CN101613391B - 3-(D-glucopyranosyl) thiazole derivative, preparation method and application thereof - Google Patents
3-(D-glucopyranosyl) thiazole derivative, preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- BWUJFQSRDBYYDO-LOFWALOHSA-N (2R,3S,4S,5R)-2-(hydroxymethyl)-6-(2H-1,3-thiazol-3-yl)oxane-3,4,5-triol Chemical class C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)N1CSC=C1 BWUJFQSRDBYYDO-LOFWALOHSA-N 0.000 title abstract description 7
- -1 chlorphenyl Chemical group 0.000 claims abstract description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000001207 fluorophenyl group Chemical group 0.000 claims abstract description 6
- 125000006303 iodophenyl group Chemical group 0.000 claims abstract description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
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- 239000007787 solid Substances 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 150000007979 thiazole derivatives Chemical class 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
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- NZUIQMYZSYQROQ-KEWYIRBNSA-N C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)C=1SC=CN1 Chemical class C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)C=1SC=CN1 NZUIQMYZSYQROQ-KEWYIRBNSA-N 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 8
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- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000003535 D-glucopyranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 5
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 2
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 abstract 1
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 41
- 150000001875 compounds Chemical class 0.000 description 27
- 239000003814 drug Substances 0.000 description 12
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 10
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 2
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
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- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
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- 229940002612 prodrug Drugs 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a 3-(D-glucopyranosyl) thiazole derivative which is shown in formula (VII); in the formula (VII), R<1> is benzoyl group, formyl group or acetyl group; R<2> is methyl, ethyl, acetyl, fluorophenyl, chlorphenyl, iodophenyl, methoxyphenyl or nitrobenzophenone; and R<3> is hydrogen, methyl, ethyl or phenyl. The invention also discloses a preparation method of the 3-(D-glucopyranosyl) thiazole derivative and the application thereof in the preparation of antineoplastic. The invention has the advantage that the new 3-(D-glucopyranosyl) thiazole derivative has anticancer activity and better inhibiting effect for HCT-8 cell, so as to be applied to the preparation of the antineoplastic.
Description
(1) technical field
The present invention relates to a kind of new 3-(D-glucopyranosyl) thiazole derivative and preparation method, and the application in the preparation antitumor drug.
(2) background technology
Saccharide compound is that big type of existing of nature has the organic cpds of phosphoramidite chemical structure and biological function, has important and complex physical effect and physiologically active in vivo.Discover that many saccharide compounds itself have antibiotic, antiviral, anti-tumor activity, but because it also can bring toxic side effect to health in the treatment disease, thereby limited its application as medicine.Sugar and verivate thereof are carried out chemically modified can improve biological activity, reduce toxic side effect, therefore caused great attention.
Contain thiazole ring in many natural compounds molecules; LyngbyabellinA, Dollabellin etc. therefrom filter out the medicine with physiologically active; The application of compound in organic synthesis and medical chemistry that contains thiazole ring all caused extensive concern, is pharmaceutical chemical in recent years one big focus.The thiazoline derivative of Masuda group study is one type of good anti-HIV-1 RT suppressor factor.
Saccharide compound is being played the part of important role's Mierocrystalline cellulose and is all being embodied the extensive special physiological properties of carbohydrate to genetic material such as DNA etc. in vital process.Can be used for synthetic glycosyl heterogeneous ring compound through the glycosyl precursor of modifying, and have advantages such as the preparation method is simple, raw material is easy to get with physiologically active and pro-drug effect.Yet not only the few content of kind is low for the naturally occurring glycosyl heterogeneous ring compound that contains thiazole ring, can not satisfy the needs of research far away, and the glycosyl heterogeneous ring compound that therefore contains thiazole ring obtains through synthesizing mean mostly.The research of basic in the past few decades glycosyl heterogeneous ring compound has had certain progress, and demonstrates prospect more and more widely in fields such as organic composite medicine exploitation, macromole.
The important feature of carbohydrate medicine is to have better water solubility; Can be present in the peripheral aqueous phase of cell; Fat-soluble strong cell interior more difficult to get access, heterocyclic compound then has fat-soluble preferably, and most heterocyclic compound has biological activity preferably.Therefore splice the thiazole of some biologically actives or pyridine fragment and saccharide compound, just might obtain and to get into the new compound that plays a role in the cell again in the extracellular.At present, very active both at home and abroad about the research of heterocyclic drug, mainly be some have a novel structure characteristic contain heterogeneous ring compound and bioactive research thereof.
The clinical indication that the carbohydrate medicine relates to mainly comprises tumour, AIDS, influenza, infectation of bacteria and carbohydrate vaccine etc., has important researching value and practical potentiality.
(3) summary of the invention
The purpose of this invention is to provide a kind of new 3-with antitumour activity characteristic (D-glucopyranosyl) thiazole derivative and preparation method thereof and the application in the preparation antitumor drug.
The structural formula of 3-according to the invention (D-glucopyranosyl) thiazole derivative is suc as formula shown in (VII):
In the formula (VII), R
1Be benzoyl group, formyl radical or ethanoyl; R
2Be methyl, ethyl, ethanoyl, fluorophenyl, chloro-phenyl-, iodophenyl, p-methoxy-phenyl or nitrophenyl; R
3Be hydrogen, methyl, ethyl or phenyl.
Said R
2Be preferably fluorophenyl, chloro-phenyl-, iodophenyl, p-methoxy-phenyl or nitrophenyl; R
3Be preferably hydrogen.
The present invention also provides preparation described 3-(D-glucopyranosyl) method of thiazole derivative; Described method is: in mass and size concentration is to add in the alkali alcosol of 0.1-0.4g/ml suc as formula the 3-shown in (VI) (2,3,4; 6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative; Stirring reaction under 20 ℃ of-80 ℃ of temperature, TLC are followed the tracks of detection reaction to reacting completely, and the reaction solution separating treatment obtains the thiazole derivative suc as formula the 3-shown in (VII) (D-glucopyranosyl); Described amount of substance ratio suc as formula (2,3,4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative of the 3-shown in (VI) and alkali is 1: 18～75;
Among the preparation method of the present invention, described alkali alcosol is one of following: KOH/EtOH solution, MeNH
2/ MeOH solution, Me
2NH/MeOH solution, NH
3/ MeOH solution or NaOMe/MeOH solution; Be preferably KOH/EtOH solution or NaOMe/MeOH solution.
The amount of substance ratio of described 3-(2,3,4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative and alkali is preferably 1: 18.
Temperature of reaction according to the invention is 20～80 ℃, is preferably 60 ℃.
The present invention adopts TLC to follow the tracks of detection reaction, and the reaction times is 4～5 hours usually.
Described reaction solution separating treatment step is: after reaction finished, it was 6.5～8.5 that reaction solution adds hydrochloric acid to pH value, the underpressure distillation evaporate to dryness; It is complete that remaining solid adds dissolve with methanol; Filter, after filtrating is condensed into solid, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography for separation obtains the thiazole derivative suc as formula the 3-shown in (VII) (D-glucopyranosyl).
3-(2,3,4 shown in the described formula of the present invention (VI); 6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative is obtained by the glycosyl thiourea compound and the ω-bromo ketone cyclization of the protection of the pivaloyl group shown in the formula V, and the glycosyl thiourea compound of the pivaloyl group protection shown in the described formula V is by 2,3 shown in the formula (IV); 4; Isosulfocyanate derivatives reaction shown in 6-four-0-pivaloyl group-D-pyran glucosamine and the formula (VIII) obtains, and the compound shown in the described formula (IV) is by 2,3 shown in the formula (III); 4,6-four-0-pivaloyl group-D-Glucopyranose nitrine obtains through Pd/C hydrogenation in methyl alcohol; Compound shown in the formula (III) is by 1,2,3,4 shown in the formula (II), and 6-five-0-pivaloyl group-D-Glucopyranose and trimethyl silicon based nitrine and tin tetrachloride reaction obtain; Compound shown in the formula (II) is a starting raw material by glucose shown in the formula (I), in chloroform and pyridine mixed solvent, obtains with the pivaloyl chloride reaction.The preparation route of above-mentioned formula (I)～formula (VI) is at Synthesis.2008, and 13, open among the 1994-1996.
Comparatively concrete, recommend the preparation method of 3-of the present invention (D-glucopyranosyl) thiazole derivative to carry out according to following steps: in mass and size concentration is to add in the alkali alcosol of 0.1-0.4g/ml suc as formula the 3-(2,3 shown in (VI); 4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative, stirring reaction is 4～5 hours under 20 ℃ of-80 ℃ of temperature; TLC follows the tracks of detection reaction to reacting completely, and it is 6.5～8.5 that reaction solution adds hydrochloric acid to pH value, the underpressure distillation evaporate to dryness; It is complete that remaining solid adds dissolve with methanol; Filter, after filtrating is condensed into solid, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography for separation obtains the thiazole derivative suc as formula the 3-shown in (VII) (D-glucopyranosyl); Described amount of substance ratio suc as formula (2,3,4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative of the 3-shown in (VI) and alkali is 1: 18～75; Described alkali alcosol is one of following: KOH/EtOH solution or NaOMe/MeOH solution.
The application of 3-of the present invention (D-glucopyranosyl) thiazole derivative in the preparation antitumor drug:
The contriver is applied to Hela cell (human cervical carcinoma cell), BEL-7402 (human liver cancer cell) and HCT-8 (human colon cancer cell) with 3-(D-glucopyranosyl) thiazole derivative of preparation; Carry out the antitumour activity test; Measure the propagation situation of above-mentioned tumour cell with mtt assay; The result shows has good inhibitory effect to the HCT-8 cell, and Hela cell, BEL-7402 cell are had certain restraining effect.
3-of the present invention (D-glucopyranosyl) thiazole derivative can be applicable to prepare in the antitumor drug colorectal carcinoma that liver cancer that the cervical cancer that described tumour causes for the Hela cell, BEL-7402 cell cause or HCT-8 cell cause.
Beneficial effect of the present invention is: a kind of new 3-with antitumour activity (D-glucopyranosyl) thiazole derivative is provided, the HCT-8 cell is had good inhibitory effect, can be applicable to prepare in the antitumor drug.
(4) Figure of description
The hydrogen spectrum of 1-benzoyl group-4-methyl-3-(D-glucopyranosyl) thiazolium compounds that Fig. 1 embodiment 1 makes
(5) embodiment
Below in conjunction with specific embodiment the present invention is further specified, but protection scope of the present invention is not limited to this.
The preparation of embodiment 1:1-benzoyl group-4-methyl-3-(D-glucopyranosyl) thiazolium compounds
Under certain temperature (60 ℃), compound concentration is the KOH/EtOH solution 10ml of 0.1g/ml, adds 716mg (1mmol) 1-benzoyl group-4-methyl-3-(2,3 then; 4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole stirred 5 hours, the detection of TLC point plate; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is developping agent, and after reacting completely, hydrochloric acid to the pH value that adds 2N is 7; Solvent removed with Rotary Evaporators desolvate, obtain yellow solid, add 10ml methyl alcohol and dissolve fully; Filter, filtrating is concentrated to solid after, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography obtains white solid 309mg, and productive rate is 81.4%; Mp 126-128 ℃.
1H NMR (CD
3OD): δ 7.96 (d, J=8Hz, 2H), 7.55-7.43 (m, 3H), 6.73 (d, J=4.8Hz, 1H), 5.91 (d, J=4.6Hz, 1H), 4,06 (d, J=2.2Hz, 1H), 3.76-3.62 (m, 5H), 3,45 (m, 1H), 2.38 (s, 3H).
13C NMR (CD
3OD): d=176.48,176.08,170.80,169.17,169.10,137.45,136.23,1301.56,129.21,127.71,104.16,82.12,77.23,72.23,69.45,65.92,61.16,15.28.Anal.Calcd forC
17H
20N
2O
6S:C, 53.67; H, 5.30; N, 7.36.Found:C, 53.61; H, 5.33; N, 7.30.
The preparation of embodiment 2:1-benzoyl group-4-(4-iodophenyl)-3-(D-glucopyranosyl) thiazolium compounds
Under certain temperature (20 ℃), compound concentration is the MeNH of 0.2g/ml
2/ MeOH solution 10ml adds 904mg (1mmol) 1-benzoyl group-4-(4-iodophenyl)-3-(2,3,4 then; 6-four-O-pivaloyl group-D-glucopyranosyl) thiazole stirred 4 hours, and TLC point plate detects, and is developping agent with ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio, after reacting completely; Hydrochloric acid to the pH value that adds 2N is 7, solvent is removed with Rotary Evaporators desolvate, and obtains yellow solid, adds 10ml methyl alcohol and dissolves fully; Filter, filtrating is concentrated to solid after, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography obtains white solid 352mg, and productive rate is 62.0%; Mp 179-181 ℃;
1H NMR (CD
3OD): δ 8.01 (q, J=8.2Hz, 2H), 7.68 (t, J=6.0Hz, 4H), 7.65 (d, J=8.8Hz; 1H), 7.56 (q, J=6.6Hz, 2H), 6.01. (d, J=6.2Hz, 1H); 5.6 (t, J=8.4Hz, 1H), 5.18-5.23 (m, 3H), 4.253 (d, J=6.2Hz; 1H), 4.18 (q, J=10.2Hz, 1H), 3.92 (t, J=6.4Hz, 1H).
13NMR (CD
3OD): δ 178.98,176.80,176.74,135.79,132.32,132.29,131.82,129.36,127.76,116.32,116.69,114.74,114.66,77.06,77.19,76.32,74.72,79.12,62.28,60.27.Anal.Calcd forC
22H
21IN
2O
6S:C, 59.14; H, 4.62; N, 7.94.Found:C, 59.17; H, 4.60; N, 7.98.
The preparation of embodiment 3:1-benzoyl group-4-(4-nitrophenyl)-3-(D-glucopyranosyl) thiazolium compounds
Under certain temperature (40 ℃), compound concentration is the Me of 0.3g/ml
2NH/MeOH solution 10ml adds 823mg (1mmol) 1-benzoyl group-4-(4-nitrophenyl)-3-(2,3,4 then; 6-four-O-pivaloyl group-D-glucopyranosyl) thiazole stirred 4 hours, and TLC point plate detects, and is developping agent with ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio, after reacting completely; Hydrochloric acid to the pH value that adds 2N is 7, solvent is removed with Rotary Evaporators desolvate, and obtains yellow solid, adds 10ml methyl alcohol and dissolves fully; Filter, filtrating is concentrated to solid after, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography obtains white solid 334.5mg, and productive rate is 68.7%; Mp101-103 ℃;
1H NMR (CD
3OD): δ 7.96 (q, J=4.4Hz, 2H), 7.54 (t, J=6.2Hz, 4H), 7.38 (d, J=10.2Hz; 1H), 7.29 (q, J=18.6Hz, 2H), 6.55 (d, J=2.8Hz, 1H); 5.55 (t, J=7.8Hz, 1H), 5.10-5.22 (m, 3H), 4.28 (d, J=8.6Hz; 1H), 4.20 (q, J=46Hz, 1H), 3.89 (t, J=5.6Hz, 1H).
13NMR (CD
3OD): δ 189.02,1787.39, and 177.82,176.75,176.45,167.58,157.30,143.42; 137.56,131.55,130.61,129.71,129.13,128.09,125.35; 122.76,83.92,75.16,71.68,71.31,67.69,60.62.Anal.Calcd for C
22H
21N
3O
8S:C, 53.23; H, 4.88; N, 8.56.Found:C, 53.27; H, 4.79; N, 8.56
The preparation of embodiment 4:4-ethanoyl-1-benzoyl group-3-(D-glucopyranosyl) thiazolium compounds
Under certain temperature (80 ℃), compound concentration is the NaOMe/MeOH solution 10ml of 0.4g/ml, adds 758mg (1mmol) 4-ethanoyl-1-benzoyl group-3-(2,3 then; 4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole stirred 5 hours, the detection of TLC point plate; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is developping agent, and after reacting completely, hydrochloric acid to the pH value that adds 2N is 7; Solvent removed with Rotary Evaporators desolvate, obtain yellow solid, add 10ml methyl alcohol and dissolve fully; Filter, filtrating is concentrated to solid after, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography obtains white solid 316.5mg, and productive rate is: 75%; Mp 174-177 ℃.
1HNMR(CDCl
3)：δ8.28(d，J＝3.6Hz，2H)，7.50-7.58(m，3H)，7.07(t，J＝4.6Hz，1H)，5.64(t，J＝4.4Hz，2H)，5.38(d，J＝4.8Hz，1H)，4.18-4.28(m，2H)，4.06(d，J＝5.2Hz，1H)，3.02(s，3H)，2.49(s，3H)，0.87-1.23(m，36H).
13C?NMR(CDCl
3)：δ190.41，177.67，177.03，176.98，176.03，174.51，167.82，143.38，135.57，132.30，129.34，128.27，118.38，83.29，75.61，72.26，69.22，66.46，60.64，38.63-38.82，30.51，26.65-27.05，14.10.Anal.Calcd?for?C
39H
54N
2O
11S：C，61.72；H，7.17；N，3.69.Found：C，61.76；H，7.10；N，3.77.
The preparation of embodiment 5:1-benzoyl group-4-(4-p-methoxy-phenyl)-3-(D-glucopyranosyl) thiazolium compounds
Under certain temperature (50 ℃), compound concentration is the NH of 0.1g/ml
3/ MeOH solution 10ml adds 808mg (1mmol) 1-benzoyl group-4-(4-p-methoxy-phenyl)-3-(2,3,4 then; 6-four-O-pivaloyl group-D-glucopyranosyl) thiazole stirred 4 hours, and TLC point plate detects, and is developping agent with ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio, after reacting completely; Hydrochloric acid to the pH value that adds 2N is 7, solvent is removed with Rotary Evaporators desolvate, and obtains yellow solid, adds 10ml methyl alcohol and dissolves fully; Filter, filtrating is concentrated to solid after, appearance on the dry method; With ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio is eluent, and column chromatography obtains white solid 339.8mg, and productive rate is: 72%; Mp 190-94 ℃.
1HNMR(CDCl
3)：δ8.05(q，J＝11.4Hz，2H)，7.97(t，J＝4.2Hz，4H)，7.53(d，J＝6.8Hz，1H)，7.50(q，J＝9.6Hz，2H)，7.27(d，J＝5.4Hz，1H)，5.22(t，J＝11.6Hz，1H)，5.19-5.22(m，3H)，4.21(d，J＝7.6Hz，1H)，3.84(q，J＝9.0Hz，3H)，0.77-1.25(m，36H)。
13C?NMR(CDCl
3)：δ197.35，190.20，143.20，133.15，137.97，136.38，133.31，129.54，128.87，128.39，128.25，126.33，122.4，77.31，76.98，76.67，76.48，44.32，40.83，29.32-31.88，22.65，14.O.Anal.Calcd?for?C
43H
56N
2O
11S：C，63.84；H，6.98；N，3.46.Found：C，63.81；H，6.70；N，3.49
Biological activity test:
For the BA of this medicine, the contriver finds that this compound can obviously suppress the growth of some tumour cell.The contriver is with Hela cell (human cervical carcinoma cell), BEL-7402 (human liver cancer cell), and HCT-8 (human colon cancer cell) is a research object, the growing state of observation of cell under the effect of this compound, and measure the propagation situation of tumour cell with mtt assay.
Choose representative compound and it is carried out the external pure article screening of body screening anti-tumor medicine, carry out Hela cell (human cervical carcinoma cell) respectively, BEL-7402 (human liver cancer cell), HCT-8 (human colon cancer cell) test, the mtt assay step is following:
Cell suspension inoculation 96 orifice plates: 90 μ L/ holes, 2 * 104/mL of cell density
↓
37 ℃, CO
2Spend the night in the incubator of concentration 5%
↓
Dosing: the dosing group adds 10 μ L/ hole respective concentration medicines, and like following table 1, control group adds 10 μ L/ hole PBS
↓
37 ℃, CO
2The incubator of concentration 5% is cultivated 44h
↓
Add MTT:10 μ L/ hole
↓
37 ℃, CO
2The incubator of concentration 5% is cultivated 4h
↓
From incubator, take out, a kind of rhyme scheme in Chinese operas serving as the prelude to a complete score for voices adds DMSO:100 μ L/ hole
↓
Jolt, the 570nm ELIASA is surveyed the OD value down
Table 1
| Numbering | Medicine | Concentration (solvent is a water) |
| H1 | 1-benzoyl group-4-methyl-3-(D-glucopyranosyl) thiazolium compounds that |
0.5mg/ml |
| H2 | 1-benzoyl group-4-that embodiment 2 makes (4-iodophenyl)-3-(D-glucopyranosyl) thiazolium compounds | 0.5mg/ml |
| H3 | 1-benzoyl group-4-that |
0.5mg/ml |
Experimental result:
1.Hela cell:
Table 1Hela cell (human cervical carcinoma cell) test experiments
2.BEL-7402 cell:
Table 2BEL-7402 cell (human liver cancer cell) test experiments
3.HCT-8 cell
Table 3HCT-8 (human colon cancer cell) test experiments
The Hela cell (human cervical carcinoma cell) of middle positive drug Cisplatin, BEL-7402 (human liver cancer cell), HCT-8 (human colon cancer cell) data are following:
Through testing the anti-Hela cell (human cervical carcinoma cell) that we find that synthetic glucone triazole class compounds and glucone thiazole compound have; BEL-7402 (human liver cancer cell); The function of HCT-8 tumour cells such as (human colon cancer cells); With the present general positive drug Cisplatin that suppresses these three types of tumour cells a certain distance is arranged; Aspect antitumor cell, there is inhibit feature but also can reflect our the glucone heterogeneous ring compound of design, has certain application prospect.
Claims (10)
1. one kind suc as formula the 3-shown in (VII) (D-glucopyranosyl) thiazole derivative;
In the formula (VII), R
1Be benzoyl group, formyl radical or ethanoyl; R
2Be methyl, ethyl, ethanoyl, fluorophenyl, chloro-phenyl-, iodophenyl, p-methoxy-phenyl or nitrophenyl; R
3Be hydrogen, methyl, ethyl or phenyl.
2. 3-as claimed in claim 1 (D-glucopyranosyl) thiazole derivative is characterized in that described R
2Be fluorophenyl, chloro-phenyl-, iodophenyl, p-methoxy-phenyl or nitrophenyl.
3. 3-as claimed in claim 1 (D-glucopyranosyl) thiazole derivative is characterized in that described R
3Be hydrogen.
4. method for preparing 3-as claimed in claim 1 (D-glucopyranosyl) thiazole derivative; It is characterized in that described method is: in mass and size concentration is to add in the alkali alcosol of 0.1-0.4g/ml suc as formula the 3-(2 shown in (VI); 3; 4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative, stirring reaction under 20 ℃ of-80 ℃ of temperature; TLC follows the tracks of detection reaction to reacting completely, and the reaction solution separating treatment obtains the thiazole derivative suc as formula the 3-shown in (VII) (D-glucopyranosyl); Described amount of substance ratio suc as formula the alkali in (2,3,4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative of the 3-shown in (VI) and the alkali alcosol is 1: 18～75;
In the formula (VI), R
1Be benzoyl group, formyl radical or ethanoyl; R
2Be methyl, ethyl, ethanoyl, fluorophenyl, chloro-phenyl-, iodophenyl, p-methoxy-phenyl or nitrophenyl; R
3Be hydrogen, methyl, ethyl or phenyl.
5. preparation method as claimed in claim 4 is characterized in that described alkali alcosol is one of following: KOH/EtOH solution, MeNH
2/ MeOH solution, Me
2NH/MeOH solution, NH
3/ MeOH solution or NaOMe/MeOH solution.
6. preparation method as claimed in claim 4 is characterized in that described alkali alcosol is one of following: KOH/EtOH solution or NaOMe/MeOH solution.
7. preparation method as claimed in claim 4 is characterized in that the amount of substance ratio of described 3-(2,3,4,6-four-O-pivaloyl group-D-glucopyranosyl) thiazole derivative and alkali is 1: 18.
8. preparation method as claimed in claim 4 is characterized in that described reaction solution separating treatment step is: after reaction finished, it was 6.5～8.5 that reaction solution adds hydrochloric acid to pH value; The underpressure distillation evaporate to dryness, it is complete that remaining solid adds dissolve with methanol, filters; After filtrating is concentrated to solid; Appearance is an eluent with ETHYLE ACETATE and 10: 1 mixing solutions of methyl alcohol volume ratio on the dry method, and column chromatography for separation obtains the thiazole derivative suc as formula the 3-shown in (VII) (D-glucopyranosyl).
9. the application of 3-as claimed in claim 1 (D-glucopyranosyl) thiazole derivative in the preparation antitumor drug.
10. application as claimed in claim 9 is characterized in that the colorectal carcinoma that cervical cancer that described tumour causes for the Hela cell, liver cancer that the BEL-7402 cell causes or HCT-8 cell cause.
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