CN104003956A - Thiazole compound, preparation method thereof and application in pharmacy - Google Patents

Thiazole compound, preparation method thereof and application in pharmacy Download PDF

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CN104003956A
CN104003956A CN201310061162.1A CN201310061162A CN104003956A CN 104003956 A CN104003956 A CN 104003956A CN 201310061162 A CN201310061162 A CN 201310061162A CN 104003956 A CN104003956 A CN 104003956A
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compound
ethyl ketone
formula
nitrothiazole
substituted
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孙宏斌
宋洁梅
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China Pharmaceutical University
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China Pharmaceutical 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
    • C07D277/36—Sulfur atoms
    • 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
    • C07D277/58—Nitro radicals
    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links

Abstract

The invention discloses a thiazole compound shown as formula I and its pharmaceutically acceptable salts, a preparation method thereof and application in pharmacy, especially application in tumor resisting. Pharmacodynamic experiment results show that, the formula I compound provided by the invention has the effect of resisting human multiple myeloma cells. Thus, the compound provided by the invention can be used for preparing drugs for prevention or treatment of tumor related diseases. (formula I).

Description

Thiazole compound, its preparation method and its purposes in pharmacy
Technical field
The present invention relates to pharmaceutical chemistry field, cystatin field specifically, is specifically related to formula I compound and preparation method thereof and purposes in pharmacy.
Background technology
Different according to catalyst mechanism, proteolytic enzyme mainly can be divided into serine protease, L-Cysteine HCL Anhydrous, aspartate protease, serine/threonine protein enzyme and metalloprotease 5 classes.L-Cysteine HCL Anhydrous mainly comprises ubiquitination enzyme (DUBs), caspase, calpain and kethepsin etc.
Tumour be to take cell self to exchange the wrong responses of the signals such as ganglion cell's growth, differentiation, function and apoptosis be feature.From in essence, these cell processes by transcribing, the regulation and control such as protein translation, synthetic and degraded, any one link is made mistakes and is all likely promoted tumour to occur, and protein degradation is often left in the basket in this importance wherein.Eukaryotic protein degradation has lysosomal pathway and proteasome pathway, the outer and transmembrane protein of the former degradation of cell, albumen in latter degradation of cell.
Proteasome pathway needs Ubiquitin-proteasome system (UPS) to participate in.This system is comprised of multiple different protein, comprises ubiquitin, ubiquitin activating enzyme E1, ubiquitin binding enzyme E2, ubiquitin ligase E3, DUB and proteasome.The protein that need to be degraded is transported to proteasome after ubiquitin label and explains on mark, and DUBs can reverse this process, and ubiquitin is cut down from substrate protein.
Increasing research shows, the de-control of UPS and the many diseases of the mankind exist substantial connection as tumour.The successful listing of proteasome inhibitor Velcade (Velcade) is also from having verified clinically the validity of this system as anticancer target spot.Yet along with the generation of miss the target side effect and resistance, the application of Velcade is still restricted.People start to pay close attention to and are positioned at inhibitor proteasome upstream, other member of this system in recent years, expectation can find specificity more by force, cancer therapy drug, especially DUBs inhibitor that toxicity is less.
DUBs is typical L-Cysteine HCL Anhydrous, has been found that it is as relevant in tumour, inflammatory disease, nerve degenerative diseases, virus infection etc. with some disease.Ubiquitin-specific protease (USP) is a class maximum in DUBs family, is also to study at present a more deep class.USP7 in this class members has been found that in the cells such as colorectal carcinoma, bladder cancer and prostate cancer and has overexpression, and can make kinds of tumors supressor inactivation, as (Biochem Soc Trans2010,38:137-143) such as p53, PTEN, FOXO4.
At present, the USP7 inhibitor of bibliographical information is mainly divided into 4 classes chemical structure: pyrrolidone compound (EP 2206725 A1), 9-chlorine tetrahydro acridine amide derivatives is as HBX19 818 (US2011/0177105, Chemistry & Biology2012, 19:467-477), itrile group Indolepiperidine analog derivative is as HBX41 108 (Mol Cancer Ther 2009, 8:2286-2295, ChemMedChem 2010, 5:552-558) and nitrothiophene analog derivative as P5091 (WO 2010/114881 A1, Cancer Cell 2012, 22:345-358).The article that Chauhan D equals to deliver on Cancer Cell for 2012 has reported that thereby P5091 is by suppressing the activity induction multiple myeloma cells apoptosis of USP7, and can overcome Velcade resistance (Cancer Cell 2012,22:345-358.).All there is the problems such as the strong not or specificity of activity is high not in these compounds of having reported, therefore, not yet has so far a molecule to enter the clinical study stage.
Summary of the invention
The invention discloses a series of as acceptable salt, hydrate in compound of Formula I and oxynitride thereof, pharmacodynamics:
Wherein:
X is selected from hydrogen atom, nitro, halogen, itrile group ,-SCF 3or-SO 2cF 3;
Y be selected from sulphur atom, Sauerstoffatom ,-SO or-SO 2;
R 1be selected from non-substituted or Z 1the aryl, the non-substituted or Z that replace 2the pyridyl replacing; Z 1, Z 2respectively be selected from non-substituted straight or branched alkyl, fluorine, chlorine, bromine, iodine, itrile group, nitro, trifluoromethyl, carboxyl, methoxy acyl group, ethoxy acyl group, the phenyl ,-NR of 1～10 carbon 3r 4,-SO 2-NR 3r 4,-SO 2-R 5,-CONR 3r 4,-NHCONR 3r 4,-NHCOR 3,-COOR 5,-SR 5,-OR 5;
R 2be selected from the non-substituted or Z of halogen, 1～10 carbon 2non-substituted or the Z of the alkyl replacing (or thiazolinyl, alkynyl), 1～10 carbon 2the acyl group ,-SO that replace 2-NR 3r 4,-SO 2-R 5,-CONR 3r 4,-NHCONR 3r 4,-NHCOR 3,-COOR 5or itrile group; Z 2as above-mentioned, define;
R 3, R 4respectively be selected from the non-substituted or Z of hydrogen atom, 1～10 carbon 2the alkyl (or cycloalkyl), the Z that replace 1substituted or non-substituted aryl (or heteroaryl); Or R 3, R 4coupled N atom forms 3～8 yuan of heterocyclic radicals together; Z 1, Z 2as above-mentioned, define;
R 5be selected from the non-substituted straight or branched alkyl of hydrogen atom, 1～6 carbon.
In formula I compound of the present invention,
The preferred hydrogen atom of X, nitro, itrile group;
The preferred sulphur atom of Y, Sauerstoffatom;
R 1preferred Z 1the aryl (or pyridyl) replacing;
R 2preferably-CORa ,-CH (OH) Ra or-CONR 3r 4;
Ra is the non-substituted straight or branched alkyl of 1～6 carbon preferably;
Z 1, R 3, R 4as above-mentioned, define.
In formula I compound of the present invention,
X is hydrogen atom, nitro more preferably;
Y is sulphur atom more preferably;
R 1more preferably Z 1the aryl (or pyridyl) replacing; Z 1as above-mentioned, define;
R 2more preferably-CORa;
Ra is selected from the non-substituted straight or branched alkyl of 1～6 carbon.
The preferred compound of the present invention is as follows:
1-[5-(2,3-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
1-[5-(3,4-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
1-[5-(2,6-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
1-[5-(2,3-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3,4-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(2,6-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(2,4 dichloro benzene base sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3,5-dichloropyridine base sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3-p-methoxy-phenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3,4-Dimethoxyphenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
Another object of the present invention has been to provide the preparation method of formula I compound, following reaction formula:
Specifically comprise the following steps:
(1) take Compound I I as starting raw material, carry out nitration reaction and make formula III compound; Prepare III compound and be characterised in that, the nitrating agent of employing is selected from nitrosonitric acid, concentrated nitric acid, concentrated nitric acid/vitriol oil, preferably nitrosonitric acid; The solvent agent adopting is selected from acetic anhydride, trifluoro-acetic anhydride, preferably trifluoro-acetic anhydride; The reaction times adopting is 1-24 hour; The temperature adopting is subzero 50 ℃ to 25 ℃, preferably subzero 25 ℃ to 0 ℃;
(2) by compound III and R 1under alkaline condition, there is nucleophilic substitution reaction and make Compound I a in SH; Prepare Compound I a and be characterised in that, the alkaline reagents of employing is selected from salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, particular methanol sodium; The solvent adopting is methyl alcohol, ethanol, acetonitrile, particular methanol; The reaction times adopting is 1-24 hour; Adopting temperature is subzero 20 ℃ to 100 ℃, preferably 25 ℃ to 70 ℃.
(3) by Compound I I and R 1under alkaline condition, there is nucleophilic substitution reaction and make Compound I a in SH; Prepare Compound I a and be characterised in that, the alkaline reagents of employing is selected from salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, particular methanol sodium; The solvent adopting is methyl alcohol, ethanol, acetonitrile, particular methanol; The reaction times adopting is 1-24 hour; Adopting temperature is subzero 20 ℃ to 100 ℃, preferably 25 ℃ to 70 ℃.
In above-mentioned reaction formula, Ra, R 1as defined in above-mentioned formula I compound.
Another object of the present invention has been to provide the purposes of formula I compound in pharmacy.
Pharmacodynamic experiment result shows, compound of Formula I of the present invention has significant anti-human multiple myeloma cells proliferation function.
Pharmacological evaluation and the result of part of compounds of the present invention below:
1. experiment purpose: adopt the impact of each compound of CCK-8 Determination Staining on RPMI-8226, MM/R, tri-kinds of multiple myeloma cells in-vitro multiplication activity of U266, and calculate half-inhibition concentration IC separately 50;
2. experiment material: the compounds of this invention dissolves and is mixed with mother liquor with DMSO, adopts perfect medium to be diluted to proper concn before using; Reagent: CCK-8 test kit is purchased from EnoGene company; Substratum: RMPI-1640 substratum is purchased from Gibco company; Foetal calf serum: purchased from Gibco company; 96 porocyte culture plates are purchased from Costar company;
3. experimental technique: get the cell that viable cell ratio reaches more than 90% and test.Cell inhibitory effect test adopts EnoGeneCell tMcounting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation, to count, make concentration be 1 * 10 5the cell suspension of individual/ml, in 96 orifice plates, every hole adds 100ul cell suspension (every hole 1 * 10 4individual cell); 96 orifice plates are placed in 37 ℃, 5%CO 2in incubator, cultivate 24 hours; With perfect medium dilution medicine, to desired concn, every hole adds 100 μ L accordingly containing the substratum of medicine, sets up negative control group simultaneously, solvent control group, 5 every group multiple holes; 96 orifice plates are placed in 37 ℃, 5%CO 2in incubator, cultivate 72 hours; Every hole adds 10ul CCK-8 solution, culture plate is hatched in incubator 4 hours, is determined at the OD value at 450nm place by microplate reader, calculates inhibiting rate and calculates IC 50value;
4. experimental result:
Result shows: part of compounds of the present invention all has significant restraining effect to the growth of multiple myeloma cells.
Embodiment
Below by embodiment, illustrate content of the present invention.In the present invention, the example of the following stated is in order better to set forth the present invention, is not for limiting the scope of the invention.
Embodiment 1
1-[5-(2,3-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
2,3-thiophenol dichlorobenzene (120.4mg, 0.68mmol), sodium methylate (36.8mg, 0.68mmol) are added to dry methyl alcohol (6mL), under room temperature, stir 20 minutes.Then in reaction solution, add 2-ethanoyl-5-diuril azoles (100mg, 0.48mmol), reaction solution continues to stir until react completely.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains yellow solid (59mg, 31%). 1HNMR(CDCl 3，300MHz)：δ2.71(s，3H)，6.90-6.93(d，1H，J＝9Hz)，7.08-7.13(t，1H)，7.34-7.36(d，1H，J＝6Hz)，8.02(s，1H)ppm.ESI?MS?m/z325.9[M+H] +；HRMS?for?C 11H 7NOS 2Cl 2+Na?cacld325.9244found325.9246.
Embodiment 2
1-[5-(3,4-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
3,4-thiophenol dichlorobenzene (120.4mg, 0.68mmol), sodium methylate (36.8mg, 0.68mmol) are added to dry methyl alcohol (6mL), under room temperature, stir 20 minutes.Then in reaction solution, add 2-ethanoyl-5-diuril azoles (100mg, 0.48mmol), reaction solution continues to stir until react completely.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains yellow solid (48mg, 26%). 1HNMR(CDCl 3，500MHz)：δ2.68(s，3H)，7.16-7.18(m，1H)，7.38-7.42(m，2H)，7.95(s，1H)ppm.ESI?MS?m/z325.9[M+H] +；HRMS?for?C 11H 7NOS 2Cl 2+Na?cacld325.9244found325.9246.
Embodiment 3
1-[5-(2,6-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
2,6-thiophenol dichlorobenzene (120.4mg, 0.68mmol), sodium methylate (36.8mg, 0.68mmol) are added to dry methyl alcohol (6mL), under room temperature, stir 20 minutes.Then in reaction solution, add 2-ethanoyl-5-diuril azoles (100mg, 0.48mmol), reaction solution continues to stir until react completely.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains yellow solid (80mg, 43%). 1HNMR(CDCl 3，500MHz)：δ2.63(s，3H)，7.27-7.32(m，1H)，7.42-7.45(m，2H)，7.90(s，1H)ppm.
Embodiment 4
1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone
The mixing solutions of trifluoroacetic anhydride (6.3mL), nitrosonitric acid (2.1mL) is cooled to subzero 20 ℃, stirs 1 hour, slowly add wherein trifluoroacetic anhydride (2mL) solution of 2-ethanoyl-5-diuril azoles (1.1g, 6.8mmol).Reaction solution continues to stir 2 hours at subzero 20 ℃.Reaction solution is concentrated, poured in frozen water, by extracted with diethyl ether, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains yellow solid (0.98g, 73%). 1HNMR(CDCl 3，300MHz)：δ2.72(s，3H)ppm.ESI?MS?m/z204.9[M-H] +；HRMS?for?C 5H 3N 2O 3SCl-H?cacld204.9475found204.9477.
Embodiment 5
1-[5-(2,3-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
2,3-thiophenol dichlorobenzene (94.2mg, 0.53mmol), sodium methylate (28.8mg, 0.53mmol) are added to dry methyl alcohol (5mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (100mg, 0.48mmol), under room temperature, continue to stir 4 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain yellow solid (129mg, 76%). 1HNMR(CDCl 3，500MHz)：δ2.67(s，3H)，7.37-7.40(m，1H)，7.72-7.73(m，2H)ppm.ESI?MSm/z371.0[M+Na] +；HRMS?for?C 11H 6N 2O 35 2Cl 2+Na?cacld370.9095found370.9097.
Embodiment 6
1-[5-(3,4-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
3,4-thiophenol dichlorobenzene (103mg, 0.58mmol), sodium methylate (31.4mg, 0.58mmol) are added to dry methyl alcohol (5mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (100mg, 0.48mmol), under room temperature, continue to stir 4 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain yellow solid (130mg, 76%). 1HNMR(CDCl 3，300MHz)：δ2.66(s，3H)，7.52-7.56(dd，1H，J＝3，6Hz)，7.64-7.66(d，1H，J＝6Hz)，7.80-7.81(d，1H，J＝3Hz)ppm.ESI?MSm/z371.0[M+Na] +；HRMS?for?C 11H 6N 2O 3S 2Cl 2+Na?cacld370.9095found370.9096.
Embodiment 7
1-[5-(2,6-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
2,6-thiophenol dichlorobenzene (103mg, 0.58mmol), sodium methylate (31.4mg, 0.58mmol) are added to dry methyl alcohol (5mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (100mg, 0.48mmol), under room temperature, continue to stir 3 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain light yellow solid (150mg, 88%). 1HNMR(CDCl 3，300MHz)：δ2.67(s，3H)，7.46-7.59(m，3H)ppm.ESI?MSm/z371.0[M+Na] +；HRMS?for?C 11H 6N 2O 3S 2Cl 2+Na?cacld370.9095found370.9096.
Embodiment 8
1-[5-(2,4 dichloro benzene base sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
2,4 dichloro benzene thiophenol (103mg, 0.58mmol), sodium methylate (31.4mg, 0.58mmol) are added to dry methyl alcohol (5mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (100mg, 0.48mmol), under room temperature, continue to stir 4 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain light yellow solid (130mg, 76%). 1HNMR(CDCl 3，300MHz)：δ2.65(s，3H)，7.41-7.44(m，1H)，7.66-7.67(d，1H，J＝3Hz)，7.70-7.73(d，1H，J＝9Hz)ppm.ESI?MS?m/z370.9[M+Na] +；HRMS?for?C 11H 6N 2O 3S 2Cl 2+Na?cacld370.9095found370.9098.
Embodiment 9
1-[5-(3,5-dichloropyridine base sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
The chloro-4-mercaptopyridine of 3,5-bis-(198.6mg, 1.1mmol), sodium methylate (60mg, 1.1mmol) are added to dry methyl alcohol (10mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (191mg, 0.92mmol), under room temperature, stir and spend the night.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain light yellow solid (163mg, 50%). 1HNMR(CD 3OD，300MHz)：δ2.62(s，3H)，8.84(s，2H)ppm.ESI?MS?m/z371.9[M+Na] +；HRMS?for?C 10H 5N 3O 3S 2Cl 2+Na?cacld371.9047found371.9049.
Embodiment 10
1-[5-(3-p-methoxy-phenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
3-methoxybenzenethiol (81.4mg, 0.58mmol), sodium methylate (31.4mg, 0.58mmol) are added to dry methyl alcohol (5mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (100mg, 0.48mmol), continue to stir 3 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain yellow solid (125mg, 88%). 1HNMR(CDCl 3，300MHz)：δ2.65(s，3H)，3.85(s，3H)，7.10-7.27(m，3H)，7.43-7.49(m，1H)ppm.ESI?MS?m/z333.0[M+Na] +；HRMS?for?C 12H 10N 2O 4S 2+Na?cacld332.9980found332.9983.
Embodiment 11
1-[5-(3,4-Dimethoxyphenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
3,4-dimethoxy thiophenol (100mg, 0.58mmol), sodium methylate (31.4mg, 0.58mmol) are added to dry methyl alcohol (5mL), under room temperature, stir 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole-2-of 5-yl) ethyl ketone (100mg, 0.48mmol), continue to stir 3 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain yellow solid (52mg, 32%). 1HNMR(CDCl 3，300MHz)：δ2.65(s，3H)，3.88(s，3H)，3.95(s，3H)，6.97(d，1H，J＝6Hz)，7.10(s，1H)，7.26(d，1H，J＝6Hz)ppm.ESI?MS?m/z341.0[M+H] +；HRMS?for?C 13H 12N 2O 5S 2+H?cacld341.0266found341.0269。

Claims (8)

1. thiazole compound, is characterized in that, described compound is the compound shown in formula I or its oxynitride or its pharmacy acceptable salt or hydrate:
Wherein:
X is selected from hydrogen atom, nitro, halogen, itrile group ,-SCF 3or-SO 2cF 3;
Y be selected from sulphur atom, Sauerstoffatom ,-SO or-SO 2;
R 1be selected from non-substituted or Z 1the aryl, the non-substituted or Z that replace 2the pyridyl replacing; Z 1, Z 2respectively be selected from non-substituted straight or branched alkyl, fluorine, chlorine, bromine, iodine, itrile group, nitro, trifluoromethyl, carboxyl, methoxy acyl group, ethoxy acyl group, the phenyl ,-NR of 1～10 carbon 3r 4,-SO 2-NR 3r 4,-SO 2-R 5,-CONR 3r 4,-NHCONR 3r 4,-NHCOR 3,-COOR 5,-SR 5,-OR 5;
R 2be selected from the non-substituted or Z of halogen, 1～10 carbon 2non-substituted or the Z of the alkyl replacing (or thiazolinyl, alkynyl), 1～10 carbon 2the acyl group ,-SO that replace 2-NR 3r 4,-SO 2-R 5,-CONR 3r 4,-NHCONR 3r 4,-NHCOR 3,-COOR 5or itrile group; Z 2as above-mentioned, define;
R 3, R 4respectively be selected from the non-substituted or Z of hydrogen atom, 1～10 carbon 2the alkyl (or cycloalkyl), the Z that replace 1substituted or non-substituted aryl (or heteroaryl); Or R 3, R 4coupled N atom forms 3～8 yuan of heterocyclic radicals together; Z 1, Z 2as above-mentioned, define;
R 5be selected from the non-substituted straight or branched alkyl of hydrogen atom, 1～6 carbon.
2. thiazole compound according to claim 1, is characterized in that, in the compound of described formula I:
X is selected from hydrogen atom, nitro, itrile group;
Y is selected from sulphur atom, Sauerstoffatom;
R 1preferred Z 1the aryl (or pyridyl) replacing;
R 2be selected from-CORa ,-CH (OH) Ra or-CONR 3r 4;
Ra is selected from the non-substituted straight or branched alkyl of 1～6 carbon;
Z 1, R 3, R 4as above-mentioned, define.
3. thiazole compound according to claim 1, is characterized in that, in the compound of described formula I:
X is selected from hydrogen atom, nitro;
Y is selected from sulphur atom;
R 1be selected from Z 1the aryl (or pyridyl) replacing; Z 1as above-mentioned, define;
R 2be selected from-CORa;
Ra is selected from the non-substituted straight or branched alkyl of 1～6 carbon.
4. compound according to claim 1, is characterized in that, described compound comprises following compounds or its oxynitride or its pharmacy acceptable salt or solvate:
1-[5-(2,3-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
1-[5-(3,4-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
1-[5-(2,6-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone
1-[5-(2,3-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3,4-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(2,6-dichlorophenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(2,4 dichloro benzene base sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3,5-dichloropyridine base sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3-p-methoxy-phenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
1-[5-(3,4-Dimethoxyphenyl sulfo-)-4-nitrothiazole-2-yl] ethyl ketone
5. the preparation method of formula I compound as claimed in claim 1, shown in following reaction formula:
Specifically comprise the following steps:
(1) take Compound I I as starting raw material, carry out nitration reaction and make formula III compound; Prepare III compound and be characterised in that, the nitrating agent of employing is selected from nitrosonitric acid, concentrated nitric acid, concentrated nitric acid/vitriol oil, preferably nitrosonitric acid; The solvent agent adopting is selected from acetic anhydride, trifluoro-acetic anhydride, preferably trifluoro-acetic anhydride; The reaction times adopting is 1-24 hour; The temperature adopting is subzero 50 ℃ to 25 ℃, preferably subzero 25 ℃ to 0 ℃;
(2) by compound III and R 1under alkaline condition, there is nucleophilic substitution reaction and make Compound I a in SH; Prepare Compound I a and be characterised in that, the alkaline reagents of employing is selected from salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, particular methanol sodium; The solvent adopting is methyl alcohol, ethanol, acetonitrile, particular methanol; The reaction times adopting is 1-24 hour; Adopting temperature is subzero 20 ℃ to 100 ℃, preferably 25 ℃ to 70 ℃;
(3) by Compound I I and R 1under alkaline condition, there is nucleophilic substitution reaction and make compounds ib in SH; Prepare compounds ib and be characterised in that, the alkaline reagents of employing is selected from salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, particular methanol sodium; The solvent adopting is methyl alcohol, ethanol, acetonitrile, particular methanol; The reaction times adopting is 1-24 hour; Adopting temperature is subzero 20 ℃ to 100 ℃, preferably 25 ℃ to 70 ℃;
In above-mentioned reaction formula, Ra, R 1as defined in above-mentioned formula I compound.
6. the application in preparation prevention or treatment tumor disease according to thiazole compound described in any one in claim 1～4.
7. purposes according to claim 6, is characterized in that, for the preparation of the medicine of prevention or treatment multiple myeloma disease.
8. a pharmaceutical composition for prevention or treatment multiple myeloma disease, is characterized in that, contains formula I compound or its pharmacy acceptable salt as activeconstituents and pharmaceutically acceptable carrier in described pharmaceutical composition.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104860900A (en) * 2014-02-25 2015-08-26 中国药科大学 Thiazole compounds, and preparation method and application thereof in pharmacy
CN105884711A (en) * 2014-12-16 2016-08-24 中国药科大学 Thiazole compounds, preparing method of thiazole compounds and application thereof in pharmacy

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030370A2 (en) * 1995-03-27 1996-10-03 Fujisawa Pharmaceutical Co., Ltd. Thiazole and thiadiazole derivatives, their preparation and pharmaceutical compositions useful in the treatment of thrombocytopenia
WO2002050071A1 (en) * 2000-12-21 2002-06-27 Bristol-Myers Squibb Company Thiazolyl inhibitors of tec family tyrosine kinases
US20070197523A1 (en) * 2005-12-22 2007-08-23 Icagen, Inc. Calcium channel antagonists
WO2010114881A1 (en) * 2009-04-01 2010-10-07 Progenra Inc. Anti-neoplastic compounds, compositions and methods
US20120172374A1 (en) * 2010-12-29 2012-07-05 Development Center For Biotechnology Novel tubulin inhibitors and methods of using the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030370A2 (en) * 1995-03-27 1996-10-03 Fujisawa Pharmaceutical Co., Ltd. Thiazole and thiadiazole derivatives, their preparation and pharmaceutical compositions useful in the treatment of thrombocytopenia
WO2002050071A1 (en) * 2000-12-21 2002-06-27 Bristol-Myers Squibb Company Thiazolyl inhibitors of tec family tyrosine kinases
US20070197523A1 (en) * 2005-12-22 2007-08-23 Icagen, Inc. Calcium channel antagonists
WO2010114881A1 (en) * 2009-04-01 2010-10-07 Progenra Inc. Anti-neoplastic compounds, compositions and methods
US20120172374A1 (en) * 2010-12-29 2012-07-05 Development Center For Biotechnology Novel tubulin inhibitors and methods of using the same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOSCO, MARCELLA ET AL: "Relative reactivity of groups bonded to positions 2 and 5 of the thiazole ring", 《JOURNAL OF THE CHEMICAL SOCIETY PERKIN TRANSACTIONS 2》 *
CHAO CHEN ET AL: "Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
R.B.西尔弗曼: "《有机药物化学》", 31 January 2008 *
赵地顺: "《精细有机合成原理及应用》", 31 March 2009 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104860900A (en) * 2014-02-25 2015-08-26 中国药科大学 Thiazole compounds, and preparation method and application thereof in pharmacy
CN105884711A (en) * 2014-12-16 2016-08-24 中国药科大学 Thiazole compounds, preparing method of thiazole compounds and application thereof in pharmacy

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