CN105457038A - Quick release type medicine phosphatide compound and medicine composition thereof - Google Patents

Quick release type medicine phosphatide compound and medicine composition thereof Download PDF

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CN105457038A
CN105457038A CN201510756327.6A CN201510756327A CN105457038A CN 105457038 A CN105457038 A CN 105457038A CN 201510756327 A CN201510756327 A CN 201510756327A CN 105457038 A CN105457038 A CN 105457038A
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compound
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diethylene glycol
buddhist nun
succinate
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李新松
杜亚伟
凌龙兵
何瑞玉
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Southeast University
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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
    • A61K31/395—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/69—Boron compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides

Abstract

The invention discloses a quick release type medicine phosphatide compound and a medicine composition thereof. In the compound, a medicine Y1 and a medicine Y2 are connected with a quick release type hydrophobic spacer arm and an enhancement type hydrophobic spacer arm through chemical bonds, the two spacer arms are cooperated to enhance the hydrophobic effect to form hydrophobic lipotropy chains, the two hydrophobic chains are connected with a phospholipid hydrophilic head to form an amphipathic molecule. The medicine composition is the quick release type medicine phosphatide compound or a combined medicine composition of the compound and a carrier acceptable in pharmacodynamics. The quick release type medicine phosphatide compound and lipidosome nano particles thereof can be used as a liquid preparation, a solid preparation, a semi-solid preparation, a sterilization preparation and a sterile preparation, are low in toxicity and can be used for efficiently treating various tumor diseases.

Description

A kind of quick-releasing type medicine phosphatide cpd and pharmaceutical composition thereof
Technical field
The present invention be a kind of there is the disease treatment effects such as antitumor quick-releasing type medicine phosphatide cpd and pharmaceutical composition and purposes, relate to medical art.
Background technology
Many small-molecule chemical medicines are because hydrophobicity is too strong or hydrophilic is too strong, and lipotropy is too poor, is difficult to permeate through cell membranes, causes the weak effect of disease therapy.
Some plant origin medicines with strong physiologically active have strong hydrophobicity, and administration difficulty, applies limited.Camptothecine (Camptothecin, CPT) and 10-hydroxycamptothecine (HCPT) are a kind of alkaloids extracted from the seed or root bark of China Nyssaceae deciduous plant Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae), have stronger cytotoxic activity.Camptothecine compounds is by forming the stable triplet complex of camptothecine-topoisomerase I-DNA, and not reproducible after DNA double helical structure is broken, can be used for treating Several Kinds of Malignancy, as colorectal cancer, gastric cancer, hepatocarcinoma, bladder cancer and leukemia etc.It is water solublity and fat-soluble all very poor that camptothecine compounds is used for the greatest drawback of oncotherapy, is difficult to the solution obtaining high valid density.In order to improve the hydrophobicity defect of CPT, HCPT, there are research institution and enterprise to carry out modification to the chemical constitution of camptothecine, synthesized hundreds of camptothecin derivative.So far having had 2 kinds to have certain hydrophilic camptothecin derivative and be approved for clinical cancer therapy, be irinotecan and topotecan respectively, but its water solublity is still lower.In addition, CPT, HCPT and analog etc. thereof also produce the serious side effects such as bone marrow depression, vomiting and diarrhoea while performance anti-tumor activity.Reason is, its activated lactone structure is easy to be destroyed, and becomes the carboxylate structure not having drug effect or cause side effect.
Paclitaxel is also a kind of alkaloid, is at present uniquely a kind ofly can promote microtubule polymerization and the stable medicine being polymerized microtubule.Research shows, paclitaxel is attached on the microtubule of polymerization, does not react with unpolymerized tubulin dimer.Understand after cells contacting paclitaxel at a large amount of microtubule of thin intracellular accumulation, the accumulation of these microtubules disturbs the various functions of cell, particularly makes cell division stop at mitotic phase, has blocked the proper splitting of cell.Paclitaxel is mainly applicable to ovarian cancer and breast carcinoma, also has certain curative effect to pulmonary carcinoma, colorectal cancer, melanoma, incidence cancer, lymphoma, cerebroma.But taxol soluble is poor, polyoxyethylene castor oil and ethanol hydrotropy need be adopted, and polyoxyethylene castor oil may cause anaphylaxis, needs to take Claritin in advance before patient medication.Research shows, the application of polyoxyethylene castor oil reduces the anti-tumor activity of paclitaxel.Meanwhile, paclitaxel, due to poor selectivity, has stronger toxic action, easily produces drug resistance, and cannot through defects such as blood brain barrier.Side effect have refer to that toe is numb, transient tachycardia and hypotension, joint and myalgia, digestive tract reaction, slight alopecia and bilirubin, alkali phosphatase, glutamic oxaloacetic transaminase, GOT rising etc.For this reason, improve the emphasis that its hydrophilic is research and development, hydrophilic is developed successfully due to the Docetaxel of paclitaxel and Cabazitaxel so far, is applied to clinical.Obviously, improve the hydrophilic of hydrophobic drug, contribute to improving drug effect.
It is oral or pass through drug administration by injection that hydrophilic medicament can be mixed with solution, but this kind of medicine is due to hydrophilic excellence, lipotropy is poor, Chang Buneng or be difficult to enter cell in the mode of Passive diffusion through cell membrane, cause drug effect to be restricted, the even most of medicine of part is excreted with proto-drug form.Nucleoside anti-metabolite anticarcinogen is the water-soluble analogues of cytosine deoxyriboside, and because water solublity is excellent, lipotropy is poor, can not enter in cell in the mode of Passive diffusion through cell membrane.Gemcitabine (2 '-deoxidation-2 ', 2 '-difluoro cytidine) be the pyrimidine nucleoside analoys that Lilly Co., Eli. researches and develops, being the Difluoronucleosides class antimetabolite anticarcinogen that can destroy cellular replication, is the substitute of a kind of inhibitory enzyme of ribonucleotide reductase.Gemcitabine is mainly used in the treatment of cancer of pancreas, bladder cancer, breast carcinoma and other entity tumors, to get the Green Light use in more than 90 countries, becomes the first-line drug for the treatment of nonsmall-cell lung cancer and " goldstandard " for the treatment of cancer of pancreas.Gemcitabine also has antiviral activity, may be used for treating the infection of the yellow fever virus coe virus comprising hepatitis C virus etc., under minimum dose within a couple of days (being 1-2 days in some cases), hepatitis C virus load in patient body can be reduced rapidly up to 2 logarithms or more.
Similar to other nucleoside medicine, due to the hydrophilic of gemcitabine excellence, can not enter in cell through cell membrane in the mode of Passive diffusion, therefore it needs specific transport protein to be transported in tumor cell.The change of nucleoside transport activity is considered to the major reason causing gemcitabine drug resistance.People's equilibrated type nucleoside transporter l (hENTl) is that the transhipment gemcitabine of discovery is at present to the important transport protein in tumor cell.The sensitivity of gemcitabine is caused to decline possibly because Intracellular drug accumulation reduces, the scientist of ClavisPharma company of Norway has synthesized 5 '-elaidic acid ester derivant CP-4126 of gemcitabine, lipotropy comparatively gemcitabine significantly improves, the mode that research discovery CP-4126 can not rely on hENTl transport protein is taken in tumor cell, is therefore expected to also show good antitumous effect at the tumour patient of the low expression of hENTl.At present as the medicine for treatment of metastatic cancer of pancreas, enter phase ii clinical trial.Obviously, by improving the lipotropy of hydrophilic medicament, effectively can promote that hydrophilic medicament permeate through cell membranes enters in cell, playing drug effect.So, administration design or structurally-modified is carried out to hydrophilic medicament, overcomes clinical shortcomings, significant.
Being wrapping to by medicine in carrier, carrying out Co ntrolled release, is another kind of important administering mode.The display of large quantity research, carrier loaded medicine carries out Co ntrolled release to a certain degree can improve drug effect, but is easy to leak due to carrier Chinese medicine, causes drug bioavailability to be difficult to reach desirable state.
Liposome is a kind of new medicinal preparation with target administration function, has extensive use in cancer therapy drug field.Phospholipid forms the main chemical compositions of liposome, forms by having the hydrophobic tail that substituent group that phosphoric acid is connected forms because of the hydrophilic head that forms and long hydrocarbyl chain.When being scattered in aqueous phase, the hydrophobic tail of molecule is tended to flock together, and avoids aqueous phase, and hydrophilic head is exposed to aqueous phase, formed have bilayer structure vesicle, i.e. liposome.During as carrier, hydrophobic drug usually in two lipid layers of liposome, in the aqueous phase of hydrophilic medicament in liposome.Due to the mobility of liposome membrane, cause medicine to be easy to leak out, make the medicine of parcel be difficult to play good drug effect.Drug molecule being formed prodrug by being covalently bound in phospholipid molecule structure, can drug leakage be avoided.Weak point is, phospholipid prodrugs, by making the chemical bond rupture between medicine and phospholipid, discharges usually with substituent medicine, and then slow releasing proto-drug.Because the speed of prodrugs release proto-drug is slow, causes being difficult to obtain sufficiently high proto-drug concentration at target site, drug effect is declined.On the other hand, drug molecule obtains liposome by being covalently bound to the prodrug formed in phospholipid molecule structure by assembling, because hydrophobic chain symmetry in phospholipid molecule and regularity destroy or the change of hydrophilic head structure, cause the stability of liposome to decline, affect effective release of proto-drug.
Therefore, be necessary to carry out structural design, develop new medicinal liposome delivery system, drug solubility, stability, permeability cell, targeting is improved to reach, improve the stability of carrier system, and discharge proto-drug fast, thus reach the object reducing toxic and side effects, improve curative effect.
The present invention utilizes hydrophobic easy fracture spacer moiety and strengthens hydrophobic lipophilic spacer moiety and forms effective easily broken hydrophobic lipophilic segment, and be connected on phosphoglyceride molecule, become amphipathic molecule, and connect drug molecule at hydrophobic end, thus molecule is made to obtain suitable lipotropy and hydrophilic; Two hydrophobic chains that the two kinds of spacerarms be connected with medicine are formed utilize two kinds of spacerarms to work in coordination with hydrophobic interaction and make amphipathic molecule be assembled into stable liposome, improve medicine stability; This amphipathic molecule and liposome can fast fracture easy fracture spacerarms under the effects such as glutathion, and by reverse attack carbonyl, medicine discharged fast with the form of proto-drug, play the effects such as efficient oncotherapy.
Summary of the invention
Technical problem: the invention provides one and there is more suitably lipotropy and hydrophilic, be easy to by cellular uptake, and the quick-releasing type medicine phosphatide cpd of 2 molecule proto-drug can be discharged fast, a kind of pharmaceutical composition based on this quick-releasing type medicine phosphatide cpd is provided simultaneously.
Technical scheme: quick-releasing type medicine phosphatide cpd of the present invention is the pharmaceutically acceptable salt that the compound of following general formula (1) or the compound of described general formula (1) and counter ion counterionsl gegenions are formed:
In formula (1), X 1, X 2all any in ester bond, amido link, amino-formate bond and carbonic acid ester bond, X 3, X 4all any in ester bond, amido link, A 1, A 2being easily broken hydrophobic spacerarm, is the carbon number that the contains cystine linkage alkylene alkyl that is 2 ~ 8, the carbon number that contains peptide bond be 2 ~ 80 alkylene alkyl, the carbon number alkylene alkyl that is 2 ~ 20 that contains amido link or the carbon number that the contains ester bond alkylene alkyl that is 2 ~ 20, Z 1, Z 2being to strengthen hydrophobic spacerarm, is the carbon number that the contains ehter bond alkylene alkyl that is 2 ~ 20, the carbon number of alkylene alkyl that the carbon number that contains ester bond is 2 ~ 20, alkylene alkyl that the carbon number that contains amido link is 2 ~ 20 or oxygen-free atom and the nitrogen-atoms alkylene alkyl/sub-alkylene that is 2 ~ 20, Y 1, Y 2for following any one medicine: taxol, Docetaxel, Cabazitaxel, code name is the compound of BAY59-8862, code name is the compound of SB-T-11033, code name is the compound of SB-T-121303, code name is the compound of SB-T-121304, code name is the compound of SB-T-1213, code name is the compound of SB-T-12162, code name is the compound of BMS-184476, code name is the compound of DJ-927, code name is the compound of BMS-275183, camptothecine, HCPT, SN38, camptothecine-10-O-ethylpyrazol, Irinotecan, TPT, 7-t-Butyldimethylsilyl-10-hydroxycamptothecine, 7-(2-trimethyl silicane ethyl)-camptothecine, code name is the camptothecin derivative of Afeletecan, 7-methylol camptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, hexacyclic camptothecins, code name is the compound of Gimatecan, code name is the compound of Belotecan, Diflomotecan, code name is the compound of BN80927, code name is the compound of TOP-0618, code name is the compound of Exatecan, code name is the compound of Lurtotecan, code name is the compound of DRF-1042, podophyllotoxin, demethylated podophyllotoxin, Teniposide, Etoposide, vincaleukoblastinum, vincristine, vinorelbine, eldisine, etoposide,Harringtonine, isoharringtonin, deoxyharringtonin, false deoxyharringtonin, homoharringtonine, Britanin, combretastatin, colchicin, fulvestrant, Vorinostat, Ipsapirone, eribulin, Simvastatin, rotigotine, Rifapentine, Zidovudine, brivudine, Lobucavir, megestrol acetate, mitolactol, salbutamol, resveratrol, hCPT compounds, aloe-emodin, curcumin, lanosterol, mamba Wei, cidofovir, aclacinomycin, carminomycin, deoxidation pyrromycin, zorubicin, the fluoro-idarubicin of 8-, nystatin, anphotericin, mitoxantrone, archen, actinomycin D, rapamycin, mithramycin, Epothilones, mitomycin, bleomycin, aspergillus fumigatus cedrol, methylprednisolone, Flavopiridol, Breviscapinun, ET-743, euphorbia plant diterpene, 2,5-PTX, matrine, Ipsapirone, the sub-chalone A4 of windmill, ubenimex, Ribavirin, Marimastat, Medroxyprogesterone, stavudine, inverase, neo-synephrine, methoxamedrine, salbutamol, isoprel, Misoprostol, Latanoprost, prostacyclin, quinindium, Propafenone, Pu Naluoer, digoxin, foxalin, dobutamine, warfarin, coumarin kind compound, Lovastatin, fluvastatin, En Gelie is clean, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, abarelix, Zoladex, galanthamine, cycloheximide, minocycline, Meloxicam, posaconazole, everolimus, Vorinostat, PTK787 alkali, abiraterone, dihydroartemisinine, prednisolone, dexamethasone, code name is the compound of AEZS-112, code name is the compound of GZ402674, code name is the compound of BCX-1777, code name is the compound of CYC682, code name is the compound of LY-2334737, O-(chloracetyl-carbamyl) fumidil, code name is the compound of SU14813, code name is the compound of BMS-275291, code name is the compound of ABT-510, code name is the compound of Aplidine, code name is the compound of NSC683551, code name is the compound of CGS27023A, code name is the compound of RO32-3555, code name is the compound of NPI-0052, for drawing ten thousand stars, code name is the compound of CEP-1347, code name is the compound of ABR-215050, code name is the compound of MonomethylauristatinE, Bicalutamide, HPR, Ansamycin, bryostatin, CCI-779, Pu Masita, tipranavir, indinavir, Ritonavir, atazanavir, viracept see nelfinaivr, Batimastat, Quercetin, flavonoids medicine, ticagrelor, Kan Geruiluo, Sebivo, Trifluridine, Adapalene, Lopinavir, Da Gelie is clean, rifaximin, fluticasone, Chinese mugwort Saperconazole, Merck, LBH589, A Wei Batan, Levonorgestrel, ethinyloestradiol, ground Rui Lawei, Olmesartan, according to cutting down Kato, bryostatin-1, alpha-galactosylceramide, EGCG, curcumin,Oridonin, genistein, triptolide, gossypol, legalon, telavancin, Ezetimibe, pseudoephedrine, ADZ6140, mometasone furoate, Deferiprone, oxybutynin, Oxymorphone, Merck, Mirabegron, teriflunomide, avanaphil, CCI-779, dust is for lattice Wei, Du Lutewei, calicheamicin, Retapamulin, tolvaptan, LUMEFANTRINE, his bit pyridine, galanthamine, Tuo Ruisaier, Ka Gelie is clean, draw for drawing Wei, buprenorphine, rope fluorine cloth Wei, Treprostinil, Dantrolene, fluticasone furoate, naloxone, Kan Gelie is clean, Suo Feibuwei, N-methylol Aripiprazole, code name is the compound of brivanib, code name is the compound of bryostatin-1, code name is the compound of combretastainA4, code name is the compound of CEP18770, code name is the compound of Ivacaftor, code name is the compound of MEK162, code name is the compound of neovastat, code name is the compound of UCN-01, code name is the compound of ridaforolimus, code name is the compound of AZD6244, code name is the compound of TAK-733, code name is the compound of AS703026, code name is the compound of PD-325901, code name is the compound of maytansine, code name is the compound of R04987655, code name is the compound of GDC-0973, code name is the compound of GSK945237, code name is the compound of ANG1009, code name is the compound of AD198, code name is the compound of Becatecarin, code name is the compound of Adva27a, code name is the compound of Benzopyranones, code name is the compound of AEZS112, code name is the compound of B00742, code name is the compound of ALCHEMIX, the compound that code name is, the compound that code name is, code name is the compound of Saintopin, code name is the compound of NCA0465, code name is the compound of GL331, code name is the compound of CAP7.1, code name is the compound of IT62B, code name is the compound of C1311, Oxycodone, department's licarbazepine, tacrolimus, Paliperidone, N-methylol Aripiprazole, draw for drawing Wei, Ka Gelie is clean, dexamethasone, Baily department he, code name is the camptothecin derivative of DX-8951f, gemcitabine, code name is the compound of CP-4126, C 1-C 20amide groups gemcitabine, FTL, Cladribine, fluorouracil, Tegafur, Carmofur, Tegadifur, doxifluridine, Ai Xila shore, capecitabine, 5 '-deoxidation-5-fluorine cytidine, 5 '-'-Deoxy-5-fluorouridine, 2'-Deoxy-5-Floxuridine, cytarabine, ancitabine, troxacitabine, 1-(2-C-cyano-2-dioxy-BETA-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, Decitabine, Bosutinib, he luxuriant and rich with fragrance for Buddhist nun, Yiluo for Buddhist nun, reach gram for Buddhist nun, HKI-272,Many Weis are for Buddhist nun, Pa Na is for Buddhist nun, Ba Fei is for Buddhist nun, department is beautiful for Buddhist nun, card is pricked for Buddhist nun, Luso is for Buddhist nun, Lu Zuo is for Buddhist nun, Ai Le is for Buddhist nun, card is rich for Buddhist nun, happy cutting down for Buddhist nun, look auspicious is for Buddhist nun, Ah method is for Buddhist nun, Sutent, Lapatinib, gram azoles is for Buddhist nun, A Pa is for Buddhist nun, Erlotinib, how card is for Buddhist nun, Axitinib, bosutinib, AMN107, Gefitinib, Dasatinib, sitagliptin, Imatinib, 6-MP, methotrexate (MTX), aminopterin, hydroxycarbamide, NSC-118994, ADA, Buddhist nun is replaced according to Shandong, Sibutramine Hydrochloride is for Buddhist nun, Luso profit is for Buddhist nun, azacitidine, clofarabine, lenalidomide, nelarabine, pazopanib, ZD6474, Ka Feizuo meter, En Zhalu amine, Da Lafeini, PTK787, Temozolomide, Elvucitabine, Beta department spit of fland, BI 1356, Prozac, Egelieting, vildagliptin, BMS-477118, Duloxetine, Atorvastatin, BCNU, Nimustine, Acadesine, 4 '-sulfo--β-D-arabino-furanosylcytosine, adefovirdipivoxil, arabinosy ladenosine, adriamycin, Epi-ADM, daunorubicin, DMDR, THP, grace is for Nuo Te, west reaches aniline, amdoxovir, Lamivudine, Entecavir, China fir fine jade, Tacrine, lenalidomide, metisazone, hydroxycarbamide, bleomycin A5, GCV, FCV, phentolamine, phenoxybenzamine, prazosin, Tamsulosin, indoramin, Brimonidine, hydrolazine, minoxidil, Mecamylamine, procainamide, mexiletine, dopamine, amrinone, Pabuk former times profit cloth, Bo Saipowei, spy draws big, huperzine, Memantine, Sorafenib, Rui Gefeini, Da Lafeini, Wei Luofeini, FTY720, Ni Danibu, trifluorothymidine, Wo Nuolazan, Aura handkerchief Buddhist nun, ifosfamide, Ai Ruibulin, code name is the compound of TAS-106, code name is the compound of VQD-002, code name is the compound of MB07133, code name is the compound of SPD754, code name is the nucleoside analog of Reverset, code name is the compound of E7974, code name is the compound of Lonafarnib, code name is the compound of Semaxanib, code name is the compound of Linifanib, code name is the compound of Crenolanib, Icatibant, code name is the compound of AZD3293, code name is the compound of LuAE58054, code name is the compound of LY2811376, code name is the compound of Alectinib, Zarnestra, Luo Nafani, An Ruinawei, intend peptide medicine, Levetiracetam, eslicarbazepine, Topiramate, vilazodone, draw iron Buddhist nun primary, 1B-d-amphetamine, Doxazosin, Oxcarbazepine, emtricitabine, Aldoforwe ester, tenofovir, valganciclovir, Milnacipran, aliskiren, ximelagatran, etravirine, rufinamide, imiquimod, famotidine, Lamotrigine, uncle's match Wei, ezogabine, colesevelam, imiquimod, chlorthalidone, Eliquis, Abacavir, (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, Te Lawan star, FTY720, sphingol, the western croak of Leo, Ao Bitawei, code name is the compound of Brostallicin,Code name is the compound of Baricitinib, code name is the compound of Buparlisib, code name is the compound of cobicistat, code name is the compound of Elacytarabine, code name is the compound of GX15-070, code name is the compound of Iniparib, code name is the compound of Ixazomib, code name is the compound of KRN7000, code name is the compound of linezolid, code name is the compound of Linsitinib, code name is the compound of Nintedanib, code name is the compound of Motesanib, code name is the compound of Voxtalisib, code name is the compound of Vatalanib, code name is the compound of Pilaralisib, code name is the compound of ONX0912, code name is the compound of Tivozanib, code name is the compound of PF-03084014, code name is the compound of Verosudil, code name is the compound of TG-101348, code name is the compound of Tivantinib, code name is the compound of Paritaprevir, code name is the compound of sonidegib, code name is the compound of Rociletinib, code name is the compound of Trametinib, code name is the compound of Regorafenib, code name is the compound of Evofosfamide, code name is the compound of Veliparib, code name is the compound of volasertib, code name is the compound of simeprevir, code name is the compound of vismodegib, code name is the compound of pomalidomide, code name is the compound of idelalisib, code name is the compound of BEZ2235, code name is the compound of GDC-0941, code name is the compound of XL147, code name is the compound of MK2206, Da Pafeini, code name is the compound of BMS-908662, code name is the compound of CI-1040, code name is the compound of GSK1120212, code name is the compound of NVP-AEW541, code name is the compound of Tivozanib, code name is the compound of masitinib, code name is the compound of SCH900105, code name is the compound of Foretinib, code name is the compound of RO5126766, code name is the compound of Cyclopentanthraquinones, code name is the compound of F14512, code name is the compound of Sitafloxacin, code name is the compound of Elinafide, code name is the compound of KW2170, code name is the compound of Lucanthone, code name is the compound of Sabarabicin, code name is the compound of Pixantrone, AZD2171, not for husky Buddhist nun, handkerchief pool former times cloth, roller pyrrole is smooth, dabigatran etcxilate, deacetylate vincaleukoblastinum list hydrazides, fourth oxygen piperazine alkane,Rilpivirine, cis-platinum, Spiroplatin, carboplatin, oxaliplatin, satraplatin, Miboplatin, Nedaplatin, Eptaplatin, lobaplatin, Cycloplatin, JM-216, picoplatin, code name is the compound of BBR-3464, 5,6-dimethyl ton ketone-4-acetic acid, Pseudolarix acid B, ganoderic acid, oleanolic acid, Rhein, 9-cis-retinoic acid, betulinic acid, VE succinic acid monoester, ATRA, Diclofenac, card glutamic acid, shellfish cholic acid difficult to understand, deoxycholic acid, sabril, Leuprorelin, tree toad element, pramlintide, corticotropin, bacitracin, Teriparatide, Goserelin, Exenatide, peace is for Anji peptide, rice lumbering peptide, romidepsin, junket silk figured silk fabrics peptide, sifuvirtide, Ai Boweitai, tyroserleutide, donipenem, Azilsartan, pitocin, cyclosporin, protirelin, Taltirelin, nafarelin, Buserelin, Histrelin, Gonadorelin, look ammonia Rayleigh, growth hormone release inhibiting hormone, secretin, Octreotide, ziconotide, T-20, Lanreotide, Vapreotide, seglitide, for degree Shandong peptide, Linaclotide, sinapultide, SOM230, Triptorelin, Tesamorelin, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], bexarotene, Pitavastatin, Rosuvastatin, bendamustine, melphalan, Lonidamine, atrasentan, melphalan, SS, pemetrexed, n-formyl sarcolysine, dinoprostone, Carboprost, Alprostadil, Gemfibrozil, Xi Luruiwei, Pepstatin, Ge La is for thunder, reed Xi Natan, Indomethacin, brufen, naproxen, DEFERASIROX, fluoquinolone, Pralatrexate, code name is the compound of Voreloxin, code name is the compound of AKR501, code name is the compound of CPI-613, code name is the compound of MK0429, code name is the compound of IDN-6556, tanomastat, marimastat, prinomastat, code name is the compound of alisertib, cilengitide, argatroban, dabigatran, Artesunate, ambrisentan, eltrombopag olamine, Valsartan, MOXIFLOXACIN, naproxen, Yi Luduo quinoline, Ge La is for thunder, tirofiban, DEFERASIROX, cefotaxime, levodopa, Carbidopa, besifloxacin, Febuxostat, prulifloxacin, cephalo is than general ester, Ceftobiprole, Gabapentin ester, mesalazine, Icatibant, Linaclotide, shellfish reaches quinoline, Sha Kubi song, according to a piperazine azoles, donipenem, ingenol first butenoate, Droxidopa, code name is the compound of lumacaftor, code name is the compound of MLN9708, code name is the compound of Sacubitril, code name is the compound of rigosertib, code name is the compound of Vosaroxin, code name is the compound of Orantinib, Carubicin, Aclarubicin, ibacitabine, Galocitabine, ancitabine, lestaurtinib, Improsulfan, mannosulfan, Ritrosulfan, Treosulfan, Ecomustine, Estramustine, Semustine, Alestramustine, gimeracil, Medorubicin, how the soft star that compares, THP, rodorubicin, Sha Rou compares star, valrubicin, zorubicin, Leurubicin, idarubicin, galarubicin, esorubicin, Detorubicin, Amrubicin, cut down and hold in the palm his shore, zalcitabine,For pricking his shore, Fiacitabine, flurocitabine, Ambamustine, Tarceva, training profit for Buddhist nun, Trimetrexate, Edatrexate, Ketotrexate, oteracil, Mitoflaxone, bortezomib;
L is 2-amino-2-carboxy ethyl, 2-amino-ethyl, 2-trimethyl amido ethyl cation, 2, the end group of 3-dihydroxypropyl, molecular weight to be the Polyethylene Glycol-amino-ethyl of the N-without targeting end group of 200-4000 or molecular weight be 200-4000 is the N-Polyethylene Glycol-amino-ethyl of targeting group.
Further, in the present invention, Y 1, Y 2it can also be the derivant of said medicine.
In the preferred version of quick-releasing type medicine phosphatide cpd of the present invention, end group is in the N-Polyethylene Glycol-amino-ethyl of targeting group, and targeting group is any one in folic acid, galactose, polypeptide, antibody, antibody fragment, hyaluronic acid, asialoglycoprotein, polysaccharide, nucleic acid, plan peptide and sulfadiazine.
In the preferred version of quick-releasing type medicine phosphatide cpd of the present invention, when in structural formula (1), L is uncharged group, described counter ion counterionsl gegenions are combinations of a kind of cation and a kind of anion, described cation be hydrion, sodium ion, potassium ion, calcium ion, iron ion, magnesium ion, ammonium ion, zinc ion any one; When in structural formula (1), L is positively charged group, described counter ion counterionsl gegenions are any one in hydrion, sodium ion, potassium ion, calcium ion, iron ion, magnesium ion, ammonium ion, zinc ion, and described anion is any one in chloride ion, sulfate ion, sulfate ion, nitrate ion, carboxylic acid ion, carbanion, bromide ion, phosphate anion, formate, acetate, citrate, lactate, fumaric acid radical, tartrate anion, gluconic acid radical ion.
Pharmaceutical composition of the present invention comprises acceptable carrier on above-mentioned quick-releasing type medicine phosphatide cpd or described quick-releasing type medicine phosphatide cpd and pharmacodynamics.
In the preferred version of pharmaceutical composition of the present invention, pharmaceutical composition is the elaioplast nanometer particle of particle diameter 10-1000 nanometer, also comprises auxiliary agent in pharmaceutical composition.In further preferred version, auxiliary agent is phospholipid or cholesterol.
In the preferred version of pharmaceutical composition of the present invention, pharmaceutical composition is liquid preparation, solid preparation, semi-solid preparation, capsule, granule, gel, injection, slow releasing preparation or controlled release preparation.
The invention still further relates to and contain as the compounds of this invention of active ingredient or the pharmaceutical composition of the compounds of this invention and customary pharmaceutical auxiliaries.Usual pharmaceutical composition of the present invention contains the phosphatide cpd of the hydrophilic medicament of the present invention of 0.1-100 % by weight.
Elaioplast nanometer particle is made, grain diameter 10-1000 nanometer by the compounds of this invention.Elaioplast nanometer particle is made by the compounds of this invention and auxiliary agent, particle diameter 10-1000 nanometer, the auxiliary agent of use be phospholipid, Polyethylene Glycol phospholipid (molecular weight polyethylene glycol 400-3000), containing one or more in the Polyethylene Glycol phospholipid of targeting group or cholesterol.Targeting group is folic acid, galactose, polypeptide, antibody, antibody fragment, hyaluronic acid, asialoglycoprotein, polysaccharide, nucleic acid and plan peptide.
Medicine compound liposome nano-particle of the present invention is liquid preparation, solid preparation, semi-solid preparation, capsule, granule, gel, injection, slow releasing preparation or controlled release preparation.
Screen from external pharmacologically active etc., the compounds of this invention shows the biological activitys such as good antitumor.Test shows that the toxicity in vivo of the compounds of this invention is less than former medicine.Therefore can be used as the medicines such as antitumor for patient.
Screen from external pharmacologically active etc., the compounds of this invention elaioplast nanometer particle shows the biological activitys such as good antitumor.Test shows that the toxicity in vivo of the compounds of this invention is much smaller than former medicine.
The preparation method of quick-releasing type medicine phosphatide cpd elaioplast nanometer particle of the present invention, the mixture by quick-releasing type medicine phosphatide cpd of the present invention or the compounds of this invention and auxiliary agent, by method preparations such as film dispersion method, reverse phase evaporation, freeze-drying, ultrasonic dispersion, spray drying method, film squeezing and pressing method or high pressure homogenization methods.
The present invention utilizes the medicine of 2 molecules to be connected as hydrophobic tail with hydrophobic distance arm, and be connected by covalent bond with phospholipid hydrophilic head, prepare quick-releasing type medicine phosphatide cpd, improve medicine water solublity and cross-film ability, separately or be mixed and made into elaioplast nanometer particle with phospholipid; Quick-releasing type medicine phosphatide cpd of the present invention is fat-soluble is better than former medicine, long half time, and antitumor isoreactivity is significantly better than former medicine.
Quick-releasing type medicine phosphatide cpd is prepared into nano-particle by the present invention, has the characteristic of liposome, and cross-film ability is strong, has the characteristic that can form liquid preparation, solid preparation, semi-solid preparation, sterilization preparation and sterile preparation, for treatments such as tumors.This quick-releasing type medicine phosphatide cpd nano-particle is not only a kind of prodrug, is also the release vehicle that medicine is brand-new, has target function; Quick-releasing type medicine phosphatide cpd of the present invention and elaioplast nanometer particle thereof are also pharmaceutical carriers, degradation in vivo rapid delivery of pharmaceuticals, play drug effect, have low toxic and side effects.
The pharmaceutically acceptable salt containing counter ion counterionsl gegenions that the quick-releasing type medicine phosphatide cpd of structural formula of the present invention (1) and these compounds are formed, there is the effects such as antitumor, prolong drug can discharge the half-life, and there is lower toxic and side effects.
Beneficial effect: the present invention compared with prior art, has the following advantages:
Quick-releasing type medicine phosphatide cpd of the present invention, in structural formula (1), A 1, A 2be the hydrophobic spacerarm containing the easy fracture such as cystine linkage, peptide bond, namely form the hydrophobic spacerarm of quick-releasing type; Z 1, Z 2be strengthen hydrophobic spacerarm, play and strengthen hydrophobic lipophilic effect; Y 1, Y 2for medicine.In structural formula (1), medicine Y 1, Y 2be connected with the hydrophobic spacerarm of enhancement mode by the hydrophobic spacerarm of chemical bond and quick-releasing type, two kinds of hydrophobic spacerarms hydrophobic and lipotropism of collaborative enhancing mutually, forms hydrophobic lipophilic chain tail; Article two, hydrophobic chain is connected with phospholipid hydrophilic head, forms amphipathic molecule.
Quick-releasing type medicine phosphatide cpd of the present invention, realizes regulating hydrophilic and lipophilic balance simultaneously, realizes fast fracture release medicine: as former medicine Y 1, Y 2have strong-hydrophobicity and lipotropy, quick-releasing type medicine phosphatide cpd of the present invention utilizes phospholipid hydrophilic head, makes it have hydrophilic more better than former medicine, overcomes medicine is insoluble in aqueous systems defect because hydrophobicity is strong; As former medicine Y 1, Y 2there is strong-hydrophobicity and lipotropy is poor, quick-releasing type medicine phosphatide cpd of the present invention utilizes phospholipid hydrophilic head, make it have hydrophilic more better than former medicine, utilize simultaneously and strengthen hydrophobic lipophilic spacerarm, make its lipotropy more better than former medicine, overcome medicine because hydrophobicity is strong and lipotropy is also poor and it is fat-soluble to cause and water solublity inequality and insoluble defect; As former medicine Y 1, Y 2there is strongly hydrophilic, quick-releasing type medicine phosphatide cpd structural formula (1) Chinese medicine Y of the present invention 1, Y 2be connected with two hydrophobic spacerarms by chemical bond, composition hydrophobic tails, namely medicine is forced and be placed in hydrophobic structure part, make quick-releasing type medicine phosphatide cpd of the present invention have hydrophobic lipophilic more better than former medicine, overcome medicine and be difficult to by the defect of cellular uptake because hydrophilic is too strong;
Quick-releasing type medicine phosphatide cpd of the present invention, two hydrophobic tails are had in structural formula (1), each hydrophobic tails is all containing easily broken spacerarm and the hydrophobic spacerarm of enhancing, give the hydrophobic enhancing of lipophilic and fast fracture function simultaneously, both to have overcome in molecule and only caused that hydrophobicity is not enough and lipotropy is not enough containing an easy fracture spacerarm and the defect that is difficult to effectively be assembled into stabilized liposome, and also overcomed and only contain a hydrophobic spacerarm and be difficult to the defect that fast fracture discharges former medicine;
The hydrophobic tail containing medicine of quick-releasing type medicine phosphatide cpd of the present invention is connected with phospholipid hydrophilic head, form amphipathic molecule, make it that there is suitable lipotropy and hydrophilic, medicine is made to be easy to by cellular uptake, obtain more excellent cross-film ability, overcome the defect of hydrophilic medicament cross-film ability, play better drug effect;
Y in its structural formula of quick-releasing type medicine phosphatide cpd (1) of the present invention 1, Y 2different medicines is selected to be connected with spacerarm by chemical bond, composition hydrophobicity lipophilic tail, namely two kinds of different medicines are placed in hydrophobic lipophilic structure division, this hydrophobic tail is connected with phospholipid hydrophilic head, form the amphipathic molecule containing two kinds of different pharmaceuticals, not only increase hydrophilic or the lipotropy of two kinds of medicines, overcome drug solubility difference or be difficult to by the problem of cellular uptake, and make quick-releasing type medicine phosphatide cpd can discharge two kinds of former medicines simultaneously, play the effect of two kinds of medicine Synergistic treatments;
Quick-releasing type medicine phosphatide cpd of the present invention utilizes the spacer moiety of hydrophobic easy fracture and strengthens hydrophobic lipophilic spacer moiety and forms effective hydrophobic lipophilic chain, and be connected on phosphoglyceride molecule, become amphipathic molecule, and connect drug molecule at hydrophobic end, the easy fracture spacerarm be connected with medicine and strengthens two hydrophobic lipophilic chains that hydrophobic spacerarm forms and utilize and work in coordination with hydrophobic interaction, makes amphipathic molecule be assembled into stable liposome;
Quick-releasing type medicine phosphatide cpd of the present invention, by being assembled into liposome, being easy to by cellular uptake, playing better drug effect;
Quick-releasing type medicine phosphatide cpd of the present invention is a kind of amphipathic molecule, and separately or assemble together with auxiliary agent and form stable liposome, when overcoming general wrapping kmedicine by liposome, medicine is easy to the shortcoming of leaking, and improves the efficiency of medicine parcel simultaneously;
Many inside tumor cells high expressed TypeⅡsecretoryphospholipaseA2s (sPLA2), this enzyme can only the ester bond of sn2 position in hydrolytic phosphatide molecule glycerol backbone, can not be hydrolyzed the ester bond of sn1 position.Therefore, in phospholipid molecule, the molecule of two equal bound drugs of hydrophobic tail is difficult to discharge the structure division containing pharmaceutical group be connected by ester bond with sn1 position in tumor cell, form the structure of the virose lysophosphatide of similar tool, cause two medicine phospholipid to be difficult to discharge whole former medicine fast.The hydrophobic tail containing medicine of quick-releasing type medicine phosphatide cpd of the present invention comprises easy fracture spacerarm, containing cystine linkage etc., can by degradeds such as glutathion fast fracture, pass through the carbonyl of " inventing a charge against " attack molecule self containing the sulfydryl in the fragment of drug molecule etc. after fracture, cause discharging former medicine fast, overcome general interval arm and be difficult to fast fracture and the defect of former medicine can not be discharged fast; And a part quick-releasing type medicine phosphatide cpd discharges the former medicine of 2 molecule fast, forms high concentration, have stronger drug effect in target cell;
The phosphatide cpd of medicine of the present invention, separately or assemble together with auxiliary agent and form stable pastille liposome, pharmaceutical group is positioned at two lipid layers of liposome, medicine was subject to good protection before performance drug effect, improve the stability of medicine, overcome the defect being subject to destruction in delivery process under normal circumstances; Further, the liposome of drug containing is easy to by cellular uptake, and discharges former medicine fast, plays drug effect;
The phosphatide cpd of medicine of the present invention can adopt membrane process etc. to be self-assembled into elaioplast nanometer particle easily, particle diameter 10-1000 nanometer; Quick-releasing type medicine phosphatide cpd of the present invention can form compound system with phospholipid, adopts membrane process etc. to be self-assembled into elaioplast nanometer particle easily, particle diameter 10-1000 nanometer;
Quick-releasing type medicine phosphatide cpd elaioplast nanometer particle of the present invention has passive target effect;
Quick-releasing type medicine phosphatide cpd of the present invention and elaioplast nanometer particle thereof are a kind of brand-new drug release carriers, are also a kind of prodrugs;
The pharmaceutical composition of compound of the present invention or compound of the present invention and Conventional pharmaceutical carriers, the compounds of this invention containing 0.1-100 % by weight, has the biological activity such as hypotoxicity and excellent antitumor;
Quick-releasing type medicine phosphatide cpd of the present invention and elaioplast nanometer particle thereof, can be used as liquid preparation, solid preparation, semi-solid preparation, sterilization preparation and sterile preparation, liposome can be formed under the aqueous phase systems such as water, phosphate buffer, citrate buffer solution;
Quick-releasing type medicine phosphatide cpd liposome of the present invention combines the phospholipid auxiliary agent containing targeting group, has active targeting effect; Quick-releasing type medicine phosphatide cpd of the present invention or phosphatide cpd liposome, in its structural formula (1), the end group of L to be molecular weight be 200-4000 is the N-Polyethylene Glycol-amino-ethyl of targeting group, the surface of liposome that this phosphatide cpd is assembled into has targeting group, has active targeting effect;
Quick-releasing type medicine phosphatide cpd of the present invention and elaioplast nanometer particle preparation technology simple;
Quick-releasing type medicine phosphatide cpd of the present invention and elaioplast nanometer particle thereof are also a kind of brand-new prodrug, in vivo through the degraded such as enzyme, glutathion, discharge proto-drug fast, play drug effect, and there is low toxic and side effects, the pharmacological actions such as antitumor are excellent.
Accompanying drawing explanation
The synthetic route chart of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine of Fig. 1.
The synthetic route chart of two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine of Fig. 2.
The one-tenth route map of two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine of Fig. 3.
Two (topotecan-20-carbonic ester-dithio diethylene glycol-diethylene glycol acid esters) the Phosphatidylcholine biosynthesis route map of Fig. 4.
Two (amycin-N-carbamate-dithio diethylene glycol-succinate-GFLG) the Phosphatidylcholine biosynthesis route map of Fig. 5.
The synthetic route chart of Fig. 6 sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinate-sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine.
Two (Docetaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) the Phosphatidylcholine biosynthesis route map of Fig. 7.
The synthetic route chart of two (the 7-ethyl-hydroxy camptothecine-10-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine of Fig. 8.
Two (podophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Fig. 9.
Two (camptothecine-9-carbamate-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 10.
Two (camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 11.
Figure 12 pair (Cabazitaxel-2 '-carbonic ester-dithio diethylene glycol-adipate ester) Phosphatidylcholine biosynthesis route map.
Two (hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 13.
Two (irinotecan-20-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 14.
Two (hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 15.
Two (difluoro camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 16.
Two (Belotecan-20-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 17.
Two (DX-8591f-N-carbamate-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 18.
Two (9-nitrocamptothecin-20-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 19.
Two (4 '-demethyl epipodophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 20.
Two (5 '-deoxidation-5-fluorine cytidine-4-carbamate-dithio diethylene triamine-succinyl) the Phosphatidylcholine biosynthesis route map of Figure 21.
Two (camptothecine-20-carbamate-dithio diethylamine-succinyl) the Phosphatidylcholine biosynthesis route map of Figure 22.
Two (all-trans-retinoic acid-dithio diethylene glycol-succinate) the Phosphatidylcholine biosynthesis route map of Figure 23.
Figure 24 pair (homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-succinate) Phosphatidylcholine biosynthesis route map.
Two (tyroserleutide-dithio diethylene triamine-succinyl) the Phosphatidylcholine biosynthesis route map of Figure 25.
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-Polyethylene Glycol synthetic route chart of Figure 26.
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-Polyethylene Glycol-N-folic acid synthetic route chart of Figure 27.
Figure 28 pair (chidamide-2 '-carbamate-dithio diethylene glycol-succinate) Phosphatidylcholine biosynthesis route map.
Two (bexarotene-GFLG-butyryl) the phosphocholine synthetic route chart of Figure 29
Two (bexarotene-ethylene glycol succinic acid-ethylene glycol succinic acid) the phosphocholine synthetic route chart of Figure 30
Two (bexarotene-ethylenediamine succinic acid-ethylenediamine succinic acid) the phosphocholine synthetic route chart of Figure 31
The synthetic route chart of the two cisplatin phospholipid phatidylcholine of Figure 32 quick-releasing type
The granularmetric analysis schematic diagram of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine liposome of Figure 33.
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the freezing transmission electron microscope picture of phosphatidylcholine elaioplast nanometer particle of Figure 34.
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine lipidosome antineoplastic activity (a) of Figure 35 and body weight change result (b).
Detailed description of the invention
Below in conjunction with Figure of description and embodiment, technical scheme of the present invention is described in further details.
Quick-releasing type medicine phosphatide cpd of the present invention is the pharmaceutically acceptable salt that the compound of following general formula (1) or the compound of described general formula (1) and counter ion counterionsl gegenions are formed:
In formula (1), A 1, A 2it is easily broken hydrophobic spacerarm; Z 1, Z 2strengthen hydrophobic spacerarm; Y 1, Y 2be medicine, have in technical scheme and specifically enumerate.
Quick-releasing type medicine phosphatide cpd of the present invention synthesizes as follows:
Medicine containing hydroxyl, the medicaments derivative of chloro-carbonic acid esterification is obtained by reacting by elder generation and solid phosgene, then with containing the easy fracture spacerarms such as cystine linkage or polypeptide key and strengthens hydrophobic spacerarm compound hydroxyl or amino react, obtain medicine to be connected by carbonic acid ester bond or amino-formate bond, and containing easy fracture spacerarm and the intermediate product strengthening hydrophobic spacerarm, then the carboxyl of intermediate product is through N, the catalyst such as N '-carbonyl dimidazoles (CDI) activate two hydroxyl reactions that are rear and choline glycerophosphatide, obtain the quick-releasing type medicine phosphatide cpd molecule containing two pharmaceutical groups accordingly.The medicine containing hydroxyl being applicable to this method comprises: paclitaxel, Docetaxel, Cabazitaxel, code name is the compound of BAY59-8862, code name is the compound of SB-T-11033, code name is the compound of SB-T-121303, code name is the compound of SB-T-121304, code name is the compound of SB-T-1213, code name is the compound of SB-T-12162, code name is the compound of BMS-184476, code name is the compound of DJ-927, code name is the compound of BMS-275183, camptothecine, hydroxy camptothecin, SN38, camptothecine-10-O-ethylpyrazol, irinotecan, topotecan, 7-t-Butyldimethylsilyl-10-hydroxycamptothecine, 7-(2-trimethyl silicane ethyl)-camptothecine, code name is the camptothecin derivative of Afeletecan, 7-methylol camptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, hexacyclic camptothecins, code name is the compound of Gimatecan, code name is the compound of Belotecan, Diflomotecan, code name is the compound of BN80927, code name is the compound of TOP-0618, code name is the compound of Exatecan, code name is the compound of Lurtotecan, code name is the compound of DRF-1042, podophyllotoxin, demethylated podophyllotoxin, teniposide, etoposide, vinblastine, vincristine, vinorelbine, vindesine, etoposide, harringtonine, isoharringtonin, deoxyharringtonin, false deoxyharringtonin, homoharringtonine, britannilactone, combretastatin, colchicine, fulvestrant, Vorinostat, ipsapirone, eribulin, simvastatin, rotigotine, rifapentine, zidovudine, brivudine, Lobucavir, megestrol, mitolactol, salbutamol, resveratrol, hCPT compounds, aloe-emodin, curcumin, lanosterol, mamba Wei, cidofovir, aklavine, carminomycin, deoxidation pyrrolomycin, zorubicin, the fluoro-idarubicin of 8-, nystatin, amphotericin, mitoxantrone, emodin, actinomycin D, rapamycin, mithramycin, Epothilones, mitomycin, bleomycin, aspergillus fumigatus cedrol, methylprednisolone, Flavopiridol, breviscapine, ET-743, euphorbia plant diterpene, 2,5-pentoxifylline, matrine, ipsapirone, the sub-chalone A4 of windmill, ubenimex, ribavirin, Marimastat, medroxyprogesterone, stavudine, Saquinavir, phenylephrine, methoxamedrine, albuterol, isoproterenol, misoprostol, latanoprost, prostacyclin, quinidine, Propafenone, Pu Naluoer, digoxin, Digitoxin, dobutamine, warfarin, coumarin kind compound, lovastatin, fluvastatin, En Gelie is clean, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, 1: PN: WO02056903 PAGE: 25 claimed protein, Zoladex, galantamine, cycloheximide, minocycline, meloxicam, posaconazole, everolimus, Vorinostat, PTK787 alkali, abiraterone, dihydroarteannuin, andrographolide, dexamethasone, code name is the compound of AEZS-112, code name is the compound of GZ402674, code name is the compound of BCX-1777, code name is the compound of CYC682, code name is the compound of LY-2334737, O-(chloracetyl-carbamyl) Amebacilin, code name is the compound of SU14813, code name is the compound of BMS-275291, code name is the compound of ABT-510, code name is the compound of Aplidine, code name is the compound of NSC683551, code name is the compound of CGS27023A, code name is the compound of RO32-3555, code name is the compound of NPI-0052, for drawing ten thousand stars, code name is the compound of CEP-1347, code name is the compound of ABR-215050, code name is the compound of MonomethylauristatinE, bicalutamide, HPR, Ansamycin, bryostatin, CCI-779, Pu Masita, tipranavir, indinavir, ritonavir, atazanavir, viracept see nelfinaivr, batimastat, Quercetin, flavonoid medicine, ticagrelor, Kan Geruiluo, Sebivo, trifluridine, adapalene, Lopinavir, Da Gelie is clean, rifaximin, fluticasone, Chinese mugwort Saperconazole, Merck, LBH589, A Wei Batan, levonorgestrel, ethinylestradiol, ground Rui Lawei, Olmesartan, according to cutting down Kato, bryostatin-1, alpha-galactosylceramide, EGCG, curcumin, rubescensine A, genistein, triptolide, gossypol, silibinin, telavancin, Ezetimibe, pseudoephedrine, ADZ6140, mometasone furoate, deferiprone, oxibutynin, oxymorphone, Merck, Mirabegron, teriflunomide, avanaphil, CCI-779, dust is for lattice Wei, Du Lutewei, calicheamicin, Retapamulin, tolvaptan, LUMEFANTRINE, his bit pyridine, galantamine, Tuo Ruisaier, Ka Gelie is clean, draw for drawing Wei, buprenorphine, rope fluorine cloth Wei, Treprostinil, dantrolene, fluticasone furoate, naloxone, Kan Gelie is clean, Suo Feibuwei, N-methylol Aripiprazole, code name is the compound of brivanib, code name is the compound of bryostatin-1, code name is the compound of combretastainA4, code name is the compound of CEP18770, code name is the compound of Ivacaftor, code name is the compound of MEK162, code name is the compound of neovastat, code name is the compound of UCN-01, code name is the compound of ridaforolimus, code name is the compound of AZD6244, code name is the compound of TAK-733, code name is the compound of AS703026, code name is the compound of PD-325901, code name is the compound of maytansine, code name is the compound of RO4987655, code name is the compound of GDC-0973, code name is the compound of GSK945237, code name is the compound of ANG1009, code name is the compound of AD198, code name is the compound of Becatecarin, code name is the compound of Adva27a, code name is the compound of Benzopyranones, code name is the compound of AEZS112, code name is the compound of B00742, code name is the compound of ALCHEMIX, the compound that code name is, the compound that code name is, code name is the compound of Saintopin, code name is the compound of NCA0465, code name is the compound of GL331, code name is the compound of CAP7.1, code name is the compound of IT62B, code name is the compound of C1311, oxycodone, department's licarbazepine, tacrolimus, Paliperidone, N-methylol Aripiprazole, draw for drawing Wei, Ka Gelie is clean, dexamethasone, carubicin, aclarubicin, ibacitabine, galocitabine, ancitabine, lestaurtinib, an improsulfan, mannomustine, ritrosulfan, treosulfan, ecomustine, estramustine, semustine, alestramustine, gimeracil, Baily department he,
Containing medicine that is amino or amido, carbamyl chloride medicaments derivative is obtained by reacting by elder generation and solid phosgene, then with containing the easy fracture spacerarms such as cystine linkage or polypeptide key and strengthens hydrophobic spacerarm compound hydroxyl or amino react, obtain medicine to be connected by carbamate or urea key, and containing easy fracture spacerarm and the intermediate product strengthening hydrophobic spacerarm, the carboxyl of latter two intermediate product molecule under the catalyst actions such as CDI with two of choline glycerophosphatide hydroxyl reactions, obtain the quick-releasing type medicine phosphatide cpd containing two pharmaceutical groups accordingly.Be applicable to comprising containing medicine that is amino or amido of this method: code name is the camptothecin derivative of DX-8951f, gemcitabine, code name are CP-4126 compound, C 1-C 20amide groups gemcitabine, fortulon, cladribine, fluorouracil, ftorafur, carmofur, Tegadifur, doxifluridine, Ai Xila shore, capecitabine, 5 '-deoxidation-5-fluorine cytidine, 5 '-'-Deoxy-5-fluorouridine, 2'-Deoxy-5-Floxuridine, cytosine arabinoside, ancitabine, troxacitabine, 1-(2-C-cyano-2-dioxy-BETA-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, decitabine, Bosutinib, he is luxuriant and rich with fragrance for Buddhist nun, Yiluo is for Buddhist nun, Da Ke is for Buddhist nun, HKI-272, many Weis are for Buddhist nun, Pa Na is for Buddhist nun, Ba Fei is for Buddhist nun, department is beautiful for Buddhist nun, card is pricked for Buddhist nun, Luso is for Buddhist nun, Lu Zuo is for Buddhist nun, Ai Le is for Buddhist nun, card is rich for Buddhist nun, pleasure is cut down for Buddhist nun, color is auspicious for Buddhist nun, Ah method is for Buddhist nun, Sutent, Lapatinib, gram azoles is for Buddhist nun, A Pa is for Buddhist nun, erlotinib, how card is for Buddhist nun, Axitinib, bosutinib, AMN107, gefitinib, Dasatinib, sitagliptin, imatinib, 6-MP, methotrexate, aminopterin, hydroxyurea, inosine dialdehyde, ADA, according to Shandong for Buddhist nun, Sibutramine Hydrochloride is for Buddhist nun, Luso profit is for Buddhist nun, azacitidine, clofarabine, lenalidomide, nelarabine 506u, pazopanib, ZD6474, Ka Feizuo meter, En Zhalu amine, Da Lafeini, PTK787, temozolomide, Elvucitabine, Beta department spit of fland, BI 1356, fluoxetine, Egelieting, vildagliptin, BMS-477118, duloxetine, atorvastatin, carmustine, nimustine, acadesine, 4 '-sulfo--β-D-arabino-furanosylcytosine, adefovirdipivoxil, vidarabine, amycin, epirubicin, daunorubicin, idarubicin, pirarubicin, grace is for Nuo Te, west reaches aniline, amdoxovir, lamivudine, Entecavir, China fir fine jade, tacrine, lenalidomide, methisazone, hydroxyurea, Bleomycin A5, ganciclovir, famciclovir, phentolamine, phenoxybenzamine, prazosin, tamsulosin, indoramine, brimonidine, hydralazine, minoxidil, mecamylamine, procainamide, mexiletine, dopamine, amrinone, Pabuk former times profit cloth, Bo Saipowei, spy draws big, huperzine A, memantine, Sorafenib, Rui Gefeini, Da Lafeini, Wei Luofeini, FTY720, Ni Danibu, trifluorothymidine, Wo Nuolazan, Aura handkerchief Buddhist nun, ifosfamide, Ai Ruibulin, code name is the compound of TAS-106, code name is the compound of VQD-002, code name is the compound of MB07133, code name is the compound of SPD754, code name is the nucleoside analog of Reverset, code name is the compound of E7974, code name is the compound of Lonafarnib, code name is the compound of Semaxanib, code name is the compound of Linifanib, code name is the compound of Crenolanib, icatibant, code name is the compound of AZD3293, code name is the compound of LuAE58054, code name is the compound of LY2811376, code name is the compound of Alectinib, Zarnestra, Luo Nafani, An Ruinawei, intend peptide medicine, levetiracetam, eslicarbazepine, topiramate, vilazodone, draw ferrum Buddhist nun primary, 1B-d-amfetamine, doxazosin, oxcarbazepine, emtricitabine, adefovir ester, tenofovir, valganciclovir, midalcipran, aliskiren, ximelagatran, etravirine, rufinamide, imiquimod, famotidine, lamotrigine, uncle's match Wei, ezogabine, colesevelam, imiquimod, chlortalidone, Eliquis, Abacavir, (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, Te Lawan star, FTY720, sphingol, the western croak of Leo, Ao Bitawei, code name is the compound of Brostallicin, code name is the compound of Baricitinib, code name is the compound of Buparlisib, code name is the compound of cobicistat, code name is the compound of Elacytarabine, code name is the compound of GX15-070, code name is the compound of Iniparib, code name is the compound of Ixazomib, code name is the compound of KRN7000, code name is the compound of linezolid, code name is the compound of Linsitinib, code name is the compound of Nintedanib, code name is the compound of Motesanib, code name is the compound of Voxtalisib, code name is the compound of Vatalanib, code name is the compound of Pilaralisib, code name is the compound of ONX0912, code name is the compound of Tivozanib, code name is the compound of PF-03084014, code name is the compound of Verosudil, code name is the compound of TG-101348, code name is the compound of Tivantinib, code name is the compound of Paritaprevir, code name is the compound of sonidegib, code name is the compound of Rociletinib, code name is the compound of Trametinib, code name is the compound of Regorafenib, code name is the compound of Evofosfamide, code name is the compound of Veliparib, code name is the compound of volasertib, code name is the compound of simeprevir, code name is the compound of vismodegib, code name is the compound of pomalidomide, code name is the compound of idelalisib, code name is the compound of BEZ2235, code name is the compound of GDC-0941, code name is the compound of XL147, code name is the compound of MK2206, Da Pafeini, code name is the compound of BMS-908662, code name is the compound of CI-1040, code name is the compound of GSK1120212, code name is the compound of NVP-AEW541, code name is the compound of Tivozanib, code name is the compound of masitinib, code name is the compound of SCH900105, code name is the compound of Foretinib, code name is the compound of RO5126766, code name is the compound of Cyclopentanthraquinones, code name is the compound of F14512, code name is the compound of Sitafloxacin, code name is the compound of Elinafide, code name is the compound of KW2170, code name is the compound of Lucanthone, code name is the compound of Sabarabicin, code name is the compound of Pixantrone, AZD2171, not for husky Buddhist nun, handkerchief pool former times cloth, roller pyrrole is smooth, dabigatran etcxilate, deacetylate vinblastine list hydrazides, fourth oxygen piperazine alkane, rilpivirine, medorubicin, how softly star is compared, pirarubicin, rodorubicin, Sha Rou compares star, valrubicin, zorubicin, leurubicin, idarubicin, galarubicin, esorubicin, detorubicin, amrubicin, cut down and hold in the palm his shore, zalcitabine, for pricking his shore, fiacitabine, flurocitabine, ambamustine, Erlotinib, Pei Li is for Buddhist nun, trimetrexate,
Medicine containing carboxyl, by first with containing the easy fracture spacerarm such as cystine linkage or polypeptide key with strengthens the hydroxyl of compound of hydrophobic spacerarm or amino reacts, obtain medicine to be connected by ester bond or amido link, and containing easy fracture spacerarm and the intermediate product strengthening hydrophobic spacerarm, the carboxyl of latter two intermediate product molecule and two hydroxyl reactions of choline glycerophosphatide react under catalyst action, obtain the quick-releasing type medicine phosphatide cpd containing two pharmaceutical groups accordingly.The medicine containing carboxyl being suitable for this method comprises: 5,6-dimethyl ton ketone-4-acetic acid, Pseudolarix acid B, Ganodenic acid, oleanolic acid, chrysophanic acid, 9-cis-retinoic acid, belulinic acid Betulinic acid, VE succinic acid monoester, all-trans-retinoic acid, diclofenac, card glutamic acid, shellfish gallbladder acid difficult to understand, deoxycholic acid, vigabatrin, leuprorelin, tree toad element, Pramlintide, thyroliberin, bacitracin, teriparatide, goserelin, Exenatide, peace is for Anji peptide, rice lumbering peptide, romidepsin, cheese silk figured silk fabrics peptide, sifuvirtide, Ai Boweitai, tyroserleutide, donipenem, Azilsartan, pitocin, cyclosporin, Protirelin, Taltirelin, nafarelin, buserelin, histrelin, gonadorelin, color ammonia Rayleigh, somatostatin, secretin, octreotide, ziconotide, T-20, Lanreotide, vapreotide, seglitide, for degree Shandong peptide, Linaclotide, sinapultide, SOM230, triptorelin, Tesamorelin, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], bexarotene, Pitavastatin, Rosuvastatin, bendamustine, melphalan, lonidamine, atrasentan, melphalan, SS, pemetrexed, formylmerphalan, dinoprostone, carboprost, Alprostadil, gemfibrozil, Xi Luruiwei, Pepstatin, Ge La is for thunder, reed Xi Natan, indomethacin, ibuprofen, naproxen, DEFERASIROX, fluoroquinolone, Pralatrexate, code name is the compound of Voreloxin, code name is the compound of AKR501, code name is the compound of CPI-613, code name is the compound of MK0429, code name is the compound of IDN-6556, tanomastat, marimastat, prinomastat, code name is the compound of alisertib, cilengitide, argatroban, dabigatran, artesunate, ambrisentan, eltrombopag olamine, valsartan, Moxifloxacin, naproxen, Yi Luduo quinoline, Ge La is for thunder, tirofiban, DEFERASIROX, ceftazidime, levodopa, Carbidopa, besifloxacin, Febuxostat, prulifloxacin, cephalo is than general ester, Ceftobiprole, gabapentin ester, mesalazine, icatibant, Linaclotide, shellfish reaches quinoline, Sha Kubi is bent, according to a piperazine azoles, donipenem, ingenol first butenoate, droxidopa, code name is the compound of lumacaftor, code name is the compound of MLN9708, code name is the compound of Sacubitril, code name is the compound of rigosertib, code name is the compound of Vosaroxin, code name is the compound of Orantinib, edatrexate, ketotrexate, oteracil, mitoflaxone, bortezomib.
Platinum medicine is first obtained by reacting carbamyl chloride medicaments derivative with solid phosgene by the part containing Amino End Group, then with containing the easy fracture spacerarms such as cystine linkage or polypeptide key and strengthens hydrophobic spacerarm compound hydroxyl or amino react, obtain medicine to be connected by carbamate or urea key, and containing easy fracture spacerarm and the intermediate product strengthening hydrophobic spacerarm, the carboxyl of latter two intermediate product molecule under the catalyst actions such as CDI with two of choline glycerophosphatide hydroxyl reactions, obtain the quick-releasing type medicine phosphatide cpd containing two platinum pharmaceutical groups accordingly.The medicine being applicable to this method comprises: cisplatin, spiroplatin, carboplatin, oxaliplatin, Satraplatin JM216 BMS 182751, Miboplatin, nedaplatin, Eptaplatin, lobaplatin, Cycloplatin, JM-216, picoplatin, code name are the compound of BBR-3464.
Quick-releasing type medicine phosphatide cpd of the present invention is preparing the application in the medicines such as antitumor, by described medicine phospholipid or its pharmaceutically acceptable salt, is prepared into medicament with acceptable carrier on pharmacodynamics.The compounds of this invention or the compounds of this invention and one or more solids or liquid pharmaceutical excipients and/or adjuvant can be combined, make and can be used as the suitable administration form or dosage form that people's medicine uses.Usual pharmaceutical composition of the present invention contains the compounds of this invention of percentage by weight 0.1-100%.
The compounds of this invention or the pharmaceutical composition route of administration containing it can be intestinal or non-bowel, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc.Can be drug administration by injection, comprise intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.Form of administration can be liquid dosage form, solid dosage forms.If liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms are tablet, capsule, drop pill, aerosol, pill, powder, solution, suspensoid, Emulsion, granule, suppository, lyophilized injectable powder etc. such as.
The compounds of this invention can be made ordinary preparation, also can be slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.
The carrier that pharmaceutical composition of the present invention adopts is that such as diluent and absorbent, as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.; Wetting agent and binding agent, as water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.; Disintegrate inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as Pulvis Talci, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet can also be made coated tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
The compounds of this invention is made injection preparation, as solution, suspensoid solution, Emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can containing acceptable carrier, diluent, binding agent, lubricant, antiseptic, surfactant or dispersant on a kind of and/or multiple pharmacodynamics.As diluent can be selected from water, ethanol, Polyethylene Glycol, 1,3-PD, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, in order to prepare isotonic injection, appropriate sodium chloride, glucose or glycerol can be added in injection preparation, in addition, conventional cosolvent, buffer agent, pH adjusting agent etc. can also be added.These adjuvants are that this area is commonly used.
Elaioplast nanometer particle is made by the compounds of this invention and auxiliary agent, particle diameter 10-1000 nanometer, the auxiliary agent used is one or more in phospholipid, pegylated phospholipids (molecular weight polyethylene glycol 200-4000), targeting pegylated phospholipids (molecular weight polyethylene glycol 200-4000) cholesterol, and targeting group is folic acid, galactose, polypeptide, antibody, antibody fragment, hyaluronic acid, asialoglycoprotein, polysaccharide, nucleic acid and plan peptide.
Elaioplast nanometer particle preparation is made, particle diameter 10-1000 nanometer by the compounds of this invention.Elaioplast nanometer particle is made, particle diameter 10-1000 nanometer by the compounds of this invention and auxiliary agent.
From the screening of extracorporeal anti-tumor isoreactivity, the antitumor isoreactivity that the compounds of this invention performance is excellent.Test shows, the toxicity in vivo of the compounds of this invention is less than former medicine.From the screening of extracorporeal anti-tumor isoreactivity, the antitumor isoreactivity that the performance of the compounds of this invention elaioplast nanometer particle is excellent.Test shows, the Via Liposomes of the compounds of this invention is endotoxic much smaller than former medicine.
The present invention utilizes the medicine of 2 molecules to be connected with two spacer segment arms to be connected by covalent bond with phospholipid hydrophilic head as hydrophobic tail, and prepare quick-releasing type medicine phosphatide cpd, hydrophilic or lipotropy are better than former medicine.
A kind of spacerarm containing easy fracture structures such as disulfide bond is had in quick-releasing type medicine phosphatide cpd molecule of the present invention.The effects such as the intracellular glutathion of this spacerarm and fast fracture, a part quick-releasing type medicine phosphatide cpd discharges the proto-drug of two molecules fast, form high concentration, improve the drug effects such as the antitumor of medicine, reach more than 2 times of proto-drug, play the function strengthening the effects such as antitumor.
Quick-releasing type medicine phosphatide cpd of the present invention is independent or assemble the stable liposome of formation together with auxiliary agent, when overcoming general wrapping kmedicine by liposome, medicine is easy to the shortcoming of leaking, improve the efficiency of medicine parcel and the stability of medicine, make the quick-releasing type medicine phosphatide cpds such as antitumor take in cell easily through liposomal form simultaneously, play drug effect.
Quick-releasing type medicine phosphatide cpd is prepared into nano-particle by the present invention, has the characteristic of liposome, has target function, has the characteristic that can form liquid preparation, solid preparation, semi-solid preparation, sterilization preparation and sterile preparation, for treatments such as tumors; Quick-releasing type medicine phosphatide cpd of the present invention and elaioplast nanometer particle thereof are a kind of brand-new prodrugs, also be pharmaceutical carrier, improve the stability of medicine, and play drug effect through degradeds such as enzymes in vivo, prolong drug can discharge the half-life, and there is lower toxic and side effects.
The preparation method of quick-releasing type medicine phosphatide cpd elaioplast nanometer particle of the present invention, the mixture by the compounds of this invention quick-releasing type medicine phosphatide cpd or the compounds of this invention and auxiliary agent, by method preparations such as film dispersion method, reverse phase evaporation, freeze-drying, ultrasonic dispersion, spray drying method, film squeezing and pressing method or high pressure homogenization methods.
Quick-releasing type medicine phosphatide cpd antitumor isoreactivity of the present invention is better than former medicine; The antitumor isoreactivity of quick-releasing type medicine phosphatide cpd liposome of the present invention is better than former medicine.
Portion of reagent code name below for using in preparation process:
DMAP4-dimethylamino naphthyridine
CDIN, N '-carbonyl dimidazoles
GPC Phosphorylcholine glycerol
DBU1,5-diazabicylo [5.4.0] 11-5-alkene
EDC1-ethyl-(3-dimethylaminopropyl) carbodiimide
NHSN-N-Hydroxysuccinimide
TFA trifluoroacetic acid
DMF dimethyl formamide
DMSO dimethyl sulfoxine
Bu 4nF tetrabutyl ammonium fluoride
(BOC) 2o Bis(tert-butoxycarbonyl)oxide
BOC tertbutyloxycarbonyl
TEA triethylamine
Folicacid folic acid
GFLG glycyl-phenylalanyl-leucyl-glycine
Triphosgene triphosgene
The lipophilic sign of medicine and lipotropy measurement method of parameters: IAM chromatography method (Acta Pharmaceutica Sinica, 2003,38 (10), 791-794; Acta Pharmaceutica Sinica, 2003,38 (6), 475-480; JOURNALOFPHARMACEUTICALSCIENCES, 2008,97 (8): 2984-3004).
Instrument: Aglient1100 highly effective liquid phase chromatographic system (adopting IAMPC.MG IAM chromatography post: 12 μm, 4.6mm × 150mm, RegisChem company of the U.S.).
The mensuration of IAM chromatography capacity factor measure uses pH7.4,0.01mol/L phosphate buffer as mobile phase from eluted substance chromatographic column.For the strong lipophilic compound not adding organic regulator and can not elute from chromatographic column, in mobile phase, add acetonitrile to strengthen its eluting power, wherein the percentage ratio of acetonitrile in mobile phase at (0 ~ 30) %.Column temperature is 35 DEG C; Flow velocity is 1.0mL/min; The ultraviolet detection wavelength of all compounds is 215nm; Test drug concentrations is 200 μm of ol/L, sampling volume 15 μ L.The reserve capability of medicine on post with its capacity factor measure logarithm value (lgk ' iAM) represent:
lgk’ IAM＝lg(T R-T 0)/T 0
In formula, T rfor medicine retention time on a column, T 0for the dead time.The capacity factor measure (k ' IAM) of medicine under different mobile phase is normalized to capacity factor measure (k when being zero iAM), it represents the immobilized artificial membrane affinity parameter of IAM chromatography system Chinese medicine.The reserve capability of medicine on post its capacity factor measure logarithm lgk iAMrepresent the partition coefficient of medicine on IAM chromatography, namely represent medicine lipotropy parameter.Lgk iAMhereinafter referred to as lipotropy parameter, its value is larger, and lipotropy is better.
Reference examples 1:
The synthesis of two (camptothecine-20-succinic acid) phosphatidylcholine
Camptothecine 1g, succinic anhydrides 0.75g, DMAP0.2g, triethylamine 0.2g, adding chloroform is reaction dissolvent, back flow reaction 12h; Dilute hydrochloric acid washs three times, filters dilute hydrochloric acid layer, gets filter cake; Add dissolve with methanol, place 12h for 4 DEG C, filter, get filter cake, dry, column chromatography separating purification, obtains intermediate product camptothecine-20-monomester succinate 0.75g.Get intermediate product camptothecine-20 monomester succinate 0.6g, add CDI0.5g, add 30mLDMSO as reaction dissolvent, add GPC0.3g and DBU0.5g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (camptothecine-20-succinic acid) the phosphatidylcholine 0.32g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)：δ8.03-7.59(10H，m)，6.25(2H，s)，4.71-4.55(7H，m)，4.21(2H，t)，3.86-3.55(8H，m)，3.30(9H，s)，2.67-2.41(8H，t)，1.98(4H，m)，1.12(6H，s)。[M+H] +m/z：1119.34。IAM chromatography method measures the lipotropy parameter lgk of product iAMvalue is 1.79.
Reference examples 2:
The preparation of two (camptothecine-20-succinic acid) phosphatidylcholine liposome
Get two (camptothecine-20-succinic acid) phosphatidylcholine 1mmol of reference examples 1, add chloroform 20mL, 60 DEG C revolve solvent evaporated; Add 20mLPBS (pH=7.4) 60 DEG C of skinnings, 200nm membrane filtration, obtain two (camptothecine-20-succinic acid) phosphatidylcholine elaioplast nanometer particle solution.The mean diameter of particle size analyzer analysis of liposomes is 210nm.
Reference examples 3:
The synthesis of two (gemcitabine-4-N-succinic acid) phosphatidylcholine
According to the gemcitabine derivant 3 '-O-BOC-5 '-O-BOC-gemcitabine that method synthesis tertbutyloxycarbonyl (BOC) in document (J.Org.Chem.1999,64,8319-8322) is protected.
3 '-O-BOC-5 '-O-BOC-gemcitabine 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, succinic anhydrides 1g, 50 DEG C of room temperature reaction 12h, gained reactant liquor, by column chromatography purification, obtains 3 '-O-BOC-5 '-O-BOC-gemcitabine-4-N-succinic acid 0.82g; Intermediate product 3 '-O-BOC-5 '-O-BOC-gemcitabine-4-N-succinic acid 0.6g is dissolved in 20mLDMSO, adds CDI0.6g, and activation 1h, adds GPC0.3g and DBU0.6g, room temperature reaction 24h, precipitate in ice ether; Solid dispersal is in chloroform; drip TFA at 0 DEG C, rise to room temperature reaction 3 hours, remove BOC protecting group; gained reactant liquor, by column chromatography purification, obtains two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine 0.46g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.0(2H，br)，6.39(2H，t)，4.64(1H，m)，4.32(2H，m)，4.11(2H，m)，3.97(2H，t)，3.91(2H，m)，3.43(2H，t)，3.30(9H，s)，2.57-2.53(8H，m)。[M+H] +m/z：948.73。Lipotropy parameter lgk iAMvalue is 1.43.
Embodiment 1:
The synthesis (synthetic route is shown in Fig. 1) of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine
Camptothecine 1g is dissolved in 100mL chloroform, add triethylamine 1.0g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains camptothecine-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.65g.Intermediate product camptothecine carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.35g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.03-7.60(10H，m)，6.74(2H，s)，4.76-4.74(4H，m)，4.64(1H，s)，4.47-4.38(4H，m)，4.22-4.13(6H，m)，4.04-3.96(8H，m)，3.61(2H，t)，3.30(9H，s)，2.85-2.64(16H，m)，1.96(4H，m)，0.90(6H，t)。[M+H] +m/z：1479.53。
IAM chromatography method measures the lipotropy parameter lgk of product iAMvalue is 2.18, shows its hydrophilic and is better than lgk iAMvalue is the former medicine of camptothecine of 4.85, and lipotropy is better than lgk iAMvalue is two (camptothecine-20-succinic acid) phosphatidylcholines of 1.83.
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 2:
The synthesis (route is shown in Fig. 2) of two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine
Paclitaxel 1.0g is dissolved in 30mL chloroform, add triethylamine 0.5mL, add 0.6g tert-butyl chloro-silicane (TBDMSCl), at 0 DEG C, react 3h, add ice ether, separate out white sedimentation, centrifugalize, further column chromatography for separation (eluant, chloroform/methanol: 7/1, v/v) obtaining paclitaxel 2 ' position end-cap product 2 '-tertiary butyl dimethyl Si base-paclitaxel 0.82g, is white powdery solids.
2 '-tertiary butyl dimethyl Si base-paclitaxel 0.5g is dissolved in 50mL chloroform, adds triethylamine 0.5g, triphosgene 0.2g, reacts 6h under room temperature, revolves steaming and desolventizes; Solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol adipate monoester 0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 2 '-tertiary butyl dimethyl Si base-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate monoester 0.36g; Intermediate product 2 '-tertiary butyl dimethyl Si base-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate monoester 0.3g is dissolved in 10mLDMSO, add CDI0.3g, activation 1h, add GPC0.1g and DBU0.3g, room temperature reaction 24h, gained reactant liquor uses tetrabutyl ammonium fluoride process further, removes TBDMS, by column chromatography purification after cold diethyl ether precipitation, obtain two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) the phosphatidylcholine 0.18g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.07-8.03(10H，m)，7.70-7.27(22H，m)，5.59-5.51(4H，m)，5.06-4.80(6H，m)，4.47-4.12(11H，m)，4.04-3.96(10H，m)，3.65-3.37(6H，m)，3.30(9H，s)，2.84-2.80(12H，m)，2.32(8H，m)，2.21(12H，s)，2.13-1.64(22H，m)，1.30(6H，s)，1.25(4H，s)。[M+H] +m/z：2546.75。
IAM chromatography method measures the lipotropy parameter lgk of product iAMvalue is 2.45, shows its hydrophilic and is better than lipotropy parameter lgk iAMvalue is the former medicine of paclitaxel of 4.26.
Two (paclitaxel-7-carbonic ester-dithio diethanol-adipate ester) phosphatidylcholine is dissolved in 0.1M potassium chloride solution, and lyophilizing obtains the phosphocholine compound solid powder containing potassium ion and chloride ion.
Embodiment 3:
The synthesis (synthetic route is shown in Fig. 3) of two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine
According to the gemcitabine derivant 3 '-O-BOC-5 '-O-BOC-gemcitabine that method synthesis tertbutyloxycarbonyl (BOC) in document (J.Org.Chem.1999,64,8319-8322) is protected.
3 '-O-BOC-5 '-O-BOC-gemcitabine 1g is dissolved in 100mL chloroform, adds triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolve steaming and desolventize; Solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 3 '-O-BOC-5 '-O-BOC-gemcitabine-4-N-carbamate-dithio diethylene glycol-monomester succinate 0.72g; Carbamate-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO intermediate product 3 '-O-BOC-5 '-O-BOC-gemcitabine-4-N-, add CDI0.6g, activation 1h, adds GPC0.3g and DBU0.6g, room temperature reaction 24h, precipitates in ice ether; Solid dispersal is in chloroform; drip TFA at 0 DEG C, rise to room temperature reaction 3 hours, remove BOC protecting group; gained reactant liquor, by column chromatography purification, obtains two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine 0.35g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：9.16(2H，d)，8.0(2H，br)，6.39(2H，t)，5.4(2H，d)，4.65(1H，m)，4.47-4.38(8H，m)，4.20(1H，s)，4.13(1H，s)，3.96(8H，m)，3.79(2H，m)，3.65-3.54(8H，m)，3.30(9H，s)，2.85-2.84(14H，m)，2.64(2H，t)。[M+H] +m/z：1309.22。
IAM chromatography method measures the lipotropy parameter lgk of product iAMvalue is 1.96, shows its lipotropy and is better than lipotropy parameter lgk iAMvalue is the former medicine of gemcitabine of 0.52, and its lipotropy is also better than lipotropy parameter lgk iAMvalue is two (gemcitabine-4-N-succinic acid acyl) phosphatidylcholines of 1.43, the enhancing hydrophobic lipophilic effect of display product two kinds of spacerarms.
Two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium phosphate aqueous solution of 0.01M, and lyophilizing obtains two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and phosphate anion.
Embodiment 4:
The synthesis (synthetic route is shown in Fig. 4) of two (topotecan-20-carbonic ester-dithio diethylene glycol-diethylene glycol acid esters) phosphatidyl choline compounds
9-dimethylamino methyl-10-hydroxycamptothecine (topotecan) 0.6g is dissolved in 50mL chloroform, adds triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes; Solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol-diglycolic acid monoesters 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains topotecan-20-carbonic ester-dithio diethylene glycol-diglycolic acid monoesters 0.48g; Intermediate product topotecan-20-carbonic ester-dithio diethylene glycol-diglycolic acid monoesters 0.4g is dissolved in 20mLDMSO, add CDI0.4g, activation 1h, add GPC0.15g and DBU0.4g, room temperature reaction 24h, precipitate in ice ether, by column chromatography purification, obtain two (topotecan-20-carbonic ester-dithio diethylene glycol-diethylene glycol acid esters) the phosphatidylcholine 0.26g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：7.80(2H，s)，7.66(2H，d)，7.19(2H，d)，6.74(2H，s)，5.35(2H，br)，4.76-4.64(5H，m)，4.47-4.33(17H，m)，4.22-4.13(6H，m)，4.04-3.96(8H，m)，3.61(2H，t)，3.0(9H，s)，2.84(8H，t)，2.16(12H，s)，1.96(4H，m)，0.90(6H，t)。[M+H] +m/z：1657.72。Lipotropy parameter lgk iAMvalue is 2.10.
Embodiment 5:
The synthesis (route is shown in Fig. 5) of two (amycin-N-carbamate-dithio diethylene glycol-succinate-GFLG) phosphatidylcholine
Doxorubicin hydrochloride 0.8g is dissolved in 30mL chloroform, add triethylamine (0.5g, 4.5mmol), 0.3gTBDMSCl, 3h is reacted under room temperature, add ice ether sedimentation, the white solid of separating out, is separated with column chromatography and obtains hydroxy-end capped product 14-O, 4 '-O-two (tertiary butyl dimethyl Si base)-amycin 0.58g.
14-O, 4 '-O-two (tertiary butyl dimethyl Si alkane)-amycin 0.5g are dissolved in 10mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, react 6h under room temperature, revolve steaming and desolventize; Solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol-monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 14-O, 4 '-O-two (tertiary butyl dimethyl Si alkane)-amycin-3 '-carbamate-dithio diethylene glycol-monomester succinate 0.46g; Intermediate product 14-O, 4 '-O-two (tertiary butyl dimethyl Si base)-amycin-3 '-carbamate-dithio diethylene glycol-monomester succinate 0.4g is dissolved in 20mLDMSO, add 0.5gEDC/0.5gNHS activation, then N-glycyl-phenylalanyl-leucyl-glycine (GFLG) 0.3g is added, room temperature reaction 24 hours, reactant liquor pillar layer separation, obtains 14-O, 4 '-O-two (tertiary butyl dimethyl Si alkane)-amycin-3 '-carbamate-dithio diethylene glycol-succinyl-N-GFLG0.31g; Above-mentioned intermediate product is dissolved in 10mLDMSO, adds CDI0.3g, and activation 1h, adds GPC0.15g and DBU0.3g, room temperature reaction 24h, separates out precipitation in cold diethyl ether; Solid is dissolved in DMF further, add tetrabutyl ammonium fluoride, room temperature reaction 6h, removes TBDMS, obtains two (amycin-N-carbamate-dithio diethylene glycol-succinate-GFLG) the phosphatidylcholine 0.16g of product after cold diethyl ether precipitation by column chromatography purification. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.03-7.88(14H，m)，7.40-7.27(12H，m)，5.35(4H，br)，4.95-4.92(4H，m)，4.69-4.38(10H，m)，4.20-3.37(44H，m)，3.30(9H，s)，3.19-3.12(4H，m)，2.84(8H，t)，2.61(2H，t)，2.49(2H，t)，2.25-1.49(14H，m)，1.18(6H，d)，0.91(12H，d)。[M+H] +m/z：2618.73。The lipotropy parameter lgk of product iAMvalue is 2.35, shows its lipotropy and is better than lipotropy parameter lgk iAMvalue is the former medicine of doxorubicin hydrochloride of 0.78, is also better than lipotropy parameter lgk iAMvalue is two (amycin-N-dithio diethyl alkyd) phosphatidylcholines of 2.12, the enhancing hydrophobic lipophilic effect of two kinds of hydrophobic spacerarms of display product.
Embodiment 6:
The synthesis (route is shown in Fig. 6) of sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinate-sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine
According to embodiment 1 method synthesis camptothecine-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.3g is dissolved in 20mLDMSO, add CDI0.3g, activation 1h, add GPC0.1g and DBU0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains intermediate product sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinyl glycerolphosphocholine 0.18g.
According to embodiment 2 method synthesis 2 '-tertiary butyl dimethyl Si base-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate monoester 0.15g is dissolved in 10mLDMSO, add CDI0.3g, activation 1h, add intermediate product sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinyl glycerolphosphocholine 0.15g, DBU0.3g, room temperature reaction 24h, gained reactant liquor uses tetrabutyl ammonium fluoride process further, remove tertiary butyl dimethyl Si base TBDMS, column chromatography purification is passed through after cold diethyl ether precipitation, obtain product sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinate-sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine 0.09g. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.07-7.27(21H，m)，6.74(1H，s)，5.59-5.51(3H，m)，5.05(1H，d)，4.80-4.64(4H，m)，4.47-4.12(10H，m)，4.04-3.96(9H，t)，3.65-3.61(3H，t)，3.37(1H，t)，3.30(9H，s)，2.85-2.80(16H，m)，2.32-2.13(11H，m)，1.64(4H，t)，1.96-1.76(8H，m)，1.30-1.25(9H，m)，0.90(3H，t)。[M+H] +m/z：2013.14。Lipotropy parameter lgk iAMvalue is 2.35.
Embodiment 7:
The synthesis (route is shown in Fig. 7) of two (Docetaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine
Docetaxel 1.0g is dissolved in 30mL chloroform, add triethylamine 1mL, add 1.0g tert-butyl chloro-silicane (TBDMSCl), 3h is reacted at 0 DEG C, add ice ether, separate out white sedimentation, centrifugalize, further column chromatography for separation obtains paclitaxel 2 ' position end-cap product 2 '-tertiary butyl dimethyl Si base-Docetaxel 0.75g, is white powdery solids.
2 '-tertiary butyl dimethyl Si base-Docetaxel 0.5g is dissolved in 50mL chloroform, adds triethylamine 0.5g, triphosgene 0.2g, reacts 6h under room temperature, revolves steaming and desolventizes; Solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol adipate monoester 0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 2 '-tertiary butyl dimethyl Si base-Docetaxel-7-carbonic ester-dithio diethylene glycol-adipate monoester 0.36g; Intermediate product 2 '-tertiary butyl dimethyl Si base-Docetaxel-7-carbonic ester-dithio diethylene glycol-adipate monoester 0.3g is dissolved in 10mLDMSO, add CDI0.3g, activation 1h, add GPC0.15g and DBU0.3g, room temperature reaction 24h, gained reactant liquor uses tetrabutyl ammonium fluoride process further, remove TBDMS, by column chromatography purification after cold diethyl ether precipitation, obtain two (Docetaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) the phosphatidylcholine 0.18g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.07-7.20(22H，m)，5.59(2H，d)，5.06-3.37(36H，m)，3.30(9H，s)，2.84-2.80(10H，m)，2.32-2.13(16H，m)，1.88-1.64(20H，m)，1.38-1.25(36H，m)。[M+H] +m/z：2454.69。Lgk iAMvalue is 2.62.
Two (Docetaxel-7-carbonic ester-dithio diethyl alkyd-adipate ester) phosphatidylcholine is dissolved in 0.1M aqueous sodium persulfate solution, and lyophilizing obtains the phosphocholine compound solid powder containing sodium ion and sulfate ion.
Embodiment 8:
The synthesis (synthetic route is shown in Fig. 8) of two (7-ethyl-hydroxy camptothecine-10-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine
SN38 1g is dissolved in 100mL chloroform, adds triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes; Solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 7-ethyl-hydroxy camptothecine-10-carbonic ester-dithio diethylene glycol-monomester succinate 0.75g; Carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO intermediate product 7-ethyl-hydroxy camptothecine-10-, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (7-ethyl-hydroxy camptothecine-10-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.35g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：7.79(2H，d)，7.29-7.25(4H，m)，6.74(2H，s)，4.76-3.96(19H，m)，3.65-3.61(4H，m)，3.30(9H，s)，2.85-2.60(20H，m)，1.87(4H，m)，1.25(6H，t)，0.90(6H，t)。[M+H] +m/z：1567.64。Lgk iAMvalue is 1.94.
Two (7-ethyl-hydroxy camptothecine-10-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (7-ethyl-hydroxy camptothecine-10-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 9:
The synthesis (synthetic route is shown in Fig. 9) of two (podophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Podophyllotoxin 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains podophyllotoxin-4-carbonic ester-dithio diethylene glycol-monomester succinate 0.72g; Intermediate product podophyllotoxin-4-carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 30mLDMSO, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (podophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.43g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：6.66-6.52(8H，m)，6.07(4H，s)，5.31(2H，m)，4.76-3.41(43H，m)，3.30(9H，s)，2.85-2.64(16H，m)。[M+H] +m/z：1611.64。Lipotropy parameter lgk iAMvalue is 2.30.
Two (podophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (podophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 10:
The synthesis (synthetic route is shown in Figure 10) of two (camptothecine-9-carbamate-dithio diethylene glycol-succinate) phosphatidyl choline compounds
9-aminocamptothecin 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains camptothecine-9-carbamate-dithio diethylene glycol-monomester succinate 0.62g; Intermediate product camptothecine-9-carbamate-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (camptothecine-9-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine 0.41g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：9.15(2H，br)，8.49(2H，d)，7.83-7.48(6H，m)，6.74(2H，s)，4.76-4.74(4H，m)，4.47-3.61(25H，m)，3.30(9H，s)，2.85-2.64(16H，t)，1.87(4H，m)，0.90(6H，t)。[M+H] +m/z：1509.56。Lgk iAMvalue is 1.94.
Two (camptothecine-9-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (camptothecine-9-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 11:
The synthesis (synthetic route is shown in Figure 11) of two (camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
7-methylol camptothecine 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h at 0 DEG C, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-monomester succinate 0.81g; Intermediate product camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.43g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.13-7.58(8H，m)，6.74(2H，s)，5.17(4H，s)，4.76-3.61(27H，m)，3.30(9H，s)，2.85-2.64(16H，m)，1.87(4H，m)，0.90(6H，t)。[M+H] +m/z：1539.58。
Two (camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (camptothecine-7-methylene-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 12:
The synthesis (route is shown in Figure 12) of two (Cabazitaxel-2 '-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine
Cabazitaxel (7 β, 10 β-dimethoxy docetaxel) 1.0g is dissolved in 50mL chloroform, add triethylamine 0.6g, triphosgene 0.2g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol adipate monoester 0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains Cabazitaxel-2 '-carbonic ester-dithio diethylene glycol-adipate monoester 0.72g; Intermediate product Cabazitaxel-2 '-carbonic ester-dithio diethylene glycol-adipate monoester 0.5g is dissolved in 10mLDMSO, add CDI0.5g, activation 1h, add GPC0.25g and DBU0.5g, room temperature reaction 24h, gained reactant liquor uses tetrabutyl ammonium fluoride process further, removes TBDMS, by column chromatography purification after cold diethyl ether precipitation, obtain product two (Cabazitaxel-2 '-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine 0.38g. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.07-7.27(22H，m)，6.10-5.80(4H，m)，5.05-3.37(31H，m)，3.30(21H，s)，3.00-2.81(14H，t)，2.35-2.13(18H，m)，1.88-1.64(20H，m)1.38(18H，s)，1.30(6H，s)，1.25(12H，s)。[M+H] +m/z：2510.80。
Two (Cabazitaxel-2 '-carbonic ester-dithio diethyl alkyd-adipate ester) phosphatidylcholine is dissolved in 0.1M sodium-chloride water solution, and lyophilizing obtains the phosphocholine compound solid powder containing sodium ion and chloride ion.
Embodiment 13:
The synthesis (synthetic route is shown in Figure 13) of two (hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Hydroxy camptothecin 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-monomester succinate 0.75g; Intermediate product hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-monomester succinate 0.7g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.7g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.43g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：7.82-7.70(4H，d)，7.32-7.15(4H，m)，6.74(2H，s)，4.76-3.96(26H，t)，3.65-3.61(4H，t)，3.30(9H，s)，2.85-2.64(16H，t)，1.87(4H，m)，0.90(6H，t)。[M+H] +m/z：1511.53。
Two (hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 14:
The synthesis (synthetic route is shown in Figure 14) of two (irinotecan-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Irinotecan (CPT11, connection piperazine camptothecine) 1g is dissolved in 100mL chloroform, adds triethylamine 0.6g, triphosgene 0.3g, 6h is reacted under room temperature, revolve steaming to desolventize, solid is dissolved in 10mLDMSO, adds triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains irinotecan-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.85g; Intermediate product irinotecan-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.8g is dissolved in 20mLDMSO, add CDI0.8g, activation 1h, add GPC0.4g and DBU0.8g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (irinotecan-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.62g of product.
1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：7.79(2H，d)，7.29-7.25(4H，d)，6.74-3.96(25H，t)，3.61-3.39(6H，m)，3.30(9H，s)，3.29(4H，m)，2.85-2.45(32H，m)，1.96-1.25(30H，t)，0.90(6H，t)。[M+H] +m/z：1956.18。
Two (irinotecan-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (irinotecan-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 15:
The synthesis (synthetic route is shown in Figure 15) of two (hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Hexacyclic camptothecins (Lurtotecan) 0.5g is dissolved in 100mL chloroform, add triethylamine 0.4g, triphosgene 0.2g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.4g, add dithio diethylene glycol monomester succinate 0.2g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.35g; Intermediate product hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.3g is dissolved in 20mLDMSO, add CDI0.3g, activation 1h, add GPC0.15g and DBU0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.16g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：7.21-7.18(4H，m)，5.76-5.56(4H，dd)，4.64-3.61(43H，t)，3.30(9H，s)，2.85-2.64(16H，m)，2.48-2.26(22H，m)，1.96(4H，m)，0.90(6H，t)。[M+H] +m/z：1823.98。
Two (hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 16:
The synthesis (synthetic route is shown in Figure 16) of two (difluoro camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Difluoro camptothecine (BN80915) 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains hexacyclic camptothecins-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.71g; Carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO intermediate product difluoro camptothecine-20-, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 12h, gained reactant liquor, by column chromatography purification, obtains two (difluoro camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.46g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：7.84-7.75(4H，m)，7.34(2H，m)，6.74(2H，s)，4.76-3.61(25H，m)，3.30(9H，s)，2.85-2.64(16H，m)，1.96(4H，m)，0.90(6H，t)。[M+H] +m/z：1551.49。
Two (difluoro camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (difluoro camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 17:
The synthesis (synthetic route is shown in Figure 17) of two (Belotecan-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Camptothecin derivative Belotecan1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 12h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains Belotecan-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.75g; Intermediate product Belotecan-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.25g and DBU0.6g, room temperature reaction 12h, gained reactant liquor, by column chromatography purification, obtains two (Belotecan-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.46g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.13-7.58(8H，m)，6.74(2H，s)，4.76-3.61(25H，m)，3.30(9H，s)，2.97-2.64(28H，m)，2.00-1.96(6H，m)，1.07-0.90(18H，t)。[M+H] +m/z：1649.83。
Two (Belotecan-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (Belotecan-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 18:
The synthesis (synthetic route is shown in Figure 18) of two (DX-8591f-N-carbamate-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Camptothecin derivative DX-8591f0.5g is dissolved in 100mL chloroform, add triethylamine 0.4g, triphosgene 0.2g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.4g, add dithio diethylene glycol monomester succinate 0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains DX-8591f-N-carbamate-dithio diethylene glycol-monomester succinate 0.32g; Intermediate product DX-8591f-N-carbamate-dithio diethylene glycol-monomester succinate 0.3g is dissolved in 10mLDMSO, add CDI0.3g, activation 1h, add GPC0.15g and DBU0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (DX-8591f-N-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine 0.14g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.03(2H，br)，7.52(2H，d)，6.74(2H，s)，4.87-3.61(31H，m)，3.30(9H，s)，2.85-1.87(34H，m)，0.90(6H，t)。[M+H] +m/z：1653.72。
Two (DX-8591f-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (DX-8591f-N-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 19:
The synthesis (synthetic route is shown in Figure 19) of two (9-nitrocamptothecin-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
9-nitrocamptothecin 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 9-nitrocamptothecin-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.72g; Intermediate product 9-nitrocamptothecin-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.5g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.25g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (9-nitrocamptothecin-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.33g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.56(2H，s)，8.18-7.88(6H，m)，6.74(2H，s)，4.76-3.61(25H，m)，3.30(9H，s)，2.85-1.96(20H，m)，0.90(6H，t)。[M+H] +m/z：1569.53。
Two (9-nitrocamptothecin-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (hydroxy camptothecin-10-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 20:
The synthesis (synthetic route is shown in Figure 20) of two (4 '-demethyl epipodophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
4 '-demethyl epipodophyllotoxin 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains 4 '-demethyl epipodophyllotoxin-4-carbonic ester-dithio diethylene glycol-monomester succinate 0.76g; Carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO intermediate product 4 '-demethyl epipodophyllotoxin-4-, add CDI0.6g, activation 1h, add GPC0.3g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (4 '-demethyl epipodophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine 0.35g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：6.66(4H，s)，6.46(4H，s)，6.07(4H，s)，5.35-5.30(4H，m)，4.76-3.41(31H，m)，3.30(9H，s)，2.85-2.64(18H，m)，。[M+H] +m/z：1583.58。
Two (4 '-demethyl epipodophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (4 '-demethyl epipodophyllotoxin-4-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 21:
The synthesis (synthetic route is shown in Figure 21) of two (5 '-deoxidation-5-fluorine cytidine-4-carbamate-dithio diethylene triamine-succinyl) phosphatidyl choline compounds
5 '-deoxidation-5-fluorine cytidine 1g is dissolved in the anhydrous N of 100mL, in dinethylformamide, add triethylamine 2g, at 0 DEG C, add tert-butyl chloro-silicane 1g, 0 DEG C of stirring reaction 1 hour, then room temperature reaction is risen to 6 hours, add water 50mL, and organic facies is washed with 10% dilute hydrochloric acid solution, saturated sodium bicarbonate solution, saturated nacl aqueous solution successively, anhydrous magnesium sulfate drying, filter, oil pump distilling under reduced pressure.Pillar layer separation obtains 2 ', 3 '-O-double T BDMS-5 '-deoxidation-5-fluorine cytidine 0.83g; 2 ', 3 '-O-double T BDMS-5 ' deoxidation-5-fluorine cytidine 0.8g is scattered in 100mL chloroform, adds triethylamine 0.6g, triphosgene 0.3g, react 6h under room temperature, revolve steaming and desolventize, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add succinyl dithio diethylene triamine 0.6g, room temperature reaction 24h, gained reactant liquor passes through column chromatography purification, obtain 2 ', 3 '-O-two TBDMS-5 '-deoxidation-5-fluorine cytidine-4-carbamate-dithio diethylene triamine-succinic acid 0.52g; Intermediate product 2 '; 3 '-O-two TBDMS-5 '-carbamate-dithio diethylene triamine-succinic acid 0.5g is dissolved in 20mLDMSO deoxidation-5-fluorine cytidine-4-; add CDI0.5g; activation 1h; add GPC0.25g and DBU0.5g; room temperature reaction 24h; gained reactant liquor passes through column chromatography purification; further with fluoridizing tetra-n-butyl ammonium process 1 hour; remove TBDMS protecting group, reactant liquor obtains two (5 '-deoxidation-5-fluorine cytidine-4-carbamate-dithio diethylene triamine-succinyl) the phosphatidylcholine 0.37g of product through column chromatography for separation. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.00(2H，br)，7.58(2H，d)，5.93(2H，m)，4.64-3.58(31H，m)，3.30(9H，s)，2.85-2.64(16H，t)，1.18(6H，d)。[M+H] +m/z：1301.38。
Embodiment 22:
The synthesis (synthetic route is shown in Figure 22) of two (camptothecine-20-carbamate-dithio diethylamine-succinyl) phosphatidyl choline compounds
Camptothecine 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 50mLDMSO, add triethylamine 0.3g, add dithio diethylamine succinic acid 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains camptothecine-20-carbamate-dithio diethylamine-succinic acid 0.58g; Intermediate product camptothecine-20-carbamate-dithio diethylamine-succinic acid 0.5g is dissolved in 20mLDMSO, add CDI0.6g, activation 1h, add GPC0.2g and DBU0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (camptothecine-20-carbamate-dithio diethylamine-succinyl) the phosphatidylcholine 0.24g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.03-7.59(14H，m)，6.74(2H，s)，4.76-3.50(22H，t)，3.30(9H，s)，3.26(4H，m)，2.82-2.49(16H，m)，1.96(4H，m)，0.90(6H，t)。[M+H] +m/z：1475.59。
Two (camptothecine-20-carbamate-dithio diethylamine-succinyl) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (camptothecine-20-carbamate-dithio diethylamine-succinyl) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 23:
The synthesis (route is shown in Figure 23) of all-trans-retinoic acid phosphatide cpd
0.6g (2mmol) all-trans-retinoic acid is dissolved in 30mL refined toluene, adds 0.34mL (4mmol) oxalyl chloride, stirring at room temperature 3h under the condition of lucifuge, isolated dampness; Remove excessive oxalyl chloride under reduced pressure, obtain dark red oil, dark red oil being dissolved in 5mL refines in dichloromethane, add triethylamine 0.3g, dithio diethylene glycol monomester succinate 0.4g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains all-trans-retinoic acid-dithio diethylene glycol-monomester succinate 0.32g; Intermediate product all-trans-retinoic acid-dithio diethylene glycol-monomester succinate 0.3g is dissolved in 20mLDMSO, add CDI0.3g, activation 1h, add GPC0.1g and DBU0.3g, room temperature reaction 12h, gained reactant liquor, by column chromatography purification, obtains two (all-trans-retinoic acid-dithio diethylene glycol-succinate) the phosphatidylcholine 0.35g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：6.51(8H，s)，6.23(2H，s)，5.58(2H，s)，4.64(1H，t)，4.47-3.61(16H，m)，3.30(9H，s)，2.85-2.64(16H，m)，2.21(12H，s)，1.96-1.57(18H，m)，1.25(12H，s)。[M+H] +m/z，1295.68。
Embodiment 24:
The synthesis (synthetic route is shown in Figure 24) of two (homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Homoharringtonine 0.5g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 50mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.4g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-monomester succinate 0.32g.Intermediate product homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-monomester succinate 0.3g is dissolved in 20mLDMSO, add CDI0.3g, activation 1h, add GPC0.15g and DBU0.3g, room temperature reaction 24h, gained reactant liquor by column chromatography purification, obtains product two (homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine 0.18g. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：6.92(2H，s)，6.88(2H，s)，6.07(4H，s)，5.13(2H，d)，4.64-3.39(38H，m)，3.30(9H，s)，2.88-2.63(26H，m)，2.30-2.20(4H，m)，1.79-1.25(32H，m)。[M+H] +m/z：1874.07。
Two (homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine is dissolved in the sodium-chloride water solution of 0.01M, and lyophilizing obtains two (homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion and chloride ion.
Embodiment 25:
The synthesis (route is shown in Figure 25) of two (tyroserleutide-dithio diethylene triamine-succinyl) phosphatidyl choline compounds
N-Boc-O-TBDMS-tyroserleutide 0.4g is dissolved in 50mLDMSO, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, succinyl dithio diethylamine 0.3g, room temperature reaction 12h, gained reactant liquor, by column chromatography purification, obtains N-Boc-O-TBDMS-tyroserleutide-dithio diethylene triamine-succinic acid 0.16g.Intermediate product N-Boc-O-TBDMS-tyroserleutide-dithio diethylene triamine-succinic acid 0.15g is dissolved in 20mLDMSO, add CDI0.2g, activation 1h, add GPC0.1g and DBU0.2g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains two (N-Boc-O-TBDMS-tyroserleutide-dithio diethylene triamine-succinyl) phosphatidylcholine 0.09g; This solid dispersal is in 10mL oxolane; drip trifluoroacetic acid (TFA); room temperature reaction 6 hours; deviate from BOC blocking group, reactant liquor precipitates in cold diethyl ether, and solid is dissolved in DMF; add tetrabutyl ammonium fluoride; room temperature reaction 6 hours, removes TBDMS protecting group, and reactant liquor obtains two (tyroserleutide-dithio diethylene triamine-succinyl) the phosphatidylcholine 0.04g of product by column chromatography purification. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.03(4H，br)，7.12(4H，d)，6.70(4H，d)，5.35-5.11(6H，m)，4.74-3.44(35H，m)，3.30(9H，s)，3.19(2H，m)，2.85-2.64(16H，m)，1.87-1.49(6H，m)，0.91(12H，d)。[M+H] +m/z：1453.75。
Embodiment 26:
The synthesis (synthetic route is shown in Figure 26) of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-polyethylene glycol compound
Camptothecine 1g is dissolved in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 50mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains camptothecine carbonic ester-dithio diethylene glycol-monomester succinate 0.72g.It is reaction dissolvent that camptothecine-20-carbonic ester-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 30mLDMSO, adds CDI0.5g, room temperature reaction 2h, add 3-(4-methoxyl group benzyloxy) propane-1,2-glycol 0.4g, DBU0.5g, room temperature reaction 8h, revolves solvent evaporated; Adding 10mL dimethyl formamide is solvent, hydrogenation under palladium/carbon catalysis, and product obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) glycerol 0.52g through pillar layer separation.
Above-mentioned product 0.5g is dissolved in chloroform, adds phosphorus oxychloride 0.5g, triethylamine 0.5g, 10 DEG C of reaction 24h, and revolve solvent evaporated, add N-t-butoxycarbonyl-amino ethanol 0.4g, triethylamine 0.3g, adds 10mL chloroform, and 10 DEG C of reaction 24h, revolve solvent evaporated; Solid is dissolved in isopropyl alcohol; drip trifluoroacetic acid aqueous solution; reacting by heating 6h, removes tertbutyloxycarbonyl protecting group, and reactant liquor obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the PHOSPHATIDYL ETHANOLAMINE 0.31g of product through column chromatography separating purification.
Terminal hydroxy group polyoxyethylene methyl ether (molecular weight 2000, mPEG) 0.5g and CDI0.2g is dissolved in 25mL chloroform, 2h is reacted under room temperature, then two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE 0.20g is added, DBU0.2g, reacting by heating 24h, reactant liquor, by column chromatography purification, obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the PHOSPHATIDYL ETHANOLAMINE N-Polyethylene Glycol 0.14g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：8.03-7.59(12H，t)，6.74(2H，s)，4.76-3.75(31H，m)，3.65-3.10(broad)，2.85-2.64(16H，m)，1.96(4H，m)，0.90(6H，t)。
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-polyethylene glycol compound is dissolved in the sodium hydrate aqueous solution of 0.01M, and lyophilizing obtains two (homoharringtonine-6 '-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine white solid powder containing sodium ion.
Embodiment 27:
The synthesis (synthetic route is shown in Figure 27) of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-Polyethylene Glycol-N-folic acid compound
Amino polyoxyethylene (mean molecule quantity 2000) 0.5g of N-BOC-that terminal hydroxy group activates through CDI is dissolved in 20mLDMSO; add DBU0.2g; add two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE 0.10g of embodiment 26; room temperature reaction 3 hours; remove amino end group protecting group BOC with TFA process after pillar layer separation, carry out purification by column chromatography process and obtain two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-polyoxyethylene 0.07g that end group is amino.Above-mentioned product joins in 10mLDMSO, add EDC0.3 and NHS0.3g, add folic acid 0.3g, room temperature reaction 24 hours, reactant liquor, through column chromatography, obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the PHOSPHATIDYL ETHANOLAMINE N-polyoxyethylene-N-folic acid 0.04g of product. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：11.57(1H，s)，11.0(1H，s)，8.57(1H，s)，8.45(1H，br)，8.03-7.56(14H，m)，6.99-6.74(6H，m)，4.76-3.96(30H，m)，3.68-3.10(broad)，2.85-2.64(16H，m)，2.10-1.96(8H，m)，0.90(6H，t)。
Embodiment 28:
The synthesis (synthetic route is shown in Figure 28) of two (chidamide-2 '-carbamate-dithio diethylene glycol-succinate) phosphatidyl choline compounds
Chidamide 1g is scattered in 100mL chloroform, add triethylamine 0.6g, triphosgene 0.3g, reacts 6h under room temperature, revolves steaming and desolventizes, solid is dissolved in 10mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.6g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains chidamide-2 '-carbamate-dithio diethylene glycol-monomester succinate 0.62g; Intermediate product chidamide-2 '-carbamate-dithio diethylene glycol-monomester succinate 0.6g is dissolved in 20mLDMSO, add CDI0.5g, activation 1h, add GPC0.25g and DBU0.5g, room temperature reaction 24h, gained reactant liquor is by column chromatography purification, and reactant liquor obtains product two (chidamide-2 '-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine 0.37g through column chromatography for separation. 1HNMR(500MHz，CD3OD∶CDCl 31∶1)δ(ppm)：9.15(4H，br)，8.84(2H，s)，8.33(2H，d)，8.03(2H，m)，7.98-7.41(18H，m)，6.96(2H，t)，6.46(2H，d)，4.64-3.61(21H，m)，3.30(9H，s)，2.85-2.64(16H，m)。[M+H] +m/z，1563.65。
Embodiment 29:
The synthesis (synthetic route is shown in Figure 29) of two (bexarotene-GFLG-butyryl) phosphocholine compound
Bexarotene 0.6g is dissolved in 30mLDMF, add 0.5gEDC/0.5gNHS activation, then N-glycyl-phenylalanyl-leucyl-glycine (GFLG) 0.8g is added, room temperature reaction 24 hours, reactant liquor pillar layer separation, obtains bexarotene-glycyl-phenylalanyl-leucyl-glycine 0.35g.Product is dissolved in 20mL dimethyl sulfoxine, add CDI0.3g and activate 1h, add 4 hydroxybutyric acid 0.15g and DBU0.3g, room temperature reaction 24h, separate out precipitation in cold diethyl ether, column chromatography for separation obtains bexarotene-glycyl-phenylalanyl-leucyl-glycinate-butanoic acid 0.21g.Above-mentioned intermediate product is dissolved in 15mL dimethyl sulfoxine, adds CDI0.3g, activation 1h, add GPC0.10g and DBU0.3g, room temperature reaction 24h, separates out precipitation in cold diethyl ether, and column chromatography for separation obtains two (bexarotene-GFLG-butyryl) phosphocholine 0.12g. 1HNMR(500MHz，CD 3OD∶CDCl 31∶1)：δ7.90-6.76(22H，m)，5.70(2H，d)，5.37(2H，d)，4.92-3.43(25H，m)，3.30(9H，s)，3.05-2.25(12H，m)，1.96-1.35(42H，m)，1.01(12H，t)，0.23(4H，m)。[M+H] +m/z，1872.27。
Embodiment 30:
The synthesis (synthetic route is shown in Figure 30) of two (bexarotene-ethylene glycol succinic acid-ethylene glycol succinic acid) phosphocholine compound
Bexarotene 0.6g is dissolved in 30mLDMF, add CDI0.6g and activate 1h, add succinic acid binaryglycol ester 0.6g and DBU0.6g, room temperature reaction 24h, separate out precipitation in cold diethyl ether, column chromatography for separation obtains bexarotene-glycol ester-succinic acid-ethylene glycol ester 0.42g.Product is dissolved in 15mLDMF, adds TEA0.3mL, room temperature reaction 24h, and separate out precipitation in cold diethyl ether, column chromatography for separation obtains bexarotene-glycol ester-succinic acid-glycol ester-succinic acid 0.26g.Above-mentioned intermediate product is dissolved in 30mLDMF, add CDI0.3g and activate 1h, add GPC0.15g and DBU0.3g, room temperature reaction 24h, separate out precipitation in cold diethyl ether, column chromatography for separation obtains two (bexarotene-ethylene glycol succinic acid-ethylene glycol succinic acid) phosphocholine 0.15g. 1HNMR(500MHz，CD 3OD∶CDCl 31∶1)：δ7.90-6.70(12H，m)，5.70(2H，d)，5.37(2H，d)，4.64-4.32(19H，m)，3.97-3.43(4H，m)，3.30(9H，s)，2.64-2.35(22H，m)，1.52-1.35(32H，m)。[M+H] +m/z，1495.64。
Embodiment 31:
The synthesis (route is shown in Figure 31) of two (bexarotene-ethylenediamine succinic acid-ethylenediamine succinic acid) phosphocholine compound
Bexarotene 0.5g is dissolved in 30mLDMF, adds 0.5gEDC/0.5gNHS activation, then adds bernaminum 0.6g, room temperature reaction 24 hours, reactant liquor pillar layer separation, obtain bexarotene-ethylenediamine-succinic acid 0.36g.Above-mentioned product 0.36g is dissolved in 20mLDMF, adds 0.5gEDC/0.5gNHS activation, then adds bernaminum 0.4g, room temperature reaction 24 hours, reactant liquor pillar layer separation, obtain bexarotene-ethylenediamine-succinic acid-ethylenediamine-succinic acid 0.25g.Above-mentioned intermediate product 0.25g is dissolved in 15mL dimethyl sulfoxine, add CDI0.3g, activation 1h, add GPC0.10g and DBU0.3g, room temperature reaction 24h, separate out precipitation in cold diethyl ether, column chromatography for separation obtains two (bexarotene-ethylenediamine succinic acid-ethylenediamine succinic acid) phosphocholine 0.14g. 1HNMR(500MHz，CD 3OD∶CDCl 31∶1)：δ7.90-6.70(12H，m)，5.70(2H，d)，5.37(2H，d)，4.64(1H，m)，4.32(2H，d)，3.97-3.43(22H，m)，3.30(9H，s)，2.57-2.35(22H，m)，1.52-1.35(32H，m)。[M+H] +m/z，1487.76。
Embodiment 32:
The synthesis (synthetic route is shown in Figure 32) of the two cisplatin phospholipid phatidylcholine of quick-releasing type
Cis-two chloro-diamidogen platinum compounds A0.4g is dissolved in 20mL chloroform, add triethylamine 0.3g, triphosgene 0.3g, reacts 2h under room temperature, revolves steaming and desolventizes, solid is dissolved in 50mLDMSO, add triethylamine 0.3g, add dithio diethylene glycol monomester succinate 0.3g, room temperature reaction 24h, gained reactant liquor, by column chromatography purification, obtains intermediate product B0.23g.Intermediate product B0.23g is dissolved in 15mLDMSO, adds CDI0.2g, activates 1 hour, add GPC0.1g and DBU0.2g, room temperature reaction 24 hours, separates out in cold diethyl ether, column chromatography for separation obtains Compound C 0.12g, i.e. the two cisplatin phospholipid phatidylcholine of quick-releasing type.[M+H] +m/z，1673.24。
Embodiment 33:
The synthesis of two (bortezomib-Dihydrocaffeic acid-dithio binaryglycol ester-succinyl) phosphatidylcholine
3-(3,4-dihydroxy phenyl) propanoic acid (Dihydrocaffeic acid) 1g is dissolved in 30mLDMSO, add CDI0.8g, activate 40 minutes, add dithio diethylene glycol monomester succinate 0.6g, DBU0.8g, room temperature reaction 12h, product obtains 3-(3,4-dihydroxy phenyl) propanoic acid-dithio binaryglycol ester-monomester succinate 0.81g through pillar layer separation.This product is dissolved in 30mLDMSO, adds CDI0.5g and activates 30 minutes, after add glycerolphosphocholine 0.3g and DBU0.5g, room temperature reaction 24h; Separate out precipitation in cold diethyl ether, dilute hydrochloric acid washs, and reactant liquor, by column chromatography purification, obtains intermediate product to two (Dihydrocaffeic acid-dithio binaryglycol ester-succinyl) phosphocholine 0.41g.This intermediate product is dissolved in DMSO the solution being mixed with 0.2M, the concentration adding same volume is the DMSO solution of the bortezomib of 0.2M, room temperature places 1 hour, separate out in ether, obtain two (bortezomib-Dihydrocaffeic acid-dithio binaryglycol ester-succinyl) the phosphatidylcholine 0.46g of product.
Embodiment 34:
The preparation of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine 1mmol of Example 1, add chloroform 20mL, 60 DEG C revolve solvent evaporated; Add 20mLPBS (pH=7.4) 60 DEG C of skinnings, 200nm membrane filtration, obtain two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine elaioplast nanometer particle solution.The following Figure 33 of granularmetric analysis result, mean diameter 270nm.Freezing transmission electron microscope (200KvTecnaiG 2the freezing transmission electron microscope of F20 Flied emission, accelerating potential 200 kilovolts, amplification 29000 times, camera is FEIEagle4kX4k camera) measure the form result of elaioplast nanometer particle, as Figure 34, show multilamelar liposome fine structure clearly.
Embodiment 35:
The preparation of two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine liposome
Two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) the phosphatidylcholine 1mmol obtained by embodiment 2, add chloroform 20mL, 60 DEG C revolve solvent evaporated; Add 20mLPBS (pH=7.4) 60 DEG C of skinnings, 200nm membrane filtration, obtain two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine elaioplast nanometer particle solution.Granularmetric analysis result display mean diameter 175nm.By two (paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester) phosphatidylcholine elaioplast nanometer particle solution lyophilizing, obtain powdered nanoparticles granule.
Embodiment 36:
The preparation of two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine liposome
Two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) the phosphatidylcholine 1mmol obtained by embodiment 3, add chloroform 20mL, 60 DEG C revolve solvent evaporated; Add 20mLPBS (pH=7.4) 60 DEG C of skinnings, 200nm membrane filtration, obtain two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine elaioplast nanometer particle solution.Granularmetric analysis result shows, mean diameter 165nm.
Embodiment 37:
The preparation of two (amycin-N-carbamate-dithio diethylene glycol-succinate-GFLG) phosphatidylcholine liposome
Two (amycin-N-carbamate-dithio diethylene glycol-succinate-GFLG) the phosphatidylcholine 0.3mmol obtained by embodiment 5, add chloroform 10ml, 60 DEG C revolve solvent evaporated; Add 10mlPBS (pH=7.4) 60 DEG C of skinnings, obtain two (amycin-N-carbamate-dithio diethylene glycol-succinate-GFLG) phosphatidylcholine elaioplast nanometer particle solution.Granularmetric analysis result shows, mean diameter 154nm.
Embodiment 38:
The preparation of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-Polyethylene Glycol-N-folic acid compound liposome
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-Polyethylene Glycol-N-folic acid compound 0.3mmol obtained by embodiment 27, add chloroform 10ml, 60 DEG C revolve solvent evaporated; Add 10mlPBS (pH=7.4) 60 DEG C of skinnings, obtain two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) PHOSPHATIDYL ETHANOLAMINE-N-Polyethylene Glycol-N-folic acid compound elaioplast nanometer particle solution.Granularmetric analysis result display mean diameter 240nm.
Embodiment 39:
The preparation of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome B
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine 0.1mmol, distearoyl phosphatidylcholine DSPC0.4mmol of Example 1, add chloroform 10ml, 60 DEG C revolve solvent evaporated; Add 10mlPBS (pH=7.4) 60 DEG C of skinnings, obtain two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome B nanoparticles solution.Granularmetric analysis display mean diameter 180nm.
Embodiment 40:
The preparation of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome C
Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine 0.1mmol of Example 1, distearoyl phosphatidylcholine DSPC0.3mmol, DSPE-PEG DSPE-PEG-folic acid (molecular weight polyethylene glycol 2000) 0.1mmol, add chloroform 10ml, 60 DEG C revolve solvent evaporated; Add 10mlPBS (pH7.4) 60 DEG C of skinnings, obtain two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome C nano particle solution.Granularmetric analysis shows, mean diameter 620nm.Lyophilization, obtains two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) Powdered nano-particle of phosphatidylcholine liposome C.
Embodiment 41:
The preparation of Sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinate-Sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine liposome
Sn1-camptothecine-20-carbonic ester-dithio the diethylene glycol obtained by embodiment 6-succinate-Sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine 0.5mmol, add chloroform 20mL, 60 DEG C revolve solvent evaporated; Add 20mLPBS (pH7.4) 60 DEG C of skinnings, 200nm membrane filtration, obtains Sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinate-Sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine elaioplast nanometer particle solution.Granularmetric analysis result display mean diameter 192nm.By Sn1-camptothecine-20-carbonic ester-dithio diethylene glycol-succinate-Sn2-paclitaxel-7-carbonic ester-dithio diethylene glycol-adipate ester-glycerolphosphocholine elaioplast nanometer particle solution lyophilizing, obtain powdered nanoparticles granule.
Embodiment 42:
The external degradation test of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome
Sample: two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholines prepared by embodiment 1 are dissolved in appropriate PBS solution and are mixed with the solution that concentration is 0.1mmol; Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine elaioplast nanometer particle 10mLPBS solution of 0.1mmol prepared by embodiment 34; Two (camptothecine-20-succinic acid) the phosphatidylcholine elaioplast nanometer particle 10mLPBS solution of 0.1mmol prepared by reference examples 2.
Above-mentioned sample is divided into 2 parts respectively, a copy of it adds the PBS buffer 0.5mL (GSH concentration 50mmol) of glutathion (GSH), another part adds PBS buffer, places and hatches at 37 DEG C in incubator, detect camptothecine content (Agilent1100LC by high performance liquid chromatography, the anti-phase C18 post of Zorbax, 150 × 4.6mm, 5 μm, sample size 20 μ L, column temperature 25 DEG C, determined wavelength λ=254nm; Gradient elution: 2-90% buffer B/A, flow velocity 1.0mL/min, the deionized water of buffer A: 0.1%TFA, the acetonitrile of buffer B: 0.1%TFA).
Result shows: the former medicine of camptothecine discharged after the former medicine of camptothecine that the PBS solution of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholines of GSH process discharged after 0.5 hour reaches 95%, 1 hour of total amount reaches 100% of total amount; The former medicine of camptothecine discharged after the former medicine of camptothecine that two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome solutions of GSH process discharged after 0.5 hour reaches 75%, 1 hour of total amount reaches 100% of total amount; Two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome solutions without GSH process does not detect the former medicine of camptothecine with two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine PBS solution after 3 hours; Two (camptothecine-20-succinic acid) phosphatidylcholine liposome solutions of GSH process and all do not detect the former medicine of camptothecine after 3 hours without pair (camptothecine-20-succinic acid) phosphatidylcholine liposome solutions of GSH process.
Obviously, two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome, two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidyl choline compounds have GSH sensitivity, under GSH effect, the cystine linkage fracture of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine, and by the carbonyl of post-rift end group sulfydryl attack carbonic acid ester bond, thus discharge the former medicine of camptothecine fast.And two (camptothecine-20-succinic acid) phosphatidylcholine liposome can not be degraded by GSH, be difficult to discharge the former medicine of camptothecine fast.
Embodiment 43:
The external degradation test of two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine liposome
Sample: two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholines prepared by embodiment 3 are dissolved in appropriate PBS solution and are mixed with the solution that concentration is 0.1mmol; Two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine elaioplast nanometer particle 10mLPBS solution of 0.1mmol prepared by embodiment 36; Appropriate two (gemcitabine-4-N-succinic acid) phosphatidylcholine prepared by reference examples 3 is dissolved in 10mLPBS solution, obtains the solution that concentration is 0.1mmol.
Above-mentioned sample is divided into 2 parts respectively, a copy of it adds the PBS buffer 0.5mL (GSH concentration 50mmol) of glutathion (GSH), another part adds PBS buffer, places and hatches at 37 DEG C in incubator, detects gemcitabine content (Agilent1100LC by high performance liquid chromatography, the anti-phase C18 post of Zorbax, 150 × 4.6mm, 5 μm, sample size 20 μ L, column temperature 25 DEG C, determined wavelength λ=254nm; Gradient elution: 2-90% buffer B/A, flow velocity 1.0mL/min, the deionized water of buffer A: 0.1%TFA, the acetonitrile of buffer B: 0.1%TFA).
Result shows: two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) former medicines of gemcitabine that the PBS solution of phosphatidylcholine discharged after 0.5 hour of GSH process reach 100% of total amount; Discharge the former medicine of gemcitabine after the former medicine of gemcitabine that two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine liposome solutions of GSH process discharged after 0.5 hour reaches 85%, 1 hour of total amount and reach 100% of total amount; Two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine liposome solutions without GSH process does not detect the former medicine of gemcitabine with two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine PBS solution after 3 hours;
The PBS solution of two (gemcitabine-4-N-succinic acid) phosphatidylcholines of GSH process and all do not detect the former medicine of gemcitabine after 3 hours without the PBS solution of pair (gemcitabine-4-N-succinic acid) phosphatidylcholines of GSH process.
Obviously, two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine liposome, two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidyl choline compounds have GSH sensitivity, under GSH effect, the cystine linkage fracture of two (gemcitabine-4-N-carbamate-dithio diethylene glycol-succinate) phosphatidylcholine, and by the carbonyl of post-rift end group sulfydryl attack amino-formate bond, thus discharge the former medicine of gemcitabine fast.And two (gemcitabine-4-N-succinic acid) phosphatidylcholine can not be degraded by GSH, be difficult to discharge the former medicine of gemcitabine.
Pharmacological evaluation
Experimental example 44:
Mtt assay human cancer cell fragmentation test: the anti-tumor activity of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome
MCF-7 human breast cancer cell is with 8 × 10 3the inoculum concentration in individual/hole is inoculated in 96 well culture plates, 5%CO 2, cultivate 24h in 37 DEG C of incubators after, two (camptothecine-20-succinic acid) phosphatidylcholine liposome solutions that every hole adds two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome solutions of the embodiment 34 of variable concentrations, prepared by reference examples 2, (camptothecine is dissolved in normal saline to contrast camptothecin drug solution, use DMSO solubilising) each 100 μ L, the medicine final concentration of final screening is made to be respectively 1,2,5,10,20 μ g/mL, after continuing to cultivate 24h; Add 50 μ LMTT incubation 4h respectively, discard culture medium, add 150 μ LDMSO, plate shaker shakes up, and microplate reader 495nm reads plate, calculates cell inhibitory rate according to the absorbance recorded.Data are expressed as average ± SD (n=6).
Result shows, to tumor cell, the fatality rate of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome is higher than the former medicine of contrast camptothecine and two (camptothecine-20-succinic acid) the phosphatidylcholine liposome of contrast, and the former shows excellent anti-tumor activity.Wherein the IC50 of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome is approximately 3.5 mcg/ml, the IC50 of two (camptothecine-20-succinic acid) the phosphatidylcholine liposome of contrast is approximately 6 mcg/ml, about 12 mcg/ml of IC50 of the former medicine of camptothecine.
Experimental example 45:
Medicine phospholipid liposome In vivotoxicity is tested
Animal: ICR mice, male, 18-22g, purchased from laboratory animal technology Co., Ltd of dimension tonneau China.
The result (table 2) of the toxicity in vivo test of two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposomees of embodiment 34 shows, its maximum tolerated dose is greater than 850mg/kg, shows that its toxicity is much smaller than the former medicine of camptothecine.
Table 2 In vivotoxicity result of the test
Experimental example 46:
Drug effect and toxicity test in body
Drug effect and toxicity test in two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine Via Liposomes
The preparation of nude mice model: collect the HepG2 cell suspension cultivated, concentration is 1 × 10 7individual/ml, is inoculated in axillary fossa on the right side of nude mouse with every 0.1ml subcutaneous.Grouping and administration: transplanted tumor in nude mice vernier caliper measurement transplanted tumor diameter, tumor growth is to 75mm 3time by animal random packet.Meanwhile, each group nude mice starts administration, and dosage regimen is shown in group and dosage regimen, uses the method measuring tumor footpath, dynamically observes the Graft Versus Tumor of given the test agent.The computing formula of gross tumor volume (TV) is: TV=1/2 × a × b 2(formula 3-2), wherein a, b represent length and width respectively.
Group and dosage regimen: blank group: normal saline, intravenous injection, once, volume is 0.2ml, continuous 3 weeks in injection in every three days.
Matched group: camptothecine is dissolved in normal saline (micro-DMSO hydrotropy, dosage 10mg/kg), intravenous injection, once, volume is 0.2ml, continuous 3 weeks in injection in every three days.
Medicine group: two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) phosphatidylcholine liposome solutions (dosage is equivalent to camptothecine 10mg/kg) of embodiment 34, intravenous injection, once, volume is 0.2ml, continuous 3 weeks in injection in every three days.Period, measure body weight change.
Anti-tumor activity and body weight change the results are shown in Figure 35.From anti-tumor activity (Figure 35 a), two (camptothecine-20-carbonic ester-dithio diethylene glycol-succinate) the phosphatidylcholine liposome of the present invention has good Tumor suppression growth, and the weight of animals does not decline (Figure 35 b), display avirulence.
Above-described embodiment is only the preferred embodiment of the present invention; be noted that for those skilled in the art; under the premise without departing from the principles of the invention; some improvement and equivalent replacement can also be made; these improve the claims in the present invention and are equal to the technical scheme after replacing, and all fall into protection scope of the present invention.

Claims (7)

1. a quick-releasing type medicine phosphatide cpd, is characterized in that, the pharmaceutically acceptable salt that the compound that this phosphatide cpd is following general formula (1) or the compound of described general formula (1) and counter ion counterionsl gegenions are formed:
In formula (1), X 1, X 2all any in ester bond, amido link, amino-formate bond and carbonic acid ester bond, X 3, X 4all any in ester bond, amido link, A 1, A 2being easily broken hydrophobic spacerarm, is the carbon number that the contains cystine linkage alkylene alkyl that is 2 ~ 8, the carbon number that contains peptide bond be 2 ~ 80 alkylene alkyl, the carbon number alkylene alkyl that is 2 ~ 20 that contains amido link or the carbon number that the contains ester bond alkylene alkyl that is 2 ~ 20, Z 1, Z 2being to strengthen hydrophobic spacerarm, is the carbon number that the contains ehter bond alkylene alkyl that is 2 ~ 20, the carbon number of alkylene alkyl that the carbon number that contains ester bond is 2 ~ 20, alkylene alkyl that the carbon number that contains amido link is 2 ~ 20 or oxygen-free atom and the nitrogen-atoms alkylene alkyl/sub-alkylene that is 2 ~ 20, Y 1, Y 2for following any one medicine: taxol, Docetaxel, Cabazitaxel, code name is the compound of BAY59-8862, code name is the compound of SB-T-11033, code name is the compound of SB-T-121303, code name is the compound of SB-T-121304, code name is the compound of SB-T-1213, code name is the compound of SB-T-12162, code name is the compound of BMS-184476, code name is the compound of DJ-927, code name is the compound of BMS-275183, camptothecine, HCPT, SN38, camptothecine-10-0-ethylpyrazol, Irinotecan, TPT, 7-t-Butyldimethylsilyl-10-hydroxycamptothecine, 7-(2-trimethyl silicane ethyl)-camptothecine, code name is the camptothecin derivative of Afeletecan, 7-methylol camptothecine, 9-nitrocamptothecin, 9-aminocamptothecin, hexacyclic camptothecins, code name is the compound of Gimatecan, code name is the compound of Belotecan, Diflomotecan, code name is the compound of BN80927, code name is the compound of TOP-0618, code name is the compound of Exatecan, code name is the compound of Lurtotecan, code name is the compound of DRF-1042, podophyllotoxin, demethylated podophyllotoxin, Teniposide, Etoposide, vincaleukoblastinum, vincristine, vinorelbine, eldisine, etoposide,Harringtonine, isoharringtonin, deoxyharringtonin, false deoxyharringtonin, homoharringtonine, Britanin, combretastatin, colchicin, fulvestrant, Vorinostat, Ipsapirone, eribulin, Simvastatin, rotigotine, Rifapentine, Zidovudine, brivudine, Lobucavir, megestrol acetate, mitolactol, salbutamol, resveratrol, hCPT compounds, aloe-emodin, curcumin, lanosterol, mamba Wei, cidofovir, aclacinomycin, carminomycin, deoxidation pyrromycin, zorubicin, the fluoro-idarubicin of 8-, nystatin, anphotericin, mitoxantrone, archen, actinomycin D, rapamycin, mithramycin, Epothilones, mitomycin, bleomycin, aspergillus fumigatus cedrol, methylprednisolone, Flavopiridol, Breviscapinun, ET-743, euphorbia plant diterpene, 2,5-PTX, matrine, Ipsapirone, the sub-chalone A4 of windmill, ubenimex, Ribavirin, Marimastat, Medroxyprogesterone, stavudine, inverase, neo-synephrine, methoxamedrine, salbutamol, isoprel, Misoprostol, Latanoprost, prostacyclin, quinindium, Propafenone, Pu Naluoer, digoxin, foxalin, dobutamine, warfarin, coumarin kind compound, Lovastatin, fluvastatin, En Gelie is clean, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, abarelix, Zoladex, galanthamine, cycloheximide, minocycline, Meloxicam, posaconazole, everolimus, Vorinostat, PTK787 alkali, abiraterone, dihydroartemisinine, prednisolone, dexamethasone, code name is the compound of AEZS-112, code name is the compound of GZ402674, code name is the compound of BCX-1777, code name is the compound of CYC682, code name is the compound of LY-2334737, 0-(chloracetyl-carbamyl) fumidil, code name is the compound of SU14813, code name is the compound of BMS-275291, code name is the compound of ABT-510, code name is the compound of Aplidine, code name is the compound of NSC683551, code name is the compound of CGS27023A, code name is the compound of R032-3555, code name is the compound of NPI-0052, for drawing ten thousand stars, code name is the compound of CEP-1347, code name is the compound of ABR-215050, code name is the compound of MonomethylauristatinE, Bicalutamide, HPR, Ansamycin, bryostatin, CCI-779, Pu Masita, tipranavir, indinavir, Ritonavir, atazanavir, viracept see nelfinaivr, Batimastat, Quercetin, flavonoids medicine, ticagrelor, Kan Geruiluo, Sebivo, Trifluridine, Adapalene, Lopinavir, Da Gelie is clean, rifaximin, fluticasone, Chinese mugwort Saperconazole, Merck, LBH589, A Wei Batan, Levonorgestrel, ethinyloestradiol, ground Rui Lawei, Olmesartan, according to cutting down Kato, bryostatin-1, alpha-galactosylceramide, EGCG, curcumin,Oridonin, genistein, triptolide, gossypol, legalon, telavancin, Ezetimibe, pseudoephedrine, ADZ6140, mometasone furoate, Deferiprone, oxybutynin, Oxymorphone, Merck, Mirabegron, teriflunomide, avanaphil, CCI-779, dust is for lattice Wei, Du Lutewei, calicheamicin, Retapamulin, tolvaptan, LUMEFANTRINE, his bit pyridine, galanthamine, Tuo Ruisaier, Ka Gelie is clean, draw for drawing Wei, buprenorphine, rope fluorine cloth Wei, Treprostinil, Dantrolene, fluticasone furoate, naloxone, Kan Gelie is clean, Suo Feibuwei, N-methylol Aripiprazole, code name is the compound of brivanib, code name is the compound of bryostatin-1, code name is the compound of combretastainA4, code name is the compound of CEP18770, code name is the compound of Ivacaftor, code name is the compound of MEK162, code name is the compound of neovastat, code name is the compound of UCN-01, code name is the compound of ridaforolimus, code name is the compound of AZD6244, code name is the compound of TAK-733, code name is the compound of AS703026, code name is the compound of PD-325901, code name is the compound of maytansine, code name is the compound of R04987655, code name is the compound of GDC-0973, code name is the compound of GSK945237, code name is the compound of ANG1009, code name is the compound of AD198, code name is the compound of Becatecarin, code name is the compound of Adva27a, code name is the compound of Benzopyranones, code name is the compound of AEZS112, code name is the compound of B00742, code name is the compound of ALCHEMIX, the compound that code name is, the compound that code name is, code name is the compound of Saintopin, code name is the compound of NCA0465, code name is the compound of GL331, code name is the compound of CAP7.1, code name is the compound of IT62B, code name is the compound of C1311, Oxycodone, department's licarbazepine, tacrolimus, Paliperidone, N-methylol Aripiprazole, draw for drawing Wei, Ka Gelie is clean, dexamethasone, Baily department he, code name is the camptothecin derivative of DX-8951f, gemcitabine, code name is the compound of CP-4126, C 1-C 20amide groups gemcitabine, FTL, Cladribine, fluorouracil, Tegafur, Carmofur, Tegadifur, doxifluridine, Ai Xila shore, capecitabine, 5 '-deoxidation-5-fluorine cytidine, 5 '-'-Deoxy-5-fluorouridine, 2'-Deoxy-5-Floxuridine, cytarabine, ancitabine, troxacitabine, 1-(2-C-cyano-2-dioxy-BETA-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, Decitabine, Bosutinib, he luxuriant and rich with fragrance for Buddhist nun, Yiluo for Buddhist nun, reach gram for Buddhist nun, HKI-272,Many Weis are for Buddhist nun, Pa Na is for Buddhist nun, Ba Fei is for Buddhist nun, department is beautiful for Buddhist nun, card is pricked for Buddhist nun, Luso is for Buddhist nun, Lu Zuo is for Buddhist nun, Ai Le is for Buddhist nun, card is rich for Buddhist nun, happy cutting down for Buddhist nun, look auspicious is for Buddhist nun, Ah method is for Buddhist nun, Sutent, Lapatinib, gram azoles is for Buddhist nun, A Pa is for Buddhist nun, Erlotinib, how card is for Buddhist nun, Axitinib, bosutinib, AMN107, Gefitinib, Dasatinib, sitagliptin, Imatinib, 6-MP, methotrexate (MTX), aminopterin, hydroxycarbamide, NSC-118994, ADA, Buddhist nun is replaced according to Shandong, Sibutramine Hydrochloride is for Buddhist nun, Luso profit is for Buddhist nun, azacitidine, clofarabine, lenalidomide, nelarabine, pazopanib, ZD6474, Ka Feizuo meter, En Zhalu amine, Da Lafeini, PTK787, Temozolomide, Elvucitabine, Beta department spit of fland, BI 1356, Prozac, Egelieting, vildagliptin, BMS-477118, Duloxetine, Atorvastatin, BCNU, Nimustine, Acadesine, 4 '-sulfo--β-D-arabino-furanosylcytosine, adefovirdipivoxil, arabinosy ladenosine, adriamycin, Epi-ADM, daunorubicin, DMDR, THP, grace is for Nuo Te, west reaches aniline, amdoxovir, Lamivudine, Entecavir, China fir fine jade, Tacrine, lenalidomide, metisazone, hydroxycarbamide, bleomycin A5, GCV, FCV, phentolamine, phenoxybenzamine, prazosin, Tamsulosin, indoramin, Brimonidine, hydrolazine, minoxidil, Mecamylamine, procainamide, mexiletine, dopamine, amrinone, Pabuk former times profit cloth, Bo Saipowei, spy draws big, huperzine, Memantine, Sorafenib, Rui Gefeini, Da Lafeini, Wei Luofeini, FTY720, Ni Danibu, trifluorothymidine, Wo Nuolazan, Aura handkerchief Buddhist nun, ifosfamide, Ai Ruibulin, code name is the compound of TAS-106, code name is the compound of VQD-002, code name is the compound of MB07133, code name is the compound of SPD754, code name is the nucleoside analog of Reverset, code name is the compound of E7974, code name is the compound of Lonafarnib, code name is the compound of Semaxanib, code name is the compound of Linifanib, code name is the compound of Crenolanib, Icatibant, code name is the compound of AZD3293, code name is the compound of LuAE58054, code name is the compound of LY2811376, code name is the compound of Alectinib, Zarnestra, Luo Nafani, An Ruinawei, intend peptide medicine, Levetiracetam, eslicarbazepine, Topiramate, vilazodone, draw iron Buddhist nun primary, 1B-d-amphetamine, Doxazosin, Oxcarbazepine, emtricitabine, Aldoforwe ester, tenofovir, valganciclovir, Milnacipran, aliskiren, ximelagatran, etravirine, rufinamide, imiquimod, famotidine, Lamotrigine, uncle's match Wei, ezogabine, colesevelam, imiquimod, chlorthalidone, Eliquis, Abacavir, (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, Te Lawan star, FTY720, sphingol, the western croak of Leo, Ao Bitawei, code name is the compound of Brostallicin,Code name is the compound of Baricitinib, code name is the compound of Buparlisib, code name is the compound of cobicistat, code name is the compound of Elacytarabine, code name is the compound of GX15-070, code name is the compound of Iniparib, code name is the compound of Ixazomib, code name is the compound of KRN7000, code name is the compound of linezolid, code name is the compound of Linsitinib, code name is the compound of Nintedanib, code name is the compound of Motesanib, code name is the compound of Voxtalisib, code name is the compound of Vatalanib, code name is the compound of Pilaralisib, code name is the compound of ONXO912, code name is the compound of Tivozanib, code name is the compound of PF-03084014, code name is the compound of Verosudil, code name is the compound of TG-101348, code name is the compound of Tivantinib, code name is the compound of Paritaprevir, code name is the compound of sonidegib, code name is the compound of Rociletinib, code name is the compound of Trametinib, code name is the compound of Regorafenib, code name is the compound of Evofosfamide, code name is the compound of Veliparib, code name is the compound of volasertib, code name is the compound of simeprevir, code name is the compound of vismodegib, code name is the compound of pomalidomide, code name is the compound of idelalisib, code name is the compound of BEZ2235, code name is the compound of GDC-0941, code name is the compound of XL147, code name is the compound of MK2206, Da Pafeini, code name is the compound of BMS-908662, code name is the compound of C1-1040, code name is the compound of GSK1120212, code name is the compound of NVP-AEW541, code name is the compound of Tivozanib, code name is the compound of masitinib, code name is the compound of SCH900105, code name is the compound of Foretinib, code name is the compound of RO5126766, code name is the compound of Cyclopentanthraquinones, code name is the compound of F14512, code name is the compound of Sitafloxacin, code name is the compound of Elinafide, code name is the compound of KW2170, code name is the compound of Lucanthone, code name is the compound of Sabarabicin, code name is the compound of Pixantrone, AZD2171, not for husky Buddhist nun, handkerchief pool former times cloth, roller pyrrole is smooth, dabigatran etcxilate, deacetylate vincaleukoblastinum list hydrazides, fourth oxygen piperazine alkane,Rilpivirine, cis-platinum, Spiroplatin, carboplatin, oxaliplatin, satraplatin, Miboplatin, Nedaplatin, Eptaplatin, lobaplatin, Cycloplatin, JM-216, picoplatin, code name is the compound of BBR-3464, 5,6-dimethyl ton ketone-4-acetic acid, Pseudolarix acid B, ganoderic acid, oleanolic acid, Rhein, 9-cis-retinoic acid, betulinic acid, VE succinic acid monoester, ATRA, Diclofenac, card glutamic acid, shellfish cholic acid difficult to understand, deoxycholic acid, sabril, Leuprorelin, tree toad element, pramlintide, corticotropin, bacitracin, Teriparatide, Goserelin, Exenatide, peace is for Anji peptide, rice lumbering peptide, romidepsin, junket silk figured silk fabrics peptide, sifuvirtide, Ai Boweitai, tyroserleutide, donipenem, Azilsartan, pitocin, cyclosporin, protirelin, Taltirelin, nafarelin, Buserelin, Histrelin, Gonadorelin, look ammonia Rayleigh, growth hormone release inhibiting hormone, secretin, Octreotide, ziconotide, T-20, Lanreotide, Vapreotide, seglitide, for degree Shandong peptide, Linaclotide, sinapultide, SOM230, Triptorelin, Tesamorelin, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], bexarotene, Pitavastatin, Rosuvastatin, bendamustine, melphalan, Lonidamine, atrasentan, melphalan, SS, pemetrexed, n-formyl sarcolysine, dinoprostone, Carboprost, Alprostadil, Gemfibrozil, Xi Luruiwei, Pepstatin, Ge La is for thunder, reed Xi Natan, Indomethacin, brufen, naproxen, DEFERASIROX, fluoquinolone, Pralatrexate, code name is the compound of Voreloxin, code name is the compound of AKR501, code name is the compound of CPI-613, code name is the compound of MKO429, code name is the compound of IDN-6556, tanomastat, marimastat, prinomastat, code name is the compound of alisertib, cilengitide, argatroban, dabigatran, Artesunate, ambrisentan, eltrombopag olamine, Valsartan, MOXIFLOXACIN, naproxen, Yi Luduo quinoline, Ge La is for thunder, tirofiban, DEFERASIROX, cefotaxime, levodopa, Carbidopa, besifloxacin, Febuxostat, prulifloxacin, cephalo is than general ester, Ceftobiprole, Gabapentin ester, mesalazine, Icatibant, Linaclotide, shellfish reaches quinoline, Sha Kubi song, according to a piperazine azoles, donipenem, ingenol first butenoate, Droxidopa, code name is the compound of lumacaftor, code name is the compound of MLN9708, code name is the compound of Sacubitril, code name is the compound of rigosertib, code name is the compound of Vosaroxin, code name is the compound of Orantinib, Carubicin, Aclarubicin, ibacitabine, Galocitabine, ancitabine, lestaurtinib, Improsulfan, mannosulfan, Ritrosulfan, Treosulfan, Ecomustine, Estramustine, Semustine, Alestramustine, gimeracil, Medorubicin, how the soft star that compares, THP, rodorubicin, Sha Rou compares star, valrubicin, zorubicin, Leurubicin, idarubicin, galarubicin, esorubicin, Detorubicin, Amrubicin, cut down and hold in the palm his shore, zalcitabine,For pricking his shore, Fiacitabine, flurocitabine, Ambamustine, Tarceva, training profit for Buddhist nun, Trimetrexate, Edatrexate, Ketotrexate, oteracil, Mitoflaxone, bortezomib;
L is 2-amino-2-carboxy ethyl, 2-amino-ethyl, 2-trimethyl amido ethyl cation, 2, the end group of 3-dihydroxypropyl, molecular weight to be the Polyethylene Glycol-amino-ethyl of the N-without targeting end group of 200-4000 or molecular weight be 200-4000 is the N-Polyethylene Glycol-amino-ethyl of targeting group.
2. quick-releasing type medicine phosphatide cpd according to claim 1, it is characterized in that, described end group is in the N-Polyethylene Glycol-amino-ethyl of targeting group, and targeting group is folic acid, galactose, polypeptide, antibody, antibody fragment, hyaluronic acid, asialoglycoprotein, polysaccharide, nucleic acid, plan peptide or sulfadiazine.
3. quick-releasing type medicine phosphatide cpd according to claim 1 and 2, it is characterized in that, when L in described structural formula (1) is uncharged group, the described counter ion counterionsl gegenions be combined with the compound of general formula (1) be hydrion, sodium ion, potassium ion, calcium ion, iron ion, magnesium ion, ammonium ion, zinc ion any one, when L in structural formula (1) is positively charged group, the described counter ion counterionsl gegenions be combined with the compound of general formula (1) are combinations of a kind of cation and a kind of anion, described cation is hydrion, sodium ion, potassium ion, calcium ion, iron ion, magnesium ion, ammonium ion, any one in zinc ion, described anion is chloride ion, sulfate ion, nitrate ion, carboxylic acid ion, carbanion, bromide ion, phosphate anion, formate, acetate, citrate, lactate, fumaric acid radical, any one in tartrate ion.
4. a pharmaceutical composition, is characterized in that, said composition comprises the quick-releasing type medicine phosphatide cpd described in claim 1,2 or 3, or comprises acceptable carrier on described quick-releasing type medicine phosphatide cpd and pharmacodynamics.
5. pharmaceutical composition according to claim 4, is characterized in that, said composition is liquid preparation, solid preparation, semi-solid preparation, capsule, granule, gel, injection, slow releasing preparation or controlled release preparation.
6. pharmaceutical composition according to claim 4, is characterized in that, said composition is the elaioplast nanometer particle of particle diameter 10-1000 nanometer, also comprises auxiliary agent in this pharmaceutical composition.
7. pharmaceutical composition according to claim 6, is characterized in that, described auxiliary agent is phospholipid or cholesterol.
CN201510756327.6A 2015-11-09 2015-11-09 Quick release type medicine phosphatide compound and medicine composition thereof Pending CN105457038A (en)

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