CN107417695A - Berbine derivative, its preparation method, pharmaceutical composition and anticancer usage - Google Patents

Berbine derivative, its preparation method, pharmaceutical composition and anticancer usage Download PDF

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CN107417695A
CN107417695A CN201610342195.7A CN201610342195A CN107417695A CN 107417695 A CN107417695 A CN 107417695A CN 201610342195 A CN201610342195 A CN 201610342195A CN 107417695 A CN107417695 A CN 107417695A
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physiologically acceptable
compound
acceptable salt
derivative
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CN107417695B (en
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秦海林
吴练秋
王波
张海婧
张志辉
王文杰
邓安珺
王楠
李志宏
李倩
李想
宋利
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses berbine derivative, its synthetic method and its application in preparing prevention, alleviating and/or treating tumour product.Described berbine derivative is the 12 amino N-1 analog derivatives or its physiologically acceptable salt and 12 N as shown in formula I, the substituted amido N-1 analog derivatives of N bis- or its physiologically acceptable salt and 12 amino jamaicin quaternary ammonium salt derivatives or its physiologically acceptable salt and the substituted amido jamaicin quaternary ammonium salt derivative of 12 N, N bis- or its physiologically acceptable salt as shown in formula II.These dissolubilities of berbine derivative in organic solvent have relatively obtained obvious improvement with raw material berberine chloride quaternary ammonium compound.Growth of the described berbine derivative to tumor cell line has an inhibitory activity, action intensity or apparently higher than jamaicin quaternary ammonium salt raw material, or suitable with positive control drug or higher than positive control, can be used to preparing prevention, alleviate and/or the product for the treatment of tumour.

Description

Berbine derivative, its preparation method, pharmaceutical composition and anticancer usage
Technical field
The present invention using improve the dissolubility of berbine derivative in organic solvent and improve its bioactivity as target, It is related to using common jamaicin quaternary ammonium compound as substrate, is obtained using the structure of modification derivative reaction in organic chemistry 12- amino-N-1 analog derivative or its physiologically acceptable salt, 12-N, bis- substituted amidos of N--N-1 class Derivative or its physiologically acceptable salt, the 12- amino-jamaicin quaternary ammonium salt derivative and substituted amido of 12-N, N- bis--small Bark of a cork tree alkali quaternary ammonium salt derivative, its preparation method and the application in preparing prevention, alleviating and/or treating tumour product.Category doctor Medicine technical field.
Background technology
Various malignant tumours (cancer) are all the major diseases for seriously endangering human health, are caused to patient and its family members huge On big body and it is spiritual pain and pressure economically.Due to so far also without the side of particularly effective treating cancer Method, clinically often it is forced to perform the operation, the means of radiation and chemotherapy combine as first-line treatment scheme and treat patient. Prevention to cancer at present, alleviation and treatment are still the very arduous research work that human society must face.Opponent Art, the treatment method of radiation and chemotherapy are evaluated, and surgical method that is fearful, dangerous and having pain, or radioactivity is treated Method (using radiant, if careless slightly, may influence important organ) is compared, if can be using only the various medicines of amic therapy method Thing suppresses the development of cancer, or conquers cancer, then and it is a big Gospel for patients, and the great body of medical science progress It is existing.Obviously can be more satisfactory with medicine treating cancer.Therefore, find has efficient therapeutic action to various malignant tumours And have great importance in the chemicals that there is feature as less toxic as possible at this stage in pharmaceutical technology field.Scientist at present Have found that some have the antineoplastic of certain curative effect, be exactly these medicines make the mean survival time (MST) of Children with Acute Leukemia by Extend to more than 5 years within past 2~3 months, be obviously prolonged the life of many patients with advanced cancer.The depth of novel anti-tumor medicine Entering research has made the chemotherapy of tumour turn into an important subject, and Internal Medicine-Oncology is learnt to be born.Elion and Nobel Prize in medicine was awarded in 1988 in Hitchings, showed that the historical achievements of antineoplastic are universally acknowledged.Certainly, This research for being not intended to antineoplastic no longer needs to develop, and conversely it is faced with formidable challenges, and here it is most common realities Body knurl such as lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer and cancer of pancreas etc. also lack active drug, and many antineoplastics are facing Drug resistance is produced in bed application process.That is, up to now, also come out without particularly effective cancer therapy drug.Therefore, grind Hair PTS is always the important topic in drug research field.
Berbine derivative is the three class benzylisoquinoline types for referring to the following rough sort in field of natural organic chemistry Alkaloid：(1) parent nucleus is 6,8,13,13a- tetrahydrochysene -5H- isoquinolin simultaneously [3,2-a] isoquinolin (6,8,13,13a- Tetrahydro-5H-isoquinolino [3,2-a] isoquinoline) the benzylisoquinoline type alkaloid of type and its various Salt (1-1), (2) parent nucleus are 6,8- dihydro -5H- isoquinolin simultaneously [3,2-a] isoquinolin (6,8-dihydro-5H- Isoquinolino [3,2-a] isoquinoline) type benzylisoquinoline type alkaloid and its various salt (1-2), (3) 6,8- 7,8- inferior amine salts (the 7,8-imine salt of6,8-dihydro-5H- of dihydro -5H- isoquinolin simultaneously [3,2-a] isoquinolin Isoquinolino [3,2-a] isoquinoline) type benzylisoquinoline quaternary alkaloid (1-3)；The class benzyl of the above three Base isoquinoline type alkaloid mother nucleus structure is shown in formula 1.Part berbine alkaloid has than more rich natural resources.Jamaicin Alkaloid is in Ranunculaceae (Ran μ nc μ laceae), Rutaceae (R μ taceae), Berberidaceae (Berberidaceae), Papaveraceae (Papaveraceae), it is distributed in Menispermaceae (Menispermaceae), Rhamnaceae (Rhamnaceae) Deng Duo sections plant；Chlorine Change jamaicin quaternary ammonium salt to have been achieved with scale as clinical application, its chemicals and bulk drug and be combined to and prepare.
Three class mother nucleus structures of the berbine alkaloid of formula 1
At present, the pharmacological activity of berbine alkaloid is had been carried out widely studying and finding that berbine is given birth to Alkaloids and its derivative have extensive pharmacological activity, including antitumor activity.However, up to the present, it has been found that it is antitumor Active spectrum of berberine compounds still has several drawbacks in terms of druggability, such as antitumor activity and specificity is poor, biological profit Expenditure is low etc., and especially as bioactive substance, the solubility property of most of natural jamaicin quaternary ammonium compounds is very poor, It has impact on its druggability.Therefore, continue to find using pharmaceutical chemical research method and there is pharmacological action and high specificity, biology Availability is high, solubility property is good, chemical property is stable and the active berbine derivative of suitable actual production is (including antitumor Compound) there is significant necessity.The present invention is according to the architectural feature of jamaicin quaternary ammonium salt alkaloid and in jamaicin 12 of class compound introducing N, the present Research that the compounds of the substituted amido substituents of N- bis- has not been reported are small by application The nitrification of the reduction reaction of bark of a cork tree alkali quaternary ammonium compound, jamaicin quaternary ammonium compound or N-1 class compound is anti- Nitros successfully should be introduced at 12 of berbine alkaloid parent, by the way that nitro is reduced into amino and by jamaicin quaternary ammonium The parent nucleus of salt compounds is reduced into N-1 class parent nucleus and obtains 12- amino-N-1 analog derivative.Using aldehyde Reductive amination process obtain 12-N, bis- substituted amidos of N--N-1 analog derivative, pass through 12- amino-N-1 The oxidation reaction of bis- substituted amidos of analog derivative and 12-N, N--N-1 analog derivative successfully obtains 12- amino-barberry Bis- substituted amidos of alkali quaternary ammonium salt derivative and 12-N, N--jamaicin quaternary ammonium salt derivative.Research shows, these jamaicins The dissolubility of analog derivative in organic solvent has relatively obtained significantly changing with raw material berberine chloride quaternary ammonium compound It is kind；The type compound has a preferable tumor cell line growth inhibitory activity, action intensity or apparently higher than jamaicin quaternary ammonium salt Raw material, or it is suitable with positive control drug or higher than positive control.Therefore the compounds of this invention is swollen in prevention, alleviation and/or treatment The application aspect of knurl is the compound of great potential.
The content of the invention
Present invention solves the technical problem that it is to improve berbine derivative dissolubility in organic solvent and raising Its bioactivity, there is provided a major class berbine derivative or its physiologically acceptable salt, its preparation method, pharmaceutical composition With its purposes in antitumor product is prepared.
The present invention is with jamaicin quaternary ammonium salt (including berberine chloride quaternary ammonium salt, Coptisine chloride quaternary ammonium salt, chlorination bar horse The various jamaicin quaternary ammonium salts such as spit of fland quaternary ammonium salt) alkaloid is raw material, had using pharmaceutical chemical research theory and strategy synthesis There is the berbine derivative of structure novel features；These berberinc derivates can also use appropriate raw material, pass through other conjunctions Prepared into route.The present invention is to improve berbine derivative dissolubility in organic solvent, to improve it thin to tumour The inhibitory activity of born of the same parents' strain growth is physics and chemistry and biological indicator, it is expected to reach and improves antitumor activity and pharmacological action specificity simultaneously Improve the goal of the invention of other druggability features such as bioavilability.
In order to solve the above technical problems, the invention provides following technical scheme：
First aspect present invention provide the amino of the 12- as shown in formula I-N-1 analog derivative or its physiologically Bis- substituted amidos of acceptable salt and 12-N, N--N-1 analog derivative or its physiologically acceptable salt and such as formula 12- amino-jamaicin quaternary ammonium salt derivative or its physiologically acceptable substituted amido of salt and 12-N, N- bis- shown in II- Jamaicin quaternary ammonium salt derivative or its physiologically acceptable salt, chemical structural formula is as shown in following formula I and II：
In formula I, R2、R3It is each independently selected from H, OH or C1-4 alkoxy or R2、R3It is connected to become OCH2O；R9、R10 It is each independently selected from H, OH or C2-4 alkoxy or R9、R10It is connected to become OCH2O；Two R12It is each independently selected from H, formula For CnH2n+1Or CmH2m-1Straight or branched aliphatic group or two R12Connect into carbocyclic ring, n is selected from 1,2,3,4,5,6,7,8,9, 10th, 11,12,13, m is selected from 2,3,4,5,6,7,8,9,10,11,12,13, the alkylene that carbocyclic ring is connected with nitrogen-atoms (two R12It is common to represent) it is the straight chain alkylene group containing 4-8 carbon atom；Physiologically acceptable salt include halogen acid salt, sulfate, Phosphate, tartrate, citrate, maleate, fumarate, malate, oxalates, benzene sulfonate.
In formula II, R2、R3It is each independently selected from H, OH or C1-4 alkoxy or R2、R3It is connected to become OCH2O；R9、 R10It is each independently selected from H, OH or C2-4 alkoxy or R9、R10It is connected to become OCH2O；Two R12It is each independently selected from H, leads to Formula is CnH2n+1Or CmH2m-1Straight or branched aliphatic group or two R12Connect into carbocyclic ring, n is selected from 1,2,3,4,5,6,7,8, 9th, 10,11,12,13, m is selected from 2,3,4,5,6,7,8,9,10,11,12,13, the alkylene (two that carbocyclic ring is connected with nitrogen-atoms Individual R12It is common to represent) it is the straight chain alkylene group containing 4-8 carbon atom；X-For acid ion.
Preferable X-It is derived from Cl-、Br-、I-、HSO4 -、H2PO4 -, bitartrate, dihydrogen citrate root, maleic acid hydrogen radical, Fumaric acid hydrogen radical, malic acid hydrogen radical, oxalic acid hydrogen radical, benzene sulfonic acid root.
Wherein, preferable C1-4 alkoxies are selected from methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygen in above-mentioned formula I and II Base, butoxy；Preferable C2-4 alkoxies are selected from ethyoxyl, propoxyl group, isopropoxy, butoxy；Preferable straight chain alkylene group Selected from butylidene, pentylidene, hexylidene, heptamethylene, octamethylene.
Most preferably compound of the invention is selected from following heterogeneous compound group：
In berbine derivative or its physiologically acceptable salt shown in formula I, following group preferably is selected from：
In berbine derivative or its physiologically acceptable salt shown in formula II, following group preferably is selected from：
The physiologically acceptable salt includes inorganic acid salt or acylate.
Preferable physiologically acceptable salt include its halogen acid salt, sulfate, phosphate, tartrate, citrate, Maleate, fumarate, malate, oxalates, benzene sulfonate.
Second aspect of the present invention provides the preparation method of the compounds of this invention：
Described 12- amino-N-1 analog derivative, 12-N, bis- substituted amidos of N--N-1 analog derivative And bis- substituted amidos of 12-N, N--jamaicin quaternary ammonium salt derivative can pass through following Scheme 1 or Scheme2 synthetic route Synthesize (specific synthesis condition is shown in embodiment)：
Scheme 1.12- amino-N-1 analog derivative, 12-N, bis- substituted amidos of N--N-1 class are spread out The synthesis of biology and bis- substituted amidos of 12-N, N--jamaicin quaternary ammonium salt derivative
Scheme 2.12- amino-N-1 analog derivative, 12-N, bis- substituted amidos of N--N-1 class are spread out The synthesis of biology and bis- substituted amidos of 12-N, N--jamaicin quaternary ammonium salt derivative
Described 12- amino-jamaicin quaternary ammonium salt derivative can synthesize (tool by following Scheme3 synthetic method Body synthesis condition is shown in embodiment)：
The synthesis of Scheme 3.12- amino-jamaicin quaternary ammonium salt derivative
Third aspect present invention further relates to be used as active ingredient using berbine derivative described in first aspect present invention Pharmaceutical composition.The pharmaceutical composition can be prepared according to method well known in the art.Can by by the compounds of this invention with it is a kind of Or a variety of pharmaceutically acceptable solids or liquid excipient and/or assistant agent combine, be made used suitable for human or animal it is any Formulation.Content of the compounds of this invention in its pharmaceutical composition is usually 0.1-99.9% (W/W).
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and method of administration can be enteron aisle Or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including O/W types, w/o type and emulsion), supensoid agent, injection (including liquid drugs injection, powder-injection And transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
The compounds of this invention can be made ordinary preparation, may be made as sustained release preparation, controlled release preparation, targeting preparation and various Particulate delivery system.
In order to which the compounds of this invention is made into tablet, various excipient well known in the art can be widely used, including it is dilute Release agent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, breast Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Ripple nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, sodium acid carbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or it is double Synusia and multilayer tablet.
, can be by active ingredient (the compounds of this invention) and diluent, glidant in order to which administration unit is made into capsule Mixing, mixture is placed directly within hard shell capsules or soft capsule.Also can by active ingredient (the compounds of this invention) first with diluent, Particle or micropill is made in binder, disintegrant, then is placed in hard shell capsules or soft capsule.For preparing the compounds of this invention tablet Each diluent, binder, wetting agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For the compounds of this invention is made into injection, water, ethanol, isopropanol, propane diols or their mixture can be used Make solvent and add appropriate solubilizer commonly used in the art, cosolvent, pH adjusting agent, osmotic pressure regulator.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjusting agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Injection, it can also add mannitol, glucose etc. and be used as proppant.
In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation Agent.
To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition known can be given with any Prescription method is administered.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or treated tumour The individual instances of degree, patient or animal, method of administration and formulation etc. can have large-scale change.In general, the present inventionization The daily Suitable dosage ranges of compound are 0.001-150mg/Kg body weight, preferably 0.1-100mg/Kg body weight, are more preferably 1-60mg/Kg body weight, most preferably 2-30mg/Kg body weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage lists Position administration, this depends on the clinical experience of doctor and including the dosage regimen with other treatment means.
The compound or composition of the present invention can individually be taken, or merge use with other treatment medicine or symptomatic drugs. When the compound of the present invention exists with other medicines to act synergistically, its dosage should be adjusted according to actual conditions.
Fourth aspect present invention provide berbine derivative described in first aspect and its physiologically acceptable salt with And application of the pharmaceutical composition described in the third aspect in preparing prevention, alleviating and/or treating tumour product.Especially pre- Application in anti-, alleviation and/or treatment colon cancer or breast cancer product.Wherein, described product includes medicine.
Advantageous effects
The compounds of this invention or its dissolubility of physiologically acceptable salt in organic solvent and raw material berberine chloride Quaternary ammonium compound has relatively obtained obvious improvement.The compounds of this invention or its physiologically acceptable salt have tumour thin Born of the same parents' strain growth inhibitory activity, action intensity or apparently higher than jamaicin quaternary ammonium salt raw material, or it is suitable with positive control drug or be higher than Positive control.Parallel test and control activity are carried out with berberine chloride quaternary ammonium salt, the most reactive compounds of the present invention suppress swollen The activity of tumor cell strain growth is improved, the IC of the strong the compounds of this invention of activity50Value even with berberine chloride quaternary ammonium The IC of salt50Value, which compares, to be improved more than 2 orders of magnitude.Parallel test and control activity are carried out with positive drug taxol, part is originally The action intensity that invention reactive compound suppresses tumor cell line growth is also significantly greater than taxol, IC50Value and taxol IC50Value compares, and activity can improve 1 order of magnitude (with the IC of positive drug taxol50It is worth and is calculated for reference standard, it is most strongly active Compound suppresses the IC of tumor cell line growth50Value maximum can be less than positive control several times), or action intensity and positive control drug Quite or higher than positive control.Other compounds show that the growth inhibition of certain tumor cell line is lived in parallel test Property.Parallel test and control activity are carried out with positive drug 5 FU 5 fluorouracil, part reactive compound of the present invention suppresses tumour cell The action intensity of strain growth is significantly higher than 5 FU 5 fluorouracil.
The present invention has obtained having no the new of document report by carrying out structural modification to jamaicin quaternary ammonium compound 12- amino N-1s analog derivative, the substituted amido N-1 analog derivative of 12-N, N- bis-, 12- amino jamaicin seasons Ammonium salt analog derivative and the substituted amido jamaicin quaternary ammonium salt derivative of 12-N, N- bis-, its key character be, these jamaicins The fat-soluble enhancing of analog derivative, dissolubility in organic solvent is compared with raw material berberine chloride quaternary ammonium compound Obvious improvement has been arrived, has made them more soluble in some solvents that substrate jamaicin quaternary ammonium compound not readily dissolves； Pass through pharmacodynamic experiment, it was confirmed that these new berbine derivatives have tumor cell line growth inhibitory activity, portion respectively Point compound activity is or suitable with positive control drug or higher than positive control apparently higher than substrate jamaicin quaternary ammonium salt, pre- It is the noval chemical compound that there is medical value pole in terms of the disease such as anti-, alleviation and/or treating cancer.
Embodiment
Limitation is not of the invention in any way for the embodiment of the present invention.
In the preparation technology and Structural Identification data of reactive compound of the present invention, wherein compound number and invention of the present invention Particular compound numbering in appearance is corresponding.
The preparation of embodiment (1) compound 1
Berberine chloride quaternary ammonium salt (20g, 53.84mmol) is weighed in reaction bulb, glacial acetic acid (250ml) is added, is placed in In ice-water bath, NaNO is slowly added in batches2(18.6g, 269.57mmol), instill dense HNO3(30ml), after being added dropwise, frozen water 5min is stirred under bath, subsequent 50 DEG C are heated to reflux 1h, and reaction is complete.Add water (200ml) into reaction solution, use chloroform/methanol (v/v=10:1) extract, by obtained organic phase be evaporated under reduced pressure, remove organic solvent, obtained crude product through silica gel column chromatography [with Chloroform/methanol=20:1 (v/v) is eluant, eluent] purify to obtain chlorination 12- nitro jamaicins, red solid 9.65g, yield 43%.1H NMR:(400MHz,DMSO-d6) δ 3.23 (t, J=6Hz, 2H, Ar-CH2CH2N),4.16(s,3H,OCH3),4.28(s,3H, OCH3), 4.96 (t, J=6Hz, 2H, Ar-CH2CH2N),6.20(s,2H,OCH2O),7.13(s,1H,Ar-H),7.83(s,1H, Ar-H),8.89(s,1H,Ar-H),9.05(s,1H,Ar-H),10.12(s,1H,Ar-H)；13C NMR:(100MHz,DMSO- d6)δ26.02,55.18,57.67,62.56,102.22,105.70,108.41,115.38,119.90,120.66,124.43, 125.18,131.71,138.90,139.94,147.19,147.86,147.90,149.65,150.51；ESI-MS(m/z): 381.2[M-Cl]+.Chlorination 12- nitros jamaicin (300mg, 0.72mmol) is weighed in reaction bulb, adds THF/ methanol (v/v =1:1,12ml) NiCl, is then added2·6H2O (855.7mg, 3.6mmol), then NaBH is added portionwise4(272mg, 7.2mmol), 66 DEG C are heated to reflux, and 20min reactions are complete.Reaction solution filters, with chloroform filter cake to without obvious color, Liquid is evaporated off in filtrate decompression, is dissolved with dichloromethane, dichloromethane solution is simultaneously washed with water 3 times, with saturated common salt water washing 1 It is secondary, dried with anhydrous magnesium sulfate.12- amino N-1s, light brown will be obtained after dried dichloromethane solution evaporated under reduced pressure Color solid 213mg, yield 83.5%.1H NMR:(400MHz,DMSO-d6)δ2.07-3.34(m,8H),3.59(s,3H, OCH3),3.69(s,3H,OCH3), 3.96 (d, J=15.2Hz, 1H), 4.68 (s, 2H, Ar-NH2),5.94,5.96(2×br s,2H,OCH2O),6.24(s,1H,Ar-H),6.66(s,1H,Ar-H),6.96(s,1H,Ar-H)；13C NMR:(100MHz, DMSO-d6)δ28.96,31.63,50.95,53.67,55.29,59.09,59.72,97.39,100.52,105.90, 108.00,110.63,127.40,128.07,131.40,135.26,142.24,145.36,145.64,150.08；ESI-MS (m/z):355.3[M+H]+.12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloro Methane (8ml), then sequentially add 37% formalin (186 μ l, 2.48mmol), sodium triacetoxy borohydride (597mg, 2.82mmol), HOAc (16 drop), react complete after stirring 2h at room temperature.Saturated sodium bicarbonate is added in reaction solution After being adjusted to pH=8,20min is stirred at room temperature, is then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, saturation food Salt solution is washed 1 time, and anhydrous magnesium sulfate is dried, and is filtered, is removed organic phase under reduced pressure, crude residue is through silica gel column chromatography [with dichloro Methane/methanol=80:1 (v/v) is eluant, eluent] purify to obtain compound 1, hazel-color solid 205mg, yield 95%.1H NMR: (400MHz,DMSO-d6) δ 2.32-3.41 (m, 8H), 2.59 (s, 6H, 2 × NCH3),3.68(s,3H,OCH3),3.79(s,3H, OCH3), 4.04 (d, J=16Hz, 1H), 5.94,5.96 (2 × br s, 2H, OCH2O),6.65(s,1H,Ar-H),6.68(s, 1H,Ar-H),6.86(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ29.08,33.45,44.08(2×C), 50.54,53.80,55.67,58.96,59.51,100.57,102.32,105.77,108.11,121.61,127.63, 128.89,131.05,140.06,145.46,145.70,148.09,149.84；ESI-MS(m/z):383.4[M+H]+。
The preparation of embodiment (2) compound 2
12- amino N-1 (250mg, 0.705mmol) is weighed in reaction bulb, adds dichloromethane (10ml), Then sequentially add 40% acetaldehyde solution (313 μ l, 3.1mmol), sodium triacetoxy borohydride (747mg, 3.525mmol), HOAc (18 drop), react complete after stirring 2h at room temperature.Saturated sodium bicarbonate is added in reaction solution and is adjusted to pH After=8,20min is stirred at room temperature, is then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, saturated aqueous common salt water Wash 1 time, anhydrous magnesium sulfate is dried, and is filtered, is removed organic phase under reduced pressure, crude residue is through silica gel column chromatography [with dichloromethane/first Alcohol=80:1 (v/v) is eluant, eluent] purify to obtain compound 2, hazel-color solid 277mg, yield 96%.1H NMR:(400MHz, CDCl3) (t, J=7.2Hz, 6H, 2 × NCH of δ 0.982CH3), 2.47-2.68 (m, 3H), 2.94 (q, J=7.2Hz, 4H, 2 × NCH2CH3),3.11-3.21(m,2H),3.41-3.56(m,3H),3.82(s,3H,OCH3),3.84(s,3H,OCH3),4.23 (d, J=16Hz, 1H), 5.93 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.61(s,1H,Ar-H),6.82(s,1H,Ar- H)；13C NMR:(100MHz,CDCl3)δ12.76(2×C),29.71,33.76,47.89(2×C),51.60,54.53, 56.09,59.91,60.33,100.89,105.68,105.97,108.50,125.29,127.93,129.02,131.41, 141.47,145.51,145.99,146.23,150.29；ESI-MS(m/z):411.3[M+H]+。
The preparation of embodiment (3) compound 3
12- amino N-1 (300mg, 0.846mmol) is weighed in reaction bulb, adds dichloromethane (10ml), Then sequentially add positive propionic aldehyde (147.4 μ l, 2.03mmol), sodium triacetoxy borohydride (537.8 mg, 2.538mmol), HOAc (12 drop), reacts complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, room temperature Lower stirring 20min, is then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous Magnesium sulfate is dried, and is filtered, is removed organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) it is eluant, eluent] purify to obtain compound 3, hazel-color solid 200mg, yield 54%.1H NMR:(400MHz,CDCl3)δ 0.83 (t, J=7.2Hz, 2 × NCH2CH2CH3), 1.43 (m, 4H), 2.51 (dd, J=10.0,14.8Hz, 1H), 2.61 (d, J =14.4Hz, 1H), 2.67 (ov, 1H), 2.82 (m, 4H), 3.13 (ov, 1H), 3.19 (ov, 1H), 3.40 (d, J=10.0Hz, 1H), 3.49 (m, 1H), 3.53 (d, J=16.0Hz, 1H), 3.82 (s, 3H, OCH3),3.83(s,3H,-OCH3),4.23(d,J =16.0Hz, 1H), 5.92,5.93 (2 × br s, 2H, OCH2O),6.60(s,1H),6.62(s,1H),6.78(s,1H)；13C NMR:(100MHz,CDCl3-d1)δ11.92(2×C),20.53(2×C),29.73,33.79,51.64,54.57,56.11(3 ×C),59.93,60.32,100.88,105.71,105.86,108.51,124.97,127.96,128.98,131.39, 141.38,145.98,146.26(2×C),150.28；ESI-MS(m/z):439.3[M+H]+。
The preparation of embodiment (4) compound 4
12- amino N-1 (250mg, 0.705mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-butanal (152 μ l, 1.69mmol), sodium triacetoxy borohydride (448mg, 2.115mmol), HOAc (10 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 4, hazel-color solid 287mg, yield 87.2%.1H NMR:(400MHz,DMSO-d6)δ0.83 (t, J=7.2Hz, 6H, 2 × NCH2CH2CH2CH3), 1.21-1.40 (m, 8H), 2.24-3.39 (m, 8H), 2.83 (t, J= 6.8Hz,4H),3.70(s,3H,OCH3),3.76(s,3H,OCH3), 4.04 (d, J=16Hz, 1H), 5.96 (s, 2H, OCH2O), 6.68(s,1H,Ar-H),6.73(br s,2H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ13.92(2×C),19.93 (2×C),28.98,29.12(2×C),33.34,50.63,53.36(2×C),53.71,55.73,58.97,59.51, 100.62,105.17,105.55,108.20,124.41,127.63,128.58,131.10,140.65,145.47,145.55, 145.73,149.85；ESI-MS(m/z):467.3[M+H]+。
The preparation of embodiment (5) compound 5
12- amino N-1 (250mg, 0.705mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add valeraldehyde (180 μ l, 1.69mmol), sodium triacetoxy borohydride (448mg, 2.115mmol), HOAc (10 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 5, pale brown oil thing 320mg, yield 91.8%.1H NMR:(400MHz,CDCl3)δ0.85 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH3),1.24(m,8H),1.40(m,4H),2.46-2.68(m,3H),2.85 (t, J=7.2Hz, 4H), 3.11-3.20 (m, 2H), 3.39-3.55 (m, 3H), 3.83 (br s, 6H, 2 × OCH3),4.23(d, J=15.6Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.62(s,1H,Ar-H),6.79(s,1H,Ar- H)；13C NMR:(100MHz,CDCl3)δ14.30(2×C),22.74(2×C),27.06(2×C),29.79,33.79, 51.67,54.19(2×C),54.55,56.09(3×C),59.91,60.33,100.89,105.65,105.88,108.50, 124.94,127.93,128.95,131.41,141.33,145.98,146.29,146.29,150.26；ESI-MS(m/z): 495.4[M+H]+。
The preparation of embodiment (6) compound 6
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-hexyl aldehyde (164 μ l, 1.354mmol), sodium triacetoxy borohydride (358mg, 1.692mmol), HOAc (10 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 6, pale brown oil thing 230mg, yield 78%.1H NMR:(400MHz,CDCl3)δ0.85(t,J =6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH3),1.23(m,12H),1.40(m,4H),2.46-2.68(m,3H),2.85 (t, J=7.2Hz, 4H), 3.12-3.20 (m, 2H), 3.39-3.56 (m, 3H), 3.82 (s, 3H, OCH3),3.83(s,3H, OCH3), 4.23 (d, J=15.6Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.62(s,1H,Ar-H), 6.79(s,1H,Ar-H)；13C NMR:(100MHz,CDCl3-d1) δ 14.17 (2 × C), 22.84 (2 × C), 27.22~31.88 (7×C),33.77,51.63,54.21(2×C),54.52,56.08,59.89,60.32,100.88,105.64,105.87, 108.48,124.88,127.89,128.92,131.38,141.31,145.99,146.29,146.29,150.25；ESI-MS (m/z):523.4[M+H]+。
The preparation of embodiment (7) compound 7
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-Heptaldehyde (189 μ l, 1.354mmol), sodium triacetoxy borohydride (358mg, 1.692mmol), HOAc (10 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 7, pale brown oil thing 272mg, yield 87.6%.1H NMR:(400MHz,CDCl3)δ0.85 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH3),1.23(m,16H),1.40(m,4H),2.46-2.68(m, 3H), 2.85 (t, J=7.2Hz, 4H), 3.12-3.21 (m, 2H), 3.39-3.55 (m, 3H), 3.82 (s, 3H, OCH3),3.83 (s,3H,OCH3), 4.23 (d, J=16Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.62(s,1H,Ar- H),6.79(s,1H,Ar-H)；13C NMR:(100MHz,CDCl3) δ 14.20 (2 × C), 22.75 (2 × C), 27.39~32.05 (9×C),33.74,51.63,54.21(2×C),54.51,56.08,59.89,60.32,100.88,105.65,105.87, 108.48,124.90,127.88,128.89,131.36,141.32,146.01,146.30,146.30,150.26；ESI-MS (m/z):551.4[M+H]+。
The preparation of embodiment (8) compound 8
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-octaldehyde (300 μ l, 1.92mmol), sodium triacetoxy borohydride (478mg, 2.256mmol), HOAc (13 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 8, pale brown oil thing 290mg, yield 88.8%.1H NMR:(400MHz,CDCl3)δ0.85 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH3),1.23(m,20H),1.40(m,4H),2.46-2.68(m, 3H), 2.85 (t, J=7.2Hz, 4H), 3.12-3.21 (m, 2H), 3.39-3.55 (m, 3H), 3.82 (s, 3H, OCH3),3.83 (s,3H,OCH3), 4.23 (d, J=16Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.61(s,1H,Ar- H),6.78(s,1H,Ar-H)；13C NMR:(150MHz,CDCl3) δ 14.23 (2 × C), 22.78 (2 × C), 27.39~31.98 (11×C),33.76,51.65,54.23(2×C),54.53,56.10,59.91,60.34,100.89,105.68,105.88, 108.49,124.92,127.89,128.93,131.39,141.33,146.01,146.31,146.31,150.27；ESI-MS (m/z):579.4[M+H]+。
The preparation of embodiment (9) compound 9
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-nonyl aldehyde (330 μ l, 1.92mmol), sodium triacetoxy borohydride (478mg, 2.256mmol), HOAc (13 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 9, pale brown oil thing 303mg, yield 88.5%.1H NMR:(400MHz,CDCl3)δ0.86 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH3),1.23(m,24H),1.39(m,4H),2.46-2.68 (m, 3H), 2.85 (t, J=7.2Hz, 4H), 3.12-3.20 (m, 2H), 3.39-3.55 (m, 3H), 3.82 (s, 3H, OCH3), 3.83(s,3H,OCH3), 4.23 (d, J=15.6Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.61(s, 1H,Ar-H),6.79(s,1H,Ar-H)；13C NMR:(100MHz,CDCl3)δ14.25(2×C),22.80(2×C),27.38 ~32.00 (13 × C), 33.75,51.65,54.22 (2 × C), 54.53,56.08,59.90,60.32,100.87,105.65, 105.88,108.48,124.91,127.89,128.91,131.38,141.32,146.00,146.29,146.30,150.25； ESI-MS(m/z):607.5[M+H]+。
The preparation of embodiment (10) compound 10
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-capric aldehyde (362 μ l, 1.92mmol), sodium triacetoxy borohydride (478mg, 2.256mmol), HOAc (13 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 10, pale brown oil thing 323mg, yield 90%.1H NMR:(400MHz,CDCl3-)δ0.87 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),1.23(m,28H),1.39(m,4H),2.46- 2.68 (m, 3H), 2.85 (t, J=7.2Hz, 4H), 3.12-3.20 (m, 2H), 3.39-3.55 (m, 3H), 3.82 (s, 3H, OCH3),3.83(s,3H,OCH3), 4.23 (d, J=16Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H),6.61 (s,1H,Ar-H),6.79(s,1H,Ar-H)；13C NMR:(100MHz,CDCl3)δ14.25(2×C),22.82(2×C), 27.38~32.04 (15 × C), 33.77,51.66,54.21 (2 × C), 54.55,56.08,59.91,60.32,100.87, 105.65,105.88,108.49,124.92,127.90,128.93,131.40,141.32,145.99,146.30,146.30, 150.25；ESI-MS(m/z):635.5[M+H]+。
The preparation of embodiment (11) compound 11
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add n-undecylic aldehyde (393 μ l, 1.92mmol), sodium triacetoxy borohydride (478mg, 2.256mmol), HOAc (13 drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min is mixed, is then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous slufuric acid Magnesium is dried, and is filtered, is removed organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1(v/v) For eluant, eluent] purify to obtain compound 11, pale brown oil thing 344mg, yield 92%.1H NMR:(400MHz,CDCl3)δ0.87 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),1.23(m,32H),1.39(m,4H), 2.45-2.68 (m, 3H), 2.85 (t, J=7.2Hz, 4H), 3.12-3.20 (m, 2H), 3.38-3.55 (m, 3H), 3.82 (s, 3H,OCH3),3.83(s,3H,OCH3), 4.23 (d, J=16Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar-H), 6.61(s,1H,Ar-H),6.78(s,1H,Ar-H)；13C NMR:(100MHz,CDCl3)δ14.27(2×C),22.83(2× ), C 27.39~32.06 (17 × C), 33.37,51.67,54.22 (2 × C), 54.55,56.09,59.92,60.34, 100.88,105.66,105.89,108.50,124.93,127.90,128.95,131.41,141.33,145.99,146.30, 146.30,150.27；ESI-MS(m/z):663.6[M+H]+。
The preparation of embodiment (12) compound 12
12- amino N-1 (200mg, 0.564mmol) is weighed in reaction bulb, adds dichloromethane (8ml), with After sequentially add positive lauric aldehyde (300 μ l, 1.35mmol), sodium triacetoxy borohydride (358mg, 1.69mmol), HOAc (10 Drop), react complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, stir at room temperature 20min, then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous magnesium sulfate Dry, filter, remove organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) be Eluant, eluent] purify to obtain compound 12, pale brown oil thing 330mg, yield 84.7%.1H NMR:(400MHz,CDCl3)δ0.87 (t, J=6.8Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),1.23(m,36H),1.40(m,4H), 2.45-2.68 (m, 3H), 2.85 (t, J=7.2Hz, 4H), 3.11-3.21 (m, 2H), 3.39-3.55 (m, 3H), 3.82 (s, 3H,OCH3),3.83(s,3H,OCH3), 4.23 (d, J=15.6Hz, 1H), 5.92 (s, 2H, OCH2O),6.60(s,1H,Ar- H),6.61(s,1H,Ar-H),6.78(s,1H,Ar-H)；13C NMR:(100MHz,CDCl3)δ14.27(2×C),22.83(2 × C), 27.39~32.06 (19 × C), 33.73,51.63,54.22 (2 × C), 54.52,56.09,59.90,60.33, 100.88,105.66,105.89,108.50,124.91,127.89,128.90,131.37,141.28,146.00,146.30, 146.30,150.26；ESI-MS(m/z):691.6[M+H]+。
The preparation of embodiment (13) compound 13
12- amino N-1 (250mg, 0.706mmol) is weighed in reaction bulb, adds dichloromethane (40ml), Then sequentially add glutaraldehyde (504 μ l, 2.824mmol), sodium triacetoxy borohydride (657.5mg, 3.106mmol), HOAc (15 drop), reacts complete after stirring 2h at room temperature.After addition saturated sodium bicarbonate is adjusted to pH=8 in reaction solution, room temperature Lower stirring 20min, is then extracted with dichloromethane；Dichloromethane extract is washed with water 3 times, and saturated aqueous common salt is washed 1 time, anhydrous Magnesium sulfate is dried, and is filtered, is removed organic phase under reduced pressure, crude residue is through silica gel column chromatography [with methylene chloride/methanol=80:1 (v/v) it is eluant, eluent] purify to obtain compound 13, pale brown oil thing 265mg, yield 89%.1H NMR:(400MHz,DMSO- d6)δ1.52(m,2H),1.63(m,4H),2.26-2.46(m,2H),2.59-2.65(m,3H),2.84-2.95(m,3H), 3.08(m,1H),3.28-3.40(m,3H),3.68(s,3H,OCH3),3.78(s,3H,OCH3), 4.04 (d, J=16Hz, 1H), 5.95,5.97(2×br s,2H,OCH2O),6.61(s,1H,Ar-H),6.68(s,1H,Ar-H),6.84(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ23.95,26.25(2×C),29.07,32.91,50.54,52.91(2×C), 53.76,55.63,58.88,59.50,100.57,102.76,105.46,108.11,121.91,127.67,128.78, 131.11,140.13,145.47,145.73,148.01,149.90。
The preparation of embodiment (14) compound 15
Weigh Compound 1 (185mg, 0.484mmol) is in reaction bulb, after adding dichloromethane (4ml) dissolving, then will DDQ dichloromethane solution (220mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Reaction solution is concentrated, the 10%HCl aqueous solution (8ml) is added in residue, 1h is stirred at room temperature, then in ice-water bath Under the conditions of with the NaOH aqueous solution be adjusted to alkalescence, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is used Water washing 3 times, with saturated aqueous common salt wash 1 time, dried with anhydrous magnesium sulfate, filter, filtrate through organic phase is evaporated off, Obtain crude residue.Crude product is through silica gel column chromatography [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 15, red solid 38mg, yield 19%.1H NMR:(400MHz,DMSO-d6)δ2.95(s,6H,2×NCH3), 3.20 (t, J= 6Hz,2H,ArCH2CH2N),4.00(s,3H,OCH3),4.09(s,3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N), 6.17(s,2H,OCH2O),7.09(s,1H,Ar-H),7.56(s,1H,Ar-H),7.87(s,1H,Ar-H),8.59(s,1H, Ar-H),9.81(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ26.40,44.83(2×C),55.10,56.95, 61.90,102.05,105.82,108.40,114.15,116.65,120.56,122.14,127.61,130.71,136.75, 138.24,145.49,147.57,147.76,149.77,150.89；ESI-MS(m/z):379.3[M-Cl]+。
The preparation of embodiment (15) compound 16
Weigh Compound 2 (257mg, 0.626mmol) is in reaction bulb, after adding dichloromethane (8ml) dissolving, then will DDQ dichloromethane solution (285mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Reaction solution is concentrated, the 10%HCl aqueous solution (8ml) is added in residue, 1h is stirred at room temperature, then in ice-water bath Under the conditions of with the NaOH aqueous solution be adjusted to alkalescence, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract It is washed with water 3 times, is washed 1 time with saturated aqueous common salt, dried with anhydrous magnesium sulfate, filter, filtrate is organic through being evaporated off Phase, obtain crude residue.Crude product is through silica gel column chromatography [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify and must change Compound 16, red solid 32mg, yield 11.6%.1H NMR:(400MHz,DMSO-d6) δ 1.02 (t, J=7.2Hz, 6H, 2 × NCH2CH3), 3.20 (t, J=6Hz, 2H, ArCH2CH2), N 3.27 (q, J=7.2Hz, 4H, 2 × NCH2CH3),4.04(s,3H, OCH3),4.07(s,3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.18(s,2H,OCH2O),7.10(s,1H, Ar-H),7.72(s,1H,Ar-H),7.76(s,1H,Ar-H),8.60(s,1H,Ar-H),9.84(s,1H,Ar-H)；13C NMR: (100MHz,DMSO-d6)δ12.04(2×C),26.39,47.68(2×C),55.08,57.15,61.93,102.09, 105.51,108.46,116.25,118.78,120.56,122.02,130.41,130.85,137.02,139.37,144.48, 145.59,147.79,149.82,150.79；ESI-MS(m/z):407.3[M-Cl]+。
The preparation of embodiment (16) compound 17
Weigh Compound 3 (100mg, 0.228mmol) is in reaction bulb, after adding dichloromethane (4ml) dissolving, then will DDQ dichloromethane solution (103mg DDQ are dissolved in 6ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (4ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 17, red solid 50mg, yield 46.6%.1H NMR:(400MHz,DMSO-d6) (t, J=7.2Hz, 6H, 2 × NCH of δ 0.852CH2CH3),1.47(m,4H), 3.19(m,6H),4.03(s,3H,OCH3),4.07(s,3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.18(s, 2H,OCH2O),7.10(s,1H,Ar-H),7.65(s,1H,Ar-H),7.78(s,1H,Ar-H),8.61(s,1H,Ar-H), 9.84(s,1H,Ar-H)；13C NMR:(150MHz,DMSO-d6)δ11.62(2×C),19.83(2×C),26.38,55.06, 55.75(2×C),57.17,61.93,102.12,105.11,108.52,115.94,119.14,120.50,121.97, 130.25,130.87,136.97,139.53,145.08,145.71,147.78,149.85,150.85；ESI-MS(m/z): 435.3[M-Cl]+。
The preparation of embodiment (17) compound 18
Weigh Compound 4 (200mg, 0.429mmol) is in reaction bulb, after adding dichloromethane (6ml) dissolving, then will DDQ dichloromethane solution (195mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, instead Should be complete.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloros in residue Methane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted under the conditions of ice-water bath with the NaOH aqueous solution Alkalescence, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, uses saturated aqueous common salt Washing 1 time, is dried with anhydrous magnesium sulfate, is filtered, and filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silicon Plastic column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 18, red solid 100mg, yield 46.7%.1H NMR:(400MHz,DMSO-d6) (t, J=7.2Hz, 6H, 2 × NCH of δ 0.842CH2CH2CH3),1.28(m,4H), 1.45(m,4H),3.21(m,6H,ArCH2CH2N,2×NCH2CH2CH2CH3),4.03(s,3H,OCH3),4.06(s,3H, OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.19(s,2H,OCH2O),7.10(s,1H,Ar-H),7.63(s,1H, Ar-H),7.76(s,1H,Ar-H),8.57(s,1H,Ar-H),9.84(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6) δ13.86(2×C),19.93(2×C),26.37,28.74(2×C),53.65(2×C),55.06,57.18,61.95, 102.14,105.09,108.55,115.89,118.86,120.50,121.99,130.14,130.88,136.95,139.43, 145.15,145.76,147.79,149.86,150.84；ESI-MS(m/z):463.3[M-Cl]+。
The preparation of embodiment (18) compound 19
Weigh Compound 5 (273mg, 0.552mmol) is in reaction bulb, after adding dichloromethane (6ml) dissolving, then will DDQ dichloromethane solution (251mg DDQ are dissolved in 10ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, instead Should be complete.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloros in residue Methane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted under the conditions of ice-water bath with the NaOH aqueous solution Alkalescence, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, uses saturated aqueous common salt Washing 1 time, is dried with anhydrous magnesium sulfate, is filtered, and filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silicon Plastic column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 19, red solid 70mg, yield 11.4%.1H NMR:(400MHz,DMSO-d6) (t, J=6.4Hz, 6H, 2 × NCH of δ 0.822CH2CH2CH2CH3),1.26(m, 8H),1.47(m,4H),3.20(m,6H,ArCH2CH2N,2×NCH2CH2CH2CH2CH3),4.04(s,3H,OCH3),4.06(s, 3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.18(s,2H,OCH2O),7.11(s,1H,Ar-H),7.60(s, 1H,Ar-H),7.78(s,1H,Ar-H),8.59(s,1H,Ar-H),9.84(s,1H,Ar-H)；13C NMR:(100MHz,DMSO- d6)δ13.99(2×C),21.96(2×C),26.31(2×C),26.37,29.03(2×C),53.85(2×C),55.04, 57.19,61.95,102.16,104.96,108.58,115.87,118.95,120.50,121.99,130.19,130.88, 136.94,139.49,145.22,145.77,147.80,149.87,150.86；ESI-MS(m/z):491.3[M-Cl]+。
The preparation of embodiment (19) compound 20
Weigh Compound 6 (167mg, 0.32mmol) is in reaction bulb, after adding dichloromethane (6ml) dissolving, then by DDQ Dichloromethane solution (145mg DDQ are dissolved in 6ml dichloromethane) be added drop-wise in reaction solution, at room temperature stir 2h after, reacted Entirely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 20, red solid 52mg, yield 29.4%.1H NMR:(400MHz,DMSO-d6) (t, J=6.4Hz, 6H, 2 × NCH of δ 0.812CH2CH2CH2CH2CH3),1.22 (m,12H),1.47(m,4H),3.20(m,6H,ArCH2CH2N,2×NCH2CH2CH2CH2CH2CH3),4.04(s,3H,OCH3), 4.06(s,3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.18(s,2H,OCH2O),7.11(s,1H,Ar-H), 7.59(s,1H,Ar-H),7.78(s,1H,Ar-H),8.58(s,1H,Ar-H),9.85(s,1H,Ar-H)；13C NMR: (100MHz,DMSO-d6) δ 13.84 (2 × C), 22.13 (2 × C), 26.37,26.43~26.60 (4 × C), 31.05 (2 × C),53.85(2×C),55.04,57.18,61.94,102.17,104.93,108.58,115.87,118.97,120.49, 121.98,130.21,130.88,136.93,139.50,145.27,145.76,147.80,149.86,150.87；ESI-MS (m/z):519.4[M-Cl]+。
The preparation of embodiment (20) compound 21
Weigh Compound 7 (208mg, 0.378mmol) is in reaction bulb, after adding dichloromethane (6ml) dissolving, then will DDQ dichloromethane solution (172mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 21, red solid 50mg, yield 22.7%.1H NMR:(400MHz,DMSO-d6)δ0.80(t-like,6H,2×NCH2CH2CH2CH2CH2CH2CH3),1.20(m, 16H),1.47(m,4H),3.19(m,6H, ArCH2CH2N,2×NCH2CH2CH2CH2CH2CH2CH2CH3),4.04(s,3H, OCH3),4.07(s,3H,OCH3), 4.93 (t, J=6Hz, 2H, ArCH2CH2N),6.18(s,2H,OCH2O),7.12(s,1H, Ar-H),7.58(s,1H,Ar-H),7.79(s,1H,Ar-H),8.59(s,1H,Ar-H),9.87(s,1H,Ar-H)；13C NMR: (100MHz,DMSO-d6) δ 13.88 (2 × C), 22.02 (2 × C), 26.38,26.65~31.32 (8 × C), 53.83 (2 × C),55.04,57.18,61.95,102.16,104.87,108.59,115.84,119.09,120.49,121.96,130.26, 130.89,136.91,139.57,145.28,145.80,147.80,149.86,150.89；ESI-MS(m/z):547.4[M- Cl]+。
The preparation of embodiment (21) compound 22
Weigh Compound 8 (220mg, 0.380mmol) is in reaction bulb, after adding dichloromethane (8ml) dissolving, then will DDQ dichloromethane solution (173mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 22, red solid 70mg, yield 30%.1H NMR:(400MHz,DMSO-d6) (t, J=6.4Hz, 6H, 2 × NCH of δ 0.802CH2CH2CH2CH2CH2CH2CH3), 1.20(m,20H),1.46(m,4H),3.19(m,6H,ArCH2CH2N,2×NCH2CH2CH2CH2CH2CH2CH2CH3),4.03(s, 3H,OCH3),4.06(s,3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.17(s,2H,OCH2O),7.11(s, 1H,Ar-H),7.58(s,1H,Ar-H),7.78(s,1H,Ar-H),8.58(s,1H,Ar-H),9.84(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6) δ 13.87 (2 × C), 22.04 (2 × C), 26.38,26.62~31.19 (10 × C), 53.79 (2×C),55.05,57.17,61.94,102.16,104.87,108.59,115.84,119.06,120.49,121.97, 130.24,130.88,136.91,139.55,145.29,145.80,147.81,149.86,150.89；ESI-MS(m/z): 575.5[M-Cl]+。
The preparation of embodiment (22) compound 23
Weigh Compound 9 (240mg, 0.396mmol) is in reaction bulb, after adding dichloromethane (8ml) dissolving, then will DDQ dichloromethane solution (180mg DDQ are dissolved in 6ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted under the conditions of ice-water bath with the NaOH aqueous solution Alkalescence, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, uses saturated aqueous common salt Washing 1 time, is dried with anhydrous magnesium sulfate, is filtered, and filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silicon Plastic column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 23, red solid 87mg, yield 34.4%.1H NMR:(400MHz,DMSO-d6) δ 0.81 (t, J=6.4Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH3),1.18(m,24H),1.46(m,4H),3.18(m,6H,ArCH2CH2N,2× NCH2CH2CH2CH2CH2CH2CH2CH2CH3),4.04(s,3H,OCH3),4.06(s,3H,OCH3), 4.92 (t, J=5.6Hz, 2H, ArCH2CH2N),6.17(s,2H,OCH2O),7.11(s,1H,Ar-H),7.57(s,1H,Ar-H),7.79(s,1H,Ar-H), 8.58(s,1H,Ar-H),9.85(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ13.91(2×C),22.03(2 × C), 26.38,26.62~31.23 (12 × C), 53.78 (2 × C), 55.05,57.17,61.94,102.15,104.85, 108.60,115.82,119.09,120.48,121.97,130.24,130.88,136.90,139.57,145.30,145.81, 147.81,149.86,150.89；ESI-MS(m/z):603.5[M-Cl]+。
The preparation of embodiment (23) compound 24
Weigh Compound 10 (315mg, 0.496mmol) is in reaction bulb, after adding dichloromethane (8ml) dissolving, then will DDQ dichloromethane solution (225mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 24, red solid 47mg, yield 14.2%.1H NMR:(400MHz,DMSO-d6) δ 0.82 (t, J=6.4Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),1.18(m,28H),1.46(m,4H),3.18(m,6H,ArCH2CH2N,2× NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),4.04(s,3H,OCH3),4.06(s,3H,OCH3), 4.92 (t, J=6Hz, 2H,ArCH2CH2N),6.17(s,2H,OCH2O),7.11(s,1H,Ar-H),7.57(s,1H,Ar-H),7.79(s,1H,Ar- H),8.58(s,1H,Ar-H),9.85(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ13.92(2×C),22.07 (2 × C), 26.37,26.61~31.23 (14 × C), 53.76 (2 × C), 55.05,57.16,61.93,102.14,104.84, 108.60,115.81,119.08,120.48,121.96,130.23,130.87,136.89,139.55,145.30,145.80, 147.80,149.85,150.88；ESI-MS(m/z):631.5[M-Cl]+。
The preparation of embodiment (24) compound 25
Weigh Compound 11 (328mg, 0.495mmol) is in reaction bulb, after adding dichloromethane (8ml) dissolving, then will DDQ dichloromethane solution (225mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 25, red solid 55mg, yield 16%.1H NMR:(400MHz,DMSO-d6) δ 0.83 (t, J=6.4Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),1.18(m,32H),1.46(m,4H),3.18(m,6H,ArCH2CH2N,2 ×NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),4.04(s,3H,OCH3),4.06(s,3H,OCH3), 4.92 (t, J= 5.6Hz,2H,ArCH2CH2N),6.17(s,2H,OCH2O),7.11(s,1H,Ar-H),7.57(s,1H,Ar-H),7.79(s, 1H,Ar-H),8.58(s,1H,Ar-H),9.85(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6)δ13.93(2×C), 22.07 (2 × C), 26.37,26.60~31.27 (16 × C), 53.74 (2 × C), 55.05,57.16,61.93,102.14, 104.83,108.60,115.80,119.08,120.47,121.96,130.23,130.87,136.89,139.56,145.30, 145.81,147.80,149.85,150.88；ESI-MS(m/z):659.6[M-Cl]+。
The preparation of embodiment (25) compound 26
Weigh Compound 12 (250mg, 0.362mmol) is in reaction bulb, after adding dichloromethane (8ml) dissolving, then will DDQ dichloromethane solution (165mg DDQ are dissolved in 8ml dichloromethane) is added drop-wise in reaction solution, after stirring 2h at room temperature, reaction Completely.Filter, wash filter cake with dichloromethane, evaporated under reduced pressure filtrate colourless to cleaning solution, the addition 1ml dichloromethanes in residue Alkane, the 10%HCl aqueous solution (8ml) is added, stirs 1h at room temperature.Then it is adjusted to alkali with the NaOH aqueous solution under the conditions of ice-water bath Property, 0.5h is stirred at room temperature, with chloroform/methanol (v/v=10:1) extract, extract is washed with water 3 times, with saturated aqueous common salt water Wash 1 time, dried with anhydrous magnesium sulfate, filtered, filtrate obtains crude residue through organic phase is evaporated off.Crude product is through silica gel Column chromatography is [with methylene chloride/methanol=25:1 (v/v) is eluant, eluent] purify to obtain compound 26, red solid 100mg, yield 38.3%.1H NMR:(400MHz,DMSO-d6) δ 0.84 (t, J=6.4Hz, 6H, 2 × NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),1.18(m,36H),1.47(m,4H), 3.18(m,6H, ArCH2CH2N,2×NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3),4.04(s,3H,OCH3),4.06(s,3H, OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.17(s,2H,OCH2O),7.11(s,1H,Ar-H),7.56(s,1H, Ar-H),7.79(s,1H,Ar-H),8.58(s,1H,Ar-H),9.84(s,1H,Ar-H)；13C NMR:(100MHz,DMSO-d6) δ 13.94 (2 × C), 22.09 (2 × C), 26.37,26.60~31.28 (18 × C), 53.74 (2 × C), 55.05,57.17, 61.94,102.14,104.81,108.61,115.79,119.10,120.47,121.97,130.22,130.88,136.89, 139.59,145.31,145.83,147.80,149.86,150.89；ESI-MS(m/z):687.6[M-Cl]+。
The preparation of embodiment (26) compound 27
Weigh Compound 13 (250mg, 0.592mmol) after adding dichloromethane (12ml) dissolving, then divides in reaction bulb Criticize and DDQ is added in reaction solution, after stirring 2h at room temperature, reaction is complete.By reaction solution evaporated under reduced pressure, 10%HCl first is added Alcoholic solution (16ml), stirs 1h at room temperature.Then alkalescence is adjusted to the NaOH aqueous solution under the conditions of ice-water bath, stirred at room temperature 0.5h.With chloroform-methanol (v:V=10:1) mixed liquor is extracted 3 times, and organic phase washed with water is washed 3 times, saturated aqueous common salt washing 1 time, anhydrous magnesium sulfate is dried, and is filtered, is removed organic phase under reduced pressure, crude product is through silica gel column chromatography [with chloroform/methanol=25:1(v/ V) it is eluant, eluent] purify to obtain compound 27, red solid 138mg, yield 51.3%.1H NMR:(400MHz,DMSO-d6)δ 1.65 (m, 2H), 1.87 (m, 4H), 3.09 (m, 4H), 3.19 (t, J=6Hz, 2H, ArCH2CH2N),4.01(s,3H,OCH3), 4.08(s,3H,OCH3), 4.92 (t, J=6Hz, 2H, ArCH2CH2N),6.18(s,2H,OCH2O),7.10(s,1H,Ar-H), 7.60(s,1H,Ar-H),7.71(s,1H,Ar-H),8.42(s,1H,Ar-H),9.83(s,1H,Ar-H)；13C NMR: (100MHz,DMSO-d6)δ23.84,25.71(2×C),26.39,54.11(2×C),55.04,56.96,61.89, 102.09,105.34,108.47,115.39,116.01,120.51,122.06,128.18,130.87,136.90,138.72, 145.60,147.39,147.81,149.85,150.96.
The preparation of embodiment (27) compound 29
Under agitation to chloride containing coptisine quaternary ammonium salt (0.17mmol) and K2CO380% ethanol solution of (0.51mmol) In (4mL) NaBH is added portionwise4(0.34mmol).Reactant mixture reacts anti-at room temperature again after 20min under reflux conditions 4h is answered, has substantial amounts of yellow solid to produce.The solid obtained after reactant mixture is filtered obtains tetrahydrochysene with 95% ethyl alcohol recrystallization Coptisine 40mg, yield 73.3%.IR(neat)νmax 2911,2799,2747,1500,1458,1037,871,797cm- 1.1H-NMR(DMSO-d6)δ:2.44-2.62(m,3H),2.87-2.93(m,1H),3.08(dd,J1=10.8Hz, J2= 5.2Hz, 1H), 3.36-3.46 (m, 2H), 3.41 (d, J=14.2Hz, 1H), 3.96 (d, J=14.2Hz, 1H), 5.94,5.95 (2×br s,2H,OCH2O),5.98,6.00(2×br s,2H,OCH2), O 6.63 (d, J=8.0Hz, 1H, ArH), 6.67 (s, 1H, ArH), 6.75 (d, J=8.0Hz, 1H, ArH), 6.92 (s, 1H, ArH)；13C-NMR(100MHz,DMSO-d6)δ:29.0, 35.8,50.5,52.2,59.1,100.5,100.8,105.7,106.5,108.1,116.6,120.9,127.4,128.6, 130.7,142.7,144.4,145.4,145.7；ESI-MS(m/z):324.1[M+H]+.Weigh Tetrahydrocoptisine (50mg, 0.155mmol) in reaction bulb, glacial acetic acid (1ml) is added, is placed in ice-water bath, is slowly added to NaNO in batches2(54mg, 0.783mmol), dense HNO is instilled3(108 μ l), after being added dropwise, 0.5h is stirred under ice-water bath, reaction is complete.Into reaction solution Adding water (3ml), ammonification water is adjusted to alkalescence, and decompression filters, and obtained crude product purifies through silica gel column chromatography (using chloroform as eluant, eluent), 12- nitro Tetrahydrocoptisine 35mg are obtained, from Tetrahydrocoptisine raw material calculated yield 61.4%.1H NMR(500MHz,DMSO)δ 2.45-3.61 (m, 8H), 4.02 (d, J=15.7Hz, 1H), 5.95,5.97 (2 × br s, 2H, OCH2O),6.24,6.25(2 ×br s,2H,OCH2O),6.69(s,1H,Ar-H),6.95(s,1H,Ar-H),7.58(s,1H,Ar-H).Weigh 12- nitros Tetrahydrocoptisine (50mg, 0.136mmol) adds THF/ methanol (v/v=1 in reaction bulb:1；2ml), then add NiCl2·6H2O (162mg, 0.681mmol), then NaBH is added portionwise4(52mg, 1.368mmol), it is heated to reflux at 66 DEG C 20min reactions are complete.Reaction solution filters, and with chloroform filter cake to washing filtrate without obvious color, filtrate decompression is evaporated off molten Agent, residue is dissolved with dichloromethane, dichloromethane solution is washed with water 3 times, with saturated common salt water washing 1 time, with anhydrous sulphur Sour magnesium is dried.12- amino Tetrahydrocoptisine 37mg, yield 80.6% will be obtained after dried dichloromethane solution evaporated under reduced pressure.1H NMR(500MHz,DMSO-d6) δ 2.08-3.38 (m, 8H), 3.86 (d, J=15.2Hz, 1H), 4.62 (s, 2H, Ar-NH2), 5.80,5.81(2×br s,2H,OCH2O),5.95,5.96(2×br s,2H,OCH2O),6.20(s,1H,Ar-H),6.67 (s,1H,Ar-H),6.97(s,1H,Ar-H)；13C NMR(150MHz,DMSO-d6)δ29.36(s),32.23(s),51.11 (s),53.20(s),59.56(s),94.76(s),100.28(s),100.97(s),106.33(s),108.45(s),111.07 (s), 116.87 (s), 127.79 (s), 131.70 (s), 134.25 (s), 140.97 (s), 145.09 (s), 145.83 (s), 146.10(s)。
The preparation of embodiment (28) compound 30
12- amino Tetrahydrocoptisine (50mg, 0.148mmol) is dissolved in dichloromethane (2ml), adds DDQ in batches (67.2mg, 0.295mmol), the solvent evaporated after 2h is reacted at room temperature, the methanol solution containing 10% hydrochloric acid is added in residue (2ml), 1h is stirred, dilute sodium hydroxide aqueous solution is added under condition of ice bath and is adjusted to alkalescence, 0.5h is stirred at room temperature, with chloroform-first Alcohol (v:V=10:1) mixed liquor extracts 3 times, organic phase washed with water, saturated sodium-chloride water solution is washed, anhydrous MgSO4It is dry Dry, decompression is filtered, solvent evaporated, and crude product is carried out into silica gel column chromatography [with chloroform/methanol=100:1 (v/v) is eluant, eluent], obtain Compound 30,24.7mg, yield 45.1%.1H-NMR(DMSO-d6)δ:3.15(br,2H,NCH2CH2),4.79(br,2H, NCH2CH2),6.15(s,2H,OCH2O),6.29(s,2H,OCH2O),6.60(s,2H,NH2),7.03(s,2H,ArH),7.84 (s,1H,ArH),8.77(s,1H,ArH),9.61(s,1H,ArH).ESI-MS(m/z):335.0[M-Cl]+。
Pharmacological evaluation
Experimental example 1：The compounds of this invention is tested the growth inhibition ratio of tumor cell line
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is respectively prepared in each tumor cell line, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.The working solution of testing compound is added, the end of use is dense Degree can be the testing compound concentration of 0.1,1,5,10,100 μM (each 4 multiple holes of concentration).Effect discards training after 72 hours Nutrient solution, 100 μ l MTT containing 0.5mg/ml 1640 culture mediums (10% serum) are added per hole.37 DEG C are placed in, 5%CO2Incubator Culture abandons liquid after 4 hours, and the μ l of DMSO 150 are added per hole, 10min is shaked under normal temperature, is completely dissolved blueness crystallization, with detection Wavelength 570nm, reference wavelength 655nm are determined per hole absorbance (OD values), based on following equation in Bio-Rad450 types ELIASA Calculate the tumor cell line growth inhibition ratio of product to be tested：
Result of the test is shown in Table one, table two and table three.
Experimental example 2：The compounds of this invention is tested by the growth inhibiting concentration dependant of tumor cell line and IC50Value calculates
(1) the compounds of this invention is to MDAMB231 human breast cancer cell growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in MDAMB231 human breast cancer cells, the culture of 96 holes is added by finite concentration Plate (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.Add the working solution of testing compound, its final concentration Gradient is:0.01st, 0.1,1,10 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, is added per hole 100 μ l MTT containing 0.5mg/ml 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon after 4 hours Liquid, DMSO150 μ l are added per hole, 10min is shaked under normal temperature, be completely dissolved blueness crystallization, with Detection wavelength 570nm, reference Wavelength 655nm is determined per hole absorbance (OD values) in Bio-Rad450 types ELIASA.IC50Value is pressed down accordingly by each concentration of compound The logarithm of rate processed and dosage does figure and calculated.
Experimental data is shown in Table one.
(2) the compounds of this invention is to MCF7 human breast cancer cell growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, by testing compound Mother liquor is diluted to working solution concentration.Cell suspension is made in MCF7 human breast cancer cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.Add the working solution of testing compound, its final concentration ladder Spend and be:0.01st, 0.1,1,10 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ are added per hole L MTT containing 0.5mg/ml 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, often Hole adds the μ l of DMSO 150, and 10min is shaked under normal temperature, is completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655nm is determined per hole absorbance (OD values) in Bio-Rad450 types ELIASA.IC50Value presses the corresponding inhibiting rate of each concentration of compound Figure is done with the logarithm of dosage and is calculated.
Experimental data is shown in Table one.
(3) the compounds of this invention is to HT29 human colon cancer cell growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in HT29 human colon cancer cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.Add the working solution of testing compound, its final concentration ladder Spend and be:0.01st, 0.1,1,10 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, is added per hole 100ul MTT containing 0.5mg/ml 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon after 4 hours Liquid, the μ l of DMSO 150 are added per hole, 10min is shaked under normal temperature, be completely dissolved blueness crystallization, with Detection wavelength 570nm, reference Wavelength 655nm is determined per hole absorbance (OD values) in Bio-Rad450 types ELIASA.IC50Value is pressed down accordingly by each concentration of compound The logarithm of rate processed and dosage does figure and calculated.
Experimental data is shown in Table one.
(4) the compounds of this invention is to HCT116 human colon cancer cell growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in HCT116 human colon cancer cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.Add the working solution of testing compound, its final concentration ladder Spend and be:0.01st, 0.1,1,10 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ are added per hole L MTT containing 0.5mg/ml 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, often Hole adds the μ l of DMSO 150, and 10min is shaked under normal temperature, is completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655 nm are determined per hole absorbance (OD values) in Bio-Rad450 types ELIASA.IC50Value is suppressed accordingly by each concentration of compound The logarithm of rate and dosage does figure and calculated.
Experimental data is shown in Table one.
(5) the compounds of this invention is to HCT-8 human colon cancer cell growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in HCT-8 human colon cancer cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.The working solution of testing compound is added, its is final concentration of: 0.1st, 1,10,100 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ l are added per hole and are contained 0.5mg/ml MTT 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, per hole The μ l of DMSO 150 are added, 10min is shaked under normal temperature, are completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655nm is determined per hole absorbance (OD values) in the type ELIASAs of Bio-Rad 450.The inhibiting rate of product to be tested is calculated by following equation：
IC50Value is done figure by the logarithm of the corresponding inhibiting rate of each concentration of compound and dosage and calculated.
Experimental result is shown in Table two.
(6) the compounds of this invention is to Bel7402 hepatoma cell growth inhibitory activity
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in Bel7402 human liver cancer cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.The working solution of testing compound is added, its is final concentration of: 0.1st, 1,10,100 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ l are added per hole and are contained 0.5mg/ml MTT 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, per hole The μ l of DMSO 150 are added, 10min is shaked under normal temperature, are completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655nm is determined per hole absorbance (OD values) in the type ELIASAs of Bio-Rad 450.The inhibiting rate of product to be tested is calculated by following equation：
IC50Value is done figure by the logarithm of the corresponding inhibiting rate of each concentration of compound and dosage and calculated.
Experimental result is shown in Table two.
(7) the compounds of this invention is to Hela growth of human cervical carcinoma Hela inhibitory activity
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in Hela human cervical carcinoma cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.The working solution of testing compound is added, its is final concentration of: 0.1st, 1,10,100 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ l are added per hole and are contained 0.5mg/ml MTT 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, per hole The μ l of DMSO 150 are added, 10min is shaked under normal temperature, are completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655nm is determined per hole absorbance (OD values) in the type ELIASAs of Bio-Rad 450.The inhibiting rate of product to be tested is calculated by following equation：
IC50Value is done figure by the logarithm of the corresponding inhibiting rate of each concentration of compound and dosage and calculated.
Experimental result is shown in Table two.
(8) the compounds of this invention is to A549 human lung carcinoma cell growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in A549 human lung carcinoma cells, 96 well culture plates (100 μ are added by finite concentration L/ holes), 37 DEG C are placed in, 5%CO2Incubator culture 24 hours.The working solution of testing compound is added, its is final concentration of:0.1、 1st, 10,100 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ l are added per hole and contain 0.5mg/ Ml MTT 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, added per hole The μ l of DMSO 150, shake 10min under normal temperature, be completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655nm in Bio-Rad450 types ELIASA measure is per hole absorbance (OD values).The inhibiting rate of product to be tested is calculated by following equation：
IC50Value is done figure by the logarithm of the corresponding inhibiting rate of each concentration of compound and dosage and calculated.
Experimental result is shown in Table three.
(9) the compounds of this invention is to BGC-823 gastric carcinoma cells growth inhibitory activities
Testing compound is dissolved with 100 μ l DMSO and uses 1640 culture mediums containing 10% serum, testing compound is female Liquid is diluted to working solution concentration.Cell suspension is made in BGC-823 gastric carcinoma cells, 96 well culture plates are added by finite concentration (100 μ l/ holes), is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.The working solution of testing compound is added, its is final concentration of: 0.1st, 1,10,100 μm of ol/L (each 4 multiple holes of concentration).Effect discards nutrient solution after 72 hours, and 100 μ l are added per hole and are contained 0.5mg/ml MTT 1640 culture mediums (10% serum).37 DEG C are placed in, 5%CO2Incubator culture abandon liquid after 4 hours, per hole The μ l of DMSO 150 are added, 10min is shaked under normal temperature, are completely dissolved blueness crystallization, with Detection wavelength 570nm, reference wavelength 655nm is determined per hole absorbance (OD values) in the type ELIASAs of Bio-Rad 450.The inhibiting rate of product to be tested is calculated by following equation：
IC50Value is done figure by the logarithm of the corresponding inhibiting rate of each concentration of compound and dosage and calculated.
Experimental result is shown in Table three.
Table one
Table two
Table three

Claims (11)

1. berbine derivative or its physiologically acceptable salt shown in formula I：
Wherein, R2、R3It is each independently selected from H, OH or C1-4 alkoxy or R2、R3It is connected to become OCH2O；
R9、R10It is each independently selected from H, OH or C2-4 alkoxy or R9、R10It is connected to become OCH2O；
Two R12It is each independently selected from H, formula CnH2n+1Or CmH2m-1Straight or branched aliphatic group or two R12Connect into Carbocyclic ring, n is selected from 2,3,4,5,6,7,8,9,10,11,12,13 selected from 1,2,3,4,5,6,7,8,9,10,11,12,13, m, when two Individual R12When connecting into carbocyclic ring, two R12The alkylene being connected with nitrogen-atoms represented jointly is selected from butylidene, pentylidene, Asia Hexyl, heptamethylene, octamethylene.
2. berbine derivative or its physiologically acceptable salt shown in formula II：
Wherein, R2、R3It is each independently selected from H, OH or C1-4 alkoxy or R2、R3It is connected to become OCH2O；
R9、R10It is each independently selected from H, OH or C2-4 alkoxy or R9、R10It is connected to become OCH2O；
Two R12It is each independently selected from H, formula CnH2n+1Or CmH2m-1Straight or branched aliphatic group or two R12Connect into Carbocyclic ring, n is selected from 2,3,4,5,6,7,8,9,10,11,12,13 selected from 1,2,3,4,5,6,7,8,9,10,11,12,13, m, when two Individual R12When connecting into carbocyclic ring, two R12The alkylene being connected with nitrogen-atoms represented jointly is selected from butylidene, pentylidene, Asia Hexyl, heptamethylene, octamethylene；
X-For acid ion.
3. berbine derivative according to claim 2 or its physiologically acceptable salt, it is characterised in that described X-Choosing From Cl-、Br-、I-、HSO4 -、H2PO4 -, bitartrate, dihydrogen citrate root, maleic acid hydrogen radical, fumaric acid hydrogen radical, hydrogen malate Root, oxalic acid hydrogen radical, benzene sulfonic acid root.
4. according to any one of claim 1-2 berbine derivative or its physiologically acceptable salt, it is characterised in that institute The C1-4 alkoxies stated are selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy；Described C2-4 alkoxies are selected from second Epoxide, propoxyl group, isopropoxy, butoxy.
5. according to any one of claim 1-2 berbine derivative or its physiologically acceptable salt, it is characterised in that institute State compound and be selected from following heterogeneous compound group：
6. according to any one of claim 1-5 berbine derivative or its physiologically acceptable salt, it is characterised in that institute The physiologically acceptable salt stated includes inorganic acid salt or acylate.
7. berbine derivative according to claim 6 or its physiologically acceptable salt, it is characterised in that described is inorganic Hydrochlorate include halogen acid salt, sulfate, phosphate, described acylate include tartrate, citrate, maleate, Fumarate, malate, oxalates, benzene sulfonate.
8. a kind of pharmaceutical composition, it is characterised in that any one of claim 1-7 containing effective dose berbine derives Thing or its physiologically acceptable salt and pharmaceutically acceptable carrier or excipient.
9. any one of claim 1-7 berbine derivative or its physiologically acceptable salt or the medicine of claim 8 Application of the composition in preparing prevention, alleviating and/or treating tumour product.
10. application according to claim 9, it is characterised in that described tumour is selected from colon cancer, breast cancer, cancer of pancreas, liver Cancer, lung cancer, stomach cancer, cervical carcinoma, cancer of the esophagus, oophoroma, CARCINOMA OF THE NASAL CAVITY, prostate cancer.
11. application according to claim 9, it is characterised in that described product is selected from medicine, health products.
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CN113599380A (en) * 2021-08-24 2021-11-05 郑州大学 Application of berberine compounds in preparing antitumor drugs
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