CN107011406A - Compound with anti-tumor effect and preparation method and application thereof - Google Patents

Compound with anti-tumor effect and preparation method and application thereof Download PDF

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CN107011406A
CN107011406A CN201610059173.XA CN201610059173A CN107011406A CN 107011406 A CN107011406 A CN 107011406A CN 201610059173 A CN201610059173 A CN 201610059173A CN 107011406 A CN107011406 A CN 107011406A
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compound
cancer
pharmaceutically acceptable
preparation
acid
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雷海民
王鹏龙
徐冰
熊磊
龚兆龙
林毅晖
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3d Medicines Ltd
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3d Medicines Ltd
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Priority to CN201610059173.XA priority Critical patent/CN107011406A/en
Priority to CN201780003139.3A priority patent/CN108137644B/en
Priority to PCT/CN2017/071276 priority patent/WO2017128981A1/en
Publication of CN107011406A publication Critical patent/CN107011406A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

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Abstract

The invention provides a compound with the following structure, a preparation method thereof and application thereof in preparing antitumor drugs. The compound of the invention has the activity of obviously inhibiting the growth of tumor cell lines (HepG-2, HT-29, Hela, BGC-823 and A549), but has less toxicity to human liver normal cell (L02) lines. Wherein, the antiproliferative activity of the compound LQC-C on a human colon cancer cell line HT-29, a human cervical cancer cell line Hela and a human lung cancer cell line A549 is superior to that of a positive drug cisplatin; but the cytotoxicity of the normal human liver cells L02 is obviously lower than that of the positive drug cisplatin.

Description

A kind of compound with antitumor action and its preparation method and application
Technical field
The present invention relates to a kind of compound and its preparation method and application, and in particular to one kind has anti-swollen Compound of knurl functionality and its preparation method and application.
Background technology
Often there is the tragedy of " cancer dead person dies ", especially liver cancer, knot in the treatment of cancer on Present clinical The current not yet specific medicament of the pernicious canceration of the multiclass such as intestinal cancer, it is that current chemotherapy is cancer to trace it to its cause One of major way, front-line chemotherapeutic agents are often caused while cancer cell is killed to normal body Serious toxic side effect, for example：Renal toxicity, hepatotoxicity wind agitation, neurotoxicity etc..It is high for obtaining The strong cancer therapy drug of effect, low toxicity, selectivity is the target that pharmacy worker seek assiduously, gratifying It is that domestic and international current research finds that cell toxicant selectively strong compound has good druggability, accords with Development trend (the Cancer Cell, 2015,28,240-252 being fated for accurate medical science；Int.J.Mol. Sci.2015,16(7),16401-16413)。
The present invention is with betulic acid (BA) and crude drug with antitumor, anti-liver disease biological activity Thing ligustrazine (TMP) is initiation material, carries out chemical split synthesis the compounds of this invention.To this The activity rating of class compound deploys mainly around in terms of antitumor (especially liver cancer, intestinal cancer etc.), Test respectively analog to 5 kinds of cancer cell systems (HepG-2, HT-29, Hela, BGC-823, A549) and non-cancerous cells system (people normal cell lines of human liver L02) cytotoxic activity.
The content of the invention
First purpose of the present invention is to provide compound with the structure of formula 1 and preparation method thereof.
Second object of the present invention is application of the compound of offer formula 1 in antineoplastic is prepared.
Third object of the present invention is to provide a kind of pharmaceutical composition with antitumor action.
The purpose of the present invention is achieved by the following technical solution：
Compound or its pharmaceutically acceptable salt with the structure of formula 1,
Further, the compound can add formulation art customary adjuvant be made tablet, capsule, The regular dosage forms such as granule, powder, oral liquid, injection.
The preparation method of compound of the present invention comprises the following steps：
Step 1, betulic acid is dissolved in organic solvent, with 2- chloromethyls -3,5,6- trimethyls Pyrazine generates midbody compound ligustrazine-betulic acid ester (midbody compound in the basic conditions TBA)；
Step 2, midbody compound TBA reacts life in the presence of catalyst with methyl amimoacetic acid Into compound L QC-C.
Further, above-mentioned reaction is carried out at -20 DEG C to 250 DEG C；The organic solvent be containing The ether of 1-20 carbon atom, alcohol, alkane, aromatic hydrocarbon, ketone, alkyl halide, acid amides, nitrile, ester or The mixture of their various ratios of person；Alkali used is triethylamine or potassium carbonate；The catalyst is 1- Hydroxybenzotriazole (HOBT), 1- ethyls -3- (3- dimethylamine propyls) carbodiimide hydrochloride (EDCI), 1,3- dicyclohexylcarbodiimides (DCC) or DMAP (DMAP).
Further, in above-mentioned preparation method, the mol ratio of raw material and chloro ligustrazine is 1:0.1~1:10； The mol ratio of raw material and alkali is 1:0.1~1:10；The mol ratio of intermediate and methyl amimoacetic acid is 1:0.1~1:10； The mol ratio of intermediate and catalyst is 1:0.1~1:10.
Reaction scheme of the present invention is：
Reaction condition and reagent:(a) AcOH, 30%H2O2, reflux, 90 DEG C, 6h；(b)Ac2O, reflux,105℃,2h；(c)THF:MeOH:H2O=3:1:1,NaOH,1h；(d),THF,Tscl, TEA,DMAP,12h.；(e)DMF,dry K2CO3,60℃,12h.(f)BOC-Sarcosine, EDCI,DMAP,DCM,25℃,12h；(g)HCl(g)in EA,0℃,1h.
The present invention also provides the compound of formula 1 or its pharmaceutically acceptable salt is preparing antineoplastic In application.
Further, the tumour is liver cancer, lung cancer, colon cancer, cervical carcinoma and gastric carcinoma cell lines.
The present invention also provides a kind of pharmaceutical composition, and said composition includes what is existed with therapeutically effective amount The mixing of the compound of formula 1 or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient Thing.
Further, the composition is also comprising at least one conventional anti-cancer drugs.
Further, the anticarcinogen be selected from endoxan, 5 FU 5 fluorouracil, taxol, adriamycin, Etoposide, Irinotecan, oxaliplatin, cis-platinum or gemzar.
The present invention also provide treating cancer method, including give patient administration effective dose formula 1 change Compound or its pharmaceutically acceptable salt.
To enable above-mentioned formulation to realize, pharmaceutically acceptable tax need to be added when preparing these formulations Shape agent, such as filler, disintegrant, lubricant, suspending agent, adhesive, sweetener, flavoring Agent, preservative etc., filler includes：Starch, pregelatinized starch, lactose, mannitol, crust Element, microcrystalline cellulose, sucrose etc., disintegrant includes：Starch, pregelatinized starch, microcrystalline cellulose Element, sodium carboxymethyl starch, PVPP, low-substituted hydroxypropyl cellulose, crosslinking carboxylic Sodium carboxymethylcellulose pyce etc., lubricant includes：Magnesium stearate, lauryl sodium sulfate, talcum powder, Silica etc., suspending agent includes：Polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, Hydroxypropyl methyl cellulose etc., adhesive includes, starch slurry, polyvinylpyrrolidone, hydroxypropyl Methylcellulose etc., sweetener includes：Saccharin sodium, aspartame, sucrose, honey element, radix glycyrrhizae Hypo acid etc., flavouring includes：Sweetener and various essence, preservative include：Parabens, benzene Formic acid, sodium benzoate, sorbic acid and its esters, benzalkonium bromide, the fixed, eucalyptus oil of acetic acid chloroethene etc..
It is of the present invention it is " pharmaceutically acceptable " expression compound or composition must in chemistry and/ Or it is compatible with the other compositions included in preparation in toxicology.
" therapeutically effective amount " represents that the compounds of this invention treats or prevents specified disease or symptom； Weaken, improve or eliminate one or more symptoms of specified disease；Or prevention or delay specified disease Or the amount of the breaking-out of symptom.
The compounds of this invention have substantially suppress tumor cell line (HepG-2, HT-29, Hela, BGC-823, A549) growth activity but be that toxicity is smaller to people's normal cell lines of human liver (L02).Its In, compound L QC-C to human colon cancer cell line HT-29, Human cervical cancer cell lines Hela with And human lung cancer cell line A549 antiproliferative activities are better than positive drug cis-platinum；But to people's normal cell lines of human liver L02 cytotoxicity is significantly lower than positive drug cis-platinum.
Experimental example 1MTT methods observe increasings of the compounds of this invention LQC-C to cancer cell and non-cancerous cells system Grow influence
1. instrument and material
The type CO2 incubators of Thermo 3111；HFsafe Biohazard Safety Equipments；Multiskan GO enzymes Mark instrument；Found board LD5-2B type table-type low-speed centrifuges in capital；Olympus IX71 are inverted fluorescence microscopy Mirror modified form RPMI-1640 culture mediums, hyclone, 0.25% trypsin solution, tetrazolium bromide, Phosphate buffer (the silent winged generation that biochemistry product Beijing Co., Ltd of match)；Amresco diformazans Base sulfoxide (DMSO)；
Bel7402 HepG-2；Human colon cancer cell line HT-29；Human cervical cancer cell lines Hela；Human gastric cancer cell line BGC-823；Human lung cancer cell line A549；People's normal cell lines of human liver L02；
Experimental agents：The compounds of this invention LQC-C (is prepared) by embodiment 1-4；Bulk drug river Rhizome of chuanxiong piperazine (TMP), betulic acid (BA)；Positive drug cisplatin for injection (DPP) (301001CF； Qilu Pharmaceutical Co., Ltd.).
2. method
The culture of 2.1 different cell lines
HepG2, HT-29, Hela, BGC-823, A549 and L02 cell culture are containing 10% In the 1640 culture medium of hyclone, 37 DEG C, 5% CO are positioned over2Incubated in incubator.Carefully Born of the same parents grow in adhered state, observe upgrowth situation under inverted microscope, treat that cell quantity is appropriate When Secondary Culture.
Thin and normal cell the inhibited proliferation of 2.2 pairs of tumours
Take the logarithm growth period HepG2, HT-29, Hela, BGC-823, A549 and L02 it is thin Born of the same parents, are inoculated in 96 well culture plates with the quantity in 3 × 103/ holes, containing 5%CO2Humidifying culture 37 DEG C of culture 24h in case；100 μ L testing compounds are separately added into per hole, make ultimate density point Not Wei 40.0,20.0,10.0,5.0,2.5,1.25 μM.Cell controls group and blank control are set Group, medicine group repeats 4 holes per concentration, and cell controls group and blank control group repeat 3 holes.Culture Continue to cultivate after 72h in case, add 20 μ L MTT to be incubated 4h, supernatant discarding per hole, then Jia 100 μ L DMSO, vibrate 10min, and ELIASA 490nm wavelength measures absorbance, records result, And calculate the IC50 values of compound, cell inhibitory rate (%)=[1- (A administration-A blank)/(A is just Normal-A blank)] × 100%.
3. result
3.1 the compounds of this invention LQC-C to 5 kinds of tumor cell lines (HepG2, HT-29, Hela, BGC-823, A549) and people's normal cell lines of human liver L02 IC50Value is as shown in table 1.
As can be seen from Table 1, compound L QC-C shows preferable suppression to various cancer cells Proliferative activity o f tumor, and its antitumor activity is better than raw material；Wherein, compound L QC-C To human colon cancer cell line HT-29 and Human cervical cancer cell lines Hela and human lung cancer cell line A549 Antiproliferative activity is better than positive drug cis-platinum；But the cytotoxicity to people's normal cell lines of human liver L02 is substantially low In positive drug cis-platinum.
IC50 values of the table 1LQC-C to different tumor cell lines and normal cell
4. conclusion
The compounds of this invention show suppress tumor cell line (HepG2, HT-29, Hela, BGC-823, A549) propagation activity.
Embodiment
The preparation of the compound 2- chloromethyl -3,5,6- trimethylpyrazines (compound 5) of embodiment 1
Take ligustrazine 21.76g (160mmol) (compound 1) to be dissolved in 50ml glacial acetic acids, add The hydrogen peroxide of 18ml (160mmol) 30% reacts 4h in 90 DEG C, supplements afterwards The hydrogen peroxide of 18ml (160mmol) 30% continues to react 2h, and TLC is monitored to reaction completely, is cooled to Room temperature, pH to 10 is adjusted with 50% sodium hydroxide, and dichloromethane is extracted, anhydrous sodium sulfate drying, Filtering, recycling design obtains white ligustrazine list nitrogen oxygen (compound 2).Add in compound 2 Enter 15.1ml (160mmol) acetic anhydride, be heated to reflux 2.5h in 105 DEG C, TLC is monitored to having reacted Quan Hou, removes excessive aceticanhydride under reduced pressure, obtains black slurry ligustrazine acetylate (compound 3). This secondary black slurry thing is placed in 100ml (THF:MeOH:H2O=3:1:1) solution, is added portionwise 19.2g (480mmol) sodium hydroxide, stirring reaction 2h, dichloromethane extraction, anhydrous sodium sulfate is done Dry, filtering is removed under reduced pressure solvent, obtains hydroxyl ligustrazine crude product, recrystallized, obtained with n-hexane 18.5g yellow needles (compound 4).This yellow crystal is finally dissolved in the anhydrous tetrahydrochysenes of 150ml In furans, 30.3g (0.159mol) Tscl, 24.64g (0.244mol) TEA, 1.5g is then added (0.122mol) DMAP, is stirred overnight, dichloromethane extraction, anhydrous sodium sulfate drying, filtering, Recycling design, obtains faint yellow chloro ligustrazine crude product, silica gel post separation [V (petroleum ether):V (acetic acid Ethyl ester)=10:1] the chloro ligustrazine (compound 5) of water white transparency, yield 80% are obtained.
The standby compound TBA of embodiment 2 preparation
Weigh 12g (26.28mmol) betulic acid, 7.25g (52.56mmol) Anhydrous potassium carbonates in In 100ml single port bottles, 50mlDMF is added, 5.4g (31.5mmol) chlorine is added after stirring half an hour For ligustrazine (compound 5), under nitrogen protection, 12h is reacted in 60 DEG C, TLC is detected to anti- Should be complete, a certain amount of water terminating reaction is added, is then extracted with dichloromethane, collected organic layer, Appropriate anhydrous sodium sulfate water removal, evaporated under reduced pressure, silica gel post separation [V (petroleum ether):V (acetone)=10:1] Obtain white solid TBA, fusing point:184.6-185.4 DEG C, yield 90%.1H-NMR(CDCl3) (ppm):0.78,0.80,0.82,0.96,0.98,1.69(s,each,3H,6×-CH3),2.51(s,3H, -CH3),2.53(s,3H,-CH3),2.57(s,3H,-CH3),3.02(m,1H),3.19(m,1H), 4.61,4.74 (each, brs, 1H ,=CH2), 5.20,5.23 (each, d, J=12.5Hz, 1H ,-CH2), 1.00–2.50(25H,methyl-and methylene-of triterpenoid structure).13C-NMR (CDCl3)(ppm):14.7,15.4,15.9,16.1,18.3,19.4,20.9,25.5,27.4,28.0,29.7, 30.6,32.1,34.4,36.9,37.2,38.1,38.7,38.9,40.7,42.4,46.9,49.5,50.6,55.4, 56.7,79.0,109.6,150.5,175.5(-COO-)；pyrazine ring:20.4(-CH3),21.4 (-CH3),21.6(-CH3),64.3(-CH2),145.4,148.7,148.9,150.9.HRMS(ESI) m/z:591.45212[M+H]+, theoretical calculation C38H58N2O3590.44474.
The compound L QC-C of embodiment 3 preparation
Weigh successively 200mg (0.338mmol) TBA, 83.25mg (0.44mmol) Boc-L- methyl amimoacetic acids, 97.20mg (0.50mmol) EDCI and 4.12mg (0.0038mmol) DMAP is placed in 50mL single port bottles In, adding 5ml anhydrous methylene chloride dissolves it, and TLC [V (dichloromethanes are stirred overnight at room temperature Alkane):V (methanol)=20:1] reaction process is detected, reaction solution is extracted with dichloromethane, collected organic layer, Appropriate anhydrous sodium sulfate water removal, evaporated under reduced pressure, silica gel post separation [V (dichloromethane):V (methanol)=40:1] Obtain white solid；It is dissolved in the ethyl acetate of the HCl containing 3M, ice salt bath stirring 1h；Decompression Reaction solution is evaporated, appropriate ethyl acetate redissolves, pH is adjusted to neutrality with the sodium bicarbonate solution of saturation, Collected organic layer, appropriate anhydrous sodium sulfate water removal, evaporated under reduced pressure, silica gel post separation [V (dichloromethanes Alkane):V (methanol)=40:1] white solid LQC-C, fusing point are obtained:172.6-173.4 DEG C, yield:76.90%.1H-NMR(CDCl3)(ppm):0.77,0.84,0.93(s,each,3H,3×-CH3,methyl of BA),0.82(brs,6H,2×-CH3,methyl of BA),1.00-2.50(31H,methyl-and methylene-of BA),2.40,2.50,2.53(s,each,3H,3×-CH3,methyl of TMP), 2.96-3.01(m,1H,-CCHCH2-),3.52(brs,2H,-CH2NH-),4.48-4.51(m,1H, - OCOCH-), 4.56,4.59 (brs, each, 1H ,=CH2), 5.17,5.20 (d, each, 1H, J=15Hz, -OCH2-).13C-NMR(CDCl3)(ppm):14.79,16.00,16.28,16.64,18.27,19.47, 20.63,23.85,25.56,28.22,29.75,30.66,32.15,34.35,34.55,37.04,37.21, 38.01,38.18,38.47,40.79,42.53,46.97,49.59,50.58,50.73,55.55, 56.79(-CH-NH2), 83.23 (- OCOCH-), 109.81 (- CH=C-), 151.10 (- CH=C-), 168.63(-COCH-),175.66(-COO-),pyrazine ring:21.02(-CH3),21.51(-CH3), 21.80(-CH3),64.48(-CH2),145.46,148.89,148.98,150.60.HRMS(ESI)m/z: [M+H]+662.48975, theoretical calculation：C41H63N3O4661.48186.
Embodiment 4
LQC-C 10g are taken, injection (including freeze drying powder injection and aseptic subpackaged dry powder injection) is added Appropriate auxiliary material, is prepared by injection (including freeze drying powder injection and aseptic subpackaged dry powder injection) technique Into antineoplastic injection.
Embodiment 5
Take LQC-C 10g, add tablet (including slow-release tablet, matrix tablet, coating tablet, scattered Piece etc.) appropriate auxiliary material, by tablet (including slow-release tablet, matrix tablet, coating tablet, dispersible tablet etc.) Technique is prepared into antineoplastic tablet.
Embodiment 6
LQC-C 10g are taken, the appropriate auxiliary material of capsule is added, is prepared into by capsule technique antitumor Drug Capsule agent.
Embodiment 7
Take LQC-C 10g, emulsion (including micro emulsion, nano-emulsion etc.) appropriate auxiliary material is added, by breast Agent (including micro emulsion, nano-emulsion etc.) technique is prepared into antincoplastic agents.
Embodiment 8
LQC-C 10g are taken, the appropriate auxiliary material of granule is added, is prepared into by granule technique antitumor Medicine granule.
Embodiment 9
LQC-C 10g are taken, the appropriate auxiliary material of sustained-release and controlled release agent is added, is made by sustained-release and controlled release agent technique Antineoplastic sustained-release and controlled release agent.
Embodiment 10
LQC-C 10g are taken, the appropriate auxiliary material of oral liquid is added, is prepared into by oral liquid technique antitumor Medicine oral liquid.
Embodiment 11
LQC-C 10g are taken, the appropriate auxiliary material of Lipidosome is added, is prepared into by lipid body technology anti- Tumour medicine Lipidosome.

Claims (10)

1. having the compound or its pharmaceutically acceptable salt of the structure of formula 1, its structural formula is：
2. the compound as claimed in claim 1 or its pharmaceutically acceptable salt, its feature exist In, add formulation art customary adjuvant be made tablet, capsule, granule, powder, oral liquid, The regular dosage forms such as injection.
3. the preparation method of compound as claimed in claim 1, it is characterised in that this method includes Following steps：
Step 1, betulic acid is dissolved in organic solvent, with 2- chloromethyls -3,5,6- trimethyls Pyrazine generates midbody compound TBA in the basic conditions；
Step 2, midbody compound TBA reacts life in the presence of catalyst with methyl amimoacetic acid The compound of an accepted way of doing sth 1.
4. preparation method as claimed in claim 3, it is characterised in that react at -20 DEG C extremely Carried out at 250 DEG C；The organic solvent is the ether containing 1-20 carbon atom, alcohol, alkane, virtue Fragrant hydrocarbon, ketone, alkyl halide, acid amides, nitrile, the mixture of ester or their various ratios；Alkali used For triethylamine or potassium carbonate；The catalyst is I-hydroxybenzotriazole, 1- ethyls -3- (3- dimethylamine Propyl group) carbodiimide hydrochloride, 1,3- dicyclohexylcarbodiimides or DMAP.
5. preparation method as claimed in claim 3, it is characterised in that betulic acid and chloro river The mol ratio of rhizome of chuanxiong piperazine is 1:0.1~1:10；The mol ratio of betulic acid and alkali is 1:0.1~1:10；TBA Mol ratio with methyl amimoacetic acid is 1:0.1~1:10；The mol ratio of TBA and catalyst is 1:0.1~1:10.
6. compound as claimed in claim 1 or its pharmaceutically acceptable salt are preparing anticarcinogen Application in thing.
7. application as claimed in claim 6, it is characterised in that the cancer be liver cancer, lung cancer, Colon cancer, cervical carcinoma or stomach cancer.
8. pharmaceutical composition, it is characterised in that the composition includes what is existed with therapeutically effective amount Claim 1 compound or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient Mixture.
9. composition as claimed in claim 8, it is characterised in that the composition is also comprising extremely A kind of few conventional anti-cancer drugs.
10. composition as claimed in claim 9, it is characterised in that the anticarcinogen is selected from ring Phosphamide, 5 FU 5 fluorouracil, taxol, adriamycin, Etoposide, Irinotecan, oxaliplatin, Cis-platinum or gemzar.
CN201610059173.XA 2016-01-28 2016-01-28 Compound with anti-tumor effect and preparation method and application thereof Pending CN107011406A (en)

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CN201610059173.XA CN107011406A (en) 2016-01-28 2016-01-28 Compound with anti-tumor effect and preparation method and application thereof
CN201780003139.3A CN108137644B (en) 2016-01-28 2017-01-16 Compound with anti-tumor effect and preparation method and application thereof
PCT/CN2017/071276 WO2017128981A1 (en) 2016-01-28 2017-01-16 Compound having anti-tumour effect and preparation method and use thereof

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CN110101872A (en) * 2019-06-13 2019-08-09 成都大学 A kind of reduction-sensitive nano-micelle and preparation method and application
CN110483419A (en) * 2019-09-11 2019-11-22 泰州学院 A kind of two alkoxide derivative of ligustrazine/azo, preparation method and its usage

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US6569842B2 (en) * 2000-08-18 2003-05-27 Board Of Trustees Of The University Of Illinois, The Method of preparing and use of prodrugs of betulinic acid derivatives
CN101230082B (en) * 2006-05-12 2010-12-01 中国药科大学 23-hydroxy betulinic acid derivative, preparation method, preparation and use thereof
CN101928321B (en) * 2010-03-02 2012-09-05 福州大学 Acidic amino acid chemically-modified ursolic acid derivatives with anti-cancer activities
CN102675401B (en) * 2011-03-09 2014-08-13 雷海民 Preparation of anti-tumor medicine LQC-Y and application thereof
CN102344482A (en) * 2011-07-29 2012-02-08 温州大学 Betulinol derivant, preparation method and usage
CN104548120A (en) * 2013-10-22 2015-04-29 北京林业大学 Polyethylene glycol-betulinic acid conjugate and preparation method thereof

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Publication number Priority date Publication date Assignee Title
CN110101872A (en) * 2019-06-13 2019-08-09 成都大学 A kind of reduction-sensitive nano-micelle and preparation method and application
CN110483419A (en) * 2019-09-11 2019-11-22 泰州学院 A kind of two alkoxide derivative of ligustrazine/azo, preparation method and its usage
CN110483419B (en) * 2019-09-11 2022-11-29 泰州学院 Ligustrazine/azonium dialkoxide derivative, preparation method and application thereof

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