CN100448445C - Application of kuianchun family compound in anti-tumor drug preparing process - Google Patents

Application of kuianchun family compound in anti-tumor drug preparing process Download PDF

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CN100448445C
CN100448445C CNB2005100283779A CN200510028377A CN100448445C CN 100448445 C CN100448445 C CN 100448445C CN B2005100283779 A CNB2005100283779 A CN B2005100283779A CN 200510028377 A CN200510028377 A CN 200510028377A CN 100448445 C CN100448445 C CN 100448445C
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furyl
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quinoxaline
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余龙
赵雪梅
陈帅
蒋华良
唐丽莎
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Fudan University
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Abstract

The invention discloses an application of new quinoxaline compound in the tumour-proof drug domain, which is characterized by the following: avoiding each untoward effect; possessing low side-effect.

Description

The application of a kind of quinoxaline chemical compound in the preparation antitumor drug
Technical field
The invention belongs to chemistry and biological field, specifically, the invention provides the application of a kind of quinoxaline chemical compound in the preparation antitumor drug.
Background technology
Tumor be body under the effect of various tumorigenesis factor, the cellular abnormality hypertrophy of local organization and the neoplasm that forms often shows as local lump.Tumor cell has unusual form, metabolism and function.Its growth is vigorous, often is the persistence growth.This persistence growth as uncontrollable will be invaded critical organ and depletion be caused death at last with causing.The human tumor of finding is existing historical more than 3000.The not only human tumor of suffering from, animal and plant also have tumor.Malignant tumor has become human the lethal the 1st or the 2nd reason at present.Taiwan Department of Health announced the Taiwan resident ten big causes of the death in 2004 on June 7th, 2005, cancer was continued to hold a post or title the umber one in continuous 23 years, secondly was heart disease and cerebrovascular disease, diabetes, accident injury, pneumonia, chronic hepatopathy and liver cirrhosis, kidney relevant disease, suicide, hypertension.According to statistics, 2004, Taiwan more than 2,200 ten thousand philtrums just had a people to die from cancer in per 14 minutes 27 seconds.
Chang Yong antitumor drug mainly contains five big classes in the market: one, influence the synthetic medicine of biological nucleic acid.As 5-fluorouracil.Two, the medicine that directly destroys DNA and stop it to duplicate.Comprise: (1) alkylating agent; (2) antibiotics; (3) cisplatin and carboplatin.Three, disturb transcription to stop the synthetic medicine of RNA.As actinomycin D; Amycin etc.Four, influence the medicine of protein synthesis, as vinca; Podophillotoxines etc.Five, hormones.
Yet quinoxaline chemical compound of the present invention does not have report as yet.
Summary of the invention
The purpose of this invention is to provide the application of a Lei quinoxaline chemical compound in the preparation antitumor drug.
The invention provides the application of a kind of quinoxaline chemical compound of a kind of quinoxaline chemical compound in the preparation antitumor drug, it is characterized in that the structural formula of Gai quinoxaline chemical compound is
Figure C20051002837700041
Above-mentioned small molecule structure is write by the molecular formula usual manner.Wherein, " O " is oxygen, and " N " is nitrogen, and " H " is hydrogen.Carbon atom is omitted, and the not enough tetravalence of carbon place is supplied by hydrogen.
R can be H, C 1-C 4Alkyl, C 1-C 4Thiazolinyl, C 1-C 4Alkoxyl, C 1-C 4One of alkanoyl, halogen, nitro, amino, cyano group or thiocyanogen;
R 1Can be H, C 1-C 4Alkyl, C 1-C 4Thiazolinyl, C 1-C 4Alkynyl, C 3-C 8Cycloalkyl, perhaps one of phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals;
R 2Can be H, C 1-C 4Alkyl, C 1-C 4Thiazolinyl, C 1-C 4Alkynyl, C 3-C 8Cycloalkyl, perhaps one of phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals;
R 3Can be H, C 1-C 4Alkyl, C 1-C 4Thiazolinyl, C 1-C 4Alkynyl, C 3-C 8Cycloalkyl, perhaps one of benzyl, phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals;
R 4Be H, C 1-C 4Alkyl, C 1-C 4Thiazolinyl, C 1-C 4Alkynyl, C 3-C 8Cycloalkyl, perhaps one of benzyl, phenyl, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, pyridine radicals.
In the structural formula of Gai quinoxaline chemical compound, R can be H, C 1-C 4One of alkyl or halogen.
In the structural formula of Gai quinoxaline chemical compound, R 1Can with R 2Identical, be H, C 1-C 4Alkyl, C 3-C 8Cycloalkyl, one of phenyl, furyl, pyrrole radicals or pyridine radicals.
In the structural formula of Gai quinoxaline chemical compound, R 3Can with R 4Identical, be H, C 1-C 4One of alkyl or halogen.
In the structural formula of Gai quinoxaline chemical compound, R 1Can with R 2Identical, be C 3-C 8Cycloalkyl, phenyl or furyl; R 3With R 4Identical, be H, C 1-C 4One of alkyl or halogen.
In the structural formula of Gai quinoxaline chemical compound, R can be H or halogen; R 1Can with R 2Identical, be C 1-C 4Cycloalkyl, phenyl or furyl; R 3Can with R 4Identical, be H or C 1-C 4Alkyl.
In the structural formula of Gai quinoxaline chemical compound, R 1Can with R 2Identical, all be furyl.
Above-mentioned De quinoxaline chemical compound can be from natural environment separation and Extraction, can also synthetic.Among the present invention, also provide a kind of preparation method of above-mentioned De quinoxaline chemical compound, this method comprises:
(1) o-phenylenediamine compounds, by with 1,2 dicarbonyl compound condensation prepared quinoxaline derivatices;
(2) 1,4-Benzodiazine aminated compoundss are by intermediate and other amine condensation prepared urea derivatives such as isocyanates, isothiocyanate, carbamates; Perhaps other aminated compounds passes through intermediate such as isocyanates, isothiocyanate, carbamate Yu 1,4-Benzodiazine aminated compounds condensation prepared urea derivative;
(3) organic replacing acid passes through condensing agent, acyl chlorides or mixed acid anhydride Yu the condensation of 1,4-Benzodiazine aminated compounds prepares amide derivatives; Perhaps the 1,4-Benzodiazine aminated compounds prepares amide derivatives with aminated compounds again after connecting a group that contains carboxyl.
In case obtained quinoxaline chemical compound of the present invention, just can be applied to preparing anti-tumor medicine, prepared antitumor drug can be injection or tablet etc.
Quinoxaline chemical compound of the present invention is to develop in the research of cyclosporin Avidin at first.Yet along with progress of research, the experimental result prompting, above-mentioned quinoxaline chemical compound may have inhibition and lethal effect to tumor cell and tissue.
The present invention has measured the kill and wound situation of above-mentioned quinoxaline chemical compound to a series of hepatoma carcinoma cell, and the result shows, above-mentioned quinoxaline chemical compound all has in various degree lethality to hepatoma carcinoma cell.
Embodiment 2 is contrast with CsA (Sigma), 5-Fu (Sangon) and Taxol (the multiple China fir bio tech ltd in Shanghai), with one of quinoxaline chemical compound of the present invention YZC-J-1 is example, has shown the kill and wound situation of above-mentioned quinoxaline chemical compound to SK, QGY and SK-CyPJ cell.
One of antitumor drug that CsA (Sigma), 5-Fu (Sangon) and Taxol are at present the most frequently used.(cyclosporin A is a kind of immunosuppressant that is used for organ transplantation and autoimmune disease CsA) to cyclosporin A, has been widely used in clinically, and annual sales amount is more than 5,000,000,000 dollars.5-Fu i.e. 5 fluorouracil, and the hydrogen that is 5 of uracil is anti-pyrimidine medicine by the derivative that fluorine replaces.Effective to kinds of tumors, particularly, also effective to ovarian cancer, cervical cancer, chorionic epithelioma, bladder cancer etc. to alimentary tract cancer and breast carcinoma good effect.Because its oral absorption is irregular, adopts intravenously administrable more.But multiple untoward reaction is arranged.Taxol is the anticancer plants component drugs, and TAXOL is otherwise known as; Paclitaxel, purple plain, special plain, purple alkane element, road Thailand, taxol.Be the wide spectrum of generally acknowledging in the world at present, strong active anticancer medicine.Untoward reaction is mainly bone marrow depression, anaphylactic reaction, hypotension or bradycardia, peripheral neuropathy, arthralgia, myalgia, alopecia etc.Because various antitumor drug are used for having shown various toxic and side effects since clinical, the influence of patient and graft survival rate is more and more caused people's attention, many scientific research persons are striving to find the lower substitute of toxic and side effects.
The YZC-J-1 of studies show that of the present invention is relative with Taxol more weak than CsA to the situation of killing and wounding of hepatoma carcinoma cell, but stronger than 5-Fu.
Zoopery shows that quinoxaline compound medicine toxic reaction of the present invention is very little.Therefore, quinoxaline chemical compound of the present invention is used to prepare antitumor drug, especially medicines resistant to liver cancer can be had complementary advantages with existing antitumor drug.
Quinoxaline chemical compound of the present invention is carried out structural modification and optimization, but better application is in the preparation antitumor drug.Above-mentioned " structural modification and optimization " comprises makes it that half-life in better hydrophilic, stronger degradation resistant, the longer body, the structure of modification of antitumor spectrum etc. widely be arranged, and increases or reduce methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclopenta, cyclohexyl, benzyl, phenyl, furyl, pyrrole radicals or a pyridine radicals etc.
The present invention has developed a class quinoxaline chemical compound, and this compounds has the effect of good killing tumor cells, especially hepatoma carcinoma cell and tissue.And such compound molecular weight is little, and structure is simple relatively, is soluble in multiple solvent, and production process is easy, is easy to absorb, and side effect is little.Quinoxaline of the present invention is used to prepare antitumor drug, and especially medicines resistant to liver cancer can be had complementary advantages with existing antitumor drug, and some tumor is had specific curative effect.Quinoxaline of the present invention is carried out structural modification and optimization, can prepare better hydrophilic is arranged, half-life in the stronger degradation resistant, longer body, the medicament of antitumor spectrum widely.
Description of drawings
Fig. 1 suppresses tumor cell proliferation figure (72h) for YZC-J-1.Data are represented with X ± S.D. from three independent experiments among the figure.850 is YZC-J-1.
Fig. 2 is the growth inhibited figure of YZC-J-1 and the common combined effect cell of Taxol.The result shows that 850 (being YZC-J-1) are used the inhibitory action that can strengthen growth of tumour cell simultaneously with taxol.
Fig. 3 reduces the Taxol spirogram for YZC-J-1.As seen, increase by 850 consumption, can reduce the consumption of cell taxol when the half suppression ratio significantly.
The specific embodiment
The preparation of embodiment 1YZC-J-1
(1) intermediate 2, the preparation of 3-difuryl-6-aminoquinoxaline
6.4 gram connection furan acyl and 10 grams 1,2,4-benzene triamine is dissolved in 70 milliliters of hot ethanols and refluxed 40 hours.Cold filtration obtains red solid.With ethyl alcohol recrystallization 2 times, obtain yellow solid 4.2 grams.HPLC：99％，EMS：278(100，M+1)。
(2) N, N dimethylamine acyl group-2, the preparation of 3-difuryl-6-aminoquinoxaline
One: 0.34 gram of method, three surpalites are dissolved in 30 milliliters of dichloromethane, 0.6 gram 2, and 3-difuryl-6-aminoquinoxaline and 0.38 milliliter of diisopropylethylamine are dissolved in 160 milliliters of dichloromethane and slowly are added drop-wise in the above-mentioned solution.Add back restir half an hour, 1 milliliter of dimethylamine is diluted in 20 milliliters of dichloromethane, and this solution is added in the above-mentioned reactant liquor apace.Stirred 45 minutes, reactant liquor washes with water 3 times, anhydrous sodium sulfate drying, evaporate to dryness solution.Residue is crossed post with silica gel (200～300 order), uses ethyl acetate: petroleum ether (1: 1 to 3: 1) drip washing.Obtain yellow solid 0.31 gram.HPLC：98.8％，EMS：349(100，M+1)
Method two: 0.6 gram 2,3-difuryl-6-aminoquinoxaline is dissolved in 10 milliliters of N, and in the N-diformamide, the frozen water cooling adds 1 milliliter of triethylamine, drips 0.2 gram N then, the solution of N-dimethylcarbamyl chloride in 2 milliliters of oxolanes.Add the back stirring at room 3 hours.Reactant liquor is separated out solid in entry, use ethyl alcohol recrystallization, obtains yellow solid 0.5 gram.HPLC：98.5％，EMS：349(100，M+1)
The gained chemical compound is N, N dimethylamine acyl group-2, and 3-difuryl-6-aminoquinoxaline, its structure is as follows:
As seen, this chemical compound is respectively to connect a furyl on the female ring of the Zai 1,4-Benzodiazine prosposition, connects diformazan on the 6th
Figure C20051002837700071
The base urea groups.
Physico-chemical analysis is measured, and the molecular weight of this micromolecular compound is 348, and crystal is brown fine granularity, dissolves in materials such as DMSO, acetone, ethanol and chloroform.DMSO is a dimethyl sulfoxide.
Similar said method is synthetic to obtain following chemical compound:
Table 1 quinoxaline chemical compound of the present invention is enumerated
No. R R1 R2 R3 R4 P*
YZC-J-2 H H H H H 7-
YZC-J-3 H H H Methyl Methyl 7-
YZC-J-4 H Furyl Furyl H Methyl 7-
YZC-J-5 H Furyl Furyl H Ethyl 7-
YZC-J-6 H Furyl Furyl H Propyl group 7-
YZC-J-7 H Furyl Furyl H Butyl 7-
YZC-J-8 H Furyl Furyl H Isopropyl 7-
YZC-J-9 H Furyl Furyl H Isobutyl group 7-
YZC-J-10 H Furyl Furyl H The tert-butyl group 7-
YZC-J-11 H Furyl Furyl H Cyclopropyl 7-
YZC-J-12 H Furyl Furyl H Cyclopenta 7-
YZC-J-13 H Furyl Furyl H Cyclohexyl 7-
YZC-J-14 H Furyl Furyl H Benzyl 7-
YZC-J-15 H Furyl Furyl H The 2-furyl 7-
YZC-J-16 H Furyl Furyl H Phenyl 7-
YZC-J-17 H Furyl Furyl Methyl Methyl 7-
YZC-J-18 H Furyl Furyl Methyl Methyl 7-
YZC-J-19 H Furyl Furyl Ethyl Ethyl 7-
YZC-J-20 H Thienyl Thienyl Ethyl Ethyl 7-
YZC-J-21 H Pyrrole radicals Pyrrole radicals Ethyl Ethyl 7-
YZC-J-22 H Furyl Furyl Propyl group Propyl group 7-
YZC-J-23 Methyl H H Methyl Phenyl 7-
YZC-J-24 Methyl Pyrrole radicals Pyrrole radicals Methyl Methyl 8-
YZC-J-25 Methyl Furyl Furyl Methyl Methyl 7-
YZC-J-26 Methyl Furyl Furyl Ethyl Ethyl 7-
YZC-J-27 Ethyl Furyl Furyl Methyl Methyl 8-
YZC-J-28 Ethyl Furyl Furyl Ethyl Ethyl 7-
YZC-J-29 Amino H H Methyl Benzyl 7-
YZC-J-30 Amino Furyl Furyl Ethyl Ethyl 8-
YZC-J-31 Cl - H H Methyl Imidazole radicals 7-
YZC-J-32 Cl - Furyl Furyl H Cyclopropyl 8-
YZC-J-33 Cl - Pyrrole radicals Pyrrole radicals Ethyl Ethyl 8-
YZC-J-34 Cl - Furyl Furyl Methyl Methyl 7-
Annotate: * is meant the position on the female ring of R Zai 1,4-Benzodiazine.
Embodiment 2YZC-J-1 is to the inhibitory action of growth of tumour cell
(1) cell culture
Human hepatoma cell strain SK, QGY derive from Fudan University heredity institute human gene research department freezing and are stored in cell strain in the liquid nitrogen.The SK-CyPJ transgenosis cell strain is provided by doctor Chen Jian of this research department.Above-mentioned cell is with the preceding recovery of carrying out cell earlier: take out frozen pipe from 37 ℃ of water-baths, disinfecting the back in alcohol opens, sucking-off cell suspension, inject centrifuge tube and add culture fluid more than 10 times (RPMI-1640), mix back low-speed centrifugal (1000rpm, 5min), remove supernatant, repeat again to wash once with culture fluid.(inoculum density is with 5 * 10 suitably to dilute the back with culture fluid 5/ ml is advisable), the inoculated and cultured bottle is put into CO 2Incubator leaves standstill cultivation, changes culture fluid next day again one time, continues to cultivate.
SK, QGY cell culture in the RPMI-1640 that contains 10% hyclone (Gibco) culture medium, 37 ℃, 5%CO 2The conventional cultivation.The SK-CyPJ transgenic cell is incubated in the limited culture fluid (400 ~ 600 μ g G418/ml RPMI-1640 culture fluid) that contains G418 (Sigma), and 37 ℃, 5%CO 2The conventional cultivation.
(2) srb assay is measured YZC-J-1 cell growth inhibitory action
SK, QGY and SK-CyPJ cell (2 ~ 5 * 10 3/ hole)) be seeded to the cultivation of 96 orifice plates respectively and made it adherent back adding YZC-J-1 (Chinese Academy of Sciences's Shanghai medicine synthesizes) and CsA (Sigma), 5-Fu (Sangon) and Taxol (the multiple China fir bio tech ltd in Shanghai) (positive control) in 24 hours, each chemical compound is established 6 Concentraton gradient, each concentration is established 3 multiple holes, and establishes corresponding zeroing hole and blank.Tumor cell is at 37 ℃, 5%CO 2Cultivate under the condition after 72 hours, outwell culture fluid, the 100 μ L that every hole adds 10%TCA (Chemical Reagent Co., Ltd., Sinopharm Group) fix 1 hour in 4 ℃, outwell fixative, with distillation washing 5 times, natural drying.Every hole adds SRB (Sigma) the 100 μ L of 4mg/ml again, and room temperature dyeing 15 minutes is abandoned it, washes natural drying 5 times with 1%HAC (going up section of Hisense chemical reagent company limited).Last every hole adds 150 μ L Tris, shakes up, and 96 orifice plate microplate reader (BIO RAD, Model 550, MICROPLATE READER) 570nm wavelength is measured the OD value down.Calculate the suppression ratio of cell growth with following formula:
Suppression ratio (%)=(OD value Control wells-OD value Dosing holes)/OD value Control wells* 100%
According to each concentration suppression ratio, adopt LOGIT method calculation of half inhibitory concentration IC 50More than each experiment repeat 3 times, get the average IC of 3 experiments 50Value is as the final index of the ability of inhibition.
The effect of table 2YZC-J-1 inhibition SK tumor cell proliferation (X ± S.D.)
Figure C20051002837700101
The effect of table 3YZC-J-1 inhibition QGY tumor cell proliferation (X ± S.D.)
Figure C20051002837700102
The effect of table 4YZC-J-1 inhibition SK-CyPJ tumor cell proliferation (X ± S.D.)
Figure C20051002837700103
Embodiment 3SRB method is measured the reduction effect of 850 pairs of taxol consumptions of chemical compound
SK-CypJ cell (2～5*10 3/ hole) be seeded to 96 orifice plates respectively and cultivate and to make it adherent back in 24 hours and add 850 (Chinese Academy of Sciences's Shanghai medicine synthesize) and taxol (the multiple China fir bio tech ltd in Shanghai), adopt Orthogonal Method determine variable concentrations 850 and taxol arrange in pairs or groups after to the inhibitory action of growth of tumour cell.850 concentration that adopt are respectively 0uM, 12.5uM and 25uM; The concentration of taxol adopts 0uM respectively, 0.006uM, 0.025uM and 0.1uM.Each concentration is set up 6 multiple holes, and sets up corresponding zeroing hole and blank.Tumor cell is at 37 ℃, 5%CO 2Cultivate under the condition after 72 hours, outwell culture fluid, the 100uL that every hole adds 10%TCA (Chemical Reagent Co., Ltd., Sinopharm Group) fixes 1 hour in 4 ℃, outwells fixative, with distillation washing 5 times, natural drying.Every hole adds SRB (Sigma) 100uL of 4mg/ml again, and room temperature dyeing 15 minutes is abandoned it, washes natural drying 5 times with 1%HAC (going up section of Hisense chemical reagent company limited).If last every hole 150uL Tris shakes up, 96 orifice plate microplate reader 570nm measure the OD value down.Calculate the suppression ratio of cell growth with following formula:
Suppression ratio (%)=(OD value Control wells-OD value Dosing holes)/OD value Control wells* 100%
Suppression ratio according under each concentration collocation adopts the regressive method of logarithm to determine half-inhibition concentration IC 50More than each experiment repeat 6 times, the meansigma methods of getting 6 experiments suppresses the final index of ability as half.
The result shows that 850 (being YZC-J-1) are used the inhibitory action (see figure 2) that can strengthen growth of tumour cell simultaneously with taxol.And, increase by 850 consumption, can reduce the consumption (see figure 3) of cell taxol when the half suppression ratio significantly.

Claims (2)

1.N, N dimethylamine acyl group-2,3-difuryl-6-aminoquinoxaline is in preparation N, N dimethylamine acyl group-2, the application in the antitumor drug of 3-difuryl-6-aminoquinoxaline and taxol coupling.
2. use according to claim 1, it is characterized in that this antitumor drug is injection or tablet.
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