CN104119330B - The synthesis of berberinc derivate and preparing the application in antitumor drug and collaborative Zorubicin antineoplastic pharmaceutical compositions - Google Patents
The synthesis of berberinc derivate and preparing the application in antitumor drug and collaborative Zorubicin antineoplastic pharmaceutical compositions Download PDFInfo
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Abstract
The present invention relates to a kind of berberinc derivate and its preparation method and application, this berberinc derivate general structure is:
wherein R is alkyl, benzyl, substituted benzyl, phenyl, substituted-phenyl, heterocyclic methyl or substituted heterocycle methyl.The composition and the said composition that the invention still further relates to above-mentioned berberinc derivate and Zorubicin are preparing the application in antitumor drug.Berberinc derivate of the present invention not only has independent and collaborative Zorubicin antitumor action; and for the myocardial damage caused over the course for the treatment of, to lose weight and Intestinal epithelial cells all has certain provide protection, be the synergistic combination medicine of doxorubicin cancer disease process middle ideal.
Description
[technical field]
The invention belongs to medicinal chemistry arts, be specifically related to a kind of berberinc derivate and its preparation method and application, and the medical composition and its use that berberinc derivate and Zorubicin are formed.
[background technology]
Malignant tumour often claims cancer, is frequently-occurring disease and the common disease of serious threat human health.Main three large methods of current treatment malignant tumour comprise chemotherapy (abbreviation chemotherapy), surgical operation therapy and radiotherapy.Application conventional cell poison class antitumour drug or anticarcinogen carry out chemotherapy and still occupy considerable status in the comprehensive therapies of tumour.Part malignant tumour such as chorioepithelioma, malignant lymphoma etc. can be cured by chemotherapeutic treatment, the targeted therapy of rising in recent years is that we cure cancer and provide new method and thinking, but still fails at present to reach gratifying curative effect in the face of the treatment of more than 90% solid tumor.Affecting the large reason of chemical therapeutic effect two is: the toxic reaction being first medicine is excessive, is secondly to create resistance to medicine.Cell toxicant based chemotherapy medicine is due to the shortage to tumor cells selectivity, and while killing and wounding tumour cell generation, normal tissue cell also can produce damaging action in various degree.And the key factor that when size of toxic reaction becomes chemotherapy of tumors, drug dose is limited.
Zorubicin, also known as Dx, is anthracycline antibiotics, between energy intercalation of DNA base, and combines closely on DNA, stops rna transcription process, suppress the synthesis of RNA, also can stop copying of DNA.S phase cell is more responsive to it.Belong to cell cycle nonspecific agent (CCNSA).Zorubicin antitumor spectra is wide, and curative effect is high, is widely used in the treatment of kinds of tumors clinically.Mainly act on the acute lymphoblastic leukemia to conventional anti-malignant-tumor agent resistance or granulocyte leukemia, malignant lymphosarcoma, mammary cancer, ovarian cancer, small cell lung cancer, cancer of the stomach, liver cancer and wing moon bright cancer etc.But larger untoward reaction constrains its application prospect and scope after its use.The most serious toxic reaction for myocardial degenerative disease can be caused, cardiac interstitium oedema and cardiac toxic.In addition, the untoward reactions such as digestive tract reaction, cutaneous pigmentation and alopecia are also had.
From natural product, excavating activeconstituents and carry out structure of modification and modification to it, is one of important channel of investigators' developing new drug.In the various kinds of drug of current Clinical practice, many all from natural product or their derivative.Berberine is the Isoquinolinium Alkaloid that extraction and isolation obtains from the plants such as the herbal medicine coptis, in Traditional Chinese Medicine, be used for the treatment of the gastrointestinal tract disease caused by bacteriological infection for a long time.Recent study find Berberine and derivative pharmacological function very abundant, as antimalarial, antibacterial, antitumor, anti-arrhythmia, hypoglycemic, tune fat etc.In antitumor action, the propagation of Berberine to kinds of tumors has restraining effect, and this compounds can suppress the growth of the kinds of tumor cells such as K562 (people's blood cell), YES (esophageal cancer cell), HepG2 (liver cancer cell), colon26/colon20 (colon cancer cell), SGC-7901 (gastric carcinoma cells); The differentiation of HL60 (people in loop), MGC-803 and SGC-7901 (gastric carcinoma cells) can be promoted; MGC-803 and BGC-823 gastric carcinoma cells apoptosis can be induced.For the research of Berberine 9 substitutive derivatives, it is the focus of berberinc derivate research always.Many investigators find that berberrubine (methoxyl group that Berberine is 9 is optionally substituted by a hydroxyl group) itself also possesses certain anti-tumor activity, but because of its to Normocellular toxicity considerable influence its exploitation as the potentiality of antitumor drug.This patent carries out the modification of new side chain structure to Berberine 9, has found that the novel berberinc derivate of a class has independent and collaborative Zorubicin antineoplastic action.
Chinese patent literature CN:201010558160.X, July 18 2012 day for announcing discloses Berberine and Zorubicin mixed preparation is preparing the application in adriamycin cardiac dysfunction or antitumor drug.This mixed preparation has certain restraining effect to Zorubicin myocardium toxicity, but Berberine and Zorubicin are used alone antineoplastic action and not obvious.
But Zorubicin is to body toxic side effect, and therefore, improving the independent and collaborative Zorubicin antineoplastic action of Berberine, is very necessary to reach the object of efficacy enhancing and toxicity reducing.
[summary of the invention]
The object of the invention is, for deficiency of the prior art, to provide the berberinc derivate with good anti-tumor activity.
Of the present invention again one object be that the preparation method of above-mentioned berberinc derivate is provided.
Another object of the present invention provides the purposes of above-mentioned berberinc derivate.
4th object of the present invention provides a kind of antineoplastic composition.
5th object of the present invention provides the purposes of described antineoplastic composition.
For achieving the above object, the technical scheme that the present invention takes is: a kind of berberinc derivate, and general structure is:
Wherein, R is alkyl, benzyl, substituted benzyl, phenyl, substituted-phenyl, heterocyclic methyl or substituted heterocycle methyl;
Described alkyl is straight or branched alkyl or the cycloalkyl with 1 ~ 20 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, cyclobutyl, 2-methyl isophthalic acid-cyclopropyl, amyl group, 2-cyclopropylethyl, cyclopentyl, hexyl, cyclohexyl, 2-cyclopentyl ethyl, heptyl, 2-cyclohexyl-ethyl, octyl group, nonyl and decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, preferably there is the alkyl of 12 ~ 20 carbon atoms, the particularly preferably alkyl of 13 ~ 18 carbon atoms, or end has the alkyl of replacement, as ethoxycarbonylmethyl group, methoxycarbonyl-methyl, ethoxycarbonyl-ethyl, ethoxycarbonylpropyl, ethoxycarbonyl butyl, ethoxycarbonyl amyl group, phenylethyl.
Substituting group in described substituted benzyl be positioned at neighbour, or contraposition, be substituted by monosubstituted or polysubstituted; Described substituting group is halogen, as fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1 ~ 6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl or new hexyl, the preferably alkyl of 3 ~ 4 carbon atoms, particularly preferably sec.-propyl or the tertiary butyl; Or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as methyl fluoride, difluoromethyl, trifluoromethyl, trifluoroethyl, four fluoropropyls, the preferably alkyl with 1 ~ 2 carbon atom of 2 ~ 3 fluorine atom replacements, particularly preferably trifluoromethyl; Or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert.-butoxy, the preferably alkoxyl group of 1 ~ 3 carbon atom, particularly preferably methoxy or ethoxy; Or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of 1 ~ 2 carbon atom of preferably 1 ~ 4 fluorine atom replacement, particularly preferably trifluoromethoxy; Or be methylene-dioxy; Or be allyloxy or the alkyl replacement allyloxy of 3 ~ 6 carbon atoms; Or be cyano group; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be 1-naphthyl; Or be 2-naphthyl; Or be phenyl or substituted-phenyl, the substituting group in described substituted-phenyl be positioned at neighbour, or contraposition, be substituted by monosubstituted or polysubstituted; Described substituting group is halogen, as fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1 ~ 6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl or new hexyl, the preferably alkyl of 3 ~ 4 carbon atoms, particularly preferably sec.-propyl or the tertiary butyl; Or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as methyl fluoride, difluoromethyl, trifluoromethyl, trifluoroethyl, four fluoropropyls, the preferably alkyl with 1 ~ 2 carbon atom of 2 ~ 3 fluorine atom replacements, particularly preferably trifluoromethyl; Or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert.-butoxy, the preferably alkoxyl group of 1 ~ 3 carbon atom, particularly preferably methoxy or ethoxy;
Substituting group in described substituted-phenyl be positioned at neighbour, or contraposition, be substituted by monosubstituted or polysubstituted; Described substituting group is halogen, as fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1 ~ 6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl or new hexyl, the preferably alkyl of 3 ~ 4 carbon atoms, particularly preferably sec.-propyl or the tertiary butyl; Or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as methyl fluoride, difluoromethyl, trifluoromethyl, trifluoroethyl, four fluoropropyls, the preferably alkyl with 1 ~ 2 carbon atom of 2 ~ 3 fluorine atom replacements, particularly preferably trifluoromethyl; Or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert.-butoxy, the preferably alkoxyl group of 1 ~ 3 carbon atom, particularly preferably methoxy or ethoxy; Or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of 1 ~ 2 carbon atom of preferably 1 ~ 4 fluorine atom replacement, particularly preferably trifluoromethoxy; Or be methylene-dioxy; Or be allyloxy or the alkyl replacement allyloxy of 3 ~ 6 carbon atoms; Or be cyano group; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be 1-naphthyl; Or be 2-naphthyl; Or be benzyloxy or substituted benzyloxy, or described substituting group be halogen, the straight or branched alkoxyl group of the straight or branched alkyl of 1 ~ 4 carbon atom replacing of the straight or branched alkyl of 1 ~ 6 carbon atom, 1 ~ 4 fluorine atom, 1 ~ 4 carbon atom, 1 ~ 4 fluorine atom the straight or branched alkoxyl group of 1 ~ 4 carbon atom, the allyloxy of 3 ~ 6 carbon atoms or the alkyl that replace replace allyloxy, cyano group, nitro; The acyloxy of 1-4 carbon atom, amino, hydroxyl; Or be heterocycle methoxyl group or substituted heterocycle methoxyl group.
Heterocycle in described heterocyclic methyl or substituted heterocycle methyl is five yuan or hexa-atomic single heterocycles and five yuan or hexa-atomic fused heterocycle, as furans, thiophene, pyrroles, pyrazoles, imidazoles, oxazole, thiazole, isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, pyridine of talking endlessly, purine or 2,3-Dihydrobenzofuranes-6-base; Or be phenyl or substituted-phenyl, described substituting group is benzyloxy or substituted benzyloxy, or described substituting group is heterocycle methoxyl group or substituted heterocycle methoxyl group, described heterocycle is five yuan or hexa-atomic single heterocycles and five yuan or hexa-atomic fused heterocycle, as furans, thiophene, pyrroles, pyrazoles, imidazoles, oxazole, thiazole, isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, pyridine of talking endlessly, purine or 2,3-Dihydrobenzofuranes-6-base; Substituting group in described substituted heterocycle be positioned at neighbour, or contraposition, be substituted by monosubstituted or polysubstituted; Substituting group in described substituted heterocycle is halogen, as fluorine, chlorine, bromine or iodine atom; Or be the straight or branched alkyl of 1 ~ 4 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl or sec-butyl, the preferably alkyl of 3 ~ 4 carbon atoms, particularly preferably sec.-propyl or the tertiary butyl; Or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert.-butoxy, preferably there is the alkoxyl group of 1 ~ 3 carbon atom, particularly preferably methoxy or ethoxy; Or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as methyl fluoride, difluoromethyl, trifluoromethyl or trifluoroethyl four fluoropropyl, the preferably alkyl of 1 ~ 2 carbon atom that replaces of 2 ~ 3 fluorine atoms, particularly preferably trifluoromethyl; Or be the straight or branched alkoxyl group with 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, as trifluoromethoxy, trifluoro ethoxy or tetrafluoro propoxy-, the alkyl of 3 ~ 4 carbon atoms of preferably 2 ~ 4 fluorine atom replacements, particularly preferably tetrafluoro propoxy-; Or be methylene-dioxy; Or replace allyloxy for the allyloxy with 3 ~ 6 carbon atoms or alkyl; Or be cyano group; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be phenyl; Or be 2-naphthyl; Or be 1-naphthyl.
Berberinc derivate of the present invention is following compounds 1-104.The general structure of this analog derivative is as follows:
The wherein following table definition of R.
Table 1 berberinc derivate
For realizing above-mentioned second object, the technical scheme that the present invention takes is:
Described berberinc derivate is preparing the application in antitumor drug.
For realizing above-mentioned 3rd object, the technical scheme that the present invention takes is: described berberinc derivate preparation method.The method comprises the following steps, reaction scheme is as follows:
(1) Compound I berberine chloride generation demethylating reaction generates Compound II per chlorination berberrubine;
(2) Compound II per chlorination berberrubine and propargyl chloride generation nucleophilic substitution reaction generate compound III;
(3) compound III generates target compound IV with replacement trinitride generation ring-closure reaction.
Described step (1) demethylating reaction is that Compound I berberine chloride reacts in appropriate solvent; Described solvent is ether, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, N, dinethylformamide or methyl-sulphoxide etc., preferred tetrahydrofuran (THF), dioxane, DMF or methyl-sulphoxide, particularly preferably DMF; The temperature of reaction of demethylating reaction is 130-190 DEG C, preferred 150-190 DEG C, particularly preferably 180-190 DEG C; The reaction times of described step (1) demethylating reaction is 0.5-2 hour, preferred 0.5-1 hour, particularly preferably 0.5 hour.
Described step (2) nucleophilic substitution reaction is Compound II per chlorination berberrubine under acid binding agent exists, and reacts in appropriate solvent; Described acid binding agent is Trimethylamine 99, triethylamine, pyridine, sodium carbonate, sodium bicarbonate, salt of wormwood, lithium hydroxide, sodium hydroxide, potassium hydroxide; Described solvent is methyl alcohol, ethanol, acetonitrile, acetone, ethylene dichloride, methylene dichloride, tetrahydrofuran (THF), dioxane, DMF or methyl-sulphoxide etc., preferred alcohol, acetonitrile, tetrahydrofuran (THF) or DMF, particularly preferably acetonitrile and tetrahydrofuran (THF); The temperature of reaction of nucleophilic substitution reaction is 50-110 DEG C, preferred 60-90 DEG C, particularly preferably 70-80 DEG C.
Described step (3) ring-closure reaction is compound III under classical " click chemistry reaction " condition, carries out in appropriate solvent; Described click chemistry reaction conditions is CuSO
45H
2o and xitix sodium water solution; Described solvent is methylene dichloride, dioxane, tetrahydrofuran (THF) or DMF etc., preferred tetrahydrofuran (THF) or DMF, particularly preferably DMF; The temperature of reaction of ring-closure reaction is-20-50 DEG C, preferred 0-30 DEG C, particularly preferably 20 DEG C; The reaction times of described step (3) ring-closure reaction is 1-12 hour, preferred 2-8 hour, particularly preferably 3-5 hour.
For realizing above-mentioned 4th object, the technical scheme that the present invention takes is:
A kind of antineoplastic composition, it comprises described berberinc derivate and Zorubicin.
Described medicine is the pharmaceutical composition be made up of as activeconstituents and pharmaceutical carrier berberinc derivate and doxorubicin compositions; The mol ratio of described berberinc derivate and doxorubicin compositions is 0.1: 1 ~ 10: 1.
Described activeconstituents is the compound be selected from berberinc derivate 1-104; Preferred compound is 13,15,21,54,69,85 or 93; More preferably 13,15 or 54.
For realizing above-mentioned 5th object, the technical scheme that the present invention takes is:
Described composition is preparing the application in antitumor drug.
The invention has the advantages that:
The anti-tumor activity of the majority of compounds 1, related in the present invention is better than Berberine, has lower cytotoxicity while the anti-tumor activity enhancing of part of compounds.
2, berberinc derivate provided by the invention and antitumour drug Zorubicin drug combination under certain proportion not only has the collaborative effect suppressing Cells Proliferation of Human Breast Cancer, simultaneously to the myocardial damage caused in doxorubicin process, to lose weight and Intestinal epithelial cells all has certain provide protection.
[accompanying drawing explanation]
Accompanying drawing 1 is berberinc derivate preparation method.
[embodiment]
Below embodiment provided by the invention is elaborated.
The synthesis of embodiment 1, chlorination berberrubine (II)
Take 8g (0.0216mol) berberine chloride, drop into 250ml flask, add DMF120ml, 190 DEG C of oil bath backflow 25-30min, TLC (methylene dichloride: methyl alcohol=10: 1) detect to raw material point just disappear and impure point does not just occur time stopped reaction (product Rf about 0.4, red).Solvent evaporated obtains BBR-1 crude product 7g, and productive rate is 85%, can be directly used in next step reaction.
The synthesis of embodiment 29-O-proyl Berberine (compound III)
Take 0.54g (1.67mmol) chlorination berberrubine (Compound II per) and drop into 100ml flask, add 0.24g (2.03mmol) propargyl bromide, 60ml acetonitrile, 70-80 DEG C of backflow 2.5h.TLC detects (methylene dichloride: methyl alcohol=10: 1), visible product point (Rf value is about 0.45, yellow), and there is product yellow mercury oxide in drag.Column chromatography (methylene dichloride: methyl alcohol=25: 1) obtain product 0.35g, productive rate is 65%.
The synthesis (in table 1 compound 3) of embodiment 3 compound 1-propyl group-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
50mgNaN is added in 50ml flask
3(0.77mmol), 76mg1-bromine n-propane (0.6mmol) 10mlDMF70 DEG C stirs 3h, and cooling drops into 9-O-proyl Berberine (II) 160mg (0.4mmol), by CuSO
4.5H
2o30mg and sodium ascorbate 50mg is mixed with the aqueous solution of 5ml respectively, adds reaction system.Continue reaction 3h, TCL and detect (methylene dichloride: methyl alcohol=10: 1), product point yellow (Rf value about 0.45).Reaction solution adds 10% ammoniacal liquor, and divide three extractions with methylene dichloride 100ml, extraction liquid washes twice with 12% hydrochloric acid 5ml, and after concentrated, column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=25: 1: trace), obtains 40mg compound 3.
1HNMR(300MHz，DMSO)δ9.72(s，1H)，8.95(s，1H)，8.40(s，1H)，8.20(dd，J＝9.2，3.8Hz，1H)，8.00(d，J＝9.1Hz，1H)，7.78(d，J＝3.3Hz，1H)，7.08(s，1H)，6.27-6.09(m，2H)，5.46(s，2H)，4.94(s，2H)，4.30(t，J＝6.9Hz，2H)，4.08(d，J＝9.0Hz，3H)，3.20(d，J＝4.7Hz，2H)，1.86-1.62(m，2H)，0.75(dt，J＝14.8，7.5Hz，3H).HR-ESI-MScalcdforC
25H
25N
4O
4[M-Cl]
+445.1875，found445.1879.13CNMR(75MHz，DMSO)δ151.37，150.34，148.18，145.70，142.75，142.05，137.90，133.41，131.10，127.04，125.65，124.41，122.41，120.85，120.75，108.92，105.92，102.58，67.01，57.56，55.85，51.38，26.84，23.59，11.05。
The synthesis (in table 1 compound 4) of secondary butane-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles of embodiment 4 compound 1-
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 4.
1HNMR(300MHz，DMSO)δ9.70(s，1H)，8.90(s，1H)，8.32(s，1H)，8.19(d，J＝8.8Hz，1H)，8.00(d，J＝8.9Hz，1H)，7.75(s，1H)，7.08(s，1H)，6.16(s，2H)，5.47(s，2H)，4.91(s，2H)，4.11(d，J＝10.6Hz，4H)，3.18(s，2H)，0.69(d，J＝6.2Hz，6H).C
26H
27N
4O
4[M-Cl]
+459.2032，found459.2027.
13CNMR(75MHz，DMSO)δ151.44，150.35，148.19，145.66，142.56，141.86，137.88，133.39，131.08，127.01，126.08，124.46，122.50，120.80，120.73，108.93，105.90，102.58，66.76，57.56，56.71，55.88，29.51，26.85，19.70。
The synthesis (in table 1 compound 6) of embodiment 5 compound 1-amyl group-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 6.
1HNMR(300MHz，DMSO)δ9.70(s，1H)，8.92(s，1H)，8.38(s，1H)，8.18(d，J＝9.2Hz，1H)，8.06-7.95(m，1H)，7.75(s，1H)，7.07(s，1H)，6.15(s，2H)，5.45(s，2H)，4.92(t，J＝6.0Hz，2H)，4.31(t，J＝7.0Hz，2H)，4.08(s，3H)，3.19(t，J＝6.0Hz，2H)，1.80-1.61(m，2H)，1.33-1.07(m，4H)，0.77(q，J＝7.5Hz，3H).HR-ESI-MScalcdforC
27H
29N
4O
4[M-Cl]
+473.2188，found473.2194.13CNMR(75MHz，DMSO)δ151.00，149.93，147.76，145.29，142.31，141.52，137.45，132.98，130.67，126.57，125.28，124.05，122.02，120.42，120.31，108.52，105.49，102.18，66.47，57.15，55.48，49.40，29.41，27.86，26.45，21.50，13.79。
The synthesis (in table 1 compound 8) of embodiment 6 compound 1-heptyl-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 8.
1HNMR(300MHz，DMSO)δ9.68(s，1H)，8.92(s，1H)，8.30(s，1H)，8.21(d，J＝9.2Hz，1H)，8.00(d，J＝9.1Hz，1H)，7.77(s，1H)，7.09(s，1H)，6.16(s，2H)，5.46(s，2H)，4.90(t，J＝5.9Hz，2H)，4.30(t，J＝6.9Hz，2H)，4.09(s，3H)，3.18(t，J＝5.6Hz，2H)，1.76-1.60(m，2H)，1.21-0.93(m，8H)，0.80(t，J＝6.9Hz，3H).HR-ESI-MScalcdforC
29H
33N
4O
4[M-Cl]
+501.2501，found501.2501.
13CNMR(75MHz，DMSO)δ151.50，151.22，150.36，148.19，145.86，142.68，137.98，133.51，131.18，127.20，125.59，124.54，122.54，120.92，120.76，108.93，106.19，102.60，67.07，57.74，57.54，49.78，31.50，30.15，28.46，27.00，26.06，22.46，14.36。
The synthesis (in table 1 compound 10) of embodiment 7, compound 1-nonyl-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 10.
1HNMR(300MHz，DMSO)δ9.69(s，1H)，8.92(s，1H)，8.33(s，1H)，8.20(d，J＝9.2Hz，1H)，8.00(d，J＝9.1Hz，1H)，7.76(s，1H)，7.08(s，1H)，6.16(s，2H)，5.46(s，2H)，4.91(s，2H)，4.30(t，J＝6.8Hz，2H)，4.09(s，3H)，3.18(s，2H)，1.77-1.55(m，2H)，1.04(dt，J＝38.9，6.7Hz，15H).HR-ESI-MScalcdforC
31H
37N
4O
4[M-Cl]
+529.2814，found529.2819.
13CNMR(75MHz，DMSO)δ151.48，150.38，148.22，145.72，142.68，141.88，137.89，133.39，131.09，127.05，125.66，124.47，122.51，120.86，120.74，108.96105.92，102.63，66.80，57.57，55.90，49.82，31.72，30.14，29.28，29.11，28.83，26.90，26.10，22.59，14.44。
The synthesis (in table 1 compound 13) of embodiment 8, compound 1-dodecane-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 13.
1HNMR(300MHz，DMSO）δ9.70(s，1H)，8.93(s，1H)，8.33(s，1H)，8.23-8.18(m，1H)，8.03(dd，J＝14.7，9.1Hz，2H)，7.77(s，1H)，7.09(s，1H)，6.17(s，2H)，5.46(s，2H)，4.92(s，2H)，4.31(t，J＝6.4Hz，2H)，4.10(d，J＝1.1Hz，3H)，3.19(s，2H)，1.68(d，J＝6.5Hz，2H)，1.20(dt，J＝59.7，24.0Hz，18H)，0.78(d，J＝1.2Hz，3H).HR-ESI-MScalcdforC34H43N4O4[M-Cl]
+571.3284，found571.3288.
13CNMR(75MHz，DMSO)δ150.98，149.92，147.75，145.38，145.26，142.24，141.48，137.44，132.94，130.79，130.64，126.59，125.16，123.99，122.02，120.39，120.27，108.49，105.45，102.15，79.85，66.42，57.23，57.11，55.44，49.37，30.55，29.87，29.66，29.13，26.42，25.34，21.90，13.85。
The synthesis (in table 1 compound 15) of embodiment 9, the compound 1-tetradecane-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 15.
1HNMR(300MHz，DMSO)δ9.59(s，1H)，8.85(s，1H)，8.32(s，1H)，8.15(d，J＝9.2Hz，1H)，7.95(d，J＝9.1Hz，1H)，)，7.77(s，1H)，7.08(d，J＝6.8Hz，1H)，6.18(d，J＝4.9Hz，2H)，6.05(s，2H)，5.44(s，2H)，4.71(t，J＝5.8Hz，2H)，4.02(s，3H)，3.09-2.98(m，2H)，2.09-1.92(m，2H)，1.90-1.34(m，22H)，1.24-0.75(m，3H).HR-ESI-MScalcdforC
36H
47N
4O
4[M-Cl]
+599.3597，found599.3593.
13CNMR(75MHz，DMSO)δ150.95，149.93，147.75，145.24，142.13，141.74，137.55，132.97，130.69，126.63，125.06，123.26，121.99，120.44，120.31，108.43，105.48，102.09，66.81，59.08，57.11，55.48，49.34，32.78，31.30，28.98，26.45，24.51，14.01。
The synthesis (in table 1 compound 20) of embodiment 10 compound 1-(methylenecyclohexane)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
50mgNaN is added in 50ml flask
3(0.77mmol), 120mg bromomethylcyclohexane (0.6mmol) 10mlDMF stirring at room temperature 3h, drops into 9-O-proyl Berberine (II) 160mg (0.4mmol), by CuSO
4.5H
2o30mg and sodium ascorbate 50mg is mixed with the aqueous solution of 5ml respectively, adds reaction system.Continue reaction 3h, TCL and detect (methylene dichloride: methyl alcohol=10: 1), product point yellow (Rf value about 0.45, very close with substrate).Reaction solution adds 10% ammoniacal liquor, and divide three extractions with methylene dichloride 100ml, extraction liquid washes twice with 12% hydrochloric acid 5ml, and after concentrated, column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=25: 1: trace), obtains 60mg compound 20.
1HNMR(300MHz，DMSO)δ9.73(s，1H)，8.95(s，1H)，8.30(s，1H)，8.20(d，J＝9.0Hz，1H)，7.99(d，J＝9.1Hz，1H)，7.77(s，1H)，7.09(s，1H)，6.17(s，2H)，5.47(s，2H)，4.93(s，2H)，4.15(d，J＝6.9Hz，2H)，4.10(s，3H)，3.19(s，2H)，1.05(ddd，J＝78.8，57.2，45.1Hz，11H).HR-ESI-MScalcdforC29H31N4O4[M-CH
+499.2345，found499.2349.
13CNMR(75MHz，)δ151.49，150.35，148.19，145.75，142.43，141.75，137.84，133.34，131.08，127.00，126.21，124.40，122.53，120.84，120.73，108.94，105.87，102.61，66.72，57.55，55.87，55.50，38.54，30.00，26.88，26.14，25.47。
The synthesis (in table 1 compound 21) of embodiment 11, compound 1-(4-methylenediphenyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 10 method feeds intake and aftertreatment obtains compound 21.
1HNMR(300MHz，DMSO)δ9.65(s，1H)，8.92(s，1H)，8.47(s，1H)，8.21(d，J＝9.4Hz，1H)，8.01(d，J＝8.4Hz，1H)，7.71(s，1H)，7.64-7.29(m，7H)，7.08(d，J＝7.2Hz，2H)，6.96(s，1H)，6.14(s，2H)，5.61(s，2H)，5.50(s，2H)，4.77(s，2H)，4.09(s，3H)，3.02(s，2H).HR-ESI-MScalcdforC35H29N4O4[M-Cl]
+569.2188，found569.2193.
13CNMR(75MHz，DMSO)δ151.12，149.83，147.67，145.09，142.48，141.22，139.80，139.19，137.35，135.15，132.82，130.43，128.84，127.90，127.60，126.81，126.49，125.65，124.07，122.10，120.19，108.34，105.28，102.06，66.07，57.05，55.23，52.30，26.25。
The synthesis (in table 1 compound 25) of embodiment 12, compound 1-benzyl-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
50mgNaN is added in 50ml flask
3(0.77mmol), 110mg cylite (0.6mmol), 10mlDMF stirring at room temperature 3h, drops into 9-O-proyl Berberine (II) 160mg (0.4mmol), by CuSO
4.5H
2o30mg and sodium ascorbate 50mg is mixed with the aqueous solution of 5ml respectively, adds reaction system.Continue reaction 3h, TCL and detect (methylene dichloride: methyl alcohol=10: 1), product point yellow (Rf value about 0.45, very close with substrate).Reaction solution adds 10% ammoniacal liquor, and divide three extractions with methylene dichloride 100ml, extraction liquid washes twice with 12% hydrochloric acid 5ml, and after concentrated, column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=25: 1: trace), obtains 60mg compound 25.
1HNMR(300MHz，DMSO)δ9.64(s，1H)，8.94(d，J＝15.5Hz，1H)，8.38(s，1H)，8.21(t，J＝9.3Hz，1H)，8.03(t，J＝12.0Hz，1H)，7.79(s，1H)，7.19(ddd，J＝38.5，14.7，7.5Hz，6H)，6.18(s，2H)，5.57(s，2H)，5.46(s，2H)，4.80(s，2H)，4.06(s，3H)，3.11(s，2H).HR-ESI-MScalcdforC
29H
25N
4O
4[M-Cl]
+494.1875，found494.1880；
13CNMR(75MHz，DMSO)δ151.49，150.38，148.22，145.65，143.07，141.82，137.89，136.48，133.36，131.11，129.17，128.51，128.07，127.03，125.94，124.52，122.50，120.87，120.78，108.93，105.92，102.61，66.82，57.53，55.78，53.24，26.81。
The synthesis (in table 1 compound 27) of embodiment 13, compound 1-(the chloro-benzyl of 2-)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 27.
1HNMR(300MHz，DMSO)δ9.65(s，1H)，8.91(s，1H)，8.40(s，1H)，8.17-8.09(m，1H)，8.00(d，J＝9.4Hz，1H)，7.75(s，1H)，7.38(d，J＝7.5Hz，1H)，7.29-7.21(m，2H)，7.05(s，2H)，6.15(s，2H)，5.64(s，2H)，5.45(s，2H)，4.82(s，2H)，4.04(s，3H)，3.10(s，2H).HR-ESI-MScalcdforC
29H
24ClN
4O
4[M-Cl]
+528.1486，found528.1477.
13CNMR(75MHz，DMSO)δ151.13，149.98，147.83，145.29，142.46，141.28，137.44，133.22，133.01，132.72，130.72，130.58，130.39，129.70，127.79，126.54，126.18，124.29，122.15，120.48，108.59，105.60，102.26，66.25，57.19，55.50，50.77，34.21，26.47。
The synthesis (in table 1 compound 28) of embodiment 14, compound 1-(the bromo-benzyl of 2-)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 28.
1HNMR(，300MHz，DMSO)δ9.66(s，1H)，8.93(s，1H)，8.34(s，1H)，8.21(d，J＝9.2Hz，1H)，8.01(d，J＝9.1Hz，1H)，7.79(s，1H)，7.60(d，J＝2.1Hz，1H)，7.45-7.38(m，1H)，7.37(d，J＝2.1Hz，1H)，7.15-6.97(m，2H)，6.18(s，2H)，5.65(s，2H)，5.48(s，2H)，4.83(s，2H)，4.08(s，3H)，3.22-3.02(m，2H).HR-ESI-MScalcdforC
29H
24BrN
4O
4[M-Cl]
+573.0980，found573.0956.
13CNMR(75MHz，DMSO)δ151.46，150.40，148.24，146.09，142.88，142.01，138.11，134.49，134.15，133.37，132.76，132.23，131.08，129.57，128.28，127.11，126.34，124.60，122.49，120.82，120.79，108.95，106.16，102.78，66.91，57.54，55.97，50.56，27.05。
The synthesis (in table 1 compound 29) of embodiment 15, compound 1-(the fluoro-benzyl of 3-)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 29.
1HNMR(300MHz，DMSO)δ9.69(s，1H)，8.93(s，1H)，8.47(s，1H)，8.20(d，J＝9.2Hz，1H)，8.00(d，J＝9.0Hz，1H)，7.78(s，1H)，7.34(dd，J＝14.2，7.5Hz，1H)，7.03(dt，J＝23.2，6.5Hz，4H)，6.18(s，2H)，5.62(s，2H)，5.47(s，2H)，4.85(s，2H)，4.07(s，3H)，3.13(s，2H).HR-ESI-MScalcdforC
29H
24FN
4O
4[M-Cl]
+512.17815，found512.17695.
13CNMR(75MHz，DMSO)δ150.96，149.93，147.78，145.38，142.65，141.46，137.47，132.99，130.90，130.73，130.58，126.66，125.63，124.02，123.78，122.00，120.34，120.23，115.13，114.83，114.49，108.39，105.52，102.16，66.59，57.01，55.51，52.20，26.39。
The synthesis (in table 1 compound 39) of embodiment 16, compound 1-(4-trifluoromethoxy-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 39.
1HNMR(300MHz，DMSO)δ9.67(s，1H)，8.91(s，1H)，8.54(s，1H)，8.16(d，J＝9.3Hz，1H)，8.02(d，J＝9.2Hz，1H)，7.75(s，1H)，7.33-7.21(m，4H)，7.05(s，1H)，6.14(s，2H)，5.62(s，2H)，5.45(s，2H)，4.84(t，J＝5.9Hz，2H)，4.04(s，3H)，3.16-3.06(m，2H).HR-ESI-MScalcdforC
30H
24F
3N
4O
5[M-Cl]
+577.1698，found577.1702.
13CNMR(75MHz，DMSO)δ151.15，150.02，148.15，147.86，145.31，142.79，141.41，137.50，135.58，133.03，130.76，129.93(3C)，126.62，125.94，124.31，122.12，121.38(2C)，120.48，120.42，108.59，105.62，102.26，66.37，57.22，55.51，52.01，26.50。
The synthesis (in table 1 compound 40) of embodiment 17, compound 1-(4-romethyl-benzy)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 40.
1HNMR(300MHz，DMSO)δ9.75(s，1H)，8.96(s，1H)，8.56(s，1H)，8.23(d，J＝9.2Hz，1H)，8.04(d，J＝9.1Hz，1H)，7.80(s，1H)，7.71(d，J＝8.1Hz，2H)，7.39(d，J＝8.0Hz，2H)，7.10(s，1H)，6.20(s，2H)，5.77(s，2H)，5.51(s，2H)，4.91(t，J＝5.5Hz，2H)，4.11(s，3H)，3.18(d，J＝5.6Hz，2H).HR-ESI-MScalcdforC
30H
24F
3N
4O
4[M-Cl]
+562.1749，found562.1755.
13CNMR(75MHz，DMSO)δ150.96，149.91，147.74，145.25，142.76，141.44，140.71，137.42，132.91，130.62，128.40(3C)，126.54，125.88，125.65，125.60，124.05，121.94，120.35，120.27，108.45，105.44，102.13，66.40，57.08，55.38，52.11，26.37。
The synthesis (in table 1 compound 43) of embodiment 18, compound 1-(4-cyanogen-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 43.
1HNMR(300MHz，DMSO)δ9.68(s，1H)，8.92(s，1H)，8.52(s，1H)，8.20(d，J＝9.0Hz，1H)，8.01(d，J＝8.9Hz，1H)，7.82-7.66(m，3H)，7.23(d，J＝7.7Hz，2H)，7.05(s，1H)，6.16(s，2H)，5.71(s，2H)，5.48(s，2H)，4.82(s，2H)，4.08(s，3H)，3.07(s，2H).HR-ESI-MScalcdforC
30H
24N
5O
4[M-Cl]
+519.1828，found519.1832.
13CNMR(75MHz，DMSO)δ151.04，150.00，147.83，145.18，142.68，141.46，141.24，137.35，132.85，132.61，130.56，128.28，126.52，126.01，124.11，122.02，120.30，118.38，110.85，108.41，105.41，102.14，66.23，57.09，55.31，52.09，26.33。
The synthesis (in table 1 compound 51) of embodiment 19, compound 1-(to methylsulphonic acid base-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 51.
1HNMR(，300MHz，DMSO)δ9.73(s，1H)，8.93(s，1H)，8.53(s，1H)，8.19(d，J＝9.2Hz，1H)，8.01(d，J＝9.2Hz，1H)，7.89(d，J＝8.3Hz，2H)，7.77(s，1H)，7.45(d，J＝8.3Hz，2H)，7.07(s，1H)，6.17(s，2H)，5.77(s，2H)，5.47(s，2H)，4.90(t，J＝5.6Hz，2H)，4.06(s，3H)，3.19(s，3H)，3.17(s，2H).HR-ESI-MScalcdforC
30H
27N
4O
6S[M-Cl]
+572.1651，found572.1656.
13CNMR(75MHz，DMSO)δ150.86，149.9l，147.75，145.27，142.83，141.71，141.57，140.52，137.47，132.94，130.65，128.60(2c)，127.45(2c)，126.54，125.84，124.01，121.87，120.36，120.27，108.45，105.47，102.13，66.54，57.08，55.40，52.12，43.44，26.39。
The synthesis (in table 1 compound 54) of embodiment 20, compound 1-n-Hexadecane-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 54.
1HNMR(300MHz，DMSO)δ9.68(s，1H)，8.92(s，1H)，8.33-8.17(m，2H)，8.00(d，J＝9.1Hz，1H)，7.78(s，1H)，7.09(s，1H)，6.17(s，2H)，5.46(s，2H)，4.90(s，2H)，4.30(t，J＝6.9Hz，2H)，4.10(s，3H)，3.19(s，2H)，1.76-1.62(m，2H)，1.23(s，26H)，0.85(t，J＝6.2Hz，3H).HR-ESI-MScalcdforC
38H
51N
4O
4[M-Cl]
+627.3910，found627.3914.
13CNMR(75MHz，DMSO)δ151.23，150.38，148.2l，145.84，145.78，142.69，142.03，141.28，138.21，137.91，133.43，131.24，131.09，127.03，125.59，124.80，124.49，122.60，122.54，120.82，108.94，105.98，105.94，102.61，80.32，79.28，67.02，61.44，57.65，57.57，55.80，31.78，30.14，29.54，29.20，28.81，26.83，26.11。
The synthesis (in table 1 compound 59) of embodiment 21, compound 1-tetramethylene-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 59.
1HNMR(300MHz，DMSO)δ10.00-9.62(m，1H)，8.96(d，J＝11.4Hz，1H)，8.55(s，1H)，8.29-8.09(m，1H)，7.99(dd，J＝9.1，3.1Hz，1H)，7.74(s，1H)，7.06(s，1H)，6.18(d，J＝16.3Hz，2H)，5.55-5.05(m，2H)，4.98(dd，J＝12.8，6.7Hz，2H)，4.07(dd，J＝7.3，3.4Hz，3H)，3.24(d，J＝31.3Hz，2H)，2.14(dd，J＝12.5，5.7Hz，1H)，2.02-1.57(m，4H).HR-ESI-MScalcdforC
25H
23N
4O
4[M-Cl]
+444.1719，found444.1726.
13CNMR(75MHz，DMSO)δ151.38，150.37，148.20，145.68，142.98，142.04，137.96，133.41，133.30，131.14，127.06，125.74，124.47，122.43，120.86，120.74，118.84，108.94，105.92，102.59，66.94，57.55，55.87，52.09，26.83。
The synthesis (in table 1 compound 62) of embodiment 22, compound 1-hexanaphthene-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 62.
1HNMR(300MHz，DMSO)δ9.69(s，1H)，8.94(d，J＝9.1Hz，1H)，8.45(s，1H)，8.19(dd，J＝9.1，4.7Hz，1H)，8.00(dd，J＝9.0，4.6Hz，1H)，7.76(s，1H)，7.08(s，1H)，6.16(s，2H)，5.44(d，J＝15.8Hz，2H)，4.92(s，2H)，4.12-4.03(m，3H)，3.17(t，J＝5.4Hz，3H)，2.18-1.92(m，2H)，1.89-1.57(m，4H)，1.55-1.30(m，2H)，1.31-0.75(m，2H).HR-ESI-MScalcdforC
28H
29N
4O
4[M-Cl]
+486.2188，found486.2185.
13CNMR(75MHz，DMSO)δ151.28，150.08，148.07，145.53，142.52，141.98，137.75，133.32，131.03，127.09，126.83，124.37，123.67，122.19，120.84，120.67，108.67，105.56，102.32，66.91，62.23，59.28，57.93，55.67，48.62，33.07，26.55，24.83。
The synthesis (in table 1 compound 64) of embodiment 23, compound 1-ethyl propionate-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 64.
1HNMR(300MHz，DMSO)δ9.70(s，1H)，8.98(d，J＝12.3Hz，1H)，8.44(s，1H)，8.21(dd，J＝9.1，6.3Hz，1H)，8.04(dd，J＝15.6，9.2Hz，1H)，7.79(d，J＝5.7Hz，1H)，7.08(s，1H)，6.16(s，2H)，5.44(s，2H)，5.02-4.87(m，2H)，4.56(t，J＝6.5Hz，2H)，4.08(d，J＝6.8Hz，3H)，3.92(q，J＝7.1Hz，2H)，3.20(s，2H)，2.92(t，J＝6.5Hz，2H)，1.11(dd，J＝28.4，21.3Hz，3H).HR-ESI-MScalcdforC
27H
27N
4O
6[M-Cl]
+503.1930，found503.1936.
13CNMR(75MHz，DMSO)δ170.72，151.35，150.29，148.15，145.69，142.70，141.97，137.92，133.40，131.13，126.97，126.12，124.46，122.42，120.90，108.91，105.92，102.57，80.31，66.85，60.71，57.55，55.83，45.74，34.27，26.81，14.42。
The synthesis (in table 1 compound 66) of embodiment 24, compound 1-Valeric acid ethylester-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 3 method feeds intake and aftertreatment obtains compound 66.
1HNMR(300MHz，DMSO)δ9.70(s，1H)，8.92(s，1H)，8.37(s，1H)，8.20(d，J＝9.2Hz，1H)，8.00(d，J＝9.1Hz，1H)，7.77(s，1H)，7.08(s，1H)，6.16(s，2H)，5.45(s，2H)，4.92(t，J＝5.8Hz，2H)，4.35(t，J＝6.9Hz，2H)，4.08(d，J＝7.5Hz，3H)，4.04-3.94(m，2H)，3.19(t，J＝5.9Hz，2H)，2.30-2.21(m，2H)，1.79-1.20(m，4H)，1.17-1.10(m，3H).HR-ESI-MScalcdforC
29H
31N
4O
6[M-Cl]
+531.2243，found531.2249.
13CNMR(75MHz，DMSO)δ173.11(d，J＝12.6Hz)，151.34，150.33，148.17，145.68，142.77，142.01，137.90，133.39，131.11，127.00，125.66，124.42，122.39，120.86，120.74，108.91，105.91，102.58，66.95，60.26，57.54，55.86，49.48，33.12，29.49，27.98，26.85，21.66，14.56。
The synthesis (in table 1 compound 69) of embodiment 25, compound 1-styroyl-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
50mgNaN is added in 50ml flask
3(0.77mmol) with 110mg (0.6mmo1) bromo ethyl phenenyl, 10mlDMF stirring at room temperature 4h, for subsequent use.Compound 9-O-proyl Berberine (II) 160mg (0.4mmol) is added successively, CuSO to above-mentioned reaction mixture
4.5H
2o (30mg) and sodium ascorbate (50mg) are mixed with the aqueous solution of 5ml respectively, continue stirring at room temperature reaction 3h, TCL detects (methylene dichloride: methyl alcohol=10: 1), product point yellow (Rf value about 0.45, very close with substrate).After reaction terminates, add 10% ammoniacal liquor at reaction solution during process, divide three extractions with methylene dichloride 100ml, extraction liquid is with 12% hydrochloric acid 10ml extracting twice again.Column chromatography (methylene dichloride: methyl alcohol=15: 1) final product 60mg compound 69.
1HNMR(300MHz，DMSO)δ9.69(s，1H)，8.94(s，1H)，8.36(s，1H)，8.20(d，J＝8.8Hz，1H)，8.01(d，J＝8.9Hz，1H)，7.78(s，1H)，7.19(t，J＝8.2Hz，3H)，7.14-7.02(m，3H)，6.16(s，2H)，5.43(s，2H)，4.92(s，2H)，4.61(t，J＝6.8Hz，2H)，4.07(s，3H)，3.14(dd，J＝16.0，8.7Hz，4H).HR-ESI-MScalcdforC
30H
27N
4O
4[M-Cl]
+508.2032，found508.2036.
13CNMR(75MHz，DMSO)δ150.79，149.88，147.72，145.22，142.26，141.59，137.55，137.45，132.95，130.66，128.59，128.38，126.57，125.17，123.92，121.86，120.41，120.30，108.46，105.45，102.12，66.51，57.08，55.40，50.43，35.64，30.71，26.38。
The synthesis (in table 1 compound 70) of embodiment 26, compound 1-(benzyl methyl ether)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 70.
1HNMR(300MHz，DMSO)δ9.72(d，J＝10.6Hz，1H)，8.93(d，J＝12.2Hz，1H)，8.61(d，J＝13.2Hz，1H)，8.20(t，J＝7.7Hz，1H)，8.01(d，J＝9.1Hz，1H)，7.83-7.69(m，1H)，7.39-7.19(m，4H)，7.18-7.00(m，2H)，6.16(s，2H)，5.83(d，J＝13.5Hz，2H)，5.48(d，J＝15.3Hz，2H)，5.03-4.81(m，2H)，4.41(s，2H)，4.12-4.04(m，3H)，3.18(dd，J＝17.1，6.3Hz，2H).HR-ESI-MScalcdforC
30H
27N
4O
5[M-Cl]
+523.1981，found523.1981.
13CNMR(75MHz，DMSO)δ151.36，150.32，148.14，145.67，143.41，141.89，137.89，137.12，133.37，131.08，129.14，128.80，128.32，128.07，127.02，126.37，124.49，122.37，120.77，120.73，108.89，105.91，102.57，78.05，70.90，66.78，62.42，57.56，55.81，26.81。
Embodiment 27, compound 3, the 4-dimethoxy-2-(synthesis (in table 1 compound 71) of (4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles-1-y1) picoline
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 71.
1HNMR(300MHz，DMSO)δ9.62(s，1H)，8.91(s，1H)，8.29-8.16(m，2H)，8.01(t，J＝7.5Hz，2H)，7.79(s，1H)，7.12-7.00(m，2H)，6.18(s，2H)，5.61(s，2H)，5.45(s，2H)，4.83(t，J＝6.0Hz，2H)，4.08(s，3H)，3.85(s，3H)，3.70(s，3H)，3.22-3.07(m，2H).HR-ESI-MScalcdforC
30H
28N
5O
6[M-Cl]
+555.2039，found555.2045.
13CNMR(75MHz，DMSO)δ158.82(s)，151.49(s)，150.37(s)，148.22(s)，148.04(s)，146.26(s)，145.74(s)，143.36(s)，142.61(s)，141.94(s)，137.84(s)，133.34(s)，131.10(s)，127.04(s)，126.60(s)，124.47(s)，122.51(s)，120.87(s)，120.72(s)，109.15(s)，108.93(s)，105.91(s)，102.62(s)，66.93(s)，61.07(s)，57.51(s)，56.55(s)，55.84(s)，50.09(s)，26.81(s)。
The synthesis (in table 1 compound 73) of embodiment 28, compound 4-(3-methoxy propoxy)-2-((4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles-1-yl) methyl) pyridine
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 73.1HNMR(300MHz，DMSO)δ9.71(s，1H)，8.95(s，1H)，8.72(s，1H)，8.64(d，J＝6.1Hz，1H)，8.19(d，J＝9.2Hz，1H)，7.99(d，J＝9.2Hz，1H)，7.79(s，1H)，7.48(dd，J＝28.6，22.2Hz，2H)，7.09(s，1H)，6.17(s，2H)，6.03(s，2H)，5.47(s，2H)，4.88(d，J＝28.1Hz，2H)，4.31(t，J＝6.1Hz，2H)，4.08(d，J＝7.3Hz，3H)，3.22(d，J＝9.4Hz，5H)，3.18(s，2H)，2.00(p，J＝6.1Hz，2H).HR-ESI-MScalcdforC
30H
32N
5O
6[M-Cl]
+583.2352，found583.2356.
13CNMR(75MHz，DMSO)δ150.72，149.85，147.69，145.23，142.70，142.61，141.49，137.42，132.86，130.66，126.49，126.19，124.84，123.89，121.81，120.38，120.24，108.92，108.45，105.47，102.13，68.02，67.54，66.41，57.99，57.08，55.43，48.31，34.00，28.29，26.36，10.06。
The synthesis (in table 1 compound 75) of embodiment 29, compound 1-(1,3 dioxolanes-4-y1)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 75.
1HNMR(300MHz，DMSO)δ9.67(s，1H)，8.94(s，1H)，8.29(s，1H)，8.20(d，J＝9.1Hz，1H)，8.00(d，J＝8.9Hz，1H)，7.77(s，1H)，7.20-6.96(m，1H)，6.16(s，2H)，5.45(s，2H)，5.15(t，J＝3.7Hz，1H)，4.91(s，2H)，4.56(t，J＝15.6Hz，2H)，4.07(d，J＝8.7Hz，4H)，3.70(t，J＝8.7Hz，3H)，3.19(s，2H).HR-ESI-MScalcdforC
26H
25N
4O
6[M-Cl]
+489.1774，found489.1781.
13CNMR(75MHz，DMSO)δ151.38，150.32，148.16，145.68，142.73，141.94，137.87，133.37，131.10，126.98，126.73，124.47，122.43，120.85，120.73，108.92，105.91，102.58，101.04，66.87，65.06，57.53，55.86，55.40，51.93，26.83。
The synthesis (in table 1 compound 77) of embodiment 30, compound 3-sec.-propyl-5-((4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles-1-yl) methyl)-1,2,4-oxadiazoles
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 77.
1HNMR(300MHz，DMSO)δ9.72(s，1H)，8.95(s，1H)，8.54(s，1H)，8.22(d，J＝9.2Hz，1H)，8.01(d，J＝9.1Hz，1H)，7.79(s，1H)，7.09(s，1H)，6.17(s，2H)，6.12(s，2H)，5.51(s，2H)，4.90(s，2H)，4.09(s，3H)，3.18(s，2H)，2.98(dt，J＝13.7，6.9Hz，1H)，1.22(d，J＝4.9Hz，1H)，1.18(d，J＝6.9Hz，6H).HR-ESI-MScalcdforC
28H
27N
6O
5[M-Cl]
+528.2042，found528.2046.
13CNMR(75MHz，DMSO)δ175.38，151.52，150.35，148.21，145.77，143.32，141.97，138.12，133.51，131.21，127.11，127.06，124.66，124.59，122.48，120.98，120.81，120.75，108.97，105.99，102.65，93.52，66.85，57.57，45.39，26.52，20.55(2C)。
The synthesis (in table 1 compound 81) of embodiment 31, compound 1-(naphthalene-1-methylene radical)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 81.
1HNMR(300MHz，DMSO)δ9.60(s，1H)，8.85(s，1H)，8.32(s，1H)，8.15(d，J＝9.2Hz，1H)，8.09-8.02(m，1H)，7.96(d，J＝9.1Hz，1H)，7.92-7.82(m，2H)，7.79(d，J＝8.4Hz，1H)，7.55-7.39(m，3H)，7.26(d，J＝6.8Hz，1H)，7.08(d，J＝6.8Hz，1H)，6.19(d，J＝4.9Hz，2H)，6.05(s，2H)，5.45(s，2H)，4.72(t，J＝5.8Hz，2H)，4.03(s，3H)，3.12-2.97(m，2H).HR-ESI-MScalcdforC
33H
27N
4O
4[M-Cl]
+544.2032，found544.2036.
13CNMR(75MHz，DMSO)δ150.93，149.88，147.72)，145.07，142.44，141.20，137.25，133.24，132.76，131.40，130.57，130.47，129.00，128.60，127.06，126.76，126.41，126.16，125.52，125.46，123.99，123.05，121.94，120.33，120.23，108.44，105.44，102.13，66.24，56.98，55.20，50.76，26.28。
The synthesis (in table 1 compound 83) of embodiment 32, compound 4-((4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles-1-yl) methyl) quinoline-2-one-
Reference embodiment 25 method feeds intake and aftertreatment obtains compound 83.
1HNMR(300MHz，DMSO)δ9.59(s，1H)，8.85(s，1H)，8.32(s，1H)，8.15(d，J＝9.2Hz，1H)，8.08-8.02(m，1H)，7.95(d，J＝9.1Hz，1H)，7.91-7.79(m，2H)，7.77(s，1H)，7.54-7.47(m，2H)，7.46-7.39(m，1H)，7.25(d，J＝6.8Hz，1H)，7.08(d，J＝6.8Hz，1H)，6.18(d，J＝4.9Hz，2H)，6.05(s，2H)，5.44(s，2H)，4.71(t，J＝5.8Hz，2H)，4.02(s，3H)，3.09-2.98(m，2H).HR-ESI-MScalcdforC
32H
26N
5O
5[M-Cl]
+561.1933，found561.1938.
13CNMR(75MHz，DMSO)δ150.93，149.89，147.72，145.08，142.45，141.20，137.25，133.25，132.76，131.41，130.57，130.48，129.01，128.60，127.06，126.76，126.41，126.16，125.52，125.46，124.00，123.05，121.94，120.34，120.24，108.45，105.45，102.13，66.25，56.98，55.20，50.76，26.28。
The synthesis (in table 1 compound 84) of embodiment 33, compound 1-(2-Methyl-benzvl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 84.
1HNMR(300MHz，DMSO)δ9.67(s，1H)，8.92(s，1H)，8.42(s，1H)，8.20(d，J＝9.2Hz，1H)，8.00(d，J＝9.1Hz，1H)，7.78(s，1H)，7.36-7.22(m，3H)，7.15-7.05(m，2H)，6.18(s，2H)，5.60(s，2H)，5.47(s，2H)，4.83(d，J＝6.0Hz，2H)，4.07(s，3H)，3.17-3.07(m，2H)，1.30-1.20(m，3H).HR-ESI-MScalcdforC
30H
27N
4O
4[M-Cl]
+508.2032，found508.1731.
13CNMR(75MHz，DMSO)δ150.97，149.94，147.83，145.38，145.25，142.68(s)，141.44，138.43，137.46，133.35，132.89，130.60，128.04)，127.65，126.61，126.39，125.64，124.09，122.02，120.43，120.32，108.51，105.50，102.22，66.44，57.02，55.35，52.06，29.09，26.39。
The synthesis (in table 1 compound 85) of embodiment 34, compound 1-(4-tert-Butyl-benzyI)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 85.
1HNMR(300MHz，DMSO)δ9.71(s，1H)，8.96(s，1H)，8.40(s，1H)，8.21(d，J＝9.1Hz，1H)，8.01(d，J＝9.1Hz，1H)，7.80(s，1H)，7.28(d，J＝8.2Hz，2H)，7.13-6.96(m，3H)，6.17(s，2H)，5.54(s，2H)，5.46(s，2H)，4.88(s，2H)，4.06(s，3H)，3.15(s，2H)，1.20(s，9H).HR-ESI-MScalcdforC
33H
33N
4O
4[M-Cl]
+550.2501，found550.2507.
13CNMR(75MHz，DMSO)δ155.73，151.21，150.25，148.07，142.78，138.13，133.60，132.96，130.98，127.28，126.64，125.38，124.41，122.13，120.38，120.30，120.22，119.12，105.65，102.35，100.43，78.61，57.21，55.56，52.50，34.45，30.95，29.23。
The synthesis (in table 1 compound 86) of embodiment 35, compound 1-(4-methyoxy-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 86.
1HNMR(300MHz，DMSO)δ9.65(s，1H)，8.94(s，1H)，8.48(s，1H)，8.17(d，J＝8.6Hz，1H)，8.01(d，J＝8.3Hz，1H)，7.76(s，1H)，7.09(d，J＝8.1Hz，3H)，6.79(d，J＝7.0Hz，2H)，6.16(s，2H)，5.47(s，2H)，5.44(s，2H)，4.83(s，2H)，4.05(s，3H)，3.64(s，3H)，3.09(s，2H).HR-ESI-MScalcdforC
30H
27N
4O
5[M-Cl]
+523.1981，found523.1987.
13CNMR(75MHz，DMSO)δ159.57，151.57，150.39，148.23，145.68，143.03，141.83，137.86，133.42，131.12，129.75，128.45，127.04，125.92，124.63，122.56，120.84，114.53，108.95，106.04，102.65，66.86，57.62，55.84，55.64，52.80.26.88。
The synthesis (in table 1 compound 93) of embodiment 36, compound 1-(2,4,6-trichloro-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 93.
1HNMR(300MHz，DMSO)δ9.57(s，1H)，8.90(s，1H)，8.17(d，J＝9.1Hz，1H)，8.07-7.92(m，2H)，7.81(s，1H)，6.75(s，2H)，6.18(s，2H)，5.44(s，4H)，4.65(s，2H)，4.05(s，3H)，3.10(s，2H).HR-ESI-MScalcdforC
29H
22Cl
3N
4O
4[M-Cl]
+596.07066，found596.2349.
13CNMR(75MHz，DMSO)δ151.15，149.93，147.80，145.19，141.93，141.05，137.72，137.53，137.32，132.81，130.59，128.98，128.62，126.51，124.99，124.06，122.19，120.40，120.25，108.50，105.50，102.29，66.02，57.03，55.17，47.50，19.22。
The synthesis (in table 1 compound 95) of embodiment 37, compound 1-(2,6-diiluoro-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 95.
1HNMR(300MHz，DMSO)δ9.66(s，1H)，8.93(s，1H)，8.34(s，1H)，8.19(d，J＝8.9Hz，1H)，8.00(d，J＝8.7Hz，1H)，7.79(s，1H)，7.43(s，1H)，7.09(s，3H)，6.18(s，2H)，5.63(s，2H)，5.44(s，2H)，4.85(s，2H)，4.06(s，3H)，3.15(s，2H).HR-ESI-MScalcdforC
29H
23F
2N
4O
4[M-Cl]
+530.1687，found530.1683.
13CNMR(75MHz，DMSO)δ159.26，150.98，150.15，149.83，147.96，145.19，142.77，141.62，137.76，133.14，131.69，130.66，126.66，125.65，124.09，122.02，120.49，112.05，111.93，111.79，108.53，108.30，105.51，102.19，99.15，66.29，57.08，55.47，26.46。
The synthesis (in table 1 compound 99) of embodiment 38, compound 1-(2,4-dibromo-benzyl)-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles
Reference embodiment 12 method feeds intake and aftertreatment obtains compound 99.
1HNMR(300MHz，DMSO)δ9.67(s，1H)，8.92(s，1H)，8.31(s，1H)，8.19(d，J＝8.1Hz，1H)，8.01(s，1H)，7.79(s，1H)，7.60(s，1H)，7.22(s，1H)，7.03(d，J＝28.1Hz，2H)，6.18(s，2H)，5.64(s，2H)，5.49(s，2H)，4.83(s，2H)，4.07(s，3H)，3.13(s，2H).HR-ESI-MScalcdforC
29H
23Cl
2N
4O
4[M-Cl]
+562.1096，found562.1091.
13CNMR(75MHz，DMSO)δ151.62，150.58，145.84，143.12，139.79，135.46，133.39，131.24，130.96，130.85，128.76，127.14，126.45，123.38，122.65，122.34，120.93，120.84，109.05，105.99，102.84，102.77，98.27，96.17，67.35，58.44，56.21，54.21，27.63。
Embodiment 39, mtt assay measure the effect (alone) of berberinc derivate of the present invention to tumor cell proliferation
1) inoculation of tumour cell: be inoculated on 96 hole enzyme plates by the tumour cell being in logarithmic phase needed for experiment by 5000-12000cell/ hole, volume is 100 μ l/ holes.
2) dosing: medicine is with two multiple proportions gradient dilutions, and 8 concentration established by every medicine, the multiple hole of each concentration 3, arrange zeroing group and blank group, 96 orifice plate cycle holes add PBS.Cell inoculation adds pastille substratum 100 μ l/ hole after spending the night.
3) mtt assay measures drug effect: after drug effect 24h/48h, exhaust pastille nutrient solution gently, by new cell culture fluid and the MTT solution for preparing in 10: 1 ratio mix, every hole adds 110 μ l, is placed in after incubator continues to cultivate 4h and takes out, add DMSO after the liquid in the every hole of sucking-off, every hole 150 μ l, on vibrator, after 600r jolting 10min, microplate reader measures OD value corresponding to every hole, take 630nm as reference wavelength, and 570nm place measures OD value.
4) cell proliferation inhibition rate is calculated: and return examination amount effect curve degree of fitting with PASWStatistics18Logit, calculate IC
50value.
Inhibiting rate (%)=(1-dosing group cell average absorbance value/cellular control unit average absorbance value) × 100%.
5) experimental result of part of compounds is in table 2.
Embodiment 40, mtt assay measure the toxicity of berberinc derivate of the present invention to HUVEC cell
1) inoculation of HUVEC cell: be inoculated on 96 hole enzyme plates by the tumour cell being in logarithmic phase needed for experiment by 5000cell/ hole, volume is 100 μ l/ holes.
2) dosing: medicine is with two multiple proportions gradient dilutions, and 8 concentration established by every medicine, the multiple hole of each concentration 3, arrange zeroing group and blank group, 96 orifice plate cycle holes add PBS.Cell inoculation adds pastille substratum 100 μ l/ hole after spending the night.
3) mtt assay measures drug effect: after drug effect 24h/48h, exhaust pastille nutrient solution gently, by new cell culture fluid and the MTT solution for preparing in 10: 1 ratio mix, every hole adds 110 μ l, is placed in after incubator continues to cultivate 4h and takes out, add DMSO after the liquid in the every hole of sucking-off, every hole 150 μ l, on vibrator, after 600r jolting 10min, microplate reader measures OD value corresponding to every hole, take 630nm as reference wavelength, and 570nm place measures OD value.
4) cell proliferation inhibition rate is calculated: and return examination amount effect curve degree of fitting with PASWStatistics18Logit, calculate IC
50value.
5) experimental result of part of compounds is in table 2.
Table 2 berberinc derivate is alone to four strain human tumor cells and Normocellular half-inhibition concentration (IC
50, μM)
The cytoactive test of embodiment 41, berberinc derivate of the present invention associating Zorubicin antagonism MCF-7
1) the inoculation bed board of MCF-7 cell: be inoculated on 96 hole enzyme plates by the MCF-7 cell being in logarithmic phase needed for experiment by 10000cell/ hole, volume is 100 μ l/ holes.96 orifice plate surroundings add PBS200 μ l.
2) dosing: (the 4th row are to the 11st row with two multiple proportions gradient dilutions for berberinc derivate, totally 8 gradients), 8 concentration established by every medicine, the multiple hole of each concentration 3,96 orifice plates first are classified as zeroing group, and second is classified as blank group, after cell inoculation is spent the night, add containing berberinc derivate substratum 50 μ l/ hole, add containing Dx substratum 50 μ l/ hole (now every hole has been 200 μ l).
3) mtt assay measures drug effect: after drug effect 24h/48h, exhaust pastille nutrient solution gently, by new cell culture fluid and the MTT solution for preparing in 10: 1 ratio mix, every hole adds 110 μ l, is placed in after incubator continues to cultivate 4h and takes out, add DMSO after the liquid in the every hole of sucking-off, every hole 150 μ l, on vibrator, after 600r jolting 10min, microplate reader measures OD value corresponding to every hole, take 630nm as reference wavelength, and 570nm place measures OD value.
4) cell proliferation inhibition rate is calculated: and return examination amount effect curve degree of fitting with PASWStatistics18Logit, calculate IC
50value.Inhibiting rate (%)=(1-dosing group cell average absorbance value/cellular control unit average absorbance value) × 100%.
5) experimental result of part of compounds is in table 3.
The cytoactive test of embodiment 42, berberinc derivate of the present invention associating Zorubicin antagonism MCF-7/ADR
1) the inoculation bed board of MCF-7/ADR cell: be inoculated on 96 hole enzyme plates by the MCF-7/ADR cell being in logarithmic phase needed for experiment by 12000cell/ hole, volume is 100 μ l/ holes.96 orifice plate surroundings add PBS200 μ l.
2) dosing: (the 4th row are to the 11st row with two multiple proportions gradient dilutions for berberinc derivate, totally 8 gradients), 8 concentration established by every medicine, the multiple hole of each concentration 3,96 orifice plates first are classified as zeroing group, and second is classified as blank group, after cell inoculation is spent the night, add containing berberinc derivate substratum 50 μ l/ hole, add containing Dx substratum 50 μ l/ hole (now every hole has been 200 μ l).
3) mtt assay measures drug effect: after drug effect 24h/48h, exhaust pastille nutrient solution gently, by new cell culture fluid and the MTT solution for preparing in 10: 1 ratio mix, every hole adds 110 μ l, is placed in after incubator continues to cultivate 4h and takes out, add DMSO after the liquid in the every hole of sucking-off, every hole 150 μ l, on vibrator, after 600r jolting 10min, microplate reader measures OD value corresponding to every hole, take 630nm as reference wavelength, and 570nm place measures OD value.
4) cell proliferation inhibition rate is calculated: and return examination amount effect curve degree of fitting with PASWStatistics18Logit, calculate IC
50value.Inhibiting rate (%)=(1-dosing group cell average absorbance value/cellular control unit average absorbance value) × 100%.
5) experimental result of part of compounds is in table 3.
Table 3 berberinc derivate works in coordination with Zorubicin antagonism MCF-7 and MCF-7/ADR inhibition rate of tumor cell (%)
Embodiment 43, mtt assay mensuration berberinc derivate 1-n-Hexadecane-4-(9-O-methylene radical Berberine)-1 hydrogen-1,2,3-triazoles (in table 1 compound 54) and Zorubicin share the impact on MCF-7 cell proliferation
(1) inoculation of MCF-7 cell: be inoculated on 96 hole enzyme plates by the MCF-7 cell being in logarithmic phase needed for experiment by 10000cell/ hole, volume is 100 μ l/ holes.
(2) dosing: medicine is with two multiple proportions gradient dilutions, and 8 concentration established by every medicine, the multiple hole of each concentration 3, arrange zeroing group and blank group, 96 orifice plate cycle holes add PBS.Cell inoculation adds pastille substratum 100 μ l/ hole after spending the night.
(3) mtt assay measures drug effect: after drug effect 24h/48h, exhaust the pastille nutrient solution in every hole, by new cell culture fluid and the MTT solution for preparing in 10: 1 ratio mix, every hole adds 110 μ l, is placed in after incubator continues to cultivate 4h and takes out, add DMSO after the liquid in the every hole of sucking-off, every hole 150 μ l, on vibrator, after 600r jolting 10min, microplate reader measures OD value corresponding to every hole, take 630nm as reference wavelength, and 570nm place measures OD value.
(4) inhibiting rate of medicine on cell proliferation is calculated: return examination amount effect curve degree of fitting with PASWstatistics18Logit, calculate IC
50value.
Inhibiting rate (%)=(cellular control unit average absorbance value-dosing group cell average absorbance value)/cellular control unit average absorbance value × 100%.
(5) A, B two calculation and evaluation of medicine association index CI: CI=A share IC
50the IC of/alone A
50+ B share IC
50the IC of/alone B
50, CI < 1 works in coordination with, and CI=1 is added, and CI > 1 has nothing to do or antagonism.
(6) data processing: experimental result data Mean ± SD represents, statistical study is carried out in the comparison t inspection between two groups of independent sample means, and assay P < 0.05 is considered to have significant difference between mean.All data all adopt PASWstatistics18 software to process.
Experimental result is in table 4.Result shows that berberinc derivate 54 and Zorubicin coupling can significantly improve the inhibiting rate to MCF-7 cell, when two medicines share under different ratios, coordinate repression is remarkable, and when 24h, berberinc derivate 54 is best with the collaborative inhibition of ratio coupling to MCF-7 cell of 3: 1 with Zorubicin; During drug effect 48h, berberinc derivate 54 is also best with the collaborative inhibition of ratio coupling to MCF-7 cell of 3: 1 with Zorubicin.
Table 4 berberinc derivate 54 and Zorubicin coupling are to the restraining effect of MCF-7 cell
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (9)
1. a berberinc derivate, is characterized in that, described berberinc derivate general structure is:
Wherein R is alkyl, benzyl, substituted benzyl, phenyl, substituted-phenyl, heterocyclic methyl or substituted heterocycle methyl;
Described alkyl is straight or branched alkyl or the cycloalkyl with 1 ~ 20 carbon atom;
The substituting group of described substituted benzyl is positioned at neighbour, between or contraposition, be substituted by monosubstituted or polysubstituted, described substituting group is halogen, or be the straight or branched alkyl of 1 ~ 6 carbon atom, or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, or be methylene-dioxy, or be the allyloxy of 3 ~ 6 carbon atoms, or be cyano group, or be nitro, or be the acyloxy of 1-4 carbon atom, or be amino, or be hydroxyl, or be 1-naphthyl, or be 2-naphthyl, or be phenyl,
Substituting group in described substituted-phenyl is positioned at neighbour, between or contraposition, be substituted by monosubstituted or polysubstituted, described substituting group is halogen, or be the straight or branched alkyl of 1 ~ 6 carbon atom, or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, or be methylene-dioxy, or be the allyloxy of 3 ~ 6 carbon atoms, or be cyano group, or be nitro, or be the acyloxy of 1 ~ 4 carbon atom, or be amino, or be hydroxyl, or be 1-naphthyl, or be 2-naphthyl, or be benzyloxy,
Heterocycle in described heterocyclic methyl or substituted heterocycle methyl is five yuan or hexa-atomic single heterocycles, or be five yuan or hexa-atomic fused heterocycle, described substituting group is benzyloxy, or described substituting group is heterocycle methoxyl group or substituted heterocycle methoxyl group, described heterocycle is five yuan or hexa-atomic single heterocycles and five yuan or hexa-atomic fused heterocycle, substituting group in described substituted heterocycle be positioned at neighbour, or contraposition, be substituted by monosubstituted or polysubstituted; Substituting group in described substituted heterocycle is halogen, or be the straight or branched alkyl of 1 ~ 4 carbon atom, or be the straight or branched alkoxyl group of 1 ~ 4 carbon atom, or be the straight or branched alkyl of 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, or be the straight or branched alkoxyl group with 1 ~ 4 carbon atom that 1 ~ 4 fluorine atom replaces, or be methylene-dioxy; Or for having the allyloxy of 3 ~ 6 carbon atoms; Or be cyano group; Or be nitro; Or be the acyloxy of 1-4 carbon atom; Or be amino; Or be hydroxyl; Or be phenyl; Or be 2-naphthyl; Or be 1-naphthyl; Described five yuan or hexa-atomic single heterocycles and five yuan or hexa-atomic fused heterocycle are selected from as follows: furans, thiophene, pyrroles, pyrazoles, imidazoles, oxazole, thiazole, isoxazole, pyrans, pyridine, pyridazine, pyrimidine, pyrazine, indoles, carbazole, benzoglyoxaline, quinoline, isoquinoline 99.9, pyridine of talking endlessly, purine or 2,3-Dihydrobenzofuranes-6-base.
2. the berberinc derivate according to claims 1, is characterized in that,
Described alkyl is the alkyl with 12 ~ 20 carbon atoms;
Substituting group in described substituted benzyl is the alkyl of 3 ~ 4 carbon atoms, or is the alkyl with 1 ~ 2 carbon atom that 2 ~ 3 fluorine atoms replace, or is the alkoxyl group of 1 ~ 3 carbon atom, or is the alkyl of 1 ~ 2 carbon atom that 1 ~ 4 fluorine atom replaces;
Substituting group in described substituted-phenyl is the alkyl of 3 ~ 4 carbon atoms, or is the alkyl with 1 ~ 2 carbon atom that 2 ~ 3 fluorine atoms replace, or is the alkoxyl group of 1 ~ 3 carbon atom, or is the alkyl of 1 ~ 2 carbon atom that 1 ~ 4 fluorine atom replaces;
Substituting group in described substituted heterocycle methyl is the alkyl of 3 ~ 4 carbon atoms, or is the alkoxyl group of 1 ~ 3 carbon atom, or is the alkyl of 1 ~ 2 carbon atom that 2 ~ 3 fluorine atoms replace, or is the alkyl of 3 ~ 4 carbon atoms that 2 ~ 4 fluorine atoms replace.
3. the berberinc derivate according to claims 1, is characterized in that,
Described alkyl is the alkyl with 13 ~ 18 carbon atoms;
Substituting group in described substituted benzyl is sec.-propyl, or is the tertiary butyl, or is trifluoromethyl, or is methoxyl group, or is oxyethyl group, or is trifluoromethoxy;
Substituting group in described substituted-phenyl is sec.-propyl, or is the tertiary butyl, or is trifluoromethyl, or is methoxyl group, or is oxyethyl group, or is trifluoromethoxy;
Substituting group in described substituted heterocycle methyl is sec.-propyl, or is the tertiary butyl, or is methoxyl group, or is oxyethyl group, or is trifluoromethyl, or is tetrafluoro propoxy-.
4. the arbitrary described berberinc derivate of claims 1-3 is preparing the application in antitumor drug.
5. the preparation method of the arbitrary described berberinc derivate of claims 1-3, is characterized in that, comprise the steps:
The first step: berberine chloride generation demethylating reaction generates chlorination berberrubine;
Second step: chlorination berberrubine is under acid binding agent condition, and generate intermediate product with propargyl chloride generation nucleophilic substitution reaction in solvent, the structural formula of described intermediate product is:
3rd step: the berberinc derivate described in intermediate product and replacement trinitride generation ring-closure reaction generate.
6. the preparation method according to claims 5, is characterized in that,
Described demethylating reaction use solvent is ether, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, DMF or methyl-sulphoxide;
Described nucleophilic substitution reaction use acid binding agent is Trimethylamine 99, triethylamine, pyridine, sodium carbonate, sodium bicarbonate, salt of wormwood, lithium hydroxide, sodium hydroxide or potassium hydroxide, described solvent is methyl alcohol, ethanol, acetonitrile, acetone, ethylene dichloride, methylene dichloride, tetrahydrofuran (THF), dioxane, DMF or methyl-sulphoxide;
Described ring-closure reaction uses solution to be CuSO
45H
2o and xitix sodium water solution, solvent for use is methylene dichloride, dioxane, tetrahydrofuran (THF) or DMF.
7. an antineoplastic composition, is characterized in that, it comprises the arbitrary described berberinc derivate of claims 1-3 and Zorubicin.
8. composition according to claim 7, is characterized in that, described berberinc derivate and Zorubicin mol ratio are: (0.1 ~ 10): 1.
9. composition according to claim 7 is preparing the application in antitumor drug.
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| CN104817556A (en) * | 2015-05-13 | 2015-08-05 | 中南大学 | 9-O-ibuprofen berberine ester compound as well as preparation method and application of 9-O-ibuprofen berberine ester compound |
| CN106928246B (en) * | 2017-03-09 | 2019-04-16 | 北京宜生堂医药科技研究有限公司 | A kind of compound and preparation method thereof and purposes |
| CN108084177B (en) * | 2018-01-23 | 2019-10-08 | 中南大学 | A kind of jamaicin 9- pyrazole derivatives and its preparation and application |
| CN108752404B (en) * | 2018-07-03 | 2019-09-27 | 山东省科学院生物研究所 | A kind of berberine salt derivative and its preparation method and application that triazole is sugar-modified |
| CN112480108A (en) * | 2020-12-25 | 2021-03-12 | 常州方圆制药有限公司 | Preparation method of berberberrubine hydrochloride |
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