CN1189169C - Dibenzo [a, KI] xanthene derivative used as anti-tumor medicine - Google Patents
Dibenzo [a, KI] xanthene derivative used as anti-tumor medicine Download PDFInfo
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- CN1189169C CN1189169C CNB021147418A CN02114741A CN1189169C CN 1189169 C CN1189169 C CN 1189169C CN B021147418 A CNB021147418 A CN B021147418A CN 02114741 A CN02114741 A CN 02114741A CN 1189169 C CN1189169 C CN 1189169C
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- dibenzo
- xanthene
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- 239000003814 drug Substances 0.000 title claims abstract description 13
- 230000000259 anti-tumor effect Effects 0.000 title description 6
- 125000001834 xanthenyl group Chemical class C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 title 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 5
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 201000007270 liver cancer Diseases 0.000 claims abstract description 4
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 201000011510 cancer Diseases 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 206010005003 Bladder cancer Diseases 0.000 abstract description 2
- 206010006187 Breast cancer Diseases 0.000 abstract description 2
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 2
- 208000005016 Intestinal Neoplasms Diseases 0.000 abstract description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 abstract description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 abstract description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 2
- 206010017758 gastric cancer Diseases 0.000 abstract description 2
- 201000002313 intestinal cancer Diseases 0.000 abstract description 2
- 208000032839 leukemia Diseases 0.000 abstract description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 abstract description 2
- 201000000849 skin cancer Diseases 0.000 abstract description 2
- 201000011549 stomach cancer Diseases 0.000 abstract description 2
- 201000005112 urinary bladder cancer Diseases 0.000 abstract description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 abstract 1
- 208000000453 Skin Neoplasms Diseases 0.000 abstract 1
- 208000002495 Uterine Neoplasms Diseases 0.000 abstract 1
- 201000004101 esophageal cancer Diseases 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 201000005202 lung cancer Diseases 0.000 abstract 1
- 208000020816 lung neoplasm Diseases 0.000 abstract 1
- 206010046766 uterine cancer Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- -1 naphthol compound Chemical class 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012531 culture fluid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention belongs to the technical field of medicine. 1-oxo-13c-alkoxyl-1, 13c-dihydrodibenz [a, kl] xanthene in structural general formula I and a derivative thereof are used as an antitumor drug. Compound I has favorable development and application prospects in drugs for treating malignant tumors, such as liver cancer, lung cancer, uterine cancer, mammary cancer, gastric cancer, intestinal cancer, esophagus cancer, nasopharyngeal carcinoma, bladder cancer, skin cancer, leukemia, etc.
Description
Technical field
The invention belongs to medical technical field, 1-oxo-13c-alkoxyl-1 of general structure I, the application in the preparation antitumor drug of 13c-dihydro-dibenzo [a, kl] xanthene and derivant thereof.
Background technology
Malignant tumor is the chronic disease that mortality rate is only second to cardiovascular and cerebrovascular disease.The statistics of announcing recently according to The World Health Organization (WHO) shows that there are cancer patient 1,004 million peoples in the whole world, annual newly-increased case 9,000,000, and dead 7,000,000 people account for 1/10 of world's death toll.China has 1,800,000 cancer patients now, annual neopathy 1,500,000 people, and dead 1,200,000 people account for 18% of death toll.The malignant tumor serious threat people's life security is brought enormous economic loss to society.Antitumor drug has huge market and social benefit, and is enlarging year by year.Only the paclitaxel of Bristol-Myers Squibb Co. (Taxol) annual sales amount just reaches 1,600,000,000 dollars.For the treatment of malignant tumor, also lack ideal medicine at present.Existing antitumor drug exists that curative effect is low, toxic and side effects is big or shortcoming such as price is high.Screening is still one of important channel of developing anti-tumor medicaments from synthetic compound.
General structure is that the chemical compound of I can prepare by the oxidation reaction of distich naphthol compound.People (Rieche, A. such as A.Rieche the earliest; Kirschke, K.and Schule, M.; Liebigs Ann.Chem., 1968,711,103) to handle with perchloric acid with potassium ferricyanide oxidation dinaphthol (1) back, the productive rate with 50% obtains a kind of perchlorate, obtains 2 (R in the general formula I at methanol solution and Feldalat NM reaction then
1=CH
3, R
2=R
3=R
4=R
5=R
6=R
7=H), productive rate 77%, gross production rate 38.5% (seeing formula 1).
Formula 1
People such as H.P.Schneider report (Schneider, H.P. afterwards; Streich, E.; Schurr, K.; Et al, Chem.Ber., 1984,117,2660) 3,3 ', 6,1 of 6 '-tetra-tert replacement can be generated the 2 (R in the general formula I that tetra-tert replaces by the direct oxidation step of the potassium ferricyanide in the methanol solution of alkalescence
1=CH
3, R
2=R
3=R
5=R
6=t-Bu, R
4=R
7=H), productive rate is not high yet, has only 38% (seeing formula 2).
Formula 2
The chemical compound of this class formation was the product that obtains in research oxidation reaction rule process at that time, was not used for the antineoplastic pharmacological testing.
Summary of the invention
The purpose of this invention is to provide a kind of chemical compound,, particularly hepatocarcinoma is had tangible curative effect malignant tumor as antitumor drug.
We find that oxygen under the catalysis of some copper-amine complex, can be oxidized to 2 to 1 in simulating oxidasic research, productive rate is up to 94% (Tan D-M, Li H-H, Wang B, Liu H-B, Xu Z-L, Chin.J.Chem., 2001,19:91), solvent methanol has participated in reaction, and the methoxyl group in the product is from methanol molecules.When in being reflected at other alcohol, carrying out, obtain having the product of corresponding alkoxyl, product 94～58% (seeing formula 3).
Formula 3
R＝CH
3，CH
2CH
3，CH
2CH
2CH
3，CH(CH
3)
2，CH
2CH(CH
3)
2，CH
2(CH
2)
2CH
3
CH
2CH
2Cl，CH
2CH
2OCH
3，CH
2CH
2OCH
2CH
3 et al
From the dinaphthol of symmetry replacement and asymmetric replacement, at different alcoholic solvent (R
1OH) carry out oxidation reaction with copper-amine complex-oxygen system in, just can obtain the chemical compound (seeing formula 4) of general formula I.R in the general formula I
1Alcohol (R from one of reactant
1OH).For some common lower alcohols, as the reaction of alcohol such as methanol, ethanol, normal propyl alcohol, isopropyl alcohol, can add a large amount of alcohol reacts, and alcohol is not only made reactant but also serve as solvent.When reacting, can also add acetone, dimethyl formamide or dimethyl sulfoxide isopolarity aprotic solvent as diluent and solubilizing agent with the bigger or solid alcohol of viscosity.
Formula 4
According to the difference of used alcohol, can obtain a series of different R
1Substituent Compound I.R
1Can be the alkyl of 1～12 carbon, and H, CH
2CH
2Cl, CH
2CH
2Br and (CH
2CH
2X)
nY[is X=NH wherein, O; Y=H, CH
3, CH
2CH
3, OAc, n=1～10] in any.
On 3 and 3 ', substituent group (R is arranged at the reaction substrate dinaphthol
2And R
5) time, R
2And R
5Appear at 2 and 8 of product I.According to the difference of raw material, R
2And R
5Can be H, CH
3, CH
2CH
3, CH
2OH, CH
2OAc, CH
2OCH
3, CH
2CH
2OH, COOH, COOCH
3, COOCH
2CH
3, CONH
2, CONHCH
3, CONHCH
2Ph, CONHPh, OH, OAc, OCH
3, OCH
2CH
3, NHAc, any among the NHCOPh.R
2And R
5Can be identical or different.
In like manner, the substituent R on 6 of the substrate dinaphthol and 6 '
3And R
6Appear at 5 and 11 of product.R wherein
3And R
6Can be H, Cl, Br, NO
2, CH
3, CH
2CH
3, CH (CH
3)
2, C (CH
3)
3With among the Ac any.R
3And R
6Can be identical or different.
In like manner, the substituent R on 7 of the substrate dinaphthol and 7 '
4And R
7Appear at 6 and 12 of product.R wherein
4And R
7Can be H, OH, OAc, OCH
3, OCH
2CH
3And OCH
2Among the Ph any.R
4And R
7Can be identical or different.
In-vitro pharmacological experiments shows, 1-oxo-13c-alkoxyl-1 shown in the said structure general formula I, 13c-dihydro-dibenzo [a, kl] xanthene and derivative used as anti-tumor medicine thereof, have tangible anti-tumor activity (the results are shown in Table 1), have good antitumor drug development prospect.R among the general structure I
1Be in the alkyl of 1～12 carbon any, and H, CH
2CH
2Cl, CH
2CH
2Br and (CH
2CH
2X)
nAmong the Y any, X=NH wherein, O; Y=H, CH
3, CH
2CH
3, OAc; N=1～10; R among the general structure I
2And R
5Be H, CH
3, CH
2CH
3, CH
2OH, CH
2OAc, CH
2OCH
3, CH
2CH
2OH, COOH, COOCH
3, COOCH
2CH
3, CONH
2, CONHCH
3, CONHCH
2Ph, CONHPh, OH, OAc, OCH
3, OCH
2CH
3, NHAc, any among the NHCOPh, R
2And R
5Can be identical or different; R among the general structure I
3And R
6Be H, Cl, Br, NO
2, CH
3, CH
2CH
3, CH (CH
3)
2, C (CH
3)
3With among the Ac any, R
3And R
6Can be identical or different; R among the general structure I
4And R
7Be H, OH, OAc, OCH
3, OCH
2CH
3And OCH
2Among the Ph any, R
4And R
7Can be identical or different.
Table 1 is the anti tumor activity in vitro result of the test of part of compounds.
Compound I a is to the IC of human liver cancer cell in the table 1
50Be 0.785 μ g/mL, and to the IC of normal human's liver epithelial cell
50Be 3.45 μ g/mL.Toxicity to hepatoma carcinoma cell is that difference is fairly obvious to normal Cytotoxic 4.4 times.Therefore, Compound I is expected to provide efficient and the medicine of low toxicity at the aspect of malignant tumor such as treatment malignant tumor, especially hepatocarcinoma, pulmonary carcinoma, uterus carcinoma, breast carcinoma, gastric cancer, intestinal cancer, esophageal carcinoma, nasopharyngeal carcinoma, bladder cancer, skin carcinoma, leukemia.
The anti tumor activity in vitro result of the test of table 1. part of compounds
| Numbering | R 1 | R 5＝R 10 | R 2＝R 3＝R 4＝R 6＝R 7＝ R 8＝R 9＝R 11 | IC 50(μ g/mL) (7402 hepatoma carcinoma cell) |
| Ia | CH 3 | H | H | 0.785 |
| Ib | CH 2CH 3 | H | H | 1.05 |
| Ic | CH 2CH 2CH 3 | H | H | 1.58 |
| Id | CH(CH 3) 2 | H | H | 10.84 |
| Ie | CH 2CH(CH 3) 2 | H | H | 7.12 |
| If | CH 2(CH 2) 2CH 3 | H | H | 11.56 |
| Ig | CH 2CH 2OCH 3 | H | H | 3.99 |
| Ih | (CH 2) 2OCH 2CH 3 | H | H | 2.08 |
| Ii | CH 2CH 2Cl | H | H | 4.53 |
| Ij | CH 3 | Br | H | 2.62 |
| Ik | CH 2CH 3 | Br | H | 3.87 |
| Il | CH 2CH 2CH 3 | Br | H | 4.16 |
| Im | CH 2(CH 2) 2CH 3 | Br | H | 14.54 |
Embodiment:
1, the universal method of synthetic I:
A certain amount of dinaphthol or replace in the alcoholic solvent that dinaphthol joins reaction (can add other solvent hydrotropy in case of necessity) and add ethanolamine and CuCl again by equimolar amounts as acetone, dimethyl formamide, dimethyl sulfoxine etc.
22H
2The catalyst that O forms reacts in the presence of oxygen.Reaction finishes back pressure reducing and steaming solvent, adds the ethyl acetate extraction Organic substance, adds weak ammonia flush away copper-amine complex again.The Organic substance of gained is purified with the method for recrystallization or column chromatography, obtains corresponding product I.
2, Ia's is synthetic:
CuCl
22H
2O 1.7g (10mmol) is dissolved in the 200mL methanol, stirs down to add 0.61g ethanolamine (10mmol), is made into the copper amine aqueous solution.Add 2.86g dinaphthol (10mmol) again, be heated to 65 ℃, the down logical O of normal pressure
2Stir.Thin layer chromatography is followed the tracks of and is reacted to raw material disappearance (about 5 hours).Pressure reducing and steaming is made an appointment with half methanol, and cool to room temperature is separated out yellow crystals, is product Ia.Isolate crystal, successively with methanol, clear water, dilute hydrochloric acid and clear water washing, in 50～70 ℃ of oven dry down.
Adding 200ml ethyl acetate and 500ml weak ammonia carry out extracting in the mother solution, branch vibration layer, ethyl acetate layer is with clear water washing back anhydrous sodium sulfate drying, again by an alumina chromatographic column, eluant is used petroleum ether-ethyl acetate 10: 1, obtains another batch product Ia.Productive rate totally 94%.mp.165-167℃，υ
max：3064(Ar-H)，2931，1700(s，C＝O)，1454，1053，807，751cm
-1.δ
H：2.83(s，3H，OCH
3)，6.26(d，J＝9.9Hz，1H，2-H)，7.06(d，J＝7.3Hz，1H，4-H)，7.09(dd，
3J＝8.2Hz，
4J＝1.0Hz，1H，6＝H)，7.19(d，J＝9.9Hz，1H，3-H)，7.32(d，J＝8.9Hz，1H，9-H)，7.37(dd，J
4H-5H＝7.3Hz，J
5H-6H＝8.2Hz，1H，5-H)，7.40-7.44(m，2H，10-H，13-H)，7.79-7.82(m，1H，11-H)，7.89(d，J＝8.9Hz，1H，8-H)，8.10-8.13(m，1H，12-H)。
The synthetic document that sees reference of other chemical compound (Tan D-M, Li H-H, Wang B, Liu H-B, Xu Z-L, Chin.J.Chem., 2001,19:91).
2, the external anticancer test of medicine (MTT colorimetry)
3 * 10
4In sub 96 well culture plates of hepatoma cell strain 7402 inoculations of/ml, every hole adds 200ul, uses the 10%MEM culture medium culturing.Remove culture fluid after cultivating 24h in the incubator, add new preparation culture fluid, and add the DMSO solution of the medicine to be measured of a series of concentration respectively, every hole adds 200ul, every dosage group is established three parallel models, and every hole adds the MTT solution 20ul of 2mg/ml behind the cultivation 48h, cultivates 4h.Culture fluid in the complete sucking-off hole, each adds the DMSO of 150ul, shakes to make the crystal dissolving in 10 minutes.Detect each hole OD value (λ=570nm) with enzyme connection detector; With the logarithm mapping of OD value to drug level, obtaining the drug level that makes the half cell death from figure is IC50.
The results are shown in preceding table.
Claims (1)
1, the oxo of the 1-shown in general structure I-13c-alkoxyl-1, the application of 13c-dihydro-dibenzo [a, kl] xanthene in the preparation medicines resistant to liver cancer,
R among the general structure I
2=R
3=R
4=R
5=R
6=R
7=H, R
1Be CH
3, CH
2CH
3, CH
2CH
2CH
3, CH (CH
3)
2, CH
2CH (CH
3)
2, CH
2(CH
2)
2CH
3, CH
2CH
2Cl, CH
2CH
2OCH
3Or CH
2CH
2OCH
2CH
3
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021147418A CN1189169C (en) | 2002-01-16 | 2002-01-16 | Dibenzo [a, KI] xanthene derivative used as anti-tumor medicine |
Applications Claiming Priority (1)
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| CNB021147418A CN1189169C (en) | 2002-01-16 | 2002-01-16 | Dibenzo [a, KI] xanthene derivative used as anti-tumor medicine |
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| CN1189169C true CN1189169C (en) | 2005-02-16 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111410660A (en) * | 2019-01-23 | 2020-07-14 | 广东省测试分析研究所（中国广州分析测试中心） | Substituted perxanthenoxanthene compounds and uses thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356108B (en) * | 2014-10-09 | 2016-09-14 | 广东药学院 | Heteroaromatic dibenzo ton compound and preparation method and application |
| CN109678874B (en) * | 2019-01-28 | 2022-04-19 | 广东药科大学 | Preparation method and application of forcible xanthene |
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2002
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111410660A (en) * | 2019-01-23 | 2020-07-14 | 广东省测试分析研究所（中国广州分析测试中心） | Substituted perxanthenoxanthene compounds and uses thereof |
| CN111410660B (en) * | 2019-01-23 | 2021-03-26 | 广东省测试分析研究所（中国广州分析测试中心） | Substituted perxanthenoxanthene compounds and uses thereof |
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| CN1364460A (en) | 2002-08-21 |
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