or N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide.
The second aspect of the technical scheme of the invention provides a preparation method of the N- (thiazole-2-yl) piperazinylamide derivative shown in the general formula I in the first aspect, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: c1～C2Alkyl radical, C3～C4Straight chain alkyl or C3～C4A branched alkyl group; r1Selected from: c1～C4Alkyl or C1～C5An alkoxycarbonyl group; x1、X3Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy radical, C1～C2Alkyleneoxy, fluoro, chloro, bromo or iodo; x2、X4Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy or C1～C2An alkyleneoxy group; x2X3Selected from: OCH (OCH)2O or OCH2CH2O; n is selected from: 1. 2 or 3; x is selected from: chlorine, bromine or iodine.
Or
Wherein R is selected from: c1～C2Alkyl radical, C3～C4Straight chain alkyl or C3～C4A branched alkyl group; x1、X3Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy radical, C1～C2Alkyleneoxy, fluoro, chloro, bromo or iodo; x2、X4Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy or C1～C2An alkyleneoxy group; x2X3Selected from: OCH (OCH)2O or OCH2CH2O; n is selected from: 1. 2 or 3; x is selected from: chlorine, bromine or iodine.
The second aspect of the technical scheme of the invention also provides a preparation method of the N- (thiazole-2-yl) piperazinylamide derivative shown in the general formula II in the first aspect, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: c1～C2Alkyl radical, C3～C4Straight chain alkyl or C3～C4A branched alkyl group; x1、X3Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2Alkoxy radical, C1～C2Alkyleneoxy, fluoro, chloro, bromo or iodo; x2、X4Selected from: hydrogen, C1～C2Alkyl radicalHydroxy, C1～C2Alkoxy or C1～C2An alkyleneoxy group; x2X3Selected from: OCH (OCH)2O or OCH2CH2O；X5、X9Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; x6、X8Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; x7Selected from: hydrogen, C1～C2Alkyl, hydroxy, C1～C2An alkoxy group; n is selected from: 1. 2 or 3; x is selected from: chlorine, bromine or iodine.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the N- (thiazol-2-yl) piperazinylamide derivative of the present invention and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention is to provide the N- (thiazole-2-yl) piperazinylamide derivatives and the pharmaceutically acceptable salts thereof in the first aspect of the invention and the application of the pharmaceutical composition in the third aspect in preparing anticancer drugs.
Furthermore, the N- (thiazole-2-yl) piperazinylamide derivatives and the pharmaceutically acceptable salts thereof in the first aspect of the invention and the application of the pharmaceutical composition in the third aspect in preparing anti-cervical cancer drugs are provided.
Furthermore, the N- (thiazole-2-yl) piperazinylamide derivatives and the pharmaceutically acceptable salts thereof in the first aspect of the invention and the application of the pharmaceutical composition in the third aspect in preparing the anti-human lung adenocarcinoma drugs are provided.
Furthermore, the N- (thiazole-2-yl) piperazinylamide derivative and the pharmaceutically acceptable salt thereof in the first aspect of the invention and the application of the pharmaceutical composition in the third aspect in preparing the anti-human breast cancer medicine are provided.
The beneficial technical effects are as follows: the N- (thiazole-2-yl) piperazinyl amide derivatives are a novel structural type of compounds with anticancer activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide
0.40g N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]Chloroacetamide and 5mL of tetrahydrofuran, stirring at normal temperature, and adding 0.24g of pyridine and 0.20g N-methylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to precipitate solid, filtering, washing with petroleum ether, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazole-2-yl]-2- (4-methylpiperazino) acetamide, yield 65.9%, m.p.168-170 ℃;1H NMR(400MHz，CDCl3)：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)。
example 2
Preparation of N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (4-ethylpiperazinyl) acetamide
0.20g N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]Chloroacetamide and 5mL of tetrahydrofuran, stirring at normal temperature, and adding 0.12g of pyridine and 0.11g N-ethylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, performing suction filtration, washing with petroleum ether, and drying to obtain beige solid N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazole-2-yl]-2- (4-ethylpiperazinyl) acetamide in 77.9% yield, m.p.173-175 ℃;1H NMR(400MHz，CDCl3)：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)。
example 3
Preparation of N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (piperazinyl) acetamide
0.39g N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]Chloroacetamide and 5mL of tetrahydrofuran were stirred at room temperature, and 0.24g of pyridine and 0.37g of 1-Boc-piperazine were added; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, performing suction filtration, washing with petroleum ether, and drying to obtain beige solid N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazole-2-yl]Dissolving 0.15g of (E) -2- (4-tert-butoxycarbonylpiperazinyl) acetamide in 5mL of dichloromethane, adding 1mL of trifluoroacetic acid, stirring at normal temperature for 2 hours, desolventizing, adding ethyl acetate, washing with saturated sodium bicarbonate solution to neutrality, drying with anhydrous sodium sulfate, desolventizing, and drying to obtain light sodium sulfateYellow solid N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2- (piperazinyl) acetamide in a yield of 94.1%, m.p.164-166 ℃;1H NMR(400MHz，CDCl3)：1.34(s，9H，3×CH3) 2.04(s, 1H, piperazine 4-H), 2.67(t, J ═ 4.4Hz, 4H, CH)2NCH2)，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)。
Example 4
Preparation of N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide
(1) Preparation of N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2-chloroacetamide
7.02g of 5- (4-chlorobenzyl) -4-tert-butyl-2-aminothiazole, 3.04g of triethylamine, a catalytic amount of DMAP and 50mL of anhydrous dichloromethane, dropwise adding 3.39g of chloroacetyl chloride in ice bath, reacting for 4h, washing the saturated sodium bicarbonate solution to be neutral, drying the saturated sodium sulfate, desolventizing, and drying the column chromatography desolventizing to obtain a white solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]2-chloroacetamide with the yield of 92.7 percent, and the m.p.153-155 ℃;1H NMR(400MHz，CDCl3)：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- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide
0.36g N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.24g pyridine and 0.20g N-methylpiperazine; reacting overnight, desolventizing, adding twoWashing chloromethane with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to precipitate solid, filtering, washing with petroleum ether, and drying to obtain light orange solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2- (4-methylpiperazinyl) acetamide, yield 45.1%, m.p.117-119 ℃;1HNMR(400MHz，CDCl3)：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)。
example 5
Preparation of N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-ethylpiperazinyl) acetamide
0.36g N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.24g pyridine and 0.23g N-ethylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, filtering, washing with petroleum ether, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazole-2-yl]-2- (4-ethylpiperazinyl) acetamide in 71.3% yield, m.p.125-127 ℃;1HNMR(400MHz，CDCl3)：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)。
example 6
Preparation of N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (piperazinyl) acetamide
0.36g N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]Chloroacetamide and 5mL of tetrahydrofuran were stirred at room temperature, and 0.24g of pyridine and 0.37g of 1-Boc-piperazine were added; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, filtering, washing with petroleum ether, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazole-2-yl]Dissolving 0.20g of (E) -2- (4-tert-butoxycarbonylpiperazinyl) acetamide in 5mL of dichloromethane, adding 1mL of trifluoroacetic acid, stirring at normal temperature for 2 hours, desolventizing, adding ethyl acetate, washing with saturated sodium bicarbonate solution to neutrality, drying with anhydrous sodium sulfate, desolventizing, and drying to obtain a yellow solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2- (piperazinyl) acetamide in 95.2% yield, m.p.105-107 ℃;1H NMR(400MHz，CDCl3)：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)。
Example 7
Preparation of N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide
(1) Preparation of N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2-chloroacetamide
6.75g of 5- (4-methoxybenzyl) -4-tert-butyl-2-aminothiazole, 2.02g of triethylamine, a catalytic amount of DMAP and 50mL of anhydrous dichloromethane, dropwise adding 2.26g of chloroacetyl chloride in ice bath, reacting for 4h, washing a saturated sodium bicarbonate solution to be neutral, drying with anhydrous sodium sulfate, desolventizing,column chromatography desolventizing and drying to obtain white solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazole-2-yl]-2-chloroacetamide, yield 44.6%, m.p.103-105 ℃;1H NMR(400MHz，CDCl3)：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- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-methylpiperazinyl) acetamide
0.36g N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.24g pyridine and 0.20g n-methylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, performing suction filtration, washing with petroleum ether, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (4-methylpiperazino) acetamide, yield 74.5%, m.p.135-136 ℃;1H NMR(400MHz，CDCl3)：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)。
example 8
Preparation of N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-ethylpiperazinyl) acetamide
0.36g N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.24g pyridine and 0.23g N-ethylpiperazine; reacting overnight, desolventizing, adding dichloromethane, and saturatingWashing with salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to precipitate solid, vacuum filtering, washing with petroleum ether, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (4-ethylpiperazinyl) acetamide in 65.1% yield, m.p.107-109 ℃;1H NMR(400MHz，CDCl3)：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)。
example 9
Preparation of N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (piperazinyl) acetamide
0.28g N- [ 4-tert-butyl-5- (4-methoxybenzylthiazol-2-yl)]Chloroacetamide and 5mL of tetrahydrofuran were stirred at room temperature, and 0.24g of pyridine and 0.30g of 1-Boc-piperazine were added; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, performing suction filtration, washing with petroleum ether, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]Dissolving 0.15g of (E) -2- (4-tert-butoxycarbonylpiperazinyl) acetamide in 5mL of dichloromethane, adding 1mL of trifluoroacetic acid, stirring at normal temperature for 2 hours, desolventizing, adding ethyl acetate, washing with saturated sodium bicarbonate solution to neutrality, drying with anhydrous sodium sulfate, desolventizing, and drying to obtain a light yellow solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (piperazinyl) acetamide in a yield of 94.2%, m.p.144-147 ℃;1H NMR(400MHz，CDCl3)：1.37(s，9H，3×CH3) 2.04(s, 1H, piperazine 4-H), 2.66(t, J ═ 4.8Hz, 4H, CH)2NCH2)，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)。
Example 10
Preparation of N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide
0.39g N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.12g pyridine and 0.32g 1-phenylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, recrystallizing with ethanol, filtering, washing with ethanol, and drying to obtain white solid N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2- (4-phenylpiperazinyl) acetamide, yield 72.3%, m.p.170-172 ℃;1H NMR(400MHz，CDCl3)：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)。
example 11
Preparation of N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide
0.20g N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 2.5mL of 1% NaOH solution and 0.18g of 1- (4-hydroxyphenyl) piperazine; reacting overnight, desolventizing, adding dichloromethane, washing with dilute hydrochloric acid, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to precipitate solid, recrystallizing with ethanol, filtering, washing with ethanol, and drying to obtain white solid N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2- [4- (4-hydroxyphenyl) piperazino]Acetamide with the yield of 64.1 percent and m.p.206-208 ℃;1H NMR(400MHz，CDCl3)：1.36(s，9H，3×CH3) 2.63(s, 8H, piperazine ring), 3.22(s, 2H, COCH)2)，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)。
Example 12
Preparation of N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide
0.36g N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.12g pyridine and 0.32g 1-phenylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, recrystallizing with ethanol, filtering, washing with ethanol, and drying to obtain white solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2- (4-phenylpiperazinyl) acetamide, yield 85.5%, m.p.179-180 ℃;1H NMR(400MHz，CDCl3)：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)。
example 13
Preparation of N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide
0.18g N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 2.5mL 1% NaOH solution and 0.18g 1- (4-hydroxyphenyl) piperazine; reacting overnight, desolventizing, adding dichloromethane, washing with dilute hydrochloric acid, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to precipitate solid, recrystallizing with ethanol, filtering, washing with ethanol, and drying to obtain light yellow solid N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2- [4- (4-hydroxyphenyl) piperazino]Acetamide with yield of 60.9%, m.p.175-177 ℃;1H NMR(400MHz，CDCl3)：
1.36(s，9H，3×CH3) 2.60(s, 8H, piperazine ring), 3.22(s, 2H, COCH)2)，4.23(s，2H，CH2)，6.70(d，J＝8.0Hz，2H，4-HOC6H42,6-H)，6.87(d，J＝8.0Hz，2H，4-HOC6H43,5-H)，7.13(d，J＝8.0Hz，2H，C6H42,6-H)，7.27(d，J＝8.0Hz，2H，C6H43,5-H)。
Example 14
Preparation of N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide
0.15g N- [ 4-tert-butyl-5- (4-)Methoxybenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 0.05g pyridine and 0.13g 1-phenylpiperazine; reacting overnight, desolventizing, adding dichloromethane, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to separate out solid, recrystallizing with ethanol, filtering, washing with ethanol, and drying to obtain white solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (4-phenylpiperazinyl) acetamide, yield 90.6%, m.p.179-180 ℃;1H NMR(400MHz，CDCl3)：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)。
example 15
Preparation of N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide
0.06g N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2-chloroacetamide and 5mL tetrahydrofuran, stirring at room temperature, adding 2.5mL 1% NaOH solution and 0.06g 1- (4-hydroxyphenyl) piperazine; reacting overnight, desolventizing, adding dichloromethane, washing with dilute hydrochloric acid, washing with saturated salt water, drying with anhydrous sodium sulfate, desolventizing, adding petroleum ether to precipitate solid, recrystallizing with ethanol, filtering, washing with ethanol, and drying to obtain milky white solid N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- [4- (4-hydroxyphenyl) piperazino]Acetamide with yield of 59.5%, m.p.212-214 deg.C;1H NMR(400MHz，CDCl3)：1.38(s，9H，3×CH3) 2.60(s, 8H, piperazine ring), 3.21(s, 2H, COCH)2)，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)。
Example 16
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) chloroacetamide
Dissolving 1.55mmol of 5-piperonyl-4-tert-butyl-2-aminothiazole and 1.7mmol of triethylamine in 15mL of dichloromethane, stirring for dissolving, and slowly dropwise adding a solution of 1.7mmol of chloroacetyl chloride in 5mL of dichloromethane in an ice bath; TLC tracks the reaction progress, after 0.5h of reaction, the reaction solution is washed for 3 times by water and anhydrous Na2SO4Drying, rotary steaming dichloromethane, adding a small amount of mixed solution of petroleum ether and ethyl acetate, slowly separating out a white solid, collecting the white solid, drying to obtain 0.45g of white solid N- (5-piperonyl-4-tert-butylthiazole-2-yl) chloroacetamide, wherein the yield is 82%, m.p.127-129 ℃,1H NMR(400MHz，CDCl3)，：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)：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。
example 17
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -3-chloropropanamide
Dissolving 1.55mmol of 5-piperonyl-4-tert-butyl-2-aminothiazole and 1.7mmol of triethylamine in 15mL of dichloromethane, stirring for dissolving, and slowly dropwise adding a 5mL dichloromethane solution of 1.7mmol of 3-chloropropionyl chloride in an ice bath; TLC tracks the reaction progress, after 0.5h of reaction, the reaction solution is washed for 3 times by water and anhydrous Na2SO4Drying, rotary steaming dichloromethane, adding a small amount of mixed liquid of petroleum ether and ethyl acetate, slowly separating out a white solid, collecting the white solid, drying to obtain 0.50g of white solid N- (5-piperonyl-4-tert-butylthiazole-2-yl) -3-chloropropamide, wherein the yield is 85%, m.p.143-145 ℃,1H NMR(400MHz，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)。13CNMR(101MHz，CDCl3)：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。
example 18
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -4-chlorobutanamide
Dissolving 1.55mmol of 5-piperonyl-4-tert-butyl-2-aminothiazole and 1.7mmol of triethylamine in 15mL of dichloromethane, stirring for dissolving, and slowly dropwise adding a 5mL dichloromethane solution of 1.7mmol of 3-chloropropionyl chloride in an ice bath; TLC tracks the reaction progress, after 0.5h of reaction, the reaction solution is washed for 3 times by water and anhydrous Na2SO4Drying, rotary steaming dichloromethane, and post-treating by column chromatography (V)Petroleum ether:VEthyl acetateSeparation 15:1) gave 0.29g of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -4-chlorobutanamide as a pale yellow viscous semisolid, 74% yield,1H NMR(400MHz，CDCl3)，: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)。
example 19
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-methylpiperazinyl) acetamide
0.55mmol of N- (5-piperonyl-4-tert-butylthiazol-2-yl) chloroacetamide, 0.83mmol of 1-methylpiperazine, 0.8mmol of triethylamine were dissolved in 10mL of tetrahydrofuran, and the mixture was stirred at room temperature for 12 hours, diluted with 50mL of ethyl acetate, washed once with water, washed once with saturated brine, and washed with anhydrous Na2SO4Drying, distilling under reduced pressure for desolventizing, adding a plurality of drops of petroleum ether, precipitating a solid, carrying out suction filtration and drying to obtain 0.21g of white solid N- (5-piperonyl-4-tert-butylthiazole-2-yl) -2- (4-methylpiperazinyl) acetamide, wherein the yield is 89%, m.p.171-173 ℃,1H NMR(400MHz，CDCl3)1.37(s，9H，3×CH3)，2.35(s，3H，CH3) 2.57 to 2.65(m, 8H, piperazine ring), 3.19(s, 2H, COCH)2)，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)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。
Example 20
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethylpiperazinyl) acetamide
0.55mmol of N- (5-piperonyl-4-tert-butylthiazol-2-yl) chloroacetamide, 0.83mmol of 1-ethylpiperazine, 0.8mmol of triethylamine were dissolved in 10mL of tetrahydrofuran, and the mixture was stirred at room temperature for 12 hours, and the reaction mixture was diluted with 50mL of ethyl acetate, washed once with water, washed once with saturated brine, and washed with anhydrous Na2SO4Drying, distilling under reduced pressure for desolventizing, adding a plurality of drops of petroleum ether, separating out a solid, carrying out suction filtration and drying to obtain 0.22g of white solid N- (5-piperonyl-4-tert-butylthiazole-2-yl) -2- (4-ethylpiperazinyl) acetamide, wherein the yield is 90%, m.p.153-156 ℃,1H NMR(400MHz，CDCl3)1.17(t，J＝6.8Hz，3H，CH3)，1.37(s，9H，3×CH3) 2.57 to 2.72(m, 8H, piperazine ring), 3.21(s, 2H, COCH)2)，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)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。
Example 21
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethoxycarbonylpiperazinyl) acetamide
0.55mmol of N- (5-piperonyl-4-tert-butylthiazol-2-yl) chloroacetamide, 0.83mmol of 1-ethoxycarbonylpiperazine, 0.8mmol of triethylamine were dissolved in 10mL of tetrahydrofuran, and the mixture was stirred at room temperature for 14 hours, diluted with 50mL of ethyl acetate, washed once with water, washed once with saturated brine, and washed with anhydrous Na2SO4Drying, distilling under reduced pressure to remove solvent, adding several drops of petroleum ether, separating out solid, vacuum filtering, and drying to obtain white solid N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethoxycarbonylpiperazinyl) acetamide 023g, yield of 85 percent, m.p.88-90 ℃,1H NMR(400MHz，CDCl3)1.27(t，J＝7.1Hz，3H，CH3)，1.39(s，9H，3×CH3) 2.56(s, 4H, piperazine ring 2,6-H), 3.22(s, 2H, COCH)2) 3.61(s, 4H, piperazine ring 3,5-H), 4.11-4.18(m, 4H, OCH)2，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)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。
Example 22
Preparation of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -3- (4-ethylpiperazinyl) propanamide
0.55mmol of N- (5-piperonyl-4-tert-butylthiazol-2-yl) -3-chloropropanamide, 0.83mmol of 1-ethylpiperazine, 0.8mmol of triethylamine dissolved in 10mL of tetrahydrofuran, stirring at room temperature for 24h, diluting the reaction mixture with 50mL of ethyl acetate, washing with water once, washing with saturated brine once, and washing with anhydrous Na2SO4Drying, distilling under reduced pressure for desolventizing, adding a plurality of drops of petroleum ether, separating out a solid, carrying out suction filtration and drying to obtain 0.20g of white solid N- (5-piperonyl-4-tert-butylthiazole-2-yl) -3- (4-ethylpiperazinyl) propionamide, wherein the yield is 89%, m.p.148-150 ℃,1H NMR(400MHz，CDCl3)1.16(t，J＝6.8Hz，3H，CH3)，1.35(s，9H，3×CH3) 1.68(s, 4H, piperazine ring 2,6-H), 2.52-2.55 (m, 4H, COCH)2，CH2) 2.75 to 2.77(m, 6H, piperazine ring 3,5-H, CH)2)，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)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。
Example 23
Antitumor activity of N- (thiazol-2-yl) piperazinylamide derivatives and salts thereof
1. Principle of antitumor activity
The MTT method is also called MTT colorimetric method, and is a method for detecting cell survival and growth. MTT analysis method uses living cell metabolite reducing agent thiazole blue [3- (4, 5-dimethyl-2-thiazole) -2, 5-diphenyl bromide tetrazole; 3- (4, 5-dimethylthiozol-2-yl) -2, 5-diphenyltetrazolium bromide, MTT ]. MTT is a dye that can accept hydrogen atoms. NADP-related dehydrogenases in the mitochondria of living cells convert yellow MTT to insoluble blue-violet formazan (formazon) in the cells, whereas dead cells do not. After the formazon is dissolved by DMSO, the optical density value is measured by a microplate reader under a certain wavelength, so that the survival rate of the cells can be quantitatively measured. And observing the inhibition effect of the sample on the tumor cells according to the change of the optical density value.
2. Experiment on antitumor Activity
Sample preparation: the compounds of the examples.
Cell line: the cervical cancer cell line Hela, the lung adenocarcinoma cell line A549 and the breast cancer cell line MCF-7 (provided by Hunan Yao medical college, Zhongnan university).
Reagent: thiazole blue (MTT), RPMI 1640 culture medium, newborn bovine serum, antibiotics (invitrogen life technologies, usa); pancreatin (AMRESCO, usa); 96-well culture plates (invitrogen life technologies, usa); dimethyl sulfoxide (Sigma, USA).
The instrument comprises the following steps: HFsafe-1500 model superclean bench, HF151UV model CO2Incubator (Shanghai Li Shen scientific instruments Co., Ltd.); XSP-15C type inverted microscope (Shanghai rectangular optics, Inc.); multiskan MK3 type microplate reader (Thermo corporation, usa); ultrapure water preparation apparatus (Milli-Q, USA).
And (3) experimental operation: test of samples on Hela cells, A549 cells and MCF-7 cells. The experimental procedure was the same for each cell, 5 concentration gradients (10 μ M, 30 μ M, 100 μ M, 300 μ M and 1000 μ M) were set for each sample during one experiment, four replicates for each concentration were run in 3 replicates for each group, and the conclusion was drawn by blank group comparison. And detecting the OD value of each hole by using a microplate reader, wherein the detection wavelength is 570 nm.
3. Evaluation of antitumor Activity
1) Calculating the cell inhibition rate:
2)IC50value calculation
Linear regression of the logarithmic value of the sample concentration and the cell inhibition rate, and calculating the half inhibition concentration IC of the sample on the cells by using software50The value is obtained. Preferred IC of the Compounds on MCF-7 cells, Hela cells and A549 cells50See tables 1-2.
TABLE 1 results of anti-MCF-7 cellular Activity of preferred Compounds
| N- (thiazol-2-yl) piperazinylamide derivatives | IC50/μM |
| N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2- (4-methylpiperazino) acetamide | 36.3±3.7 |
| N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2- (4-ethylpiperazinyl) acetamide | 15.3±0.5 |
| N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl]-2- (piperazinyl) acetamide | 14.8±0.4 |
| N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2- (4-ethylpiperazinyl) acetamide | 12.5±1.4 |
| N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl]-2- (piperazinyl) acetamide | 13.7±1.7 |
| N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (4-methylpiperazino) acetamide | 23.4±0.1 |
| N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (4-ethylpiperazinyl) acetamide | 24.8±2.0 |
| N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl]-2- (piperazinyl) acetamide | 24.4±3.9 |
TABLE 2 results of the activity of preferred compounds against A549 cells and Hela cells
The activity test result shows that the N- (thiazole-2-yl) piperazinylamide derivative has good inhibitory activity on cervical cancer cells (Hela cells), human lung adenocarcinoma cells (A549 cells) and human breast cancer cells (MCF-7 cells), and can be used for preparing antitumor drugs.
Claims (7)
1. A class of N- (thiazol-2-yl) piperazinyl amide derivatives represented by the chemical structural formula I and pharmaceutically acceptable salts thereof:
characterized in that the N- (thiazol-2-yl) piperazinylamide derivatives are selected from:
n- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-methylpiperazinyl) acetamide,
N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethylpiperazinyl) acetamide or
N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethoxycarbonylpiperazinyl) acetamide.
2. A class of N- (thiazole-2-yl) piperazinyl amide derivatives represented by a chemical structural formula II and pharmaceutically acceptable salts thereof:
characterized in that the N- (thiazol-2-yl) piperazinylamide derivatives are selected from:
n- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide,
N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide,
N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide,
N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide or
N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide.
3. A process for the preparation of N- (thiazol-2-yl) piperazinylamide derivatives according to claim 1, characterized in that it is prepared by the following reaction:
wherein the N- (thiazol-2-yl) piperazinylamide derivatives of formula I are as defined in claim 1; x is selected from: chlorine, bromine or iodine.
4. Process for the preparation of N- (thiazol-2-yl) piperazinylamide derivatives according to claim 2, characterized in that it is prepared by the following reaction:
wherein the N- (thiazol-2-yl) piperazinylamide derivatives of formula II are as defined in claim 2; x is selected from: chlorine, bromine or iodine.
5. The N- (thiazol-2-yl) piperazinylamide derivative of claim 1 or 2; wherein N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (2, 4-dichlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- (4-phenylpiperazinyl) acetamide, N- [ 4-tert-butyl-5- (4-chlorobenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide or N- [ 4-tert-butyl-5- (4-methoxybenzyl) Application of thiazole-2-yl ] -2- (4-phenylpiperazinyl) acetamide in preparation of anti-cervical cancer drugs or anti-human lung adenocarcinoma drugs.
6. The N- (thiazol-2-yl) piperazinylamide derivative of claim 1 or 2; wherein N- (5-piperonyl-4-tert-butylthiazol-2-yl) -2- (4-ethoxycarbonylpiperazinyl) acetamide or N- [ 4-tert-butyl-5- (4-methoxybenzyl) thiazol-2-yl ] -2- [4- (4-hydroxyphenyl) piperazinyl ] acetamide is applied to preparation of anti-cervical cancer drugs.
7. The N- (thiazol-2-yl) piperazinylamide derivative of claim 1; wherein, the N- (5-piperonyl-4-tert-butylthiazole-2-yl) -2- (4-methylpiperazinyl) acetamide is applied to the preparation of the anti-human lung adenocarcinoma drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610317454.0A CN107365280B (en) | 2016-05-13 | 2016-05-13 | N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610317454.0A CN107365280B (en) | 2016-05-13 | 2016-05-13 | N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107365280A CN107365280A (en) | 2017-11-21 |
| CN107365280B true CN107365280B (en) | 2020-11-06 |
Family
ID=60304255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610317454.0A Active CN107365280B (en) | 2016-05-13 | 2016-05-13 | N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107365280B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286115B (en) * | 2017-05-10 | 2021-06-04 | 南华大学 | N- (5-arylmethylthiazol-2-yl) piperazinylamides and their use as NA inhibitors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 2016-05-13 CN CN201610317454.0A patent/CN107365280B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107365280A (en) | 2017-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2721371C (en) | Small molecule inhibitors of the pleckstrin homology domain and methods for using same | |
| KR101444489B1 (en) | Compounds for the prevention and treatment of cardiovascular diseases | |
| US10350210B2 (en) | EGFR and ALK dual inhibitor | |
| ES2528796T3 (en) | Benzo [c] pseudobasic phenanthridines with improved efficacy, stability and safety | |
| KR20020093086A (en) | Condensed heteroaryl derivatives | |
| CA2924206A1 (en) | Pyrimidine fgfr4 inhibitors | |
| WO2008001883A1 (en) | α-AMINO ACID DERIVATIVE AND PHARMACEUTICAL COMPRISING THE SAME AS ACTIVE INGREDIENT | |
| WO2020177744A1 (en) | Salicylic acid berberine-type alkaloid quaternary ammonium compound and use thereof for preparing medicines | |
| WO2019024908A1 (en) | Substituted penta- and hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof | |
| JP6706023B2 (en) | Small molecule inhibitors of fibrosis | |
| CN108530444B (en) | Novel NAMPT and IDO dual inhibitor and preparation method and medical application thereof | |
| CN108440468B (en) | 2- (benzofuran-5-yl) phenol and application thereof as anticancer drug | |
| CN107245075A (en) | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines | |
| JP2022533740A (en) | Disubstituted sulfamide-based selective BCL-2 inhibitors containing methyl and trifluoromethyl groups | |
| CN107459476A (en) | Anti- aminated compounds of indole ring third and preparation method thereof, pharmaceutical composition and purposes | |
| CN103080109A (en) | Deuterium-enriched heterocyclic compounds as kinase inhibitors | |
| Abbhi et al. | Design and synthesis of benzimidazole-based Rho kinase inhibitors for the treatment of glaucoma | |
| CN108727343A (en) | Quinazolinones PARP-1/2 inhibitor containing 3- amino nafoxidines and preparation method thereof, pharmaceutical composition and purposes | |
| TW201641492A (en) | Substituted 1,2,3-triazoles, the use thereof, and pharmaceutical composition including the same | |
| CN111548345A (en) | Benzimidazole derivative and preparation method and application thereof | |
| JP2022502497A (en) | Inhibitors of HDAC1 and 2 | |
| CN107365280B (en) | N- (thiazol-2-yl) piperazinyl amide derivatives and their use as anti-cancer agents | |
| CN106938989B (en) | N- (5- benzyls thiazol-2-yl) acetamide derivative and the preparation method and application thereof | |
| DE102006029795A1 (en) | New urea derivatives and their uses | |
| CN109456279A (en) | Thiazoleamino benzamide acetic ester derivative and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |