CN110025789A - A kind of drug phosphatide cpd and its pharmaceutical composition and application - Google Patents
A kind of drug phosphatide cpd and its pharmaceutical composition and application Download PDFInfo
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- CN110025789A CN110025789A CN201910255311.5A CN201910255311A CN110025789A CN 110025789 A CN110025789 A CN 110025789A CN 201910255311 A CN201910255311 A CN 201910255311A CN 110025789 A CN110025789 A CN 110025789A
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- 235000009508 confectionery Nutrition 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
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- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
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- 230000002346 endotoxic effect Effects 0.000 description 1
- 229950004126 ensartinib Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 125000003929 folic acid group Chemical group 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
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- 239000000499 gel Substances 0.000 description 1
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- 229930182470 glycoside Natural products 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- DASWEROEPLKSEI-UIJRFTGLSA-N monomethyl auristatin e Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 DASWEROEPLKSEI-UIJRFTGLSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
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- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
- A61K47/544—Phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明公开了一种药物磷脂化合物及其药物组合物和应用，该磷脂化合物为下列通式(1)的化合物或所述通式(1)的化合物与抗衡离子所形成的在药学上可接受的盐：式(1)中，m是2‑10的正整数，n是5‑10的正整数；X是药物；L是2‑氨基乙基、2‑三甲基胺基乙基阳离子。该药物组合物包括所述的药物磷脂化合物或所述的药物磷脂化合物与药效学上可接受的载体。所述药物磷脂化合物在制备抗肿瘤药物中的应用是将所述药物磷脂化合物或其在药学上可接受的盐，与药效学上可接受的载体制备成药剂。本发明的药物磷脂化合物及其脂质体纳米颗粒，可用作液体制剂、固体制剂、半固体制剂、灭菌制剂和无菌制剂，可在水相体系下形成脂质体。
The present invention discloses a pharmaceutical phospholipid compound, a pharmaceutical composition and application thereof. The phospholipid compound is a compound of the following general formula (1) or a pharmaceutically acceptable compound formed by the compound of the general formula (1) and a counter ion. of salt: In formula (1), m is a positive integer of 2-10, n is a positive integer of 5-10; X is a drug; L is 2-aminoethyl, 2-trimethylaminoethyl cation. The pharmaceutical composition comprises the pharmaceutical phospholipid compound or the pharmaceutical phospholipid compound and a pharmacodynamically acceptable carrier. The application of the pharmaceutical phospholipid compound in the preparation of antitumor drugs is to prepare the pharmaceutical phospholipid compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier into a medicament. The pharmaceutical phospholipid compounds and liposome nanoparticles of the present invention can be used as liquid preparations, solid preparations, semi-solid preparations, sterile preparations and sterile preparations, and can form liposomes in an aqueous system.
Description
Technical field
The present invention is a kind of drug phosphatide cpd with antitumor action and its pharmaceutical composition and purposes, is related to curing
Medicine technical field.
Background technique
Liposome is a kind of important pharmaceutical carrier, can be with the various drugs of loaded control release.Hydrophobic drug is usually in lipid
In double lipid layers of body.But drug is easy to leak out from liposome, influences the performance of drug effect.Drug molecule is passed through altogether
Valence link is integrated in phospholipid molecule structure and constitutes prodrug, can be to avoid drug leakage.Drug is by ester bond in conjunction with lysophosphatide
It is another scheme, but the degradation of ester bond is slowly, drug is difficult to quick release and comes out.
Patent (ZL201510598251.9) uses the cystine linkage for being easy to degrade, by two drug molecules and phosphoglycerol
Choline is connected.Cystine linkage can with rapid delivery of pharmaceuticals, but due to double drug glycerophosphocholine molecules not fatty acids long-chain,
Its is amphipathic uncontrollable, and compared with Fatty acids Phospholipids molecule, double drug structure of phospholipid are unfavorable for regular assembling, and assemble structure
The liposome built is unstable, is unfavorable in vivo release.
It is accordingly required in particular to invent a kind of existing good assembling ability, and it is easy and fast to the amphipathic drug of release drug,
Burst drug release is avoided simultaneously.
Taxol is a kind of alkaloid being extracted from plants.It can be accumulated in the cell after cell contact taxol a large amount of
Micro-pipe, the accumulation of these micro-pipes disturb the various functions of cell, cell division are especially made to stop at m period, block
The proper splitting of cell.Clinical research shows that taxol is primarily adapted for use in oophoroma and breast cancer, to lung cancer, colorectal cancer, black
Melanoma, head-neck carcinoma, lymthoma, brain tumor also have certain curative effect.
Taxol soluble is poor, need to use Emulsifier EL-60 and ethyl alcohol hydrotropy.Studies have shown that Emulsifier EL-60
Application reduce the anti-tumor activity of taxol, while taxol has stronger toxic effect, easily produces due to poor selectivity
The disadvantages of giving birth to drug resistance, blood-brain barrier can not be penetrated.The toxic side effect of taxol solvent can be reduced using loading liposomes, but
Drug effect is without significantly improving.Using macromolecule or albumin it is paclitaxel loaded be also overcome taxol solvent side effect have efficacious prescriptions
Formula, but drug is easy to leak out from carrier.Therefore, it is necessary to invent a kind of method, taxol solvent side effect is overcome,
Prevent drug leakage.
Camptothecine is also a kind of alkaloid, has stronger cytotoxic activity, can be used for treating Several Kinds of Malignancy, such as stomach
Cancer, liver cancer, bladder cancer and leukaemia etc..Camptothecine compounds are the specific inhibitors of classical Topo I.Camptothecine and
Its analog also generates the serious side effects such as bone marrow suppression, vomiting and diarrhea while playing its anti-tumor activity.It is maximum
Defect is water-soluble and fat-soluble inequality, it is difficult to obtain the solution of high concentration.Therefore, it is necessary to assign its hydrophily appropriate and parent
Lipid.
Contain an Alpha-hydroxy lactone in the molecule of camptothecine and the like, is easy open loop.Human serum albumins is preferential
In conjunction with the open loop form of camptothecine, stable compound is formed, so that anti-tumor activity is because in closed loop in this kind of compound body
Ester content declines and reduces.The serious toxicity of camptothecine compounds is primarily due to camptothecine after drug enters in human body
Caused by open loop form and albumin are combined closely.It is accordingly required in particular to which inventing a kind of method prevents lactone open loop, closed loop is kept
Lactone structure.
Anthracene nucleus medicament such as Doxorubicin etc. is a kind of important anti-tumor drug, but usually has cardiac toxic, marrow
Toxicity etc..Its toxicity can be reduced to a certain degree by being carried in liposome, but be easily leaked out, and be released the drug too fast.Using polyethylene glycol
The liposome vectors of macromolecular phosphatide building can extend pharmaceutical release time, but too long circulation time causes liposome to be easy to
In brothers' site deposition, cause brothers sick.It is accordingly required in particular to invent a kind of tumor locus microenvironment response quickly degradation drug release
Method prevents from leaking, but is easy and fast to the drug delivery system of drug release in tumor locus.
Although there is good targeting for Buddhist nun's class molecular targeted agents, but its side effect can not be ignored, including fash, abdomen
It rushes down, Cardiovascular Toxicity etc..In addition, this kind of drug also has drug resistance phenomenon.Therefore, it is necessary to improve the administration route for replacing Buddhist nun's class drug,
Overcome these defects.
Summary of the invention
Technical problem: the purpose of the present invention is to provide a kind of drug phosphatide cpd and its pharmaceutical composition and application,
It is a kind of phosphatide cpd in tumor locus quick release anti-tumor drug, improves the dissolubility and drug effect of anti-tumor drug,
Simultaneously provide a kind of pharmaceutical composition based on the drug phosphatide cpd and the drug phosphatide cpd prepare it is antitumor
Application in drug.
Technical solution: a kind of drug phosphatide cpd of the invention is the compound or the general formula (1) of general formula (1)
Compound and counter ion counterionsl gegenions be formed by pharmaceutically acceptable salt:
In formula (1), m is the positive integer of 2-10, and n is the positive integer of 5-10；X is drug；L is 2- amino-ethyl, 2- front three
Base amido ethyl cation.
In the preferred embodiment of drug phosphatide cpd of the invention, the counter ion counterionsl gegenions be it is a kind of cation and it is a kind of yin from
The combination of son.
In the preferred embodiment of drug phosphatide cpd of the invention, the drug is following one of which: taxol, polyenoid
Taxol, Cabazitaxel, camptothecine, hydroxycamptothecin, 7-Ethyl-10-hydroxycamptothecin, Irinotecan, topotecan, 7- hydroxyl
Methyl camptothecine, vincristine, vinorelbine, Ansamycin, code name be Monomethyl auristatin E compound,
Cytarabine, mitoxantrone, Doxorubicin, zorubicin, epirubicin, idarubicin, Sha bar are than star, lenalidomide, Pa Bo
Former times cloth, grace for Nuo Te, Bosutinib, according to Shandong for Buddhist nun, Yiluo for Buddhist nun, up to gram for Buddhist nun, linatinib, more Weis for Buddhist nun, Ba Fei for Buddhist nun,
Department beauty for Buddhist nun, Ai Le for Buddhist nun, Ceritinib, Afatinib, Sutent, Lapatinib, gram azoles for Buddhist nun, Erlotinib, card how
It is replaced for Buddhist nun, Axitinib, bosutinib, nilotinib, Gefitinib, Dasatinib, pelitinib, Trimetinib, Luso benefit
Buddhist nun, olaparib replace Buddhist nun, Imatinib, the husky change for Buddhist nun, Suo Fan for Buddhist nun, code name for Vorolanib of love according to Shandong for Buddhist nun, peace sieve
Object, alanine Bu Linibu are closed, drug is connected by formic acid esters or urethane bond with phosphatide.
Pharmaceutical composition of the invention, including above-mentioned drug phosphatide cpd or the drug phosphatide cpd and medicine
Effect learns upper acceptable carrier.
Pharmaceutical composition of the invention is liquid preparation, solid pharmaceutical preparation, semisolid preparation, capsule, granule, gel
Agent, injection, sustained release preparation or controlled release preparation.
In the preferred embodiment of pharmaceutical composition of the present invention, pharmaceutical composition is partial size 10-1000 nanometers of liposome nanometer
Particle.
Drug phosphatide cpd application in preparation of anti-tumor drugs of the invention, by drug phosphatide cpd or its
Acceptable carrier is prepared into medicament on pharmaceutically acceptable salt, with pharmacodynamics.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle
Or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.
Injection preparation is made in the compounds of this invention, such as solution, suspension solution, emulsion, freeze drying powder injection, this
Kind of preparation can be it is aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent, adhesive,
Lubricant, preservative, surfactant or dispersing agent.
From the point of view of anti tumor activity in vitro screening, the compounds of this invention shows good anti-tumor activity.Experiments have shown that this
The toxicity in vivo of invention compound is less than raw medicine.
From the point of view of anti tumor activity in vitro screening, the compounds of this invention elaioplast nanometer particle shows good antitumor work
Property.
From the point of view of external degradation speed, the compounds of this invention performance restores sensitive fast degradation.
The preparation method of drug phosphatide cpd elaioplast nanometer particle of the invention is by the compounds of this invention drug phosphorus
The mixture of compound or the compounds of this invention and auxiliary agent by film dispersion method, reverse phase evaporation, freeze-drying, surpasses
The preparation of the methods of sound wave dispersion method, spray drying process, film extrusion or high pressure homogenization method.
The utility model has the advantages that compared with prior art, the present invention having the advantage that
Drug phosphatide cpd of the invention contains easy fracture cystine linkage spacerarm in structural formula (1), in tumor locus or
In the presence of tumour cell middle and high concentration glutathione, cystine linkage fast fracture, the sulfydryl attack of generation adjacent formic acid esters or ammonia
The carbonyl of carbamate key forms high concentration raw medicine so that the raw medicine being attached thereto is fast released in the short time, play medicine
Effect；
Contain hydrophilic head part and hydrophobic fat acid long-chain in drug phosphatide cpd structural formula (1) of the invention,
Make drug phosphatide cpd and meanwhile have it is fat-soluble and water-soluble, be better than raw medicine, have hypotoxicity and excellent anti-tumor activity；
Drug phosphatide cpd of the invention have it is amphipathic, so that drug phosphatide cpd is assembled into stable liposome and receive
The shortcomings that rice grain, drug easily leaks out when overcoming general liposome anti-tumor drug, improves the efficiency of drug package；
The compound system of drug phosphatide cpd or the compositions such as itself and phosphatide auxiliary agent of the invention can use simple process,
Such as membrane process, high pressure homogenization method are easily assembled into elaioplast nanometer particle, and 10-1000 nanometers of partial size, drug and phosphorus
Rouge molecule has chemical bond to be connected, and drug will not leak out；
Drug phosphatide cpd of the invention is assembled into stable elaioplast nanometer particle, has the film knot similar with cell
Structure is easy to enter drug phosphatide cpd by liposomal form by cellular uptake intracellular, and release drug, played
Stronger drug effect, is not likely to produce drug resistance；
Drug phosphatide cpd elaioplast nanometer particle of the invention has passive target effect, is easy in tumour cell
Aggregation plays drug effect；
The pharmaceutical composition of the compound of the present invention or the compound of the present invention and Conventional pharmaceutical carriers resists with excellent
Tumor promotion；
Drug phosphatide cpd of the invention and its elaioplast nanometer particle can be used as liquid preparation, solid pharmaceutical preparation, half admittedly
Body preparation, sterilization preparation and sterile preparation can form liposome under aqueous phase system.
Detailed description of the invention
Fig. 1 stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 2 stearic acid-sn-2- camptothecine formic acid esters ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 3 palmitinic acid-sn-2-7- ethyl-10-hydroxycamptothecin -20- formic acid esters ethyl dithiopropionic acid phosphoglycerol
Choline synthetic route
Fig. 4 stearic acid-sn-2- vincristine formic acid esters ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 5 stearic acid-sn-2- adriamycin amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 6 palmitinic acid-sn-2- cytarabine amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 7 stearic acid-sn-2- up to gram replace Buddhist nun's formic acid esters ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 8 stearic acid-sn-2- Dasatinib formic acid esters ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Fig. 9-sn-2- grams of azoles of stearic acid replace Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 10 stearic acid-sn-2- lenalidomide amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
The synthesis of the thio hendecanoic acid choline glycerophosphatide of Figure 11 stearic acid-sn-2- lenalidomide amido formate ethyl two
Route
Figure 12 stearic acid-sn-2- Imatinib amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 13 stearic acid-sn-2- replaces Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route according to Shandong
Figure 14 stearic acid-sn-2- pa wins former times cloth amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 15 stearic acid-sn-2- pacifies sieve and replaces Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 16 stearic acid-sn-2- olaparib amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 17 stearic acid-sn-2-MMAE amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 18 stearic acid-sn-2- grace replaces promise spy amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
Figure 19 lauric acid-sn-2- love is husky to replace Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide synthetic route
The grain of Figure 20 stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide liposome
Diameter distribution.
Figure 21 stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide liposome nanometer
Particle transmission electron microscope picture.
Figure 22 stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide Liposomal delivery
Animal tumor volume change (a) and last tumor weight (b) afterwards.
Specific embodiment
Further details of the technical solution of the present invention with embodiment with reference to the accompanying drawings of the specification.
Drug phosphatide cpd of the invention is the compound with the compound or the general formula (1) of general formula (1)
Pharmaceutically acceptable salt is formed by with counter ion counterionsl gegenions:
In formula (1), m is the positive integer of 2-10, and n is the positive integer of 5-10；X is drug；L is 2- amino-ethyl, 2- front three
Base amido ethyl cation.
Counter ion counterionsl gegenions described above are the combinations of a kind of cation and a kind of anion.
Said medicine is taxol, Docetaxel, Cabazitaxel, camptothecine, hydroxycamptothecin, 7- ethyl -10- hydroxyl
Camptothecine, Irinotecan, topotecan, 7- methylol camptothecine, vincristine, vinorelbine, Ansamycin, code name are
The compound of Monomethyl auristatin E, cytarabine, mitoxantrone, Doxorubicin, zorubicin, epirubicin,
Idarubicin, Sha bar win former times cloth, grace than star, lenalidomide, pa and replace Buddhist nun, Da Ke for Nuo Te, Bosutinib, according to Shandong for Buddhist nun, Yiluo
For Buddhist nun, linatinib, more Weis for Buddhist nun, Ba Fei for Buddhist nun, department beauty for Buddhist nun, Ai Le for Buddhist nun, Ceritinib, Afatinib, Sutent,
Lapatinib, gram azoles replace Buddhist nun, Erlotinib, Canertinib, Axitinib, bosutinib, nilotinib, Gefitinib, reach sand
It is replaced for Buddhist nun, pelitinib, Trimetinib, Luso benefit for Buddhist nun, olaparib, according to Shandong for Buddhist nun, peace sieve for Buddhist nun, Imatinib, love sand
Buddhist nun, Suo Fan are for Buddhist nun, compound, the alanine Bu Linibu that code name is Vorolanib.
Pharmaceutical composition of the invention, which is characterized in that the composition is the drug phosphatide cpd or the medicine
Acceptable carrier on object phosphatide cpd and pharmacodynamics.
Pharmaceutical composition of the invention, which is characterized in that the composition be liquid preparation, solid pharmaceutical preparation, semisolid preparation,
Capsule, granule, gelling agent, injection, sustained release preparation or controlled release preparation.
Pharmaceutical composition of the invention, which is characterized in that it is characterized in that, the composition is partial size 10-1000 nanometers
Elaioplast nanometer particle further includes auxiliary agent in the pharmaceutical composition.The auxiliary agent is phosphatide, cholesterine.
Drug phosphatide cpd application in preparation of anti-tumor drugs of the invention, which is characterized in that this method is by institute
Drug phosphatide or its pharmaceutically acceptable salt are stated, is prepared into medicament with carrier acceptable in pharmacodynamics.It can will be of the invention
In conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant, being made be can be used as compound or the compounds of this invention
The administration form or dosage form appropriate that people's medicine uses.
The compounds of this invention can be enteron aisle or non-bowel containing its pharmaceutical composition administration route, such as oral, muscle,
Subcutaneously, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc..It can be drug administration by injection, including intravenous injection, intramuscular injection, subcutaneous
Injection, intracutaneous injection and acupoint injection therapy etc..Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be very
Solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, capsule, dripping pill, aerosol, ball
Agent, pulvis, solution, suspension, emulsion, granule, suppository, freeze drying powder injection etc..
The compounds of this invention can be made ordinary preparation, be also possible to sustained release preparation, controlled release preparation, targeting preparation and various
Particulate delivery system.
Elaioplast nanometer particle is made by the compounds of this invention and auxiliary agent, 10-1000 nanometers of partial size, the auxiliary agent used is phosphorus
Rouge, targeting one of phosphatide or cholesterol or a variety of.Targeting group in targeting phosphatide is folic acid, galactolipin, polypeptide, resists
Any one of body, antibody fragment, hyaluronic acid, asialoglycoprotein, polysaccharide.
From the point of view of anti tumor activity in vitro screening, the compounds of this invention shows good anti-tumor activity.Experiments have shown that this
The toxicity in vivo of invention compound is less than raw medicine.From the point of view of anti tumor activity in vitro screening, the compounds of this invention liposome nanometer
Particle shows good anti-tumor activity.Experiments have shown that the toxicity in vivo of the compounds of this invention is much smaller than raw medicine.From external degradation
From the point of view of speed, the compounds of this invention shows reduction response quickly degradability, and releases raw medicine.
The preparation method of drug phosphatide cpd elaioplast nanometer particle of the invention is by the compounds of this invention drug phosphorus
The mixture of compound or the compounds of this invention and auxiliary agent by film dispersion method, reverse phase evaporation, freeze-drying, surpasses
The preparation of the methods of sound wave dispersion method, spray drying process, film extrusion or high pressure homogenization method.
The following are portion of reagent code names used in preparation process:
DMAP 4-dimethylaminopyridine
DCC N, N- dicyclohexylcarbodiimide
Bis- sulphur of 2PDS 2,2'-, two pyridine
TFA trifluoroacetic acid
DMF dimethylformamide
DMSO dimethyl sulfoxide
(BOC)2O di-tert-butyl dicarbonate
BOC tertbutyloxycarbonyl
BTC triphosgene
GSH glutathione
NPC p-nitrophenyl chloroformate ester
It is following that the present invention is further illustrated by embodiment, but the present invention is not limited to following embodiments.
Embodiment 1
Stearic acid (or palmitinic acid, lauric acid)-sn-2- mercaptopropionic acid (or undecanoic acid) choline glycerophosphatide, stearic acid (or
Palmitinic acid, lauric acid)-sn-2- ethoxy dithiopropionic acid (or undecanoic acid) choline glycerophosphatide synthesis
It is General synthetic procedure below: mercaptopropionic acid (or undecanoic acid), the stearic acid of suitable trityl (trt) protection
(or lauric acid, palmitinic acid) lysophosphatide is dissolved in dimethyl sulfoxide, and catalytic amount DCC and DMAP is added, is stirred to react 12 at room temperature
Hour.After the reaction was completed, it is precipitated with ether, distillation washing is extracted with dichloromethane, and organic phase is dry with magnesium sulfate.After concentration
Stearic acid (or palmitinic acid, lauric acid)-sn-2-trt- mercaptopropionic acid (or undecanoic acid) phosphoglycerol gallbladder is obtained with pillar layer separation
Alkali.It is deprotected with trifluoro formic acid, through pillar layer separation, with chromatogram purification is prepared, obtains stearic acid (or palmitinic acid, lauric acid)-
Sn-2- mercaptopropionic acid (or undecanoic acid) choline glycerophosphatide (is denoted as X-SY-PC, X is fatty acid carbon atoms number, and Y is sulfydryl alkanoic acid
Carbon atom number, as stearic acid-sn-2- mercaptopropionic acid choline glycerophosphatide is denoted as 18-S3-PC).Product further with ethoxy
Dithiopyridines reaction, column chromatography separating purification obtain stearic acid (or palmitinic acid, lauric acid)-sn-2- ethoxy two thio third
Sour (or undecanoic acid) choline glycerophosphatide (is denoted as X-SSY-PC, X is fatty acid carbon atoms number, and Y is the carbon atom of sulfydryl alkanoic acid
Number, as stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide is denoted as 18-SS3-PC).Wherein, stearic acid-sn-2-
Ethoxy dithiopropionic acid choline glycerophosphatide characterization result is as follows:
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ4.66-4.32(3H,m),3.30(9H,s),3.96-3.43
(8H,m),2.96-2.25(8H,m),1.68-0.96(33H,m)。MS m/z:C31H62NO9PS2[M+H]+, calculated value 688.93,
Measured value 688.36.
Embodiment 2
(route is shown in figure for the synthesis of stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide
1)
(1) 2'-OH of taxol protects (2'-TBDMS-PTX)
0.6g taxol, 0.5g imidazoles, 30mL DMF are added in 100mL round-bottomed flask, stirring and dissolving.Thereto slowly
1.2g tert-butyl chloro-silicane is added dropwise, 20min continues to react at room temperature 12h after being added dropwise to complete.After reaction, it is added
The extraction of 100mL methylene chloride, is sufficiently washed with deionized water.Organic phase is dry with anhydrous magnesium sulfate, concentrated by rotary evaporation.It is chromatographed with column
Method purified product obtains white solid 2 '-tertiary butyl dimethyl Si alkane-taxol (2'-TBDMS-PTX) 0.62g, yield
95%.
1H NMR(500MHz,CDCl3):δ0.46(s,6H,Si(CH3)2),0.83(s,9H,tert-butyl),1.17
(s,3H,H17),1.24(s,3H,H16),1.71(s,3H,H19),1.82(s,3H,H18),1.94-2.06(m,2H,H6),
2.27 (s, 3H, 10-AcO), 2.42 (s, 3H, 4-AcO), 3.82 (d, J=7.3Hz, 1H, H3), 4.22 (d, J=8.4Hz, 1H,
), H20 4.33 (d, J=8.2Hz, 1H, H20), 4.82 (m, 1H, H7), 4.97 (d, J=8.4Hz, 1H, H5), 5.70 (d, J=
7.1Hz, 1H, H2 '), 5.82 (d, J=8.8Hz, 1H, H2), 6.26 (d, J=8.6Hz, 1H, H13), 6.30 (s, 1H, H10),
7.02 (d, J=8.7Hz, 1H, N-H), 7.32-7.54 (m, 9H, Ph1, m-Ph2, m-Ph3), 7.63 (t, J=7.8Hz, 2H, p-
Ph2, p-Ph3), 7.77 (d, J=7.4Hz, 2H, o-Ph2), 8.16 (d, J=7.4Hz, 2H, o-Ph3) .MS m/z:
C53H65NO14Si[M+H]+, calculated value 969.42, measured value 969.42 [M+H]+.
(2) synthesis of stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide
0.53g2'-TDMBS-PTX, 0.30g p-nitrophenyl chloroformate ester (NPC) are dissolved in 25mL anhydrous methylene chloride, are mixed
It closes uniform.The dichloromethane solution of 0.20g DMAP is slowly added dropwise, reaction 30min is stirred at room temperature.It is washed with distilled water, it is anhydrous
MgSO4Dry organic phase is simultaneously concentrated, and is purified by silica gel column chromatography, obtains intermediate product.Intermediate product is dissolved in 15mL methylene chloride
In, two thiopyridines of 1g ethoxy are added, 0.30g DMAP reacts 3 hours, equally progress silica gel column chromatography separating purification, obtains
Two thiopyridines of 2'-TDMBS-PTX-7- carbonic ester ethyl.
Two thiopyridines of 2'-TDMBS-PTX-7- carbonic ester ethyl are dissolved in 10mL methylene chloride, and 0.50g stearic acid-is added
Sn-2- mercaptopropionic acid choline glycerophosphatide 18-S3-PC, room temperature reaction is overnight.Later, thick production is washed with 0.1M dilute hydrochloric acid solution
Object, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product, obtains white solid.White solid is dissolved in tetrahydrofuran,
0.4g tetrabutyl ammonium fluoride (Bu is added4NF), it is stirred to react 1h at room temperature.It is washed with distilled water crude product, anhydrous MgSO4It is dry
Organic phase is simultaneously concentrated, and through column chromatographic purifying, it is sweet to obtain product stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid
Oleophosphoric acid choline 0.21g is white solid.
1H-NMR(500MHz,CH3OH-d4):δ1.26(s,32H,-CH2CH2-),1.31(s,3H,H16),1.64(s,3H,
H19),1.81(s,3H,H18),2.17(s,3H,10-AcO),2.40(s,3H,4-AcO),2.65(m,4H,H2”,H5”),
3.25(s,9H,-N+(CH3)3), 3.68 (m, 4H, H1 " ', H2 " '), 3.97 (d, J=7.2Hz, 2H, H3 "), 4.04 (d, J=
7.3Hz, 1H, H3), 4.22-4.25 (m, 4H, H16), 5.05 (d, J=9.6Hz, 2H, H5), 5.68 (d, J=6.9Hz, 2H,
H2 '), 6.17-6.26 (m, 4H, H10, H13), 7.34-7.53 (m, 18H, Ph1, m-Ph2, m-Ph3), 7.65 (t, J=
7.3Hz, 4H, p-Ph2, p-Ph3), 7.82 (m, 4H, O-Ph2), 8.16 (d, J=7.1Hz, 4H, o-Ph3) ppm.TOF-MS m/
z:C79H111N2O24PS2[M+H]+, calculated value 1567.41；Measured value 1567.40 [M+H]+。
Embodiment 3:
The synthesis of stearic acid-sn-2- camptothecine formic acid esters ethyl dithiopropionic acid choline glycerophosphatide (route is shown in Fig. 2)
0.53g camptothecine, 0.20g triphosgene (BTC) are uniformly mixed in 100mL anhydrous methylene chloride.In nitrogen atmosphere
Under, the dichloromethane solution of 0.30g DMAP is slowly added dropwise, reaction 2h is stirred at room temperature.It is added at one time into above-mentioned system
0.50g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, reaction is overnight.Later, with 0.1M dilute hydrochloric acid solution
Wash crude product, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- camptothecine
Formic acid esters ethyl dithiopropionic acid choline glycerophosphatide 0.35g is yellow solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.06-7.42(5H,m),6.74(1H,s),4.75-4.64
(3H, m), 4.46-4.22 (6H, d), 3.97-3.77 (4H, d), 3.43 (2H, t), 3.30 (9H, s), 2.95-2.25 (6H, m),
1.96-1.71(4H,m),1.33-1.21(28H,m),1.01-0.95(6H,m)。TOF-MS m/z:C52H76N3O14PS2[M+
H]+, calculated value 1064.46；Measured value 1064.40.
Embodiment 4:
Palmitinic acid-sn-2-7- ethyl-10-hydroxycamptothecin -20- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide
Synthesis (route is shown in Fig. 3)
The protection of 7-Ethyl-10-hydroxycamptothecin: 2.0g7- ethyl-10-hydroxycamptothecin (SN38), two dimethyl dicarbonates
Anhydrous pyridine 8mL is added dropwise in 150mL anhydrous methylene chloride in butyl ester 1.0g mix suspending, is stirred to react at room temperature overnight.It crosses
Filter, filtrate three times, washed once with 0.5M salt acid elution with saturated sodium bicarbonate solution, separate organic phase and use anhydrous magnesium sulfate
It is dry.After drying, vacuum removes solvent, obtains 10- t-butyl carbonate -7- Ethyl-camptothecin (BOC-SN38,1.22g, 80%).
1H NMR(300MHz,CDCl3):δ1.00(3H,t,J)7.3Hz),1.40(3H,t,J)7.7Hz),1.62(9H,s),1.81–
1.97(2H,m),3.13(2H,q,J)7.7Hz),4.39(1H,s,OH),5.23(2H,s),5.29(1H,d,J)16.5Hz),
5.73(1H,d,J)16.5Hz),7.63(1H,dd,J)2.6,9.1Hz),7.69(1H,s),7.84(1H,d,J)2.2Hz),
8.23(1H,d,J)9.1Hz).13C NMR(75.4MHz,CDCl3):δ7.90,13.98,23.17,27.73,31.62,
49.33,66.18,72.80,84.26,98.06,113.88,118.53,124.98,127.13,127.19,131.83,
145.15,146.50,147.00,149.70,150.02,151.28,151.60,157.38,173.53.MS(ESI)
C27H28N2O7[M+H]+: calculated value 494.20, measured value: 494.20.
Palmitinic acid-sn-2-7- ethyl-10-hydroxycamptothecin -20- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide
Synthesis: 0.80g10- t-butyl carbonate -7- Ethyl-camptothecin, 0.30g triphosgene (BTC) are in 100mL anhydrous methylene chloride
It is uniformly mixed.Under nitrogen atmosphere, the dichloromethane solution of 0.30g DMAP is slowly added dropwise, reaction 2h is stirred at room temperature.To above-mentioned
0.50g palmitinic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide is added at one time in system, reaction is overnight.Later,
Crude product, MgSO are washed with 0.1M dilute hydrochloric acid solution4Dry organic phase is simultaneously concentrated.Column chromatography purifying obtains producing among yellow
Object.Intermediate product is dissolved in methylene chloride, and trifluoroacetic acid 0.5mL is added, and reacts 2h.Thick production is washed with 0.1M dilute hydrochloric acid solution
Object, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains product palmitinic acid-sn-2-7- ethyl -10- hydroxyl
Camptothecine -20- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide 0.53g is yellow solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ7.98-7.06(3H,m),6.74(1H,s),4.74-4.63
(3H, m), 4.46-4.20 (6H, d), 3.97-3.76 (4H, d), 3.43 (2H, t), 3.30 (9H, s), 2.96-2.25 (8H, m),
1.96-1.72(4H,m),1.33-1.20(27H,m),1.01-0.94(6H,m)。TOF-MS m/z:C52H76N3O15PS2[M+
H]+, calculated value 1079.45；Measured value 1079.40.
Embodiment 5:
The synthesis of stearic acid-sn-2- vincristine formic acid esters ethyl dithiopropionic acid choline glycerophosphatide (route is shown in Fig. 4)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.3g vincristine (vincristine) is added into above-mentioned system, reaction is overnight.Later, molten with 0.1M dilute hydrochloric acid
Liquid washs crude product, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains the Changchun product stearic acid-sn-2-
New alkali formic acid esters ethyl dithiopropionic acid choline glycerophosphatide 0.23g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.06(1H,s),7.25-7.01(6H,m),5.75-5.70
(2H, m), 4.66-4.32 (6H, m), 3.97-3.43 (15H, m), 3.30 (9H, s), 2.85-2.10 (25H, m), 1.85-1.51
(6H,m),1.33-1.21(28H,m),1.01-0.95(6H,m)。TOF-MS m/z:C77H114N5O19PS2[M+H]+, calculated value
1059.85；Measured value 1059.80.
Embodiment 6:
(route is shown in figure for the synthesis of stearic acid-sn-2- adriamycin amido formate ethyl dithiopropionic acid choline glycerophosphatide
5)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.2g adriamycin (DOX) is added into above-mentioned system, reacts 3h.Later, thick production is washed with 0.1M dilute hydrochloric acid solution
Object, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- adriamycin amidocarbonic acid
Ester ethyl dithiopropionic acid choline glycerophosphatide 0.22g is red solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ7.45-7.05(3H,m),5.00-4.20(11H,m),3.97-
3.43 (12H, m), 3.30 (9H, s), 2.95-2.10 (10H, m), 1.95-1.65 (3H, m), 1.33-1.21 (31H, m),
1.01-0.95(3H,t)。TOF-MS m/z:C59H89N2O21PS2[M+H]+, calculated value 1058.44；Measured value 1058.56.
Embodiment 7:
(route is shown in for the synthesis of palmitinic acid-sn-2- cytarabine amido formate ethyl dithiopropionic acid choline glycerophosphatide
Fig. 6)
0.35g palmitinic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.15g cytarabine (Cytarabine) is added into above-mentioned system, reacts 3h.Later, with 0.1M dilute hydrochloric acid solution
Wash crude product, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains product palmitinic acid-sn-2- arabinose born of the same parents
Glycosides amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.25g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ5.95(1H,s),4.64-4.20(7H,m),3.97-3.63
(11H, m), 3.30 (9H, s), 2.95-2.00 (11H, m), 1.33-1.21 (26H, m), 1.01-0.95 (3H, t).TOF-MS
m/z:C39H69N4O15PS2[M+H]+, calculated value 930.39；Measured value 930.46.
Embodiment 8:
Stearic acid-sn-2- reaches gram synthesis for replacing Buddhist nun's formic acid esters ethyl dithiopropionic acid choline glycerophosphatide (route is shown in Fig. 7)
0.20g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.Into above-mentioned system be added 0.1g up to gram replace Buddhist nun (Dacomitinib), react 3h.Later, with 0.1M dilute hydrochloric acid solution
Wash crude product, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- up to gram replacing
Buddhist nun amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.12g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.40-6.40(8H,m),4.66-3.40(13H,m),3.30
(9H,s),3.05-2.10(12H,m),1.60-0.96(39H,m)。TOF-MS m/z:C56H85ClFN6O12PS2[M+H]+, calculate
Value 1184.86；Measured value 1184.56.
Embodiment 8:
The synthesis of stearic acid-sn-2- Dasatinib formic acid esters ethyl dithiopropionic acid choline glycerophosphatide (route is shown in Fig. 8)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g Dasatinib (Dasatinib) is added into above-mentioned system, reacts 3h.Later, it is washed with 0.1M dilute hydrochloric acid solution
Wash crude product, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- adriamycin amine
Carbamate ethyl dithiopropionic acid choline glycerophosphatide 0.15g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.20-6.80(5H,m),5.30(1H,s),4.63-4.32
(7H,m),3.30(9H,s),3.96-3.43(6H,m),3.16(4H,m),2.96-2.25(20H,m),1.63-0.96(33H,
m)。TOF-MS m/z:C54H86ClN8O12PS3[M+H]+, calculated value 1202.93；Measured value 1202.66.
Embodiment 10:
- sn-2- grams of azoles of stearic acid for the synthesis of Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide, (be shown in by route
Fig. 9)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g grams of azoles is added into above-mentioned system and replaces Buddhist nun (Crizotinib), reacts 3h.Later, with 0.1M dilute hydrochloric acid solution
Wash crude product, MgSO4Dry organic phase is simultaneously concentrated.Column chromatography purified product obtains-sn-2- grams of azoles of product stearic acid and replaces
Buddhist nun amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.18g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.40-6.70(7H,m),5.10(1H,s),4.63-4.32
(5H,m),3.30(9H,s),3.96-3.43(7H,m),2.96-2.25(12H,m),1.93-0.96(40H,m)。TOF-MS m/
z:C53H82Cl2FN6O11PS2[M+H]+, calculated value 1265.26；Measured value 1165.56.
Embodiment 11:
(route is shown in for the synthesis of stearic acid-sn-2- lenalidomide amido formate ethyl dithiopropionic acid choline glycerophosphatide
Figure 10)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g lenalidomide (Lenalidomide) is added into above-mentioned system, reacts 3h.Later, molten with 0.1M dilute hydrochloric acid
Liquid washing crude product, the dry organic phase of MgSO4 are simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- and comes that
Amine amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.14g is spent, is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ7.80-7.20(3H,m),4.64-4.22(8H,m),3.30
(9H,s),3.96-3.43(6H,m),2.96-2.11(12H,m),1.68-0.96(32H,m)。TOF-MS m/z:
C45H73N4O13PS2[M+H]+, calculated value 974.18；Measured value 974.24.
Embodiment 12:
Synthesis (the road of the thio hendecanoic acid choline glycerophosphatide of stearic acid-sn-2- lenalidomide amido formate ethyl two
Line is shown in Figure 11)
The thio hendecanoic acid choline glycerophosphatide of 0.30g stearic acid-sn-2- ethoxy two, 0.10g triphosgene (BTC) in
It is uniformly mixed in 100mL anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP, room is slowly added dropwise
Temperature is stirred to react 2h.0.1g lenalidomide (Lenalidomide) is added into above-mentioned system, reacts 3h.Later, dilute with 0.1M
Hydrochloric acid solution washing crude product, the dry organic phase of MgSO4 are simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-
The thio hendecanoic acid choline glycerophosphatide 0.11g of 2- lenalidomide amido formate ethyl two is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ7.80-7.20(3H,m),4.64-4.22(8H,m),3.30
(9H,s),3.96-3.43(6H,m),2.96-2.11(12H,m),1.68-0.96(48H,m)。TOF-MS m/z:
C53H89N4O13PS2[M+H]+, calculated value 1086.56；Measured value 1086.26.
Embodiment 13:
(route is shown in for the synthesis of stearic acid-sn-2- Imatinib amido formate ethyl dithiopropionic acid choline glycerophosphatide
Figure 12)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g Imatinib (Imatinib) is added into above-mentioned system, reacts 3h.Later, it is washed with 0.1M dilute hydrochloric acid solution
It washs the dry organic phase of crude product, MgSO4 and is concentrated.Column chromatography purified product obtains product stearic acid-sn-2- Imatinib
Amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.17g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.80-7.24(13H,m),4.64-4.22(6H,m),3.30
(9H,s),3.96-3.43(8H,m),2.96-2.25(22H,m),1.68-0.96(33H,m)。TOF-MS m/z:
C61H91N8O11PS2[M+H]+, calculated value 1208.53；Measured value 1208.40.
Embodiment 14:
Stearic acid-sn-2- according to Shandong, for the synthesis of Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide, (be shown in by route
Figure 13)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g is added into above-mentioned system and replaces Buddhist nun (Imatinib) according to Shandong, reacts 3h.Later, it is washed with 0.1M dilute hydrochloric acid solution
It washs the dry organic phase of crude product, MgSO4 and is concentrated.Column chromatography purified product obtains product stearic acid-sn-2- according to Shandong for Buddhist nun
Amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.12g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.40-6.92(10H,m),6.62-5.55(3H,m),4.66-
4.32(5H,m),3.30(9H,s),3.96-3.34(11H,m),2.96-2.25(8H,m),1.94-0.96(37H,m)。TOF-
MS m/z:C57H84N7O12PS2[M+H]+, calculated value 1155.42；Measured value 1155.56.
Embodiment 15:
(route is shown in for the synthesis of the rich former times cloth amido formate ethyl dithiopropionic acid choline glycerophosphatide of stearic acid-sn-2- pa
Figure 14)
0.35g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g pa is added into above-mentioned system and wins former times cloth (Palbociclib), reacts 3h.Later, with 0.1M dilute hydrochloric acid solution
The dry organic phase of washing crude product, MgSO4 is simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- pa and wins former times
Cloth amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.24g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.10-6.95(4H,m),4.66-4.32(5H,m),3.30
(9H,s),3.96-3.19(13H,m),2.96-2.25(8H,m),1.94-0.96(44H,m)。TOF-MS m/z:
C56H89N8O12PS2[M+H]+, calculated value 1162.46；Measured value 1162.64.
Embodiment 16:
Stearic acid-sn-2- pacifies sieve, and for the synthesis of Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide, (route is shown in
Figure 15)
0.40g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g peace sieve is added into above-mentioned system and replaces Buddhist nun (Anlotinib), reacts 3h.Later, it is washed with 0.1M dilute hydrochloric acid solution
It washs the dry organic phase of crude product, MgSO4 and is concentrated.Column chromatography purified product obtains product stearic acid-sn-2- peace sieve for Buddhist nun
Amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.28g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.55-6.10(7H,m),4.66-4.12(7H,m),3.30
(9H,s),3.96-3.19(9H,m),2.96-2.25(11H,m),1.94-0.46(37H,m)。TOF-MS m/z:
C55H82FN4O13PS2[M+H]+, calculated value 1122.36；Measured value 1122.68.
Embodiment 17:
Synthesis (the road of behenic acid-sn-2- olaparib amido formate ethyl dithiopropionic acid choline glycerophosphatide
Line is shown in Figure 16)
0.30g behenic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) in
It is uniformly mixed in 100mL anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP, room is slowly added dropwise
Temperature is stirred to react 2h.0.1g olaparib (Olaparib) is added into above-mentioned system, reacts 3h.Later, with 0.1M dilute hydrochloric acid
Solution washing crude product, the dry organic phase of MgSO4 are simultaneously concentrated.Column chromatography purified product obtains product behenic acid-sn-
2- olaparib amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.22g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.10-7.03(7H,m),4.66-4.32(5H,m),3.30
(9H,s),3.96-3.43(14H,m),2.96-2.25(10H,m),1.94-0.46(46H,m)。TOF-MS m/z:
C60H91FN5O13PS2[M+H]+, calculated value 1205.59；Measured value 1205.56.
Embodiment 18:
(route is shown in figure for the synthesis of stearic acid-sn-2-MMAE amido formate ethyl dithiopropionic acid choline glycerophosphatide
17)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g compound MMAE (Monomethyl auristatin E) is added into above-mentioned system, reacts 3h.Later, it uses
0.1M dilute hydrochloric acid solution washing crude product, the dry organic phase of MgSO4 are simultaneously concentrated.Column chromatography purified product obtains product tristearin
Acid-sn-2-MMAE amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.13g is white solid.
TOF-MS m/z:C71H127N6O17PS2[M+H]+, calculated value 1432.84；Measured value 1432.64.
Embodiment 19:
Stearic acid-sn-2- grace for the synthesis of promise spy amido formate ethyl dithiopropionic acid choline glycerophosphatide, (be shown in by route
Figure 18)
0.30g stearic acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.0.1g grace is added into above-mentioned system and replaces Nuo Te (Entinostat), reacts 3h.Later, with 0.1M dilute hydrochloric acid solution
The dry organic phase of washing crude product, MgSO4 is simultaneously concentrated.Column chromatography purified product obtains product stearic acid-sn-2- grace for promise
Special amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.12g is white solid.
1H NMR(500MHz,CD3OD:CDCl3 1:1):δ8.55-6.98(12H,m),5.34(2H,s),4.66-4.22
(7H,m),3.30(9H,s),3.96-3.43(6H,m),2.96-2.25(8H,m),1.94-0.96(33H,m)。TOF-MS m/
z:C53H80N5O13PS2[M+H]+, calculated value 1091.33；Measured value 1091.24.
Embodiment 20:
The husky synthesis for Buddhist nun's amido formate ethyl dithiopropionic acid choline glycerophosphatide of lauric acid-sn-2- love (be shown in by route
Figure 19)
0.30g lauric acid-sn-2- ethoxy dithiopropionic acid choline glycerophosphatide, 0.10g triphosgene (BTC) are in 100mL
It is uniformly mixed in anhydrous methylene chloride.Under nitrogen atmosphere, the dichloromethane solution of 0.15g DMAP is slowly added dropwise, is stirred at room temperature
React 2h.It is husky for Buddhist nun (Ensartinib) that 0.1g love is added into above-mentioned system, reacts 3h.Later, with 0.1M dilute hydrochloric acid solution
The dry organic phase of washing crude product, MgSO4 is simultaneously concentrated.Column chromatography purified product obtains product lauric acid-sn-2- love sand and replaces
Buddhist nun amido formate ethyl dithiopropionic acid choline glycerophosphatide 0.14g is white solid.
TOF-MS m/z:C51H73Cl2FN7O13PS2[M+H]+, calculated value 1178.17；Measured value 1178.36.
Embodiment 21:
The preparation of drug phospholipid liposome
Drug phosphatide (stearic acid-sn-2- taxol -7- formic acid esters the ethyl two of embodiment 2 obtained by embodiment 2-20
Propane thioic acid choline glycerophosphatide etc.) 0.5mmol, Distearoyl Phosphatidylcholine DSPC0.5mmol, cholesterol 0.3mmol points
Not Jia Ru chloroform 20ml, 60 DEG C of rotation solvent evaporateds.20ml PBS (pH7.4) solution, 60 DEG C of skinnings, 200nm filter membrane is added
Filtering, obtains drug phospholipid liposome nanoparticles solution.Using laser particle analyzer measure partial size, average grain diameter 120-180nm, thoroughly
Radio mirror measures the form of nano particle, shows spherical structure.Drug phospholipid liposome nanoparticles solution is lyophilized, powder is obtained
Shape nano particle.
Embodiment 22:
The preparation of drug phospholipid liposome
Stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid phosphoglycerol gallbladder is prepared using film dispersion method
Alkali long circulating liposome.Specific step is as follows: weighing lecithin, cholesterol, distearyl acyl group phosphorus according to molar ratio 90:10:5:3
Acyl ethanol amine-polyethylene glycol (DSPE-PEG2000, polyethylene glycol average molecular weight 2000), stearic acid-sn-2- taxol-
7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide is dissolved respectively at being placed in 100mL eggplant-shape bottle with chloroform, and 37 DEG C slowly
Revolving evaporation film forming.10mL PBS (pH7.4) buffer solution is added, aquation skinning 30min at a temperature of 60 DEG C shakes 10min and obtains
To stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide nano liposomes aqueous solution.With matching
There is the liposome extruder homogenizing of 0.22 μm of filter membrane three times.
The common long circulating liposome sample preparation of physically encapsulation taxol is similar with above-mentioned liposome, i.e., is rubbed using identical
The matrix material and taxol (90:10:5:3) of your ratio, but stearic acid-sn-2- taxol -7- formic acid esters second is replaced with taxol
Base dithiopropionic acid choline glycerophosphatide, taxol are equimolar amounts.
Partial size is measured using laser particle analyzer, transmission electron microscope measures the form of nano particle, shows spherical structure.By drug
The freeze-drying of phospholipid liposome nanoparticles solution, obtains powdered nanoparticles particle.Figure 20 is stearic acid-sn-2- taxol -7- formic acid esters
Ethyl dithiopropionic acid choline glycerophosphatide liposomal particle size is distributed (laser particle analyzer), and Figure 21 is its transmission electron microscope picture.
Embodiment 23:
The preparation of drug phosphatide long circulating liposome
Drug phosphatide (stearic acid-sn-2- taxol -7- formic acid esters the ethyl two of embodiment 2 obtained by embodiment 2-20
Propane thioic acid choline glycerophosphatide etc.) 0.5mmol, Distearoyl Phosphatidylcholine DSPC0.5mmol, cholesterol 0.3mmol, two
Stearoyl phosphatidyl ethanol amine-polyethylene glycol (DSPE-PEG2000, polyethylene glycol average molecular weight 2000) 0.05mmol, point
Not Jia Ru chloroform 20ml, 60 DEG C of rotation solvent evaporateds.20ml PBS (pH7.4) solution, 60 DEG C of skinnings, 200nm filter membrane is added
Filtering, obtains drug phosphatide long circulating liposome nanoparticles solution.Partial size, average grain diameter 120- are measured using laser particle analyzer
190nm, transmission electron microscope measure the form of nano particle, show spherical structure.Drug phospholipid liposome nanoparticles solution is frozen
It is dry, obtain powdered nanoparticles particle.
Embodiment 24:
The external degradation of stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide liposome
Test
0.1mmol stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid glycerol phosphorus prepared by embodiment 22
Sour choline elaioplast nanometer particle 10mL PBS solution is divided into 2 parts, and the PBS buffer solution of glutathione (GSH) is added in a copy of it
0.5mL (GSH concentration 50mmol), PBS buffer solution 0.5mL is added in another.Reference substance is the general of load same amount taxol
Elongated circulating liposome (embodiment 22).It places and is incubated in incubator 37 DEG C, with high performance liquid chromatography detection taxol
(Agilent1100LC, Zorbax reverse phase C18 column, 150 × 4.6mm, 5 μm, 20 μ L of sample volume, detects wave to content by 25 DEG C of column temperature
Long 254nm；Gradient elution: 2-90% buffer solution B/A, flow velocity 1.0mL/min, buffer solution A: the deionized water of 0.1%TFA is delayed
The acetonitrile of fliud flushing B:0.1%TFA).
The result shows that stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid phosphoglycerol the gallbladder of GSH processing
The taxol that alkali liposome solutions release after 10 hours reaches the 75% of total amount；Stearic acid-sn-2- without GSH processing
Taxol -7- formic acid esters released after ethyl dithiopropionic acid choline glycerophosphatide liposome solutions 10 hours taxol be only
The 8.5% of total amount.The taxol discharged behind common long circulating liposome 10 hours of physical load taxol is the 28% of total amount.
So stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide liposome has reduction sensitive
Property, the quick release taxol raw medicine under GSH effect, rate of release is far faster than common long circulating liposome.Due to tumour cell
In have the glutathione of high concentration, above-mentioned liposome restores response, quick release raw medicine taxol in tumour cell.
Experimental example 25:
Mtt assay human cancer cell fragmentation test
Drug and reagent: calf serum is Nanjing Sheng Xing Bioisystech Co., Ltd product；DMSO analysis is pure；RPMI1640
For GIBCO product.
Instrument: BIORAD680 type microplate reader.Well-grown tumour cell MCF-7: human breast cancer cell is collected, with containing
The RPMI1640 culture medium of 10% calf serum is configured to 8 × 103/ mL cell suspension, is inoculated in 96 well culture plates, every sky
100 μ L (contain 1000 tumour cells), set 37 DEG C, and dosing after culture 24 hours in 5%CO2 incubator: the difference of embodiment 22 is dense
Stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide long circulating liposome 200 μ the L of degree is right
It is that 200 μ L RPMI-1640 culture mediums, blank group is added in paclitaxel loaded common long circulating liposome (embodiment 22) according to group
200 μ L culture mediums of (cell-free) addition.Given the test agent sets 6 concentration, 3 parallel holes of every concentration, sets 37 DEG C, in 5%CO2 incubator
Culture 48 hours.Culture solution is discarded, 100 μ L of MTT solution (0.4mg/mL, RPMI1640 are prepared) is added in every hole, and 37 DEG C of incubations 4 are small
When.Discard supernatant liquid, every hole is added 150 μ L of MTT solution, dissolved particles, after gentle agitation, with microplate reader (Bio-Rad model
680) OD value is measured at Detection wavelength 540nm, reference wavelength 450nm.As a result it calculates: with the various concentration of drug and to cell
Inhibiting rate mapping dose-effect curve can be obtained, therefrom find out half-inhibitory concentration (IC50).
As a result: it is anti-swollen from vitro that the compounds of this invention liposome the results are shown in Table 1. to the anti-tumor activity of human tumor cell line
From the point of view of tumor activity screening, the compounds of this invention stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid phosphoglycerol
The IC50 of choline long circulating liposome is respectively less than common long circulating liposome, illustrates its activity better than conventional liposome.This be because
For stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide liposome is by double after cellular uptake
Sulfide linkage goes out raw medicine taxol, kills cell because of reduction response fracture, quick release.And conventional liposome is paclitaxel loaded, although
It is physically encapsulation, but taxol release speed is slower, the ability decline of killing tumor cell.
Anti-tumor activity result of the 1. the compounds of this invention liposome of table to human tumor cell line MCF-7
Experimental example 26:
Taxanes phosphatide cpd is tested in In vivotoxicity
Animal: ICR mouse, male, 18-22g are purchased from Nanjing KaiJi Biology Science Development Co., Ltd.
The body of the compounds of this invention stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid choline glycerophosphatide
Endotoxic test the results are shown in Table 2.The result shows that the maximum tolerated dose of the compounds of this invention taxanes phosphatide cpd is equal
Greater than 100mg/kg, toxicity is much smaller than taxol.
2 taxanes phosphatide cpd of table is in In vivotoxicity test result
Experimental example 27:
Drug effect and toxicity test in bis- (two thiodiethanol of taxol -7- acid) phosphatidyl choline compounds Via Liposomes
The preparation of nude mice model: collecting the MCF-7 cell suspension of culture, and concentration is 1 × 107A/ml, with every 0.1ml
It is subcutaneous to be inoculated in armpit on the right side of nude mouse, until 0.1 cubic centimetre of tumour mean size.Grouping and administration: transplanted tumor in nude mice is used
Vernier caliper measurement transplantable tumor diameter, tumour growth to 75mm3When animal is grouped at random.Meanwhile each group nude mice starts to be administered,
Dosage regimen is shown in group and dosage regimen, uses the method for measurement knurl footpath, the anti-tumor effect of dynamic observation given the test agent.Tumour
The calculation formula of volume (TV) are as follows: TV=1/2 × a × b2(formula 3-2), wherein a, b respectively indicate length and width.
Group and dosage regimen: blank group: physiological saline, intravenous injection, injection is primary every three days, volume 0.2ml, even
It is 3 weeks continuous.
Control group: taxol: being formulated (taxol is dissolved in Emulsifier EL-60 and ethyl alcohol) according to marketed drug taxol,
Physiological saline, intravenous injection, injection is primary every three days, volume 0.2ml, and continuous 3 weeks.
The common long circulating liposome of taxol: embodiment 22 prepares the common long circulating liposome of taxol, intravenous injection, often
Injection in three days is primary, volume 0.2ml, and continuous 3 weeks.
Medicine group: the stearic acid-sn-2- taxol -7- formic acid esters ethyl dithiopropionic acid phosphoglycerol gallbladder of embodiment 22
Alkali long circulating liposome solution (dosage is equivalent to taxol 5mg/kg, and with the common long circulating liposome of taxol and taxol
Dose of paclitaxel it is consistent), intravenous injection, injection is primary every three days, volume 0.2ml, continuous 3 weeks.Period measures tumour body
Product, changes of weight, anatomic measurement tumor weight after experiment.
Anti-tumor activity result is shown in Figure 22.From the point of view of anti-tumor activity, stearic acid-sn-2- taxol -7- formic acid of the present invention
Ester ethyl dithiopropionic acid choline glycerophosphatide long circulating liposome has inhibits tumour growth effect well, and is substantially better than
The common long circulating liposome of taxol.In addition, the weight of animals of medication group and control group does not decline, display is non-toxic.
Above-described embodiment is only the preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill of the art
For personnel, without departing from the principle of the present invention, several improvement and equivalent replacement can also be made, these are to the present invention
Claim improve with the technical solution after equivalent replacement, each fall within protection scope of the present invention.
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