CN101928254A - Benzotriazole derivatives and preparation method and use thereof - Google Patents
Benzotriazole derivatives and preparation method and use thereof Download PDFInfo
- Publication number
- CN101928254A CN101928254A CN201010222902.1A CN201010222902A CN101928254A CN 101928254 A CN101928254 A CN 101928254A CN 201010222902 A CN201010222902 A CN 201010222902A CN 101928254 A CN101928254 A CN 101928254A
- Authority
- CN
- China
- Prior art keywords
- triazole
- benzo
- benzotriazole derivatives
- preparation
- och
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 125000003354 benzotriazolyl group Chemical class N1N=NC2=C1C=CC=C2* 0.000 title claims abstract 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 4
- 230000001028 anti-proliverative effect Effects 0.000 claims abstract description 4
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 3
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 15
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 239000012964 benzotriazole Substances 0.000 claims description 4
- -1 methoxyl group Chemical group 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 201000005296 lung carcinoma Diseases 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 150000001559 benzoic acids Chemical class 0.000 claims 1
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 14
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 201000009030 Carcinoma Diseases 0.000 abstract description 2
- 201000005202 lung cancer Diseases 0.000 abstract description 2
- 208000020816 lung neoplasm Diseases 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 3
- 230000004663 cell proliferation Effects 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000001565 benzotriazoles Chemical class 0.000 description 12
- 239000012467 final product Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
- OMZYUVOATZSGJY-UHFFFAOYSA-N 4,5,6,7-tetrabromo-2h-benzotriazole Chemical compound BrC1=C(Br)C(Br)=C(Br)C2=NNN=C21 OMZYUVOATZSGJY-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 102000019197 Superoxide Dismutase Human genes 0.000 description 2
- 108010012715 Superoxide dismutase Proteins 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 229940032362 superoxide dismutase Drugs 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000005274 4-hydroxybenzoic acid group Chemical group 0.000 description 1
- PGZRSQWUAZGZLL-UHFFFAOYSA-L Cl[Cu]Cl.N1(C=NCC1)N1NC2=C(N1)C=CC=C2 Chemical compound Cl[Cu]Cl.N1(C=NCC1)N1NC2=C(N1)C=CC=C2 PGZRSQWUAZGZLL-UHFFFAOYSA-L 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical group [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000008856 allosteric binding Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses benzotriazole derivatives, which are characterized by having the following general formula, wherein A=H or OCH3; R=H or OH or OCH3; and R'=H or OH or OCH3. The benzotriazole derivatives have higher antiproliferative activity on human oral epithelial cancer cells, lung cancer cells and gastric cancer cells. Therefore, the benzotriazole derivatives can be applied to preparing medicaments for resisting tumor cell proliferation. The invention discloses a preparation method for the benzotriazole derivatives.
Description
Technical field
The present invention relates to benzotriazole derivatives and preparation method thereof with in the application of preparation in the cancer therapy drug.
Background technology
In recent years, a large amount of research has disclosed the various biological activity and the clinical application potential of benzotriazole derivatives, so they are the important potentiality medicines of a class.Important pharmacological activities such as for example, the 1H-benzotriazole has anti-inflammatory, and is antiviral.4,5,6,7-tetrabromo-1H-benzotriazole (TBB) is the inhibitor of a kind of extraordinary protein kinase C K2, it by with the allosteric binding site of nucleosides be used for bringing into play its effect.Steroidal C-17 benzoxazole has restraining effect to the growth of prostate tumor cells.The title complex that a kind of benzotriazole and bivalent cupric ion form, [2-(4,5-dihydro-1H-imidazolyl)-1H-benzotriazole]-dichloro copper shows the activity of very strong superoxide-dismutase (SOD), and seven kinds of human body tumour cell strains are had restraining effect.People have synthesized a series of [4-(2 hydrogen-1,2,3-benzotriazole base) phenoxy group] paraffinic acid, and tested their biological activitys as peroxidase vegetation activated receptor (PPAR γ) agonist.PPAR γ is inhibited or induce its apoptotic effect to the growth of kinds of tumor cells and in-vivo tumour model.3-(1H-benzo [d] [1,2,3] triazole)-1-(4-p-methoxy-phenyl)-1-acetone-phenylformic acid (BmOB) can be pressed by increasing oxidation, follows injury of mitochondria to suppress the propagation of human liver cancer cell simultaneously.
Though benzotriazole and derivative thereof do not exist at occurring in nature, because that it has is antitumor, antimycotic, anti-inflammatory, antidepressants etc. are biological activity extensively, therefore its research as the potential drug lead compound is had bigger potentiality.
Summary of the invention
The object of the present invention is to provide a class benzotriazole derivatives and their preparation method and purposes.
Technical scheme of the present invention is as follows:
One class benzotriazole derivatives is characterized in that it has following general formula:
In the formula: A=H or OCH
3R=H or OH or OCH
3R '=H or OH or OCH
3
Above-mentioned benzotriazole derivatives is prepared by laxative remedy:
The preparation of 1H-benzo [d] [1,2,3]-triazole-1-alcohol:
The o-Nitrochlorobenzene that in the 1-of 10ml enanthol solution, adds 788mg, slowly drip the hydrazine hydrate of 1.2ml, react 5h, the sodium hydroxide solution neutralization reaction liquid of adding 40% down in 110-120 ℃, underpressure distillation, hydrochloric acid with 1M is transferred between the pH to 3.2-3.5, filters out throw out, the ice sodium chloride solution washing with 5%, use the methylene chloride recrystallization again, obtain white crystal 1H-benzo [d] [1,2,3]-triazole-1-alcohol.
The preparation of 6-methoxyl group-1H-benzo [d] [1,2,3]-triazole-1-alcohol:
Method and 1H-benzo [d] [1,2,3]-triazole-1-alcohol similar, only its used reactant is not an o-Nitrochlorobenzene, but 1-chloro-4-methoxyl group-2-oil of mirbane of 938mg, 6-methoxyl group-1H-benzo [d] [1 that reaction obtains, 2,3]-triazole-1-alcohol also is white crystal.
The preparation of 1H-benzo [d] [1,2,3]-triazole:
Add 541mg 1 in the acetic acid solution of 10ml, the 2-phenylenediamine adds the sodium nitrite in aqueous solution of 25ml 1M again, in 70-80 ℃ of reaction 1h, and sodium hydroxide solution with 40% or the hydrochloric acid of 1M accent pH to 4.4-4.6.Filter, the ice sodium chloride solution washing precipitate with 5% is used the methylene chloride recrystallization, obtains white crystal 1H-benzo [d] [1,2,3]-triazole.
A kind of method for preparing benzotriazole derivatives of the present invention, it is to add 1H-benzo [d] [1 in methylene dichloride, 2,3]-triazole-1-alcohol, or 6-methoxyl group-1H-benzo [d] [1,2,3]-triazole-1-alcohol, or 1H-benzo [d] [1,2,3]-triazole, and then add the phenylformic acid that phenylformic acid or hydroxyl or methoxyl group replace, and add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) as catalyzer, ratio by amount of substance is 1: 1: 1.2 (benzotriazole cpd: phenylformic acid or substituted benzoic acid: raw material ratio reaction EDCHCl), room temperature reaction 24h removes reaction solvent under the reduced pressure, and column chromatography purification obtains benzotriazole derivatives of the present invention.
The elutriant of the column chromatography described in the above-mentioned method for making is an ethyl acetate: the solution of sherwood oil=1: 1.
Benzotriazole derivatives of the present invention, to the human oral cavity epithelial cancer cells, lung carcinoma cell and stomach cancer cell have stronger antiproliferative activity, and therefore, benzotriazole derivatives of the present invention can be used in the medicine of preparation anti-tumour cell proliferative.
Embodiment
Embodiment one: the preparation of 1H-benzo [d] [1,2,3]-triazole-1-alcohol
The o-Nitrochlorobenzene that in the 1-of 10ml enanthol solution, adds 788mg, slowly drip the hydrazine hydrate of 1.2ml, react 5h, the sodium hydroxide solution neutralization reaction liquid of adding 40% down in 110-120 ℃, underpressure distillation, hydrochloric acid with 1M is transferred between the pH to 3.2-3.5, filters out throw out, the ice sodium chloride solution washing with 5%, use the methylene chloride recrystallization again, obtain white crystal 1H-1,2,3-benzotriazole-1-alcohol.Productive rate: 95%.Mp：155-157℃。
Embodiment two: the preparation of 6-methoxyl group-1H-benzo [d] [1,2,3]-triazole-1-alcohol
The preparation method is with example one, and with 1-chloro-4-methoxyl group-2-oil of mirbane replacement o-Nitrochlorobenzene of 938mg, the white crystal that obtains is 6-methoxyl group-1H-1, and 2,3-benzotriazole-1-alcohol.Productive rate: 90%.Mp：169-171℃。
Embodiment three: the preparation of 1H-benzo [d] [1,2,3]-triazole
Add 541mg 1 in the acetic acid solution of 10ml, the 2-phenylenediamine adds the sodium nitrite in aqueous solution of 25ml 1M again, in 70-80 ℃ of reaction 1h, and the hydrochloric acid accent pH to 4.4-4.6 of the sodium hydroxide solution/1M with 40%.Filter, the ice sodium chloride solution washing precipitate with 5% is used the methylene chloride recrystallization, obtains white crystal 1H-benzo [d] [1,2,3]-triazole.Productive rate: 90%.Mp：98-100℃。
Embodiment four: 3, the preparation of 5-resorcylic acid-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 1)
With product and 385mg 3 that 337mg embodiment one obtains, the 5-resorcylic acid joins in the 30ml methylene dichloride, adds 575mg EDCHCl as catalyzer, at room temperature reacts 24h.Reaction system is spin-dried for, and petrol ether/ethyl acetate=1: 1 is carried out column chromatography purification and is obtained white crystal and be final product.Productive rate: 75%.Mp：193-194℃.ESI?MS：272.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.11(d，J＝8.1Hz，1H，Bt?Ar-H)，7.60-7.57(m，1H，Bt?Ar-H)，7.46-7.41(m，2H，Bt?Ar-H)，7.46(d，J＝2.2Hz，2H，Ar-H)，6.90(d，J＝2.2Hz，1H，Ar-H).Anal.Calc?for?C
13H
9N
3O
4：C，57.57；H，3.34；N，15.49％.Found：C，57.42；H，3.61；N，15.32％.
Embodiment five: 3, the preparation of 5-dimethoxybenzoic acid-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 2)
The preparation method is with embodiment four, and with 3, the 5-dimethoxybenzoic acid replaces 3, and the 5-resorcylic acid obtains white crystal and is final product.Productive rate: 84%.Mp：162-163℃.ESI?MS：300.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.10(d，J＝8.2Hz，1H，Bt?Ar-H)，7.58-7.54(m，1H，Bt?Ar-H)，7.45-7.40(m，2H，BtAr-H)，7.36(d，J＝2.2Hz，2H，At-H)，6.86(d，J＝2.2Hz，1H，Ar-H)，3.98(s，6H，OCH
3).Anal.Calc?for?C
15H
13N
3O
4：C，60.20；H，4.38；N，14.04％.Found：C，60.26；H，4.16；N，14.28％.
Embodiment six: 3,4, the preparation of 5-trimethoxybenzoic acid-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 3)
The preparation method is with embodiment four, and with 3,4, the 5-trimethoxybenzoic acid replaces 3, and the 5-resorcylic acid obtains white crystal and is final product.Productive rate: 85%.Mp：175-176℃.ESI?MS：330.1([M+H]
+).
1H-NMR(CDCl
3)δ：8.12(1H，d，J＝8.4Hz，Bt?Ar-H)，7.60-7.54(1H，m，Bt?Ar-H)，7.52(2H，s，Ar-H)，7.50-7.43(2H，m，Bt?Ar-H)，4.00(3H，s，OCH
3)，3.97(6H，s，OCH
3).
13C-NMR(CDCl
3)δ：162.4，153.4(2C)，144.2，143.6，128.9，128.7，124.8，120.6，119.1，108.4，108.1(2C)，61.1，56.5(2C).EIMS(m/z)：212(100％)，197(56％)，195(27％)，119(12％)，91(9％).Anal.Calc?forC
16H
15N
3O
5：C，58.36；H，4.59；N，12.76.Found：C，58.65；H，4.62；N，12.64.
Embodiment seven: the preparation of phenylformic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 4)
Product and 305mg phenylformic acid that 413mg embodiment two is obtained join in the 30ml methylene dichloride, add 575mgEDCHCl as catalyzer, at room temperature react 24h.Reaction system is spin-dried for, and petrol ether/ethyl acetate=1: 1 is carried out column chromatography purification and is obtained white crystal and be final product.Productive rate: 81%.Mp：96-97℃.ESI?MS：270.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.26-8.24(m，2H，Ar-H)，8.02(d，J＝8.4Hz，1H，BtAr-H)，7.78-7.74(m，1H，Ar-H)，7.60-7.57(m，2H，Ar-H)，7.46-7.42(m，1H，Bt?Ar-H)，7.10-7.05(m，2H，Bt?Ar-H)，3.92(s，3H，OCH
3).Anal.Calc?for?C
14H
11N
3O
3：C，62.45；H，4.12；N，15.61％.Found：C，62.35；H，4.02；N，15.76％.
Embodiment eight: the preparation of 4-hydroxy-benzoic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 5)
The preparation method replaces phenylformic acid with embodiment seven with the 4-hydroxy-benzoic acid, obtains white crystal and is final product.Productive rate: 78%.Mp：185-186℃.ESI?MS：286.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.05(d，J＝8.2Hz，1H，Bt?Ar-H)，7.95(d，J＝8.4Hz，2H，Ar-H)，7.49-7.44(m，1H，Bt?Ar-H)，7.18-7.13(m，2H，Bt?Ar-H)，7.21(d，J＝8.4Hz，2H，Ar-H)，3.95(s，3H，Bt?OCH
3).Anal.Calc?forC
14H
11N
3O
4：C，58.95；H，3.89；N，14.73％.Found：C，58.81；H，3.78；N，14.85％.
Embodiment nine: 3, the preparation of 5-resorcylic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 6)
The preparation method is with embodiment seven, and with 3, the 5-resorcylic acid replaces phenylformic acid, obtains white crystal and is final product.Productive rate: 72%.Mp：205-206℃.ESI?MS：302.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.01(d，J＝8.4Hz，1H，Bt?Ar-H)，7.45-7.41(m，1H，Bt?Ar-H)，7.36(d，J＝2.3Hz，2H，Ar-H)，7.12-7.07(m，2H，Bt?Ar-H)，7.20(d，J＝8.5Hz，2H，Ar-H)，6.85(d，J＝2.3Hz，1H，Ar-H)，3.91(s，3H，Bt?OCH
3).Anal.Calc?for?C
14H
11N
3O
5:C，55.82；H，3.68；N，13.95％.Found：C，56.02；H，3.78；N，13.78％.
Embodiment ten: 3,4, the preparation of 5-trihydroxybenzoic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 7)
The preparation method is with embodiment seven, and with 3,4, the 5-trihydroxybenzoic acid replaces phenylformic acid, obtains white crystal and is final product.Productive rate: 68%.Mp：208-209℃.ESI?MS：318.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：7.99(d，J＝8.5Hz，1H，Bt?Ar-H)，7.58(s，2H，Ar-H)，7.49-7.45(m，1H，Bt?Ar-H)，7.36(d，J＝2.2Hz，2H，Ar-H)，7.21-7.15(m，2H，Bt?Ar-H)，3.95(s，3H，Bt?OCH
3).Anal.Calc?for?C
14H
11N
3O
6：C，53.00；H，3.49；N，13.24％.Found：C，53.07；H，3.62；N，13.05％.
Embodiment 11: the preparation of 4-methoxybenzoic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 8)
The preparation method replaces phenylformic acid with embodiment seven with the 4-methoxybenzoic acid, obtains white crystal and is final product.Productive rate: 83%.Mp：161-162℃.ESI?MS：300.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.03(d，J＝8.3Hz，1H，Bt?Ar-H)，7.92(d，J＝8.5Hz，2H，Ar-H)，7.47-7.43(m，1H，Bt?Ar-H)，7.15-7.12(m，2H，Bt?Ar-H)，7.18(d，J＝8.5Hz，2H，Ar-H)，4.02(s，3H，Ar?OCH
3)，3.93(s，3H，BtOCH
3).Anal.Calc?for?C
15H
13N
3O
4：C，60.20；H，4.38；N，14.04％.Found：C，60.02；H，4.56；N，13.92％.
Embodiment 12: 3, and the preparation of 5-dimethoxybenzoic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 9)
The preparation method is with embodiment seven, and with 3, the 5-dimethoxybenzoic acid replaces phenylformic acid, obtains white crystal and is final product.Productive rate: 85%.Mp：176-177℃.ESI?MS：330.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：7.98(d，J＝8.4Hz，1H，Bt?Ar-H)，7.44-7.40(m，1H，Bt?Ar-H)，7.32(d，J＝2.2Hz，2H，Ar-H)，7.10-7.06(m，2H，Bt?Ar-H)，7.18(d，J＝8.5Hz，2H，Ar-H)，6.82(d，J＝2.2Hz，1H，Ar-H)，3.96(s，6H，Ar?OCH
3)，3.88(s，3H，Bt?OCH
3).Anal.Calc?for?C
16H
15N
3O
5：C，58.36；H，4.59；N，12.76％.Found：C，58.55；H，4.74；N，12.41％.
Embodiment 13: 3,4, and the preparation of 5-trimethoxybenzoic acid-6-methoxyl group-1H-benzo [d] [1,2,3] triazole-1-alcohol ester (compound 10)
The preparation method is with embodiment seven, and with 3,4, the 5-trimethoxybenzoic acid replaces phenylformic acid, obtains white crystal and is final product.Productive rate: 81%.Mp：182-183℃.ESI?MS：360.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：7.96(d，J＝8.5Hz，1H，Bt?Ar-H)，7.55(s，2H，Ar-H)，7.46-7.42(m，1H，Bt?Ar-H)，7.32(d，J＝2.2Hz，2H，Ar-H)，7.18-7.14(m，2H，Bt?Ar-H)，4.02(s，3H，Ar?OCH
3)，3.99(s，6H，ArOCH
3)，3.91(s，3H，Bt?OCH
3).Anal.Calc?for?C
17H
17N
3O
6：C，56.82；H，4.77；N，11.69％.Found：C，56.71；H，4.88；N，11.42％.
Embodiment 14: the preparation of 1-(3,5-dihydroxy-benzene formyl radical)-1H-benzo [d] [1,2,3] triazole (compound 11)
With product and 385mg 3 that 298mg embodiment three obtains, the 5-resorcylic acid joins in the 30ml methylene dichloride, adds 575mg EDCHCl as catalyzer, at room temperature reacts 24h.Reaction system is spin-dried for, and petrol ether/ethyl acetate=1: 1 is carried out column chromatography purification and is obtained white crystal and be final product.Productive rate: 78%.Mp：144-145℃.ESI?MS：256.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.36(d，J＝8.4Hz，1H，Bt?Ar-H)，8.19-8.16(m，1H，Bt?Ar-H)，7.73-7.69(m，1H，Bt?Ar-H)，7.55-7.51(m，1H，Bt?Ar-H)，7.46(d，J＝2.3Hz，2H，At-H)，6.95(d，J＝2.3Hz，1H，Ar-H).Anal.Calc?for?C
13H
9N
3O
3：C，61.18；H，3.55；N，16.46％.Found：C，61.26；H，3.42；N，16.39％.
Embodiment 15: the preparation of 1-(3,4,5-trihydroxybenzene formyl radical)-1H-benzo [d] [1,2,3] triazole (compound 12)
The preparation method is with embodiment 14, and with 3,4, the 5-trihydroxybenzoic acid replaces 3, and the 5-resorcylic acid obtains white crystal and is final product.Productive rate: 75%.Mp：157-158℃.ESI?MS：272.1([M+H]
+).
1H?NMR(CDCl
3，δppm)：8.35(d，J＝8.3Hz，1H，Bt?Ar-H)，8.16-8.13(m，1H，Bt?Ar-H)，7.78-7.75(m，1H，Bt?Ar-H)，7.59-7.55(m，1H，Bt?Ar-H)，7.27(s，2H，At-H).Anal.Calc?for?C
13H
9N
3O
4：C，57.57；H，3.34；N，15.49％.Found：C，57.51；H，3.51；N，15.58％.
Embodiment 16: benzotriazole derivatives is to the antiproliferative activity research of three-type-person's tumour cell
(1) cultivation of tumour cell: cultivator oral epithelium KB cancer cells, lung cancer H460 cancer cells and cancer of the stomach MKN45 cancer cells in containing the RPMI-1640 substratum of 5% foetal calf serum.The cancer cells that will be in logarithmic phase is cultivated in No. 24 culture dish with the density of every milliliter in 5000 cells.
(2) dosing: add the compound of different concns in the tumour cell of cultivating, continue to cultivate 72 hours.Use the methylene radical blue laws to go of the influence of evaluation test medicine to above-mentioned growth of tumour cell, by with the comparison of positive controls, obtain the 50% inhibition concentration (IC of compound to above-mentioned three kinds of tumour cells
50).Property of medicine control group medicine used herein is a Zorubicin.
Benzotriazole derivatives of the present invention is to reaching positive controls to KB, the inhibition IC of H460 and MKN45 cancer cells
50Be worth as shown in the table.
Claims (4)
1. a class benzotriazole derivatives is characterized in that it has following general formula:
In the formula: A=H or OCH
3R=H or OH or OCH
3R '=H or OH or OCH
3
2. method for preparing the described benzotriazole derivatives of claim 1, it is characterized in that: it is to add 1H-benzo [d] [1 in methylene dichloride, 2,3]-triazole-1-alcohol, or 6-methoxyl group-1H-benzo [d] [1,2,3]-triazole-1-alcohol, or 1H-benzo [d] [1,2,3]-triazole, and then add the phenylformic acid that phenylformic acid or hydroxyl or methoxyl group replace, and add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) as catalyzer, ratio by amount of substance is: benzotriazole cpd: the raw material ratio reaction of phenylformic acid or substituted benzoic acid: 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride=1: 1: 1.2, room temperature reaction 24h removes reaction solvent under the reduced pressure, and column chromatography purification obtains benzotriazole derivatives.
3. according to the described method for making of claim 2, it is characterized in that: the elutriant of described column chromatography is an ethyl acetate: the solution of sherwood oil=1: 1.
4. the described benzotriazole derivatives of claim 1 is in preparation oral squamous carcinoma cell, the application in the anti proliferative medicine of lung carcinoma cell and stomach cancer cell.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102229021A CN101928254B (en) | 2010-07-09 | 2010-07-09 | Benzotriazole derivatives and preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102229021A CN101928254B (en) | 2010-07-09 | 2010-07-09 | Benzotriazole derivatives and preparation method and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101928254A true CN101928254A (en) | 2010-12-29 |
| CN101928254B CN101928254B (en) | 2012-05-02 |
Family
ID=43367735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102229021A Expired - Fee Related CN101928254B (en) | 2010-07-09 | 2010-07-09 | Benzotriazole derivatives and preparation method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101928254B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875483A (en) * | 2012-10-26 | 2013-01-16 | 陈守文 | Synthesis technique of benzotriazole |
| CN103450103A (en) * | 2013-05-08 | 2013-12-18 | 如皋市金陵化工有限公司 | Synthesis process of 1-hydroxybenzotriazole |
| CN103848826A (en) * | 2012-11-30 | 2014-06-11 | 南京大学 | Preparation method and use of 1,3,4-oxadiazole derivative having benzotriazole structure |
| CN103848827A (en) * | 2012-11-30 | 2014-06-11 | 南京大学 | Application of benzotriazole derivatives in anti-cancer drugs |
| CN103848828A (en) * | 2012-11-30 | 2014-06-11 | 南京大学 | Application of oxadiazole derivatives in anti-cancer drugs |
| CN109761961A (en) * | 2019-02-28 | 2019-05-17 | 贵州医科大学 | A kind of Benzotriazole Derivative is as Sirtuin inhibitor and its application |
| CN115043822A (en) * | 2022-06-23 | 2022-09-13 | 中国石油天然气集团有限公司 | Benzotriazole derivative, preparation method thereof, benzotriazole corrosion inhibitor and application thereof |
| CN115160314A (en) * | 2022-07-28 | 2022-10-11 | 南方医科大学 | Heterocyclic aromatic amide compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390122A (en) * | 1999-10-27 | 2003-01-08 | 苏诺尔分子公司 | Tissue factor antagonists and methods of use thereof |
| US20050202341A1 (en) * | 2004-02-26 | 2005-09-15 | Fuji Photo Film Co., Ltd. | Polymerizable composition, photopolymerizing method and process for producing lithographic printing plate using the polymerizable composition |
| EP1666551A1 (en) * | 2004-12-03 | 2006-06-07 | Fuji Photo Film Co., Ltd. | Ink for ink jet-recording curable through irradiation and method for preparing lithographic printing plates using the same |
-
2010
- 2010-07-09 CN CN2010102229021A patent/CN101928254B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1390122A (en) * | 1999-10-27 | 2003-01-08 | 苏诺尔分子公司 | Tissue factor antagonists and methods of use thereof |
| US20050202341A1 (en) * | 2004-02-26 | 2005-09-15 | Fuji Photo Film Co., Ltd. | Polymerizable composition, photopolymerizing method and process for producing lithographic printing plate using the polymerizable composition |
| EP1666551A1 (en) * | 2004-12-03 | 2006-06-07 | Fuji Photo Film Co., Ltd. | Ink for ink jet-recording curable through irradiation and method for preparing lithographic printing plates using the same |
Non-Patent Citations (2)
| Title |
|---|
| 《Chem. Pharm. Bull.》 20071231 Fujisaki F. et al A conventional new procedure for N-acylation of unprotected amino acids 第124-127页 1-3 第55卷, 第1期 2 * |
| 《化学试剂》 20070731 祝丹华等 具有自组装功能的氨基甲酸酯类化合物的合成 第389-393页 1 第29卷, 第7期 2 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875483A (en) * | 2012-10-26 | 2013-01-16 | 陈守文 | Synthesis technique of benzotriazole |
| CN103848826A (en) * | 2012-11-30 | 2014-06-11 | 南京大学 | Preparation method and use of 1,3,4-oxadiazole derivative having benzotriazole structure |
| CN103848827A (en) * | 2012-11-30 | 2014-06-11 | 南京大学 | Application of benzotriazole derivatives in anti-cancer drugs |
| CN103848828A (en) * | 2012-11-30 | 2014-06-11 | 南京大学 | Application of oxadiazole derivatives in anti-cancer drugs |
| CN103450103A (en) * | 2013-05-08 | 2013-12-18 | 如皋市金陵化工有限公司 | Synthesis process of 1-hydroxybenzotriazole |
| CN109761961A (en) * | 2019-02-28 | 2019-05-17 | 贵州医科大学 | A kind of Benzotriazole Derivative is as Sirtuin inhibitor and its application |
| CN115043822A (en) * | 2022-06-23 | 2022-09-13 | 中国石油天然气集团有限公司 | Benzotriazole derivative, preparation method thereof, benzotriazole corrosion inhibitor and application thereof |
| CN115160314A (en) * | 2022-07-28 | 2022-10-11 | 南方医科大学 | Heterocyclic aromatic amide compound and preparation method and application thereof |
| CN115160314B (en) * | 2022-07-28 | 2023-12-05 | 南方医科大学 | Heterocyclic aromatic amide compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101928254B (en) | 2012-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101928254B (en) | Benzotriazole derivatives and preparation method and use thereof | |
| CN105037355B (en) | The indazole inhibitors and its therapeutical uses of Wnt signal transduction paths | |
| EP2253625B1 (en) | Pyridazinones, the preparation and the use thereof | |
| ES2463097T3 (en) | Compounds for the prevention and treatment of cardiovascular diseases | |
| Gokcen et al. | A class of sulfonamides as carbonic anhydrase I and II inhibitors | |
| KR101421140B1 (en) | Sphaelactone derivatives, their pharmaceutical compositions, preparation methods and uses | |
| Shamim et al. | Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5, 6-diphenyl-1, 2, 4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase | |
| US20140364431A1 (en) | Quinoline and cinnoline derivatives and their applications | |
| CN101121711A (en) | Pyrazolcarbazone derivatives and application thereof | |
| WO2018019084A1 (en) | Benzamide compound and use thereof in preparing drugs inhibiting cancer cell proliferation and/or treating cancer | |
| JP5649652B2 (en) | Substituted hydrazide compounds and their applications | |
| CN102850283B (en) | Triazolyl-containing amino-dithio formic ether compound as well as preparation method and application of compound | |
| JP7018514B2 (en) | Compounds and their pharmaceutical applications | |
| JP2009516658A (en) | 3,6-dihydro-2-oxo-6H-1,3,4-thiadiazine derivative | |
| CN102260260B (en) | 8-phenyl xanthine compound, preparation method, medicine composition including the compound and purpose thereof | |
| CN102108078B (en) | 1,4-substituted phthalazine compound and preparation method and applications thereof | |
| CN105541828A (en) | Acylaminoimidazole derivative and use thereof | |
| Tashkandi et al. | Design, synthesis, molecular docking and antimicrobial activities of novel triazole‐ferulic acid ester hybrid carbohydrates | |
| CN107879975A (en) | Histon deacetylase (HDAC) inhibitor and its application | |
| JP5701387B2 (en) | Dicarboximide derivative of berbamine, its preparation method and use | |
| Kolluri et al. | Design, synthesis of novel (Z)-2-(3-(4-((3-benzyl-2, 4-dioxothiazolidin-5-ylidene) methyl)-1-phenyl-1H-pyrazol-3-yl) phenoxy)-N-arylacetamide derivatives: Evaluation of cytotoxic activity and molecular docking studies | |
| B Palkar et al. | Novel series of coumarinyl substituted-thiazolidin-2, 4-dione analogs as anticancer agents: design, synthesis, spectral studies and cytotoxicity evaluation | |
| CN104163772A (en) | Substituted diaryl ester compound, and preparation method and application thereof | |
| CN105061430A (en) | Preparation method of anti-tumor compound and application of compound | |
| CN101402587B (en) | Substituted acethydrazide derivatives, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120502 Termination date: 20150709 |
|
| EXPY | Termination of patent right or utility model |