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

Abstract

The invention discloses an immediate-release drug phospholipid compound and a pharmaceutical composition thereof. In the compound, drugs Y ₁ and Y ₂ are connected to an immediate-release hydrophobic spacer arm and an enhanced hydrophobic spacer arm through chemical bonds, and the two spacer arms are connected to each other. Synergistically enhance the hydrophobic effect to form a hydrophobic and lipophilic chain; two hydrophobic chains are connected to the hydrophilic head of phospholipids to form an amphiphilic molecule. The pharmaceutical composition is an immediate-release drug phospholipid compound or a combined pharmaceutical composition of the compound and a pharmacodynamically acceptable carrier. The quick-release drug phospholipid compound and its liposome nanoparticle can be used as liquid preparation, solid preparation, semi-solid preparation, sterilized preparation and aseptic preparation, have low toxicity, and can be used for efficient treatment of various tumors and other diseases.

Description

A kind of immediate-release drug phospholipid compound and its pharmaceutical composition

technical field

The invention relates to a quick-release drug phospholipid compound with anti-tumor and other disease-treating effects, its pharmaceutical composition and application, and relates to the technical field of medicine.

Background technique

Many small-molecule chemical drugs are difficult to penetrate cell membranes because of their strong hydrophobicity, strong hydrophilicity, and poor lipophilicity, resulting in poor efficacy in treating diseases.

Some plant-derived drugs with strong physiological activities are strongly hydrophobic, making administration difficult and their applications limited. Camptothecin (CPT) and 10-hydroxycamptothecin (HCPT) are alkaloids extracted from the seeds or root bark of Camptothecin, a deciduous plant of the Davidiaceae family, and have strong cytotoxic activity. Camptothecin compounds form a stable triplet complex of camptothecin-topoisomerase I-DNA, so that the DNA double helix structure cannot be replicated, and can be used to treat various malignant tumors, such as colorectal cancer, gastric cancer, Liver cancer, bladder cancer and leukemia etc. The biggest defect of camptothecin compounds for tumor treatment is that their water solubility and fat solubility are very poor, and it is difficult to obtain a solution with a high effective concentration. In order to improve the hydrophobic defects of CPT and HCPT, some research institutions and enterprises have modified the chemical structure of camptothecin and synthesized hundreds of camptothecin derivatives. So far, two camptothecin derivatives with certain hydrophilicity have been approved for clinical tumor treatment, namely irinotecan and topotecan, but their water solubility is still low. In addition, CPT, HCPT and their analogues have anti-tumor activity while producing serious side effects such as myelosuppression, vomiting and diarrhea. The reason is that its active lactone structure is easily destroyed and becomes a carboxylate structure that has no drug effect or causes side effects.

Paclitaxel is also an alkaloid and is currently the only drug that can promote microtubule polymerization and stabilize the polymerized microtubules. Studies have shown that paclitaxel binds to polymerized microtubules and does not react with unpolymerized tubulin dimers. After the cells are exposed to paclitaxel, a large number of microtubules will accumulate in the cells. The accumulation of these microtubules interferes with various functions of the cells, especially stopping cell division at the mitotic stage and blocking the normal division of cells. Paclitaxel is mainly applicable to ovarian cancer and breast cancer, and also has a certain effect on lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma, and brain tumor. However, paclitaxel is poorly soluble in water, so polyoxyethylene castor oil and ethanol are needed to help dissolve it, and polyoxyethylene castor oil may cause allergic reactions, so patients need to take anti-allergic drugs before taking the drug. Studies have shown that the application of polyoxyethylene castor oil reduces the antitumor activity of paclitaxel. At the same time, due to poor selectivity, paclitaxel has strong toxic effects, is prone to drug resistance, and cannot penetrate the blood-brain barrier and other defects. Side effects include finger and toe numbness, transient tachycardia and hypotension, joint and muscle pain, gastrointestinal reactions, mild hair loss, and elevated bilirubin, alkaline phosphatase, aspartate aminotransferase, etc. For this reason, improving its hydrophilicity is the focus of research and development. So far, docetaxel and cabazitaxel, which are hydrophilic due to paclitaxel, have been successfully developed and applied clinically. Obviously, improving the hydrophilicity of hydrophobic drugs can help improve drug efficacy.

Hydrophilic drugs can be formulated into solutions orally or administered by injection. However, due to their excellent hydrophilicity and poor lipophilicity, these drugs often cannot or are difficult to pass through the cell membrane and enter cells by passive diffusion, resulting in limited drug efficacy. Some or even most of the drug is excreted as the original drug. Nucleoside anti-metabolite anticancer drugs are water-soluble analogues of deoxycytidine. Due to their excellent water solubility and poor lipophilicity, they cannot pass through the cell membrane and enter cells by passive diffusion. Gemcitabine (2'-deoxy-2', 2'-difluorocytidine) is a pyrimidine nucleoside analog developed by Eli Lilly and Company. It is a difluoronucleoside anti-metabolite anticancer drug that can destroy cell replication. An inhibitory enzyme substitute for ribonucleotide reductase. Gemcitabine is mainly used for the treatment of pancreatic cancer, bladder cancer, breast cancer and other solid tumors. It has been approved for use in more than 90 countries and has become the first-line drug for the treatment of non-small cell lung cancer and the "gold standard" for the treatment of pancreatic cancer. Gemcitabine also has antiviral activity and can be used to treat infections of the Flavivirus family including hepatitis C virus, etc., and can rapidly decrease within a few days (1-2 days in some cases) at the lowest dose The patient's HCV load was as high as 2 logs or more.

Similar to other nucleoside drugs, due to its excellent hydrophilicity, gemcitabine cannot pass through the cell membrane into cells by passive diffusion, so it needs specific transporters to be transported into tumor cells. Changes in nucleoside transport activity are considered to be an important cause of gemcitabine resistance. Human equilibrated nucleoside transporter 1 (hENT1) is an important transporter found to transport gemcitabine into tumor cells. Since the reduction of intracellular drug accumulation is likely to lead to a decrease in the sensitivity of gemcitabine, scientists from the Norwegian ClavisPharma company synthesized CP-4126, a 5'-elaidine derivative of gemcitabine, which has significantly improved lipophilicity compared with gemcitabine. The study found that CP-4126 It can be taken into tumor cells in a way independent of hENT1 transporter, so it is expected to show better anti-tumor effect in tumor patients with low expression of hENT1. At present, as a treatment drug for metastatic pancreatic cancer, it has entered the second phase of clinical trials. Obviously, by improving the lipophilicity of the hydrophilic drug, the hydrophilic drug can be effectively promoted to enter the cell through the cell membrane and exert its drug effect. Therefore, it is of great significance to design drug administration or modify the structure of hydrophilic drugs to overcome clinical defects.

Encapsulating drugs into carriers for controlled release is another important way of drug delivery. A large number of studies have shown that controlled release of drugs loaded on carriers can improve drug efficacy to a certain extent, but due to the easy leakage of drugs in carriers, it is difficult to achieve an ideal bioavailability of drugs.

Liposome is a new type of drug preparation with targeted drug delivery function, and it has been widely used in the field of anticancer drugs. Phospholipids are the main chemical components that make up liposomes, consisting of a hydrophilic head with phosphate-linked substitution genes and a hydrophobic tail with long hydrocarbon chains. When dispersed in the aqueous phase, the hydrophobic tails of the molecules tend to gather together and avoid the aqueous phase, while the hydrophilic heads are exposed to the aqueous phase, forming closed vesicles with a bilayer structure, namely liposomes. As a carrier, hydrophobic drugs are usually in the double lipid layer of liposomes, and hydrophilic drugs are in the aqueous phase of liposomes. Due to the fluidity of the liposome membrane, the drug is easy to leak out, making it difficult for the encapsulated drug to exert a good drug effect. Combining drug molecules into the phospholipid molecular structure through covalent bonds constitutes a prodrug, which can avoid drug leakage. The downside is that phospholipid prodrug molecules typically release the drug with a substituent by breaking the chemical bond between the drug and the phospholipid, followed by a slow release of the parent drug. Due to the slow release rate of the prototype drug from the prodrug molecule, it is difficult to obtain a high enough concentration of the prototype drug at the target site, resulting in a decrease in drug efficacy. On the other hand, the prodrug formed by covalently bonding the drug molecule into the phospholipid molecular structure is assembled into a liposome. Due to the destruction of the symmetry and regularity of the hydrophobic chain in the phospholipid molecule or the change of the hydrophilic head structure, the lipid The stability of the plastid decreases, affecting the effective release of the prototype drug.

Therefore, it is necessary to carry out structural design and develop a new drug liposome release system to achieve improved drug solubility, stability, cell permeability, targeting, improve the stability of the carrier system, and quickly release the prototype drug, In order to achieve the purpose of reducing toxic and side effects and improving curative effect.

The present invention utilizes the hydrophobic easy-to-break spacer part and the enhanced hydrophobic-lipophilic spacer part to form an effective easily-breakable hydrophobic lipophilic segment, which is connected to the glycerophospholipid molecule to become an amphiphilic molecule, and the drug molecule is connected to the hydrophobic end. So that the molecule can obtain suitable lipophilicity and hydrophilicity; the two hydrophobic chains formed by the two spacer arms connected to the drug use the two spacer arm synergistic hydrophobic interactions to assemble the amphiphilic molecule into a stable liposome, improving the drug Stability; the amphiphilic molecule and liposome can quickly break the easy-to-break spacer arm under the action of glutathione, etc., and the drug can be released quickly in the form of the prototype drug by reverse attacking the carbonyl group, and play an efficient tumor treatment, etc. effect.

Contents of the invention

Technical problem: The present invention provides an immediate-release drug phospholipid compound that has more suitable lipophilicity and hydrophilicity, is easy to be taken up by cells, and can quickly release two molecules of the prototype drug, and simultaneously provides a drug based on the immediate release Pharmaceutical composition of type drug phospholipid compound.

Technical solution: The immediate-release drug phospholipid compound of the present invention is a pharmaceutically acceptable salt formed by the compound of the following general formula (1) or the compound of the general formula (1) and a counter ion:

In formula (1), X ₁ and X ₂ are any one of ester bond, amide bond, carbamate bond and carbonate bond; X ₃ and X ₄ are any one of ester bond and amide bond species; A ₁ and A ₂ are easy-to-break hydrophobic spacer arms, which are alkylene groups with 2 to 8 carbon atoms containing disulfide bonds, alkylene groups with 2 to 80 carbon atoms containing peptide bonds, and amides An alkylene group with 2 to 20 carbon atoms in the bond or an alkylene group with 2 to 20 carbon atoms containing an ester bond; Z ₁ and Z ₂ are enhanced hydrophobic spacer arms, and the carbon atoms containing an ether bond are An alkylene group of 2 to 20 carbon atoms, an alkylene group of 2 to 20 carbon atoms containing an ester bond, an alkylene group of 2 to 20 carbon atoms containing an amide bond, or a carbon atom free of oxygen atoms and nitrogen atoms Alkylene group/alkene group whose number is 2 to 20; Y ₁ and Y ₂ are any of the following drugs: paclitaxel, docetaxel, cabazitaxel, the compound code-named BAY59-8862, code-named SB-T- Compound 11033, compound code-named SB-T-121303, compound code-named SB-T-121304, compound code-named SB-T-1213, compound code-named SB-T-12162, compound code-named BMS-184476 Compound, compound code-named DJ-927, compound code-named BMS-275183, camptothecin, hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin, camptothecin-10-O-ethylpyridine Azole, irinotecan, topotecan, 7-tert-butyldimethylsilyl-10-hydroxycamptothecin, 7-(2-trimethylsilylethyl)-camptothecin, hibiscus with the code name Afeletecan Thecamptothecin derivatives, 7-hydroxymethylcamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, hexacyclic camptothecin, compound code-named Gimatecan, compound code-named Belotecan, difluorocamptothecin Kang, compound code-named BN80927, compound code-named TOP-0618, compound code-named Exatecan, compound code-named Lurtotecan, compound code-named DRF-1042, podophyllotoxin, norepipodophyllotoxin, tenipo glycoside, etoposide, vinblastine, vincristine, vinorelbine, vindesine, etoposide, harringtonine, isoharringtonine, deoxyharringtonine, pseudodeoxy Harringtonine, homoharringtonine, inulalide, combretastatin, colchicine, fulvestrant, vorinostat, ixabepilone, eribulin, simva Statins, rotigotine, rifapentine, zidovudine, bromfuridine, lobucavir, megestrol, dibromodulcitol, salbutamol, resveratrol, homocamptothecin Compound, aloe-emodin, curcumin, lanosterol, mambavir, cidofovir, aclarmycin, carmine, deoxypyrromycin, zorubicin, 8-fluoro-idarubicin, Mycomycin, amphotericin, mitoxantrone, emodin, actinomycin D, rapamycin, mithramycin, epothilone, mitomycin , bleomycin, fumagillol, methylprednisolone, flapine, breviscapine, trabectedin, diterpenoids of Euphorbiaceae, 2,5-pentoxifylline, matrine, Ixabepilone, pinstatin A4, ubenimex, ribavirin, marimastat, medroxyprogesterone, stavudine, saquinavir, phenylephrine, methoxamine, albuterol, isoproterenol, misoprostol, latanoprost, prostacyclin, quinidine, propafenone, propafenolol, digoxin, digitoxin, dobutamine, Farin, coumarin compounds, lovastatin, fluvastatin, empagliflozin, degarelix, abarelix, Norad, galantamine, cycloheximide, minol Cyclocycline, meloxicam, posaconazole, everolimus, vorinostat, vatalanide, abiraterone, dihydroartemisinin, hydroprednisone, dexamethasone, code name The compound of AEZS-112, the compound with the code GZ402674, the compound with the code BCX-1777, the compound with the code CYC682, the compound with the code LY-2334737, O-(chloroacetyl-carbamoyl) fumagillin, the code The compound named SU14813, the compound coded BMS-275291, the compound coded ABT-510, the compound coded Aplidine, the compound coded NSC683551, the compound coded CGS27023A, the compound coded RO32-3555, the compound coded NPI -0052 compound, tiravancin, compound code-named CEP-1347, compound code-named ABR-215050, compound code-named Monomethylauristatin E, bicalutamide, retinolamide, ansamycin, bryostatin , temsirolimus, pramastat, tipranavir, indinavir, ritonavir, atazanavir, nelfinavir, batimastat, quercetin, flavonoids, Ticagrelor, cangrelor, telbivudine, trifluridine, adapalene, lopinavir, dapagliflozin, rifaximin, fluticasone, isavuconazole, raltegravir , panobinostat, avibactam, levonorgestrel, ethinylestradiol, darungravir, olmesartan, ivacaftor, bryostatin-1, α-galactosylceramide, epigalloc Catechin gallate, curcumin, oridonin, genistein, triptolide, gossypol, silibinin, teravancin, ezetimibe, pseudoephedrine, ticagrelor , mometasone furoate, deferiprone, oxybutynin, oxymorphone, raltegravir, mirabegron, teriflunomide, avanafil, temsirolimus, evitagravir, Dolutegravir, calicheamicin, retapamulin, tolvaptan, lumefantrine, tapitidine, galantamine, torisel, canagliflozin, raltegravir, buprofen Norphine, sofosbuvir, treprostinil, dantrolene, fluticasone furoate, naloxone, canagliflozin, sofosbuvir, N-hydroxymethyl aripiprazole, the compound code-named brivanib, The compound code-named bryostatin-1, the The compound named combretastainA4, the compound code-named CEP18770, the compound code-named Ivacaftor, the compound code-named MEK162, the compound code-named neovastat, the compound code-named UCN-01, the compound code-named ridaforolimus, the compound code-named AZD6244, The compound code-named TAK-733, the compound code-named AS703026, the compound code-named PD-325901, the compound code-named maytansine, the compound code-named R04987655, the compound code-named GDC-0973, the compound code-named GSK945237, the compound code-named Compounds of ANG1009, compounds coded AD198, compounds coded Becatecarin, compounds coded Adva27a, compounds coded Benzopyranones, compounds coded AEZS112, compounds coded B00742, compounds coded ALCHEMIX, compounds coded , the compound code-named , the compound code-named Saintopin, the compound code-named NCA0465, the compound code-named GL331, the compound code-named CAP7.1, the compound code-named IT62B, the compound code-named C1311, Oxycodone, Sirlein Carazepine, Tacrolimus, Paliperidone, N-Hydroxymethyl Aripiprazole, Raltegravir, Canagliflozin, Dexamethasone, Bellinostat, Camptophyllus DX-8951f Alkali derivatives, gemcitabine, compound code-named CP-4126, C ₁ -C ₂₀ amido gemcitabine, fluferon, cladribine, fluorouracil, tegafur, carmofur, bisfururacil, doxifluridine , Ecirapine, Capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, 2'-deoxy-5-fluorouridine, cytarabine, cyclo Cytidine, troxatabine, sapatitabine, decitabine, bosutinib, tafitinib, ibrutinib, dacomitinib, neratinib, dovitinib, pana Tini, Bafetinib, Selumetinib, Cazatinib, Ruxolitinib, Ruzotinib, Alectinib, Cabozantinib, Lenvatinib, Ceritinib, Alfa Tini, sunitinib, lapatinib, crizotinib, apatinib, erlotinib, canertinib, axitinib, bosutinib, nilotinib, gemfi Tini, Dasatinib, Sitagliptin, Imatinib, 6-Mercaptopurine, Methotrexate, Amhotrexate, Hydroxyurea, Inosine Dialdehyde, Adenosine Dialdehyde, Ibrutinib, trametinib, ruxolitinib, azacitidine, clofarabine, lenalidomide, nelarabine, pazopanib, vandetanib, carfilzomib, enzalutamide, Rafenib, vatalanib, temozolomide, effitabine, bepotahistine, linagliptin, fluoxetine, alogliptin, vildagliptin, saxagliptin, duloxetine, Atorvastatin, carmustine, nimustine, academia Neo, 4'-thio-β-D-arabinofuranosylcytosine, adefovir, vidarabine, doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin pirarubicin, entinostat, chidanilide, amdosovir, lamivudine, entecavir, picantron, tacrine, lenalidomide, metisazone, hydroxyurea, Pingyang Mycin, ganciclovir, famciclovir, phentolamine, phenoxybenzamine, prazosin, tamsulosin, indolamin, brimonidine, hydralazine, minoxidil, mecamylamine, Procainamide, mexiletine, dopamine, amrinone, palbociclib, boceprevir, telaprevir, huperzine A, memantine, sorafenib, regorafenib, Dabrafenib, Vemurafenib, Fingolimod, Nintedanib, Trifluorothymidine, Vonorazan, Olaparib, Ifosfamide, Eribulin, code name TAS-106 Compounds with the code VQD-002, MB07133, SPD754, Reverset nucleoside analogs, E7974, Lonafarnib, Semaxanib, The compound code-named Linifanib, the compound code-named Crenolanib, icatibant, the compound code-named AZD3293, the compound code-named LuAE58054, the compound code-named LY2811376, the compound code-named Alectinib, Tipifarnib, Lonafarnib , enprenavir, peptidomimetic drugs, levetiracetam, eslicarbazepine, topiramate, vilazodone, latinib, L-lysine-d-amphetamine, doxazosin, Carzepine, emtricitabine, adefovir dipivoxil, tenofovir, valganciclovir, milnacipran, aliskiren, ximelagatran, etravirine, rufinamide, imiquimod Tetra, famotidine, lamotrigine, boceprevir, ezogabine, colesevelam, imiquimod, chlorthalidone, apixaban, abacavir, silodosin , degarelix, telavancin, fingolimod, sphingosine, riociguat, ombitasvir, compound code-named Brostallicin, compound code-named Baricitinib, compound code-named Buparlisib, code-named cobicistat Compounds code-named Elacytarabine, compounds code-named GX15-070, compounds code-named Iniparib, compounds code-named Ixazomib, compounds code-named KRN7000, compounds code-named linezolid, compounds code-named Linsitinib, compounds code-named Nintedanib Compounds code-named Motesanib, compounds code-named Voxtalisib, compounds code-named Vatalanib, compounds code-named Pilaralisib, compounds code-named ONX0912, compounds code-named Tivoza Nib compound, compound code-named PF-03084014, compound code-named Verosudil, compound code-named TG-101348, compound code-named Tivantinib, compound code-named Paritaprevir, compound code-named sonidegib, compound code-named Rociletinib, Compounds code-named Trametinib, compounds code-named Regorafenib, compounds code-named Evofosfamide, compounds code-named Veliparib, compounds code-named volasertib, compounds code-named simeprevir, compounds code-named vismodegib, compounds code-named pomalidomide, compounds code-named Compounds of idelalisib, compounds code-named BEZ2235, compounds code-named GDC-0941, compounds code-named XL147, compounds code-named MK2206, dapafenib, compounds code-named BMS-908662, compounds code-named CI-1040 , the compound code-named GSK1120212, the compound code-named NVP-AEW541, the compound code-named Tivozanib, the compound code-named masitinib, the compound code-named SCH900105, the compound code-named Foretinib, the compound code-named RO5126766, the compound code-named Cyclopentanthraquinones , the compound code-named F14512, the compound code-named Sitafloxacin, the compound code-named Elinafide, the compound code-named KW2170, the compound code-named Lucanthone, the compound code-named Sabarabicin, the compound code-named Pixantrone, cediranib, Motif Shani, palbocoxib, rolapitant, dabigatran etexilate, deacetylvinblastine monohydrazide, butoxoperane, rilpivirine, cisplatin, spiroplatin, carboplatin, oxaliplatin , Scitraplatin, Miplatin, Nedaplatin, Heptaplatin, Lobaplatin, Cycloplatin, Oxalate Platinum, Methidine Platinum, the compound code-named BBR-3464, 5,6-dimethylxanthone-4-acetic acid, Hibiscus bark acetic acid, ganoderma acid, oleanolic acid, rhein, 9-cis retinoic acid, betulinic acid, vitamin E succinic acid monoester, all-trans retinoic acid, diclofenac, carglutamic acid, obeticholic acid , deoxycholic acid, vigabatrin, leuprolide, cerulein, pramlintide, corticotropin, bacitracin, teriparatide, goserelin, exenatide, antiangitide, Mivawood peptide, romidepsin, tyroservalide, sifuvirtide, Aiboweitai, tyroserleutide, doripenem, azilsartan, oxytocin, cyclosporine, Proper Relin, tatirelin, nafarelin, buserelin, histrelin, gonadorelin, tryptorelin, somatostatin , secretin, octreotide, ziconotide, enfuvirtide, lanreotide, vapreotide, siglipide, teduglutide, linaclotide, cinapretide, pasireotide, tripeptide Relin, Temorelin, Liraglutide, Bexarotene, Pitavastatin, Rosuvastatin, Bendamustine, Melphalan, Lonidamine, Atrasentan, Melphalan , sulindone, pemetrexed, azepine, dinoprostone, carboprost, alprostadil, gemfibrozil, ciluprevir, peptistatin, glatiramer, luxinatan, indole Domethacin, ibuprofen, naproxen, deferasirox, fluoroquinolones, pralatrexate, compound code-named Voreloxin, compound code-named AKR501, compound code-named CPI-613, compound code-named MK0429 , the compound code-named IDN-6556, tannostat, marimastat, prinomastat, the compound code-named alisertib, cilengitide, argatroban, dabigatran, artesunate, Ambrisentan, eltrombopag, valsartan, moxifloxacin, naproxen, irudoline, glatiramer, tirofiban, deferasirox, ceftazidime, levodopa, cabedopa , besifloxacin, febuxostat, prulifloxacin, cefbiproxil, cefbiproxil, gabapentin pivoxil, mesalazine, icatibant, linaclotide, bedaquiline, sacubitril , ebiprazole, doripenem, ingenyl methacrylate, droxidopa, compound code-named lumacaftor, compound code-named MLN9708, compound code-named Sacubitril, compound code-named rigosertib, code-named The compound of Vosaroxin, the compound code-named Orantinib, carrubicin, arubicin, ibacitabine, gallocitabine, ancitabine, letatinib, improsulfan, mannosulfan, Qushufan, Quaoshufan, Ecomustine, Estramustine, Semustine, Aestramustine, Gemeracin, Medorubicin, Nerubicin, Pirarubicin, Rhodobisin, Sharubicin, Valrubicin, Zorubicin, Liurubicin, Idarbisin, Garubicin, Esopubicin, Detobysin, Amrubicin, Vatocitabine, zalcitabine, tezatabine, fecitabine, flucitabine, amustine, erlotinib, pelitinib, trimetrexate, edatrexate, ketone Trixa, oteracil, mitoradone, bortezomib;

L is 2-amino-2-carboxyethyl, 2-aminoethyl, 2-trimethylaminoethyl cation, 2,3-dihydroxypropyl, molecular weight 200-4000 without targeting end group N-polyethylene glycol-aminoethyl group or N-polyethylene glycol-aminoethyl group whose molecular weight is 200-4000 end group is targeting group.

Furthermore, in the present invention, Y ₁ and Y ₂ may also be derivatives of the above drugs.

In the preferred version of the immediate-release drug phospholipid compound of the present invention, in the N-polyethylene glycol-aminoethyl group whose terminal group is a targeting group, the targeting group is folic acid, galactose, polypeptide, antibody, antibody fragment , hyaluronic acid, asialoglycoprotein, polysaccharide, nucleic acid, peptidomimetic and sulfadiazine.

In the preferred version of the immediate-release drug phospholipid compound of the present invention, when L is an uncharged group in the structural formula (1), the counter ion is a combination of a cation and an anion, and the cation is a hydrogen ion, Any of sodium ions, potassium ions, calcium ions, iron ions, magnesium ions, ammonium ions, zinc ions; when L is a positively charged group in the structural formula (1), the counter ion is a hydrogen ion, a sodium ion , any one of potassium ion, calcium ion, iron ion, magnesium ion, ammonium ion, zinc ion, and described anion is chloride ion, sulfate ion, sulfate ion, nitrate ion, carboxylate ion, carbonate ion , Bromide, Phosphate, Formate, Acetate, Citrate, Lactate, Fumarate, Tartrate, Gluconate.

The pharmaceutical composition of the present invention comprises the above-mentioned immediate-release drug phospholipid compound or the immediate-release drug phospholipid compound and a pharmacodynamically acceptable carrier.

In a preferred embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is a liposome nanoparticle with a particle diameter of 10-1000 nanometers, and the pharmaceutical composition also includes an auxiliary agent. In a further preferred embodiment, the auxiliary agent is phospholipid or cholesterol.

In a preferred embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is a liquid preparation, a solid preparation, a semi-solid preparation, a capsule, a granule, a gel, an injection, a sustained-release preparation or a controlled-release preparation.

The present invention also relates to pharmaceutical compositions comprising, as active ingredient, the compound according to the invention or the compound according to the invention and conventional pharmaceutical auxiliaries. Usually the pharmaceutical composition of the present invention contains 0.1-100% by weight of the phospholipid compound of the hydrophilic drug of the present invention.

Liposome nanoparticles are prepared from the compound of the present invention, and the particle size is 10-1000 nanometers. Liposome nanoparticles are made from the compounds of the present invention and auxiliary agents, and the particle size is 10-1000 nanometers. The auxiliary agents used are phospholipids, polyethylene glycol phospholipids (polyethylene glycol molecular weight 400-3000), targeting group-containing One or more of polyethylene glycol phospholipids or cholesterol. Targeting groups are folic acid, galactose, polypeptides, antibodies, antibody fragments, hyaluronic acid, asialoglycoproteins, polysaccharides, nucleic acids, and peptidomimetics.

The pharmaceutical composition liposome nanoparticle of the present invention is a liquid preparation, a solid preparation, a semi-solid preparation, a capsule, a granule, a gel, an injection, a sustained-release preparation or a controlled-release preparation.

From the screening of in vitro pharmacological activity, etc., the compound of the present invention exhibits good antitumor and other biological activities. Tests show that the in vivo toxicity of the compound of the present invention is less than that of the original drug. Therefore, it can be used as anti-tumor and other drugs for patients.

From the screening of in vitro pharmacological activity, etc., the compound liposome nanoparticle of the present invention exhibits good antitumor and other biological activities. Tests show that the in vivo toxicity of the compound of the present invention is far less than that of the original drug.

The preparation method of the immediate-release drug phospholipid compound liposome nanoparticle of the present invention is a mixture of the immediate-release drug phospholipid compound of the present invention or the compound of the present invention and an auxiliary agent, through a thin film dispersion method, a reverse phase evaporation method, and a freeze-drying method. , Ultrasonic dispersion method, spray drying method, film extrusion method, or high pressure homogenization method.

In the present invention, two molecules of medicine are connected with hydrophobic spacer arms as hydrophobic tails, and are connected with phospholipid hydrophilic heads through covalent bonds to prepare quick-release drug phospholipid compounds, improve the water solubility and transmembrane ability of drugs, and be used alone or with phospholipids. Liposome nanoparticle is made by mixing; the rapid-release drug phospholipid compound of the present invention is superior to the original drug in fat solubility, long half-life, and significantly better in antitumor and other activities than the original drug.

The present invention prepares quick-release drug phospholipid compounds into nanoparticles, which have the characteristics of liposomes, strong transmembrane ability, and the characteristics of being able to form liquid preparations, solid preparations, semi-solid preparations, sterilized preparations and aseptic preparations. In the treatment of tumors, etc. This immediate-release drug phospholipid compound nanoparticle is not only a prodrug, but also a brand-new drug release carrier with a targeting function; the immediate-release drug phospholipid compound and liposome nanoparticle of the present invention are also drug carriers. Degradation in the body quickly releases the drug, exerts the drug effect, and has low toxicity and side effects.

The immediate-release drug phospholipid compound of structural formula (1) of the present invention and the pharmaceutically acceptable salts containing counter ions formed by these compounds have anti-tumor effects, can prolong the half-life of drug release, and have lower toxic and side effects .

Beneficial effect: compared with the prior art, the present invention has the following advantages:

In the immediate-release drug phospholipid compound of the present invention, in the structural formula ( ₁ ), A ₁ and A ₂ are hydrophobic spacer arms containing disulfide bonds, peptide bonds, etc. ₂ is to strengthen the hydrophobic spacer to enhance the hydrophobic and lipophilic effect; Y ₁ and Y ₂ are drugs. In the structural formula (1), the drugs Y ₁ and Y ₂ are connected to the quick-release hydrophobic spacer and the enhanced hydrophobic spacer through chemical bonds, and the two hydrophobic spacers cooperate with each other to enhance the hydrophobic and lipophilic effects, forming a hydrophobic and lipophilic chain tail; Two hydrophobic chains are connected to the hydrophilic head of the phospholipid to form an amphiphilic molecule.

The immediate-release drug phospholipid compound of the present invention can simultaneously adjust the balance of hydrophilicity and lipophilicity, and realize rapid release of the drug: when the original drugs Y ₁ and Y ₂ have strong hydrophobicity and lipophilicity, the immediate-release drug phospholipid compound of the present invention The phospholipid hydrophilic head is used to make it more hydrophilic than the original drug, and overcome the defect that the drug is difficult to dissolve in the water system due to strong hydrophobicity; when the original drug Y ₁ and Y ₂ have strong hydrophobicity and poor lipophilicity , the instant-release drug phospholipid compound of the present invention utilizes the phospholipid hydrophilic head to make it have better hydrophilicity than the original drug, and utilizes the enhanced hydrophobic lipophilic spacer to make it better lipophilic than the original drug to overcome The drug has the defect of being poorly soluble due to its strong hydrophobicity and poor lipophilicity; when the original drug Y ₁ and Y ₂ have strong hydrophilicity, the immediate-release drug phospholipid compound structural formula of the present invention ( 1) Chinese medicine Y ₁ and Y ₂ are connected to two hydrophobic spacer arms through chemical bonds to form a hydrophobic tail, that is, the medicine is forced to be placed in the hydrophobic structure part, so that the immediate-release medicine phospholipid compound of the present invention has more Good hydrophobicity and lipophilicity, overcome the defect that the drug is difficult to be taken up by cells due to its strong hydrophilicity;

The immediate-release drug phospholipid compound of the present invention has two hydrophobic tails in the structural formula (1), and each hydrophobic tail contains an easily broken spacer and a reinforced hydrophobic spacer, and simultaneously imparts lipophilic and hydrophobic enhanced and rapid break functions, It not only overcomes the defect that the molecule contains only one easy-to-break spacer arm, which leads to insufficient hydrophobicity and lipophilicity, making it difficult to effectively assemble into stable liposomes, but also overcomes the defect that only one hydrophobic spacer arm is difficult to quickly break and release the original drug;

The drug-containing hydrophobic tail of the immediate-release drug phospholipid compound of the present invention is connected with the phospholipid hydrophilic head to form an amphiphilic molecule, so that it has suitable lipophilicity and hydrophilicity, so that the drug is easily taken up by cells, and a more stable drug is obtained. Excellent transmembrane ability, overcomes the defect of poor crossmembrane ability of hydrophilic drugs, and exerts better drug efficacy;

In the instant-release drug phospholipid compound of the present invention, in the structural formula (1), Y ₁ and Y ₂ are selected from different drugs connected to the spacer arm through chemical bonds to form a hydrophobic lipophilic tail, that is, two different drugs are placed in a hydrophobic lipophilic tail. The hydrophobic tail is connected with the hydrophilic head of the phospholipid to form an amphiphilic molecule containing two different drugs, which not only improves the hydrophilicity or lipophilicity of the two drugs, but also overcomes the poor solubility of the drug or the difficulty of being taken up by cells. In addition, the rapid-release drug phospholipid compound can simultaneously release two kinds of original drugs, and bring into play the synergistic therapeutic effect of the two drugs;

The instant-release drug phospholipid compound of the present invention utilizes the easily-breakable spacer part of the hydrophobic part and the enhanced hydrophobic lipophilic spacer part to form an effective hydrophobic lipophilic chain, and is connected to the glycerophospholipid molecule to become an amphiphilic molecule, and to The end is connected to the drug molecule, and the two hydrophobic and lipophilic chains formed by the easy-to-break spacer and the enhanced hydrophobic spacer connected to the drug make use of the synergistic hydrophobic effect to assemble the amphiphilic molecule into a stable liposome;

The immediate-release drug phospholipid compound of the present invention is assembled into a liposome, which is easily taken up by cells and exerts better drug effects;

The immediate-release drug phospholipid compound of the present invention is a kind of amphiphilic molecule, which can be assembled alone or together with auxiliary agents to form a stable liposome, which overcomes the shortcoming that the drug is easy to leak when the general liposome encapsulates the drug, and at the same time improves the ability of the drug to wrap. s efficiency;

Secreted phospholipase A2 (sPLA2) is highly expressed in many tumor cells. This enzyme can only hydrolyze the ester bond at the sn2 position in the glycerol skeleton of the phospholipid molecule, but cannot hydrolyze the ester bond at the sn1 position. Therefore, it is difficult for the molecule in the phospholipid molecule, in which the two hydrophobic tails are combined with drugs, to release the structural part containing the drug group connected to the sn1 position through an ester bond in the tumor cell, forming a structure similar to the toxic lysophospholipid, resulting in a double-drug phospholipid It is difficult to quickly release all the original drug. The drug-containing hydrophobic tail of the immediate-release drug phospholipid compound of the present invention includes a breakable spacer arm, contains a disulfide bond, etc., can be degraded by glutathione, etc. and quickly breaks, and after breaking, it contains sulfhydryl groups in the fragments of the drug molecule. Attacking the carbonyl group of the molecule itself by "biting back" leads to rapid release of the original drug, which overcomes the defect that the common spacer arm is difficult to break quickly and cannot release the original drug quickly; and one molecule of the immediate-release drug phospholipid compound quickly releases two molecules of the original drug, It forms a high concentration in the target cells and has a stronger drug effect;

The phospholipid compound of the drug of the present invention is assembled alone or together with auxiliary agents to form a stable drug-containing liposome, and the drug group is located in the double lipid layer of the liposome, and the drug is well protected before it exerts its drug effect, improving It improves the stability of the drug and overcomes the defect that it is easily damaged during the drug delivery process; moreover, the drug-containing liposome is easy to be taken up by cells, and quickly releases the original drug to exert its drug effect;

The phospholipid compound of the drug of the present invention can be self-assembled into liposome nanoparticles very easily by using a thin film method, etc., with a particle size of 10-1000 nanometers; It is very easy to self-assemble into liposome nanoparticles, with a particle size of 10-1000 nanometers;

The quick-release drug phospholipid compound liposome nanoparticle of the present invention has a passive targeting effect;

The instant-release drug phospholipid compound and liposome nanoparticle of the present invention are a brand-new drug release carrier and a prodrug;

The compound of the present invention or the pharmaceutical composition of the compound of the present invention and a conventional drug carrier, containing 0.1-100% by weight of the compound of the present invention, has low toxicity and excellent anti-tumor and other biological activities;

The instant-release drug phospholipid compound of the present invention and liposome nanoparticles thereof can be used as liquid preparations, solid preparations, semi-solid preparations, sterilized preparations and aseptic preparations, and can be prepared in water, phosphate buffer, citrate buffer Liposomes are formed in the aqueous phase system;

The immediate-release drug phospholipid compound liposome of the present invention is combined with a phospholipid auxiliary agent containing a targeting group, and has an active targeting effect; the immediate-release drug phospholipid compound or phospholipid compound liposome of the present invention has the structural formula (1) Among them, L is an N-polyethylene glycol-aminoethyl group whose end group is a targeting group with a molecular weight of 200-4000. The surface of the liposome assembled by the phospholipid compound has a targeting group and has an active targeting effect. ;

The preparation process of the quick-release drug phospholipid compound and liposome nanoparticle of the present invention is simple;

The instant-release drug phospholipid compound and its liposome nanoparticles of the present invention are also a brand-new drug prodrug, which can be degraded by enzymes and glutathione in the body to release the prototype drug quickly, exert drug effect, and have low Toxic and side effects, anti-tumor and other pharmacological effects are excellent.

Description of drawings

Fig. 1 is a synthetic route diagram of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Fig. 2 is a synthetic route diagram of bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine.

Figure 3. Route diagram for the formation of bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Figure 4 is a synthetic route diagram of bis(topotecan-20-carbonate-dithiodiethylene glycol-diglycolate) phosphatidylcholine.

Figure 5 is a synthetic route diagram of bis(doxorubicin-N-carbamate-dithiodiethylene glycol-succinate-GFLG) phosphatidylcholine.

Figure 6 sn1-camptothecin-20-carbonate-dithiodiethylene glycol-succinate-sn2-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate-glycerol phosphatidylcholine Synthetic scheme of the base.

Figure 7 is a synthetic route diagram of bis(docetaxel-7-carbonate-dithiodiethylene glycol-adipate)phosphatidylcholine.

Fig. 8 is a synthetic route diagram of bis(7-ethyl-hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 9 is a synthetic route diagram of bis(podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Fig. 10 is a synthetic route diagram of bis(camptothecin-9-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 11 is a synthetic route diagram of bis(camptothecin-7-methylene-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 12 is a synthetic route diagram of bis(cabazitaxel-2'-carbonate-dithiodiethylene glycol-adipate)phosphatidylcholine.

Figure 13 is a synthetic route diagram of bis(hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Figure 14 is a synthetic route diagram of bis(irinotecan-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Figure 15 is a synthetic route diagram of bis(hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Figure 16 is a synthetic route diagram of bis(difluorocamptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Figure 17 is a synthetic route diagram of bis(Belotecan-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

Figure 18 is a synthetic route diagram of bis(DX-8591f-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 19 is a synthetic route diagram of bis(9-nitrocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 20 is a synthetic route diagram of bis(4'-desmethyl epipodophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 21 is a synthetic route diagram of bis(5'-deoxy-5-fluorocytidine-4-carbamate-dithiodiethylenediamine-succinyl)phosphatidylcholine.

Figure 22 is a synthetic route diagram of bis(camptothecin-20-carbamate-dithiodiethylamine-succinyl)phosphatidylcholine.

Figure 23 is a synthetic route diagram of bis(all-trans retinoic acid-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 24 is a synthetic route diagram of bis(homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 25 is a synthetic route diagram of bis(tyroserleutide-dithiodiethylenediamine-succinyl)phosphatidylcholine.

Figure 26 is a synthetic route diagram of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine-N-polyethylene glycol.

Figure 27 is a synthetic route diagram of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine-N-polyethylene glycol-N-folate.

Figure 28 is a synthetic route diagram of bis(chidamide-2'-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine.

Figure 29 Bis(bexarotene-GFLG-butyryl) phosphorylcholine synthesis route

Figure 30 Bis(bexarotene-ethylene glycol succinic acid-ethylene glycol succinic acid) phosphorylcholine synthetic route

Figure 31 Bis(bexarotene-ethylenediaminesuccinic acid-ethylenediaminesuccinic acid) phosphorylcholine synthetic route

Figure 32 The synthetic route diagram of immediate-release biscisplatin compound phosphatidylcholine

Figure 33 is a schematic diagram of particle size analysis of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes.

Figure 34 Cryo-TEM images of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome nanoparticles.

Figure 35 Bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome antitumor activity (a) and body weight change results (b).

detailed description

The technical solution of the present invention will be described in further detail below in conjunction with the accompanying drawings and embodiments of the description.

The immediate-release drug phospholipid compound of the present invention is a pharmaceutically acceptable salt formed by the compound of the following general formula (1) or the compound of the general formula (1) and a counter ion:

In formula (1), A ₁ and A ₂ are easily broken hydrophobic spacers; Z ₁ and Z ₂ are enhanced hydrophobic spacers; Y ₁ and Y ₂ are drugs, which are specifically listed in the technical scheme.

Immediate-release drug phospholipid compound of the present invention is synthesized according to the following method:

For drugs containing hydroxyl groups, react with solid phosgene to obtain chloroformate-esterified drug derivatives, and then react with hydroxyl groups or amino groups of compounds containing disulfide bonds or polypeptide bonds that are easy to break spacer arms and enhance hydrophobic spacer arms, The obtained drug is connected by a carbonate bond or a carbamate bond, and contains an intermediate product of an easily cleavable spacer arm and a reinforced hydrophobic spacer arm, and then the carboxyl group of the intermediate product is activated by a catalyst such as N, N'-carbonyldiimidazole (CDI) React with the two hydroxyl groups of glycerol phosphorylcholine to obtain the corresponding immediate-release drug phospholipid compound molecule containing two drug groups. Hydroxyl-containing drugs suitable for this method include: paclitaxel, docetaxel, cabazitaxel, the compound with the code name BAY59-8862, the compound with the code name SB-T-11033, the compound with the code name SB-T-121303, the compound with the code name Compound SB-T-121304, Compound Code SB-T-1213, Compound Code SB-T-12162, Compound Code BMS-184476, Compound Code DJ-927, Code BMS-275183 Compounds of camptothecin, hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin, camptothecin-10-O-ethylpyrazole, irinotecan, topotecan, 7-tert-butyl Dimethylsilyl-10-hydroxycamptothecin, 7-(2-trimethylsilylethyl)-camptothecin, a camptothecin derivative code-named Afeletecan, 7-hydroxymethylcamptothecin, 9 -Nitrocamptothecin, 9-aminocamptothecin, hexacyclic camptothecin, compound code-named Gimatecan, compound code-named Belotecan, diflutecan, compound code-named BN80927, compound code-named TOP-0618 , the compound code-named Exatecan, the compound code-named Lurtotecan, the compound code-named DRF-1042, podophyllotoxin, norepipodophyllotoxin, teniposide, etoposide, vinblastine, vincristine, vinorel Bin, vindesine, etoposide, harringtonine, isoharringtonine, deoxyharringtonine, pseudodeoxyharringtonine, homoharringtonine, large flower ring Inulalide, combretastatin, colchicine, fulvestrant, vorinostat, ixabepilone, eribulin, simvastatin, rotigotine, rifapentine, zidov Ding, bromfuridine, lobucavir, megestrol, dibromodulcitol, salbutamol, resveratrol, homocamptothecin compounds, aloe-emodin, curcumin, lanosterol, mambavir , cidofovir, aclarmycin, carmine, deoxypyrromycin, zorubicin, 8-fluoro-idarubicin, nystatin, amphotericin, mitoxantrone, emodin, Actinomycin D, rapamycin, mithramycin, epothilone, mitomycin, bleomycin, fumagillol, methylprednisolone, flapindu, breviscapine, Trabectedin, diterpenoids of Euphorbiaceae, 2,5-pentoxifylline, matrine, ixabepilone, pinstatin A4, ubenimex, ribavirin, marimastat , medroxyprogesterone, stavudine, saquinavir, phenylephrine, methoxamine, albuterol, isoproterenol, misoprostol, latanoprost, prostacyclin, quinidine, propafenone, propafenolol, digoxin, digitoxin, dobutamine, warfarin, coumarins, lovastatin, fluvastatin, empagliflozin, Garelix, Abarelix, Noredex, Galantamine, Cycloheximide, Minocycline, Meloxicam, Posaconazole, Everolimus, Vorinostat, Vata Lanitine, abiraterone, dihydroartemisinin, prednisone, dexamethasone Pine, the compound code-named AEZS-112, the compound code-named GZ402674, the compound code-named BCX-1777, the compound code-named CYC682, the compound code-named LY-2334737, O-(chloroacetyl-carbamoyl) nigari Mycin, the compound code-named SU14813, the compound code-named BMS-275291, the compound code-named ABT-510, the compound code-named Aplidine, the compound code-named NSC683551, the compound code-named CGS27023A, the compound code-named RO32-3555 , the compound code-named NPI-0052, tiravancin, the compound code-named CEP-1347, the compound code-named ABR-215050, the compound code-named Monomethylauristatin E, bicalutamide, retinoic acid, ansamycin , bryostatin, temsirolimus, pramastat, tipranavir, indinavir, ritonavir, atazanavir, nelfinavir, batimastat, quercetin, Flavonoids, ticagrelor, cangrelor, telbivudine, trifluridine, adapalene, lopinavir, dapagliflozin, rifaximin, fluticasone, isavuconazole, Raltegravir, panobinostat, avibactam, levonorgestrel, ethinyl estradiol, darungravir, olmesartan, ivacaftor, bryostatin-1, alpha-galactose Amides, Epigallocatechin Gallate, Curcumin, Oridonin, Genistein, Triptolide, Gossypol, Silybin, Tylavancin, Ezetimibe, Pseudoephedrine , ticagrelor, mometasone furoate, deferiprone, oxybutynin, oxymorphone, raltegravir, mirabegron, teriflunomide, avanafil, temsirolimus, Tegvir, dolutegravir, calicheamicin, retapamulin, tolvaptan, lumefantrine, tabitidine, galantamine, torecel, canagliflozin, ralteira Wei, buprenorphine, sofosbuvir, treprostinil, dantrolene, fluticasone furoate, naloxone, canagliflozin, sofosbuvir, N-hydroxymethyl aripiprazole, code name The compound of brivanib, the compound code-named bryostatin-1, the compound code-named combretastainA4, the compound code-named CEP18770, the compound code-named Ivacaftor, the compound code-named MEK162, the compound code-named neovastat, the compound code-named UCN-01, The compound code-named ridaforolimus, the compound code-named AZD6244, the compound code-named TAK-733, the compound code-named AS703026, the compound code-named PD-325901, the compound code-named maytansine, the compound code-named RO4987655, the compound code-named GDC- Compound 0973, compound code-named GSK945237, compound code-named ANG1009, code-named A Compound D198, compound code-named Becatecarin, compound code-named Adva27a, compound code-named Benzopyranones, compound code-named AEZS112, compound code-named B00742, compound code-named ALCHEMIX, compound code-named, compound code-named, The compound code-named Saintopin, the compound code-named NCA0465, the compound code-named GL331, the compound code-named CAP7.1, the compound code-named IT62B, the compound code-named C1311, oxycodone, silicarbazepine, tacromol Division, paliperidone, N-hydroxymethyl aripiprazole, raltegravir, canagliflozin, dexamethasone, carrubicin, arubicin, ibacitabine, gallocitabine , Ancitabine, Letatinib, Improsufan, Manlusufan, Ritrasufan, Triosufan, Ecomustine, Estramustine, Semustine, Alestremustine , gimeracil, belistat;

Drugs containing amino or amine groups are obtained by reacting with solid phosgene to obtain carbamoyl chloride drug derivatives, and then reacting with hydroxyl or amino groups of compounds containing disulfide bonds or polypeptide bonds that are easy to break spacer arms and enhance hydrophobic spacer arms, The obtained drug is connected by a carbamate or urea bond, and contains an intermediate product of an easy-to-break spacer arm and a reinforced hydrophobic spacer arm. The carboxyl groups of the last two intermediate product molecules are combined with the two hydroxyl groups of glycerophosphorylcholine under the action of a catalyst such as CDI. reaction to obtain the corresponding immediate-release drug phospholipid compound containing two drug groups. Drugs containing amino groups or amine groups suitable for this method include: camptothecin derivatives code-named DX-8951f, gemcitabine, compounds code-named CP-4126, C ₁ -C ₂₀ amido gemcitabine, fluferolone, carat Drubine, fluorouracil, tegafur, carmofur, bisfururacil, doxifluridine, icirabine, capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5 -fluorouridine, 2'-deoxy-5-fluorouridine, cytarabine, cyclocytidine, troxatabine, sapatitabine, decitabine, bosutinib, tafitinib, Ibrutinib, Dacomitinib, Neratinib, Dovitinib, Ponatinib, Bafetinib, Selumetinib, Cazatinib, Ruxolitinib, Ruzotinib, alectinib, cabozantinib, lenvatinib, ceritinib, afatinib, sunitinib, lapatinib, crizotinib, apatinib, erlotinib, Canertinib, Axitinib, Bosutinib, Nilotinib, Gefitinib, Dasatinib, Sitagliptin, Imatinib, 6-Mercaptopurine, Methotrexate, Aminopterin, hydroxyurea, inosine dialdehyde, adenosine dialdehyde, ibrutinib, trametinib, ruxolitinib, azacitidine, clofarabine, lenalidomide, nelarabine , pazopanib, vandetanib, carfilzomib, enzalutamide, dabrafenib, vatalanib, temozolomide, effitabine, bepotahistine, linagliptin, fluoxetine alogliptin, vildagliptin, saxagliptin, duloxetine, atorvastatin, carmustine, nimustine, akadesine, 4'-thio-β- D-arabinofuranosylcytosine, adefovir, vidarabine, doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin, pirarubicin, entino Tetra, chidaniline, amdosovir, lamivudine, entecavir, picantron, tacrine, lenalidomide, metisazone, hydroxyurea, pingyangmycin, ganciclovir, famciclovir, Phentolamine, phenoxybenzamine, prazosin, tamsulosin, indolamin, brimonidine, hydralazine, minoxidil, mecamylamine, procainamide, mexiletine, Dopamine, amrinone, palbociclib, boceprevir, telaprevir, huperzine A, memantine, sorafenib, regorafenib, dabrafenib, vemurafenib, Fingolimod, nintedanib, trifluridine, vonoprazan, olaparib, ifosfamide, eribulin, compound code-named TAS-106, compound code-named VQD-002 , the compound code-named MB07133, the compound code-named SPD754, the nucleoside analogue code-named Reverset, the compound code-named E7974, the compound code-named Lonafarnib, the compound code-named Semaxanib, the compound code-named Linifanib, the code-named Crenolanib Compound, icatibant, compound code-named AZD3293, compound code-named LuAE58054, compound code-named LY2811376, compound code-named Alectinib, tipifarnib, lonafarnib, amprenavir, peptidomimetics Drugs, levetiracetam, eslicarbazepine, topiramate, vilazodone, latinib, L-lysine-d-amphetamine, doxazosin, oxcarbazepine, emtricitabine, Adefovir dipivoxil, tenofovir, valganciclovir, milnacipran, aliskiren, ximelagatran, etravirine, rufinamide, imiquimod, famotidine, Motrigine, Boceprevir, Ezogabine, Colesevelam, Imiquimod, Chlorthalidone, Apixaban, Abacavir, Sirodosin, Degarelix, Tetra Wanxing, Fingolimod, Sphingosine, Riociguat, Obitasvir, the compound code-named Brostallicin, the compound code-named Baricitinib, the compound code-named Buparlisib, the compound code-named cobicistat, the compound code-named Elacytarabine , the compound code-named GX15-070, the compound code-named Iniparib, the compound code-named Ixazomib, the compound code-named KRN7000, the compound code-named linezolid, the compound code-named Linsitinib, the compound code-named Nintedanib, the compound code-named Motesanib , the compound code-named Voxtalisib, the compound code-named Vatalanib, the compound code-named Pilaralisib, the compound code-named ONX0912, the compound code-named Tivozanib, the compound code-named PF-03084014, the compound code-named Verosudil, the code-named TG-101348 Compounds code-named Tivantinib, compounds code-named Paritaprevir, compounds code-named sonidegib, compounds code-named Rociletinib, compounds code-named Trametinib, compounds code-named Regorafenib, compounds code-named Evofosfamide, compounds code-named Veliparib , the compound code-named volasertib, the compound code-named simeprevir, the compound code-named vismodegib, the compound code-named pomalidomide, the compound code-named idelalisib, the compound code-named BEZ2235, the compound code-named GDC-0941, the compound code-named XL147 , the compound code-named MK2206, dapafenib, the compound code-named BMS-908662, the compound code-named CI-1040, the compound code-named GSK1120212, the compound code-named NVP-AEW541, the compound code-named Tivozanib, the code-named compound Compounds of masitinib, compounds code-named SCH900105, compounds code-named Foretinib, code-named RO512676 6, the compound code-named Cyclopentanthraquinones, the compound code-named F14512, the compound code-named Sitafloxacin, the compound code-named Elinafide, the compound code-named KW2170, the compound code-named Lucanthone, the compound code-named Sabarabicin, the compound code-named Pixantrone compound, cediranib, motisanib, palbocoxib, rolapitant, dabigatran etexilate, deacetylvinblastine monohydrazide, butoxipane, rilpivirine, medrubicin , Nerubicin, Piraubicin, Rhodobiicin, Sharubicin, Valrubicin, Zorubicin, Liurubicin, Idarby, Garrubicin, Esorubicin , detorubicin, amrubicin, vatocitabine, zalcitabine, tizatabine, fecitabine, flucitabine, amustine, erlotinib, peritinib , trimetholone;

For drugs containing carboxyl groups, react with hydroxyl or amino groups of compounds containing easy-to-break spacer arms such as disulfide bonds or polypeptide bonds and enhance hydrophobic spacer arms to obtain drugs linked by ester bonds or amide bonds, and contain easy-to-break spacer arms and The intermediate product of the hydrophobic spacer arm is enhanced, and the carboxyl groups of the last two intermediate product molecules react with the two hydroxyl groups of glycerophosphocholine under the action of a catalyst to obtain the corresponding immediate-release drug phospholipid compound containing two drug groups. Carboxyl group-containing drugs suitable for this method include: 5,6-dimethylxanthone-4-acetic acid, hibiscus bark acetic acid, ganoderma acid, oleanolic acid, rhein, 9-cis retinoic acid, betulinic acid , vitamin E monosuccinate, all-trans retinoic acid, diclofenac, carboglutamic acid, obeticholic acid, deoxycholic acid, vigabatrin, leuprolide, cerulein, pramlintide, adrenocorticotropic Hormone, bacitracin, teriparatide, goserelin, exenatide, antiangitide, mivawoodide, romidepsin, tyroservalide, sifuvirtide, aiboweitai, tyrosine Serleutide, doripenem, azilsartan, oxytocin, cyclosporine, prorelin, tatirelin, nafarelin, buserelin, histrelin, gona Relin, tryptide, somatostatin, secretin, octreotide, ziconotide, enfuvirtide, lanreotide, vapretide, siglipide, teduglutide, linaclotide, Cinapretide, Pasireotide, Triptorelin, Temorelin, Liraglutide, Bexarotene, Pitavastatin, Rosuvastatin, Bendamustine, Melphalan, Loni Damamine, atrasentan, melphalan, sulindone, pemetrexed, azepine, dinoprostone, carboprost, alprostadil, gemfibrozil, cilruprevir, peptistatin , Glatiramer, Lucinatan, Indomethacin, Ibuprofen, Naproxen, Deirasirox, Fluoroquinolones, Pralatrexate, the compound code-named Voreloxin, the compound code-named AKR501, the compound code-named Compounds of CPI-613, compounds code-named MK0429, compounds code-named IDN-6556, tannostat, marimastat, prinomastat, compounds code-named alisertib, cilengitide, argatroban , dabigatran, artesunate, ambrisentan, eltrombopag, valsartan, moxifloxacin, naproxen, iludoline, glatiramer, tirofiban, deferasirox , ceftazidime, levodopa, cabedopa, besifloxacin, febuxostat, prulifloxacin, cefbiproxil, cefbiproxil, gabapentin pivoxil, mesalazine, icatibant, linarol Peptide, bedaquiline, sacubitril, ebiprazole, doripenem, ingenyl methacrylate, droxidopa, the compound code-named lumacaftor, the compound code-named MLN9708, the compound code-named Compounds of Sacubitril, compounds code-named rigosertib, compounds code-named Vosaroxin, compounds code-named Orantinib, edatrexate, ketotrexate, oteracil, mitoradone, bortezomib.

Platinum drugs first react with solid phosgene to obtain carbamoyl chloride drug derivatives through ligands containing terminal amino groups, and then react with hydroxyl groups or amino groups of compounds containing disulfide bonds or polypeptide bonds and other easily cleavable spacer arms and enhanced hydrophobic spacer arms , the drug is connected through carbamate or urea bonds, and contains an intermediate product that is easy to break the spacer arm and strengthen the hydrophobic spacer arm. The hydroxyl group reacts to obtain the corresponding immediate-release drug phospholipid compound containing two platinum drug groups. Drugs suitable for this method include: cisplatin, spiroplatin, carboplatin, oxaliplatin, sateplatin, miplatin, nedaplatin, heptaplatin, lobaplatin, cycloplatin, oxaliplatin, meciplatin, code name A compound of BBR-3464.

The application of the immediate-release drug phospholipid compound of the present invention in the preparation of anti-tumor drugs, etc., is to prepare the drug phospholipid or its pharmaceutically acceptable salt and a pharmacodynamically acceptable carrier into a medicament. The compound of the present invention or the compound of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to make an appropriate administration form or dosage form that can be used as human medicine. Usually the pharmaceutical composition of the present invention contains 0.1-100% by weight of the compound of the present invention.

The route of administration of the compound of the present invention or the pharmaceutical composition containing it can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneal or rectal, etc. It can be administered by injection, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and point injection. The dosage forms for administration may be liquid dosage forms or solid dosage forms. For example, the liquid dosage forms can be true solutions, colloids, particulate dosage forms, emulsion dosage forms, and suspension dosage forms. Other dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, etc.

The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

The carriers used in the pharmaceutical composition of the present invention are, for example, diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline Cellulose, aluminum silicate, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, arabic mucilage, gelatin paste, carboxylate Sodium methylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate , polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil etc.; absorption enhancers, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

The compound of the present invention is made into injection preparations, such as solutions, suspension solutions, emulsions, and lyophilized powder injections. This preparation can be aqueous or non-aqueous, and can contain one and/or more pharmacodynamic agents. Acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added. These excipients are commonly used in the art.

Liposome nanoparticles are made from the compound of the present invention and auxiliary agents, and the particle size is 10-1000 nanometers. The auxiliary agents used are phospholipids, pegylated phospholipids (polyethylene glycol molecular weight 200-4000), targeted pegylated One or more of phospholipids (polyethylene glycol molecular weight 200-4000) cholesterol, the targeting group is folic acid, galactose, polypeptide, antibody, antibody fragment, hyaluronic acid, asialoglycoprotein, polysaccharide, nucleic acid and peptidomimetics.

The liposome nanoparticle preparation is prepared from the compound of the present invention, and the particle diameter is 10-1000 nanometers. The liposome nanoparticle is prepared from the compound of the present invention and an auxiliary agent, and the particle diameter is 10-1000 nanometers.

From the screening of anti-tumor and other activities in vitro, the compound of the present invention exhibits excellent anti-tumor and other activities. Tests show that the in vivo toxicity of the compound of the present invention is less than that of the original drug. From the screening of anti-tumor and other activities in vitro, the liposome nanoparticle of the compound of the present invention exhibits excellent anti-tumor and other activities. Tests show that the toxicity of the liposome of the compound of the present invention is far less than that of the original drug.

In the present invention, two molecules of medicine are connected with two spacer arms as hydrophobic tails and phospholipid hydrophilic heads through covalent bonds to prepare immediate-release drug phospholipid compounds, and the hydrophilicity or lipophilicity is better than that of the original medicine.

The immediate-release drug phospholipid compound molecule of the present invention has a spacer arm containing disulfide bonds and other easily broken structures. The glutathione in the cells of the spacer arm is quickly broken by the action of the glutathione, etc., and one molecule of the immediate-release drug phospholipid compound quickly releases two molecules of the prototype drug, forming a high concentration, improving the anti-tumor efficacy of the drug, and reaching the prototype. More than 2 times that of the drug, and play the function of enhancing the anti-tumor effect.

The immediate-release drug phospholipid compound of the present invention is assembled alone or together with auxiliary agents to form a stable liposome, which overcomes the disadvantage that the drug is easy to leak when the general liposome encapsulates the drug, improves the efficiency of drug encapsulation and the stability of the drug, and at the same time The phospholipid compounds of immediate-release drugs such as anti-tumor drugs are easily absorbed into cells through liposomes to exert their drug effects.

In the present invention, the quick-release drug phospholipid compound is prepared into nanoparticles, which have the characteristics of liposomes, have targeting functions, and have the characteristics of being able to form liquid preparations, solid preparations, semi-solid preparations, sterilized preparations and aseptic preparations. For the treatment of tumors; the instant-release drug phospholipid compound and its liposome nanoparticles of the present invention are a brand-new prodrug and also a drug carrier, which improves the stability of the drug and exerts its drug effect through degradation by enzymes in the body. It can prolong the half-life of drug release and has lower toxic and side effects.

The preparation method of the immediate-release drug phospholipid compound liposome nanoparticle of the present invention is a mixture of the instant-release drug phospholipid compound of the present invention or the compound of the present invention and an auxiliary agent, through film dispersion, reverse phase evaporation, and freeze-drying. method, ultrasonic dispersion method, spray drying method, film extrusion method, or high pressure homogenization method.

The anti-tumor and other activities of the quick-release drug phospholipid compound of the present invention are better than the original drug; the anti-tumor activities of the quick-release drug phospholipid compound liposome of the present invention are better than the original drug.

The following are part of the reagent codes used in the preparation process:

DMAP4-dimethylaminopyridine

CDIN, N′-carbonyldiimidazole

GPC Phosphorylcholine Glycerol

DBU1,5-diazabicyclo[5.4.0]undec-5-ene

EDC1-ethyl-(3-dimethylaminopropyl)carbodiimide

NHSN-Hydroxysuccinimide

TFA trifluoroacetic acid

DMF Dimethylformamide

DMSO Dimethyl Sulfoxide

Bu ₄ NF tetrabutylammonium fluoride

(BOC) ₂ O di-tert-butyl dicarbonate

BOC tert-butoxycarbonyl

TEA triethylamine

Folic acid folic acid

GFLG Glycyl-Phenylalanyl-Leucyl-Glycine

Triphosgene

Lipophilic characterization and lipophilic parameter measurement methods of drugs: phospholipid membrane chromatography (Acta Pharmaceutica Sinica, 2003, 38 (10), 791-794; Acta Pharmaceutica Sinica, 2003, 38 (6), 475-480; JOURNALOFPHARMACEUTICALSCIENCES, 2008, 97(8):2984-3004).

Instrument: Aglient1100 high-performance liquid chromatography system (using IAMPC.MG phospholipid membrane column: 12 μm, 4.6mm×150mm, American RegisChem Company).

The determination of the capacity factor of phospholipid membrane chromatography uses pH 7.4, 0.01mol/L phosphate buffer as the mobile phase to elute drugs from the chromatographic column. For strong lipophilic compounds that cannot be eluted from the chromatographic column without adding an organic modifier, acetonitrile is added to the mobile phase to enhance its elution ability, and the percentage of acetonitrile in the mobile phase In (0~30)%. The column temperature was 35°C; the flow rate was 1.0 mL/min; the ultraviolet detection wavelength of all compounds was 215 nm; the concentration of the tested drug was 200 μmol/L, and the injection volume was 15 μL. The retention capacity of the drug on the column is expressed by the logarithm value of its capacity factor (lgk' _IAM ):

lgk' _IAM = lg(T _R -T ₀ )/T ₀

In the formula, T _R is the retention time of the drug on the chromatographic column, and T ₀ is the dead time. The capacity factor (k'IAM) of the drug under different mobile phases was normalized to The capacity factor (k _IAM ) when is zero, which represents the phospholipid membrane affinity parameter of the drug in the phospholipid membrane chromatography system. The retention capacity of the drug on the column is expressed by the logarithm of its capacity factor lgk _IAM to represent the distribution coefficient of the drug on the phospholipid membrane chromatography, that is, to represent the lipophilicity parameter of the drug. lgk _IAM is hereinafter referred to as the lipophilic parameter, and the larger the value, the better the lipophilicity.

Comparative example 1:

Synthesis of Bis(camptothecin-20-succinate)phosphatidylcholine

Camptothecin 1g, succinic anhydride 0.75g, DMAP 0.2g, triethylamine 0.2g, add chloroform as reaction solvent, reflux for 12h; wash with dilute hydrochloric acid three times, filter dilute hydrochloric acid layer, take filter cake; add methanol to dissolve , placed at 4°C for 12h, filtered, and the filter cake was taken, dried, and purified by column chromatography to obtain 0.75 g of the intermediate camptothecin-20-succinic acid monoester. Take 0.6 g of camptothecin-20 succinic acid monoester as an intermediate product, add 0.5 g of CDI, add 30 mL of DMSO as a reaction solvent, add 0.3 g of GPC and 0.5 g of DBU, and react at room temperature for 24 hours. The obtained reaction solution is purified by column chromatography to obtain the product Bis(camptothecin-20-succinate)phosphatidylcholine 0.32g. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1): 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. The lipophilic parameter lgk _IAM value of the product measured by phospholipid membrane chromatography was 1.79.

Comparative example 2:

Preparation of bis(camptothecin-20-succinate)phosphatidylcholine liposomes

Take 1 mmol of bis(camptothecin-20-succinic acid) phosphatidylcholine of Comparative Example 1, add 20 mL of chloroform, and evaporate the solvent at 60°C; Filtrate to obtain bis(camptothecin-20-succinic acid) phosphatidylcholine liposome nanoparticle solution. The average particle size of the liposomes analyzed by particle size analyzer was 210nm.

Comparative example 3:

Synthesis of Bis(gemcitabine-4-N-succinate)phosphatidylcholine

The gemcitabine derivative 3'-O-BOC-5'-O-BOC-gemcitabine protected by tert-butoxycarbonyl (BOC) was synthesized according to the method in the literature (J.Org.Chem.1999, 64, 8319-8322).

Dissolve 1 g of 3′-O-BOC-5′-O-BOC-gemcitabine in 100 mL of chloroform, add 0.6 g of triethylamine and 1 g of succinic anhydride, react at room temperature at 50°C for 12 h, and purify the resulting reaction solution by column chromatography. Obtain 0.82g of 3'-O-BOC-5'-O-BOC-gemcitabine-4-N-succinic acid; intermediate product 3'-O-BOC-5'-O-BOC-gemcitabine-4-N-succinic acid Dissolve 0.6g in 20mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.3g of GPC and 0.6g of DBU, react at room temperature for 24h, precipitate in glacial ether; the solid is dispersed in chloroform, add TFA dropwise at 0°C, rise to React at room temperature for 3 hours to remove the BOC protecting group, and the resulting reaction solution was purified by column chromatography to obtain the product bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine Base 0.46g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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. The lipophilic parameter lgk _IAM value was 1.43.

Example 1:

Synthesis of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine (see Figure 1 for the synthetic route)

Dissolve 1 g of camptothecin in 100 mL of chloroform, add 1.0 g of triethylamine, 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, and add dithio 0.6 g of diethylene glycol succinic acid monoester was reacted at room temperature for 24 hours, and the obtained reaction solution was purified by column chromatography to obtain 0.65 g of camptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester. Dissolve 0.6g of the intermediate camptothecin carbonate-dithiodiethylene glycol-succinic acid monoester in 20mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.3g of GPC and 0.6g of DBU, react at room temperature for 24h, and the obtained reaction The solution was purified by column chromatography to obtain 0.35 g of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

The lipophilic parameter lgk _IAM value of phospholipid membrane chromatography measurement product is 2.18, shows that its hydrophilicity is better than the camptothecin former medicine that lgk _IAM value is 4.85, lipophilicity is better than the bis(camptothecin whose lgk _IAM value is 1.83 -20-succinate) phosphatidylcholine.

Bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and freeze-dried to obtain bis( Camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine white solid powder.

Example 2:

Synthesis of bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine (see Figure 2 for the route)

Dissolve 1.0 g of paclitaxel in 30 mL of chloroform, add 0.5 mL of triethylamine, add 0.6 g of tert-butyldimethylsilyl chloride (TBDMSCl), react at 0°C for 3 h, add glacial ether, precipitate a white precipitate, and centrifuge. Further separation by column chromatography (eluent, chloroform/methanol: 7/1, v/v) obtained 0.82 g of paclitaxel 2'-blocked product 2'-tert-butyldimethylsilyloxy-paclitaxel, as White powdery solid.

Dissolve 0.5 g of 2'-tert-butyldimethylsilyloxy-paclitaxel in 50 mL of chloroform, add 0.5 g of triethylamine and 0.2 g of triphosgene, react at room temperature for 6 h, and remove the solvent by rotary evaporation; dissolve the solid in 10 mL of DMSO , add 0.3g of triethylamine, add 0.3g of dithiodiethylene glycol adipate monoester, react at room temperature for 24h, and the resulting reaction solution is purified by column chromatography to obtain 2'-tert-butyldimethylsilyloxy -Paclitaxel-7-carbonate-dithiodiethylene glycol-adipate monoester 0.36g; intermediate product 2'-tert-butyldimethylsilyloxy-taxol-7-carbonate-dithiodi Dissolve 0.3g of ethylene glycol-adipate monoester in 10mL of DMSO, add 0.3g of CDI, activate for 1h, add 0.1g of GPC and 0.3g of DBU, react at room temperature for 24h, and the resulting reaction solution is further treated with tetrabutylammonium fluoride, TBDMS was removed, precipitated with cold ether and purified by column chromatography to obtain 0.18 g of bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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.

The lipophilic parameter lgk _IAM value of the product measured by phospholipid membrane chromatography is 2.45, showing that its hydrophilicity is better than the original drug of paclitaxel whose lipophilic parameter lgk _IAM value is 4.26.

Bis(paclitaxel-7-carbonate-dithiodiethanol-adipate) phosphatidylcholine was dissolved in 0.1M potassium chloride aqueous solution, and freeze-dried to obtain a solid powder of phosphorylcholine compound containing potassium ions and chloride ions .

Example 3:

Synthesis of bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine (see Figure 3 for the synthetic route)

The gemcitabine derivative 3'-O-BOC-5'-O-BOC-gemcitabine protected by tert-butoxycarbonyl (BOC) was synthesized according to the method in the literature (J.Org.Chem.1999, 64, 8319-8322).

Dissolve 1 g of 3′-O-BOC-5′-O-BOC-gemcitabine in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, and remove the solvent by rotary evaporation; dissolve the solid in 10 mL of DMSO , add 0.3 g of triethylamine, add 0.6 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and purify the resulting reaction solution by column chromatography to obtain 3'-O-BOC-5'-O-BOC - Gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinic acid monoester 0.72g; intermediate 3'-O-BOC-5'-O-BOC-gemcitabine-4-N-amino Dissolve 0.6g of formate-dithiodiethylene glycol-succinic acid monoester in 20mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.3g of GPC and 0.6g of DBU, react at room temperature for 24h, and precipitate in ice ether; solid Disperse in chloroform, add TFA dropwise at 0°C, rise to room temperature and react for 3 hours to remove the BOC protecting group, and the resulting reaction solution is purified by column chromatography to obtain the product bis(gemcitabine-4-N-carbamate - dithiodiethylene glycol-succinate) phosphatidylcholine 0.35 g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

The lipophilic parameter lgk _IAM value of the product measured by phospholipid membrane chromatography is 1.96, showing that its lipophilicity is better than that of gemcitabine whose lipophilic parameter lgk _IAM value is 0.52, and its lipophilicity is also better than that of lipophilic parameter lgk _IAM value of 1.43 Bis(gemcitabine-4-N-succinoyl)phosphatidylcholine, showing enhanced hydrophobic-lipophilic interaction of the two spacer arms of the product.

Two (gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M sodium phosphate aqueous solution, and lyophilized to obtain sodium ion and phosphate ion containing Bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 4:

Synthesis of bis(topotecan-20-carbonate-dithiodiethylene glycol-diglycolate) phosphatidylcholine compound (see Figure 4 for the synthetic route)

Dissolve 0.6 g of 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) in 50 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, and remove the solvent by rotary evaporation Dissolve the solid in 10mLDMSO, add 0.3g of triethylamine, add 0.6g of dithiodiethylene glycol-diglycolic acid monoester, react at room temperature for 24h, and purify the resulting reaction solution by column chromatography to obtain topotecan-20 -carbonate-dithiodiethylene glycol-diglycolic acid monoester 0.48g; the intermediate product topotecan-20-carbonate-dithiodiethylene glycol-diglycolic acid monoester 0.4g was dissolved in In 20mLDMSO, add CDI0.4g, activate for 1h, add GPC0.15g and DBU0.4g, react at room temperature for 24h, precipitate in glacial ether, and purify by column chromatography to obtain the product bis(topotecan-20-carbonate-disulfide Diethylene glycol-diglycolate) phosphatidylcholine 0.26g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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. The lipophilic parameter lgk _IAM value was 2.10.

Example 5:

Synthesis of bis(doxorubicin-N-carbamate-dithiodiethylene glycol-succinate-GFLG) phosphatidylcholine (see Figure 5 for the route)

Dissolve 0.8g of doxorubicin hydrochloride in 30mL of chloroform, add triethylamine (0.5g, 4.5mmol) and 0.3g of TBDMSCl, react at room temperature for 3h, add glacial ether to precipitate, the precipitated white solid is analyzed by column chromatography 0.58 g of the hydroxyl-terminated product 14-O, 4'-O-bis(tert-butyldimethylsilyloxy)-doxorubicin was obtained by separation by the method.

Dissolve 0.5 g of 14-O, 4'-O-bis(tert-butyldimethylsiloxane)-doxorubicin in 10 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, and react at room temperature 6h, the solvent was removed by rotary evaporation; the solid was dissolved in 10mLDMSO, 0.3g of triethylamine was added, 0.6g of dithiodiethylene glycol-succinic acid monoester was added, and the reaction was carried out at room temperature for 24h. The obtained reaction solution was purified by column chromatography to obtain 14 -O, 4'-O-bis(tert-butyldimethylsiloxane)-doxorubicin-3'-carbamate-dithiodiethylene glycol-succinic acid monoester 0.46g; intermediate product 14-O, 4'-O-bis(tert-butyldimethylsilyloxy)-doxorubicin-3'-carbamate-dithiodiethylene glycol-succinic acid monoester 0.4g dissolved in In 20mLDMSO, add 0.5gEDC/0.5gNHS to activate, then add N-glycyl-phenylalanyl-leucyl-glycine (GFLG) 0.3g, react at room temperature for 24 hours, and the reaction solution is separated by column chromatography to obtain 14- O, 4'-O-bis(tert-butyldimethylsiloxane)-doxorubicin-3'-carbamate-dithiodiethylene glycol-succinyl-N-GFLG0.31g; above Dissolve the intermediate product in 10mL of DMSO, add 0.3g of CDI, activate for 1h, add 0.15g of GPC and 0.3g of DBU, react at room temperature for 24h, precipitate in cold ether; further dissolve the solid in DMF, add tetrabutylammonium fluoride, and Reaction for 6h, removal of TBDMS, precipitation by cold ether and purification by column chromatography to obtain the product bis(doxorubicin-N-carbamate-dithiodiethylene glycol-succinate-GFLG) phosphatidylcholine 0.16 g. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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 lipophilic parameter lgk _IAM value of the product is 2.35, shows that its lipophilicity is better than the doxorubicin hydrochloride original drug that the lipophilic parameter lgk _IAM value is 0.78, is also better _than the bis(A Mycin-N-dithioglycolic acid) phosphatidylcholine, showing enhanced hydrophobic-lipophilic interaction of the two hydrophobic spacer arms of the product.

Embodiment 6:

sn1-camptothecin-20-carbonate-dithiodiethylene glycol-succinate-sn2-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate-glycerophosphatidylcholine The synthesis (route is shown in Figure 6)

Camptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester 0.3g synthesized according to the method of Example 1 was dissolved in 20mLDMSO, CDI0.3g was added, activated for 1h, GPC0.1g and DBU0. 3 g, reacted at room temperature for 24 hours, and the resulting reaction solution was purified by column chromatography to obtain 0.18 g of the intermediate product sn1-camptothecin-20-carbonate-dithiodiethylene glycol-succinylglycerophosphatidylcholine.

0.15 g of 2'-tert-butyldimethylsilyloxy-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate monoester synthesized according to the method in Example 2 was dissolved in 10 mL of DMSO, and CDI0. 3g, activated for 1h, adding the intermediate product sn1-camptothecin-20-carbonate-dithiodiethylene glycol-succinylglycerophosphatidylcholine 0.15g, DBU0.3g, reacting at room temperature for 24h, the resulting reaction solution was further used Tetrabutylammonium fluoride treatment, removal of tert-butyldimethylsilyloxy TBDMS, cold ether precipitation and purification by column chromatography to obtain the product sn1-camptothecin-20-carbonate-dithiodiethylenedi Alcohol-succinate-sn2-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate-glycerophosphatidylcholine 0.09g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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. The lipophilic parameter lgk _IAM value was 2.35.

Embodiment 7:

Synthesis of bis(docetaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine (see Figure 7 for the route)

Dissolve 1.0g of docetaxel in 30mL of chloroform, add 1mL of triethylamine, add 1.0g of tert-butyldimethylsilyl chloride (TBDMSCl), react at 0°C for 3h, add glacial ether, precipitate a white precipitate, and centrifuge , and further separated by column chromatography to obtain 0.75 g of 2'-tert-butyldimethylsilyloxy-docetaxel, a white powdery solid, of the 2'-position-capped product of paclitaxel.

Dissolve 0.5 g of 2'-tert-butyldimethylsilyloxy-docetaxel in 50 mL of chloroform, add 0.5 g of triethylamine and 0.2 g of triphosgene, react at room temperature for 6 h, and remove the solvent by rotary evaporation; In 10mL of DMSO, add 0.3g of triethylamine, add 0.3g of dithiodiethylene glycol adipate monoester, and react at room temperature for 24h. The resulting reaction solution is purified by column chromatography to obtain 2'-tert-butyldimethylsilyl Oxy-docetaxel-7-carbonate-dithiodiethylene glycol-adipate monoester 0.36g; intermediate product 2'-tert-butyldimethylsilyloxy-docetaxel-7-carbonic acid Dissolve 0.3g of ester-dithiodiethylene glycol-adipate monoester in 10mL of DMSO, add 0.3g of CDI, activate for 1h, add 0.15g of GPC and 0.3g of DBU, react at room temperature for 24h, and the obtained reaction solution is further treated with tetrabutyl treated with ammonium fluoride, removed TBDMS, and purified by column chromatography after cold ether precipitation to obtain the product bis(docetaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine 0.18g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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. The lgk _IAM value is 2.62.

Bis(docetaxel-7-carbonate-dithiodiethanol-adipate)phosphatidylcholine was dissolved in 0.1M sodium sulfate aqueous solution, and lyophilized to obtain phosphorylcholine containing sodium ions and sulfate ions Compound solid powder.

Embodiment 8:

Synthesis of bis(7-ethyl-hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine (see Figure 8 for the synthetic route)

Dissolve 1g of 7-ethyl-10-hydroxycamptothecin in 100mL of chloroform, add 0.6g of triethylamine and 0.3g of triphosgene, react at room temperature for 6h, and remove the solvent by rotary evaporation; dissolve the solid in 10mL of DMSO, add triethylamine Add 0.3 g of amine, add 0.6 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and the resulting reaction solution is purified by column chromatography to obtain 7-ethyl-hydroxycamptothecin-10-carbonate-disulfide Diethylene glycol-succinic acid monoester 0.75g; intermediate product 7-ethyl-hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinic acid monoester 0.6g was dissolved in 20mLDMSO, added CDI0.6g, activated for 1h, added GPC0.3g and DBU0.6g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain the product bis(7-ethyl-hydroxycamptothecin-10-carbonate-disulfide Diethylene glycol-succinate) phosphatidylcholine 0.35g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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. The lgk _IAM value is 1.94.

Bis(7-ethyl-hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution and freeze-dried to obtain Bis(7-ethyl-hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder with chloride ion.

Embodiment 9:

Synthesis of bis(podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 9 for the synthetic route)

Dissolve 1 g of podophyllotoxin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, and add dithio 0.6 g of diethylene glycol succinic acid monoester was reacted at room temperature for 24 hours, and the resulting reaction solution was purified by column chromatography to obtain 0.72 g of podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinic acid monoester; Dissolve 0.6g of the product podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinic acid monoester in 30mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.3g of GPC and 0.6g of DBU, react at room temperature for 24h, The resulting reaction solution was purified by column chromatography to obtain 0.43 g of bis(podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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. The lipophilic parameter lgk _IAM value was 2.30.

Bis(podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and lyophilized to obtain bis( Podophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine white solid powder.

Example 10:

Synthesis of bis(camptothecin-9-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 10 for the synthetic route)

Dissolve 1 g of 9-aminocamptothecin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, and add Dithiodiethylene glycol succinic acid monoester 0.6g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain camptothecin-9-carbamate-dithiodiethylene glycol-succinic acid monoester Ester 0.62g; intermediate camptothecin-9-carbamate-dithiodiethylene glycol-succinic acid monoester 0.6g was dissolved in 20mLDMSO, added CDI0.6g, activated for 1h, added GPC0.3g and DBU0 .6g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain 0.41g of the product bis(camptothecin-9-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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. The lgk _IAM value is 1.94.

Bis(camptothecin-9-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and freeze-dried to obtain sodium ion and chloride ion containing Bis(camptothecin-9-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 11:

Synthesis of bis(camptothecin-7-methylene-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 11 for the synthetic route)

Dissolve 1 g of 7-hydroxymethyl camptothecin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at 0°C for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine g, add 0.6g of dithiodiethylene glycol succinate monoester, react at room temperature for 24h, and the resulting reaction solution is purified by column chromatography to obtain camptothecin-7-methylene-carbonate-dithiodiethylene Alcohol-succinic acid monoester 0.81g; intermediate product camptothecin-7-methylene-carbonate-dithiodiethylene glycol-succinic acid monoester 0.6g was dissolved in 20mL DMSO, added CDI0.6g, activated for 1h , add GPC0.3g and DBU0.6g, react at room temperature for 24h, and the resulting reaction solution is purified by column chromatography to obtain the product bis(camptothecin-7-methylene-carbonic acid ester-dithiodiethylene glycol-succinic acid ester) phosphatidylcholine 0.43g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(camptothecin-7-methylene-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution and lyophilized to obtain Ionic bis(camptothecin-7-methylene-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 12:

Synthesis of bis(cabazitaxel-2'-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine (see Figure 12 for the route)

Dissolve 1.0 g of cabazitaxel (7β, 10β-dimethoxydocetaxel) in 50 mL of chloroform, add 0.6 g of triethylamine and 0.2 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, and dissolve the solid In 10mL of DMSO, add 0.3g of triethylamine, add 0.3g of dithiodiethylene glycol adipate monoester, react at room temperature for 24h, and the resulting reaction solution is purified by column chromatography to obtain cabazitaxel-2'-carbonate- Dithiodiethylene glycol-adipate monoester 0.72g; intermediate product cabazitaxel-2'-carbonate-dithiodiethylene glycol-adipate monoester 0.5g was dissolved in 10mLDMSO, and added CDI. .5g, activated for 1h, added GPC0.25g and DBU0.5g, reacted at room temperature for 24h, the resulting reaction solution was further treated with tetrabutylammonium fluoride, removed TBDMS, purified by column chromatography after cold ether precipitation, and obtained the product bis( Cabazitaxel-2'-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine 0.38g. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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.

Bis(cabazitaxel-2'-carbonate-dithiodiglycolic acid-adipate) phosphatidylcholine was dissolved in 0.1M sodium chloride aqueous solution and lyophilized to obtain phosphocholine containing sodium ions and chloride ions Alkali compound solid powder.

Example 13:

Synthesis of bis(hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 13 for the synthetic route)

Dissolve 1 g of hydroxycamptothecin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, and add disulfide Diethylene glycol succinic acid monoester 0.6g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinic acid monoester 0.75g ; The intermediate product hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinic acid monoester 0.7g was dissolved in 20mLDMSO, added CDI0.6g, activated for 1h, added GPC0.3g and DBU0.7g, at room temperature After reacting for 24 hours, the resulting reaction solution was purified by column chromatography to obtain 0.43 g of bis(hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and freeze-dried to obtain bis (Hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 14:

Synthesis of bis(irinotecan-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 14 for the synthetic route)

Dissolve 1 g of irinotecan (CPT11, bipipercamptothecin) in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add triphosgene Add 0.3 g of ethylamine, add 0.6 g of dithiodiethylene glycol succinate monoester, react at room temperature for 24 hours, and purify the resulting reaction solution by column chromatography to obtain irinotecan-20-carbonate-dithiodiethylene glycol - 0.85g of succinic acid monoester; the intermediate product irinotecan-20-carbonate-dithiodiethylene glycol-succinic acid monoester 0.8g was dissolved in 20mL DMSO, added CDI0.8g, activated for 1h, added GPC0.4g React with DBU0.8g at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain 0.62g of the product bis(irinotecan-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine.

¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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.

Bis(irinotecan-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and freeze-dried to obtain bis( Irinotecan-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine white solid powder.

Example 15:

Synthesis of bis(hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 15 for the synthetic route)

Dissolve 0.5 g of Lurtotecan in 100 mL of chloroform, add 0.4 g of triethylamine and 0.2 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.4 g of triethylamine g, add 0.2 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and the resulting reaction solution is purified by column chromatography to obtain hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol- Succinic acid monoester 0.35g; intermediate product hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester 0.3g was dissolved in 20mL DMSO, added CDI0.3g, activated for 1h, added GPC0. 15g and DBU0.3g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain the product bis(hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine 0.16g. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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.

Bis(hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and freeze-dried to obtain sodium ion and chloride ion containing Bis(hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 16:

Synthesis of bis(difluorocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 16 for the synthetic route)

Dissolve 1 g of difluorocamptothecin (BN80915) in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine , add 0.6 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and the resulting reaction solution is purified by column chromatography to obtain hexacyclic camptothecin-20-carbonate-dithiodiethylene glycol-succinate Acid monoester 0.71g; intermediate product difluorocamptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester 0.6g was dissolved in 20mL DMSO, added CDI0.6g, activated for 1h, added GPC0.3g and DBU0.6g, reacted at room temperature for 12h, and the resulting reaction solution was purified by column chromatography to obtain the product bis(difluorocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine 0.46 g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(difluorocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M sodium chloride aqueous solution, and freeze-dried to obtain sodium ion and chloride ion containing Bis(difluorocamptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 17:

Synthesis of bis(Belotecan-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 17 for the synthetic route)

Dissolve 1g of camptothecin derivative Belotecan in 100mL of chloroform, add 0.6g of triethylamine and 0.3g of triphosgene, react at room temperature for 12h, remove the solvent by rotary evaporation, dissolve the solid in 10mL of DMSO, add 0.3g of triethylamine, add di Thiodiethylene glycol succinic acid monoester 0.6g, react at room temperature for 24h, the resulting reaction solution was purified by column chromatography to obtain Belotecan-20-carbonate-dithiodiethylene glycol-succinic acid monoester 0.75g; intermediate Dissolve 0.6g of the product Belotecan-20-carbonate-dithiodiethylene glycol-succinic acid monoester in 20mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.25g of GPC and 0.6g of DBU, react at room temperature for 12h, and the obtained reaction The solution was purified by column chromatography to obtain 0.46 g of bis(Belotecan-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(Belotecan-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution and lyophilized to obtain bis(Belotecan- 20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine white solid powder.

Example 18:

Synthesis of bis(DX-8591f-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 18 for the synthetic route)

Dissolve 0.5 g of camptothecin derivative DX-8591f in 100 mL of chloroform, add 0.4 g of triethylamine and 0.2 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.4 g of triethylamine g, add 0.3 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and the resulting reaction solution is purified by column chromatography to obtain DX-8591f-N-carbamate-dithiodiethylene glycol- Succinic acid monoester 0.32g; intermediate product DX-8591f-N-carbamate-dithiodiethylene glycol-succinic acid monoester 0.3g was dissolved in 10mL DMSO, added CDI0.3g, activated for 1h, added GPC0. 15g and DBU0.3g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain the product bis(DX-8591f-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine 0.14g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(DX-8591f-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution and lyophilized to obtain sodium ion and chloride ion containing Bis(DX-8591f-N-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 19:

Synthesis of bis(9-nitrocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 19 for the synthetic route)

Dissolve 1 g of 9-nitrocamptothecin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, Add 0.6 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and the resulting reaction solution is purified by column chromatography to obtain 9-nitrocamptothecin-20-carbonate-dithiodiethylene glycol- Succinic acid monoester 0.72g; intermediate product 9-nitrocamptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester 0.5g was dissolved in 20mL DMSO, added CDI0.6g, activated for 1h, added GPC0.25g and DBU0.6g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain the product bis(9-nitrocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) Phosphatidylcholine 0.33g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(9-nitrocamptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M sodium chloride aqueous solution and lyophilized to obtain Ionic bis(hydroxycamptothecin-10-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 20:

Synthesis of bis(4'-desmethyl epipodophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 20 for the synthetic route)

Dissolve 1 g of 4'-desmethyl epipodophyllotoxin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add triethylamine 0.3g, add 0.6g of dithiodiethylene glycol succinate monoester, react at room temperature for 24h, the resulting reaction solution is purified by column chromatography to obtain 4'-desmethyl epipodophyllotoxin-4-carbonate-disulfide Diethylene glycol-succinic acid monoester 0.76g; intermediate product 4'-desmethyl epipodophyllotoxin-4-carbonate-dithiodiethylene glycol-succinic acid monoester 0.6g was dissolved in 20mLDMSO, Add 0.6g of CDI, activate for 1h, add 0.3g of GPC and 0.6g of DBU, react at room temperature for 24h, the resulting reaction solution is purified by column chromatography, and the product bis(4'-desmethyl epipodophyllotoxin-4-carbonate- Dithiodiethylene glycol-succinate) phosphatidylcholine 0.35g. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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.

Bis(4'-desmethylepipodophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution and lyophilized to obtain sodium-containing Bis(4'-desmethylepipodophyllotoxin-4-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine white solid powder with ions and chlorides.

Example 21:

Synthesis of bis(5′-deoxy-5-fluorocytidine-4-carbamate-dithiodiethylenediamine-succinyl) phosphatidylcholine compound (see Figure 21 for the synthetic route)

Dissolve 1 g of 5′-deoxy-5-fluorocytidine in 100 mL of anhydrous N,N-dimethylformamide, add 2 g of triethylamine, add 1 g of tert-butyldimethylsilyl chloride at 0°C, and stir at 0°C React for 1 hour, then rise to room temperature and react for 6 hours, add 50 mL of water, wash the organic phase with 10% dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution successively, dry over anhydrous magnesium sulfate, filter, and distill under reduced pressure with an oil pump . 0.83 g of 2',3'-O-bis-TBDMS-5'-deoxy-5-fluorocytidine was obtained by column chromatography; 0.8 g of 2',3'-O-bis-TBDMS-5'-deoxy-5-fluorocytidine Disperse in 100mL of chloroform, add 0.6g of triethylamine, 0.3g of triphosgene, react at room temperature for 6h, remove the solvent by rotary evaporation, dissolve the solid in 10mL of DMSO, add 0.3g of triethylamine, add succinyldithiodiethyl Diamine 0.6g, reacted at room temperature for 24h, the resulting reaction solution was purified by column chromatography to obtain 2',3'-O-diTBDMS-5'-deoxy-5-fluorocytidine-4-carbamate-disulfide Diethylenediamine-succinic acid 0.52g; intermediate product 2′,3′-O-diTBDMS-5′-deoxy-5-fluorocytidine-4-carbamate-dithiodiethylenediamine- Dissolve 0.5 g of succinic acid in 20 mL of DMSO, add 0.5 g of CDI, activate for 1 h, add 0.25 g of GPC and 0.5 g of DBU, and react at room temperature for 24 h. The resulting reaction solution is purified by column chromatography, and further treated with tetra-n-butylammonium fluoride Hours, the TBDMS protecting group was removed, and the reaction solution was separated by column chromatography to obtain the product bis(5'-deoxy-5-fluorocytidine-4-carbamate-dithiodiethylenediamine-succinyl)phosphatidyl Choline 0.37g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Example 22:

Synthesis of bis(camptothecin-20-carbamate-dithiodiethylamine-succinyl)phosphatidylcholine compound (see Figure 22 for the synthetic route)

Dissolve 1 g of camptothecin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 50 mL of DMSO, add 0.3 g of triethylamine, and add dithio Diethylamine succinic acid 0.6g, reaction at room temperature for 24h, the resulting reaction solution was purified by column chromatography to obtain camptothecin-20-carbamate-dithiodiethylamine-succinic acid 0.58g; intermediate product camptothecin Dissolve 0.5g of -20-carbamate-dithiodiethylamine-succinic acid in 20mL of DMSO, add 0.6g of CDI, activate for 1h, add 0.2g of GPC and 0.6g of DBU, react at room temperature for 24h, and the resulting reaction solution passes through the column Purified by chromatography to obtain 0.24 g of the product bis(camptothecin-20-carbamate-dithiodiethylamine-succinyl)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(camptothecin-20-carbamate-dithiodiethylamine-succinyl)phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution, and freeze-dried to obtain bis( Camptothecin-20-carbamate-dithiodiethylamine-succinyl)phosphatidylcholine white solid powder.

Example 23:

Synthesis of all-trans retinoic acid phospholipid compound (see Figure 23 for the route)

Dissolve 0.6g (2mmol) of all-trans retinoic acid in 30mL of refined toluene, add 0.34mL (4mmol) of oxalyl chloride, and stir at room temperature for 3 hours under the condition of avoiding light and moisture; evaporate the excess oxalyl chloride under reduced pressure, Obtain a dark red oil, dissolve the dark red oil in 5 mL of refined dichloromethane, add 0.3 g of triethylamine, 0.4 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and the resulting reaction solution passes through the column Purified by chromatography to obtain all-trans retinoic acid-dithiodiethylene glycol-succinic acid monoester 0.32g; the intermediate product all-trans retinoic acid-dithiodiethylene glycol-succinic acid monoester 0.3g was dissolved in In 20mLDMSO, add CDI0.3g, activate for 1h, add GPC0.1g and DBU0.3g, react at room temperature for 12h, and the resulting reaction solution is purified by column chromatography to obtain the product bis(all-trans retinoic acid-dithiodiethylene glycol - succinate) phosphatidylcholine 0.35 g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Example 24:

Synthesis of bis(homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 24 for the synthetic route)

Dissolve 0.5g of homoharringtonine in 100mL of chloroform, add 0.6g of triethylamine and 0.3g of triphosgene, react at room temperature for 6h, remove the solvent by rotary evaporation, dissolve the solid in 50mL of DMSO, add 0.3g of triethylamine, add 0.4 g of dithiodiethylene glycol succinic acid monoester, reacted at room temperature for 24 hours, and the resulting reaction solution was purified by column chromatography to obtain homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinic acid Monoester 0.32g. Dissolve 0.3g of the intermediate product homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinic acid monoester in 20mL of DMSO, add 0.3g of CDI, activate for 1h, add 0.15g of GPC and 0.3g of DBU, After reacting at room temperature for 24 hours, the resulting reaction solution was purified by column chromatography to obtain 0.18 g of the product bis(homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Bis(homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine was dissolved in 0.01M aqueous sodium chloride solution and lyophilized to obtain Bis(homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 25:

Synthesis of bis(tyroserleutide-dithiodiethylenediamine-succinyl) phosphatidylcholine compound (see Figure 25 for the route)

Dissolve 0.4g of N-Boc-O-TBDMS-tyroserleutide in 50mL of DMSO, add 0.6g of triethylamine and 0.3g of triphosgene, react at room temperature for 6h, remove the solvent by rotary evaporation, dissolve the solid in 10mL of DMSO, add triethylamine 0.3g, 0.3g of succinyldithiodiethylamine, reacted at room temperature for 12h, and the resulting reaction solution was purified by column chromatography to obtain N-Boc-O-TBDMS-tyroserleutide-dithiodiethylenediamine-succinate Acid 0.16g. The intermediate product N-Boc-O-TBDMS-tyroserleutide-dithiodiethylenediamine-succinic acid 0.15g was dissolved in 20mL DMSO, added CDI0.2g, activated for 1h, added GPC0.1g and DBU0.2g, at room temperature After reacting for 24 hours, the resulting reaction solution was purified by column chromatography to obtain 0.09 g of bis(N-Boc-O-TBDMS-tyroserleutin-dithiodiethylenediamine-succinyl) phosphatidylcholine; the solid was dispersed in Add trifluoroacetic acid (TFA) dropwise to 10 mL tetrahydrofuran, react at room temperature for 6 hours, remove the BOC protecting group, precipitate the reaction solution in cold ether, dissolve the solid in DMF, add tetrabutylammonium fluoride, and react at room temperature for 6 hours , The TBDMS protecting group was removed, and the reaction solution was purified by column chromatography to obtain 0.04 g of the product bis(tyroserleutide-dithiodiethylenediamine-succinyl)phosphatidylcholine. ¹ HNMR (500MHz, CD3OD: CDCl ₃ 1:1) 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.

Example 26:

Synthesis of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylethanolamine-N-polyethylene glycol compound (see Figure 26 for the synthetic route)

Dissolve 1 g of camptothecin in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 50 mL of DMSO, add 0.3 g of triethylamine, and add dithio 0.6 g of diethylene glycol succinic acid monoester was reacted at room temperature for 24 hours, and the resulting reaction liquid was purified by column chromatography to obtain 0.72 g of camptothecin carbonate-dithiodiethylene glycol-succinic acid monoester. Dissolve 0.6g of camptothecin-20-carbonate-dithiodiethylene glycol-succinic acid monoester in 30mL DMSO as the reaction solvent, add 0.5g of CDI, react at room temperature for 2h, add 3-(4-methoxybenzyloxy base) propane-1,2-diol 0.4g, DBU0.5g, react at room temperature for 8h, and evaporate to dryness; add 10mL dimethylformamide as solvent, hydrogenate under palladium/carbon catalysis, and the product is separated by column chromatography 0.52 g of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)glycerol was obtained.

Dissolve 0.5g of the above product in chloroform, add 0.5g of phosphorus oxychloride, 0.5g of triethylamine, react at 10°C for 24h, spin dry the solvent, add 0.4g of N-tert-butoxycarbonyl-aminoethanol, triethylamine 0.3g, add 10mL chloroform, react at 10°C for 24h, and dry the solvent by rotary evaporation; dissolve the solid in isopropanol, add trifluoroacetic acid aqueous solution dropwise, and heat for 6h to remove the tert-butoxycarbonyl protecting group, and the reaction solution is passed through Separation and purification by column chromatography yielded 0.31 g of the product bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine.

Hydroxyl-terminated polyoxyethylene methyl ether (molecular weight 2000, mPEG) 0.5g and CDI0.2g were dissolved in 25mL chloroform, reacted at room temperature for 2h, then added bis(camptothecin-20-carbonate-dithiodi Ethylene glycol-succinate) phosphatidylethanolamine 0.20g, DBU0.2g, heat reaction 24h, reaction solution is purified by column chromatography, obtains product bis(camptothecin-20-carbonate-dithiodiethylene glycol - succinate) phosphatidylethanolamine N-polyethylene glycol 0.14 g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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).

Bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine-N-polyethylene glycol compound was dissolved in 0.01M aqueous sodium hydroxide solution and lyophilized to obtain sodium-containing Ionic bis(homoharringtonine-6'-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine white solid powder.

Example 27:

Synthesis of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylethanolamine-N-polyethylene glycol-N-folate compound (see Figure 27 for the synthetic route)

0.5 g of N-BOC-aminopolyoxyethylene (average molecular weight 2000) activated by CDI at the terminal hydroxyl group was dissolved in 20 mL of DMSO, DBU 0.2 g was added, and the bis(camptothecin-20-carbonate-dithio Diethylene glycol-succinate) phosphatidylethanolamine 0.10g, reacted at room temperature for 3 hours, treated with TFA after separation by column chromatography to remove the amino end group protecting group BOC, and carried out column chromatography purification treatment to obtain the end group as amino bis(hi Resin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine-polyoxyethylene 0.07g. Add the above product into 10mLDMSO, add EDC0.3 and NHS0.3g, add folic acid 0.3g, react at room temperature for 24 hours, and the reaction solution is subjected to column chromatography to obtain the product bis(camptothecin-20-carbonate-dithiobis Ethylene glycol-succinate) phosphatidylethanolamine N-polyoxyethylene-N-folate 0.04g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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).

Example 28:

Synthesis of bis(chidamide-2'-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine compound (see Figure 28 for the synthetic route)

Disperse 1 g of chidamide in 100 mL of chloroform, add 0.6 g of triethylamine and 0.3 g of triphosgene, react at room temperature for 6 h, remove the solvent by rotary evaporation, dissolve the solid in 10 mL of DMSO, add 0.3 g of triethylamine, and add disulfide Diethylene glycol succinic acid monoester 0.6g, reacted at room temperature for 24h, and the resulting reaction solution was purified by column chromatography to obtain chidamide-2'-carbamate-dithiodiethylene glycol-succinic acid monoester Ester 0.62g; intermediate product chidamide-2'-carbamate-dithiodiethylene glycol-succinic acid monoester 0.6g was dissolved in 20mL DMSO, added CDI0.5g, activated for 1h, added GPC0.25g and DBU0.5g, reacted at room temperature for 24h, the resulting reaction solution was purified by column chromatography, and the reaction solution was separated by column chromatography to obtain the product bis(chidamide-2'-carbamate-dithiodiethylene glycol- Succinate) phosphatidylcholine 0.37g. ¹ HNMR (500MHz, CD3OD: _CDCl3 1:1) 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.

Example 29:

Synthesis of bis(bexarotene-GFLG-butyryl) phosphorylcholine compound (see Figure 29 for the synthetic route)

Dissolve 0.6g of bexarotene in 30mL of DMF, add 0.5gEDC/0.5gNHS to activate, then add 0.8g of N-glycyl-phenylalanyl-leucyl-glycine (GFLG), react at room temperature for 24 hours, and the reaction solution It was separated by column chromatography to obtain 0.35 g of bexarotene-glycyl-phenylalanyl-leucyl-glycine. The product was dissolved in 20 mL of dimethyl sulfoxide, activated by adding 0.3 g of CDI for 1 h, added 0.15 g of 4-hydroxybutyric acid and 0.3 g of DBU, and reacted at room temperature for 24 h. The precipitate was precipitated in cold ether, and separated by column chromatography to obtain bexarotene- Glycyl-phenylalanyl-leucyl-glycine ester-butyric acid 0.21g. The above intermediate product was dissolved in 15 mL of dimethyl sulfoxide, added CDI0.3g, activated for 1h, added GPC0.10g and DBU0.3g, reacted at room temperature for 24h, precipitated in cold ether, separated by column chromatography to obtain bis(bexarotene -GFLG-butyryl) phosphorylcholine 0.12g. ¹ HNMR (500MHz, CD ₃ OD:CDCl ₃ 1:1): 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.

Example 30:

Synthesis of bis(bexarotene-ethylene glycol succinic acid-ethylene glycol succinic acid) phosphorylcholine compound (see Figure 30 for the synthetic route)

Dissolve 0.6 g of bexarotene in 30 mL of DMF, add 0.6 g of CDI to activate for 1 h, add 0.6 g of diethylene glycol succinate and 0.6 g of DBU, react at room temperature for 24 h, precipitate in cold ether, and separate by column chromatography to obtain Bexarotene Rotin-ethylene glycol ester-succinic acid-ethylene glycol monoester 0.42g. The product was dissolved in 15 mL of DMF, added with 0.3 mL of TEA, reacted at room temperature for 24 hours, precipitated in cold ether, and separated by column chromatography to obtain 0.26 g of bexarotene-ethylene glycol ester-succinic acid-ethylene glycol ester-succinic acid. The above intermediate product was dissolved in 30mL of DMF, activated by adding 0.3g of CDI for 1h, adding 0.15g of GPC and 0.3g of DBU, and reacted at room temperature for 24h, and precipitated in cold ether, separated by column chromatography to obtain bis(bexarotene-ethylene glycol succinate) Acid-ethylene glycol succinate) phosphorylcholine 0.15g. ¹ HNMR (500MHz, CD ₃ OD:CDCl ₃ 1:1): 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.

Example 31:

Synthesis of bis(bexarotene-ethylenediaminesuccinic acid-ethylenediaminesuccinic acid) phosphorylcholine compound (see Figure 31 for the route)

Dissolve 0.5 g of bexarotene in 30 mL of DMF, add 0.5 g of EDC/0.5 g of NHS to activate, then add 0.6 g of ethylenediamine succinate, react at room temperature for 24 hours, and separate the reaction solution by column chromatography to obtain bexarotene-ethylenediamine - 0.36 g of succinic acid. Dissolve 0.36 g of the above product in 20 mL DMF, add 0.5 g EDC/0.5 g NHS to activate, then add 0.4 g ethylenediamine succinate, react at room temperature for 24 hours, and separate the reaction solution by column chromatography to obtain bexarotene-ethylenediamine-succinate Acid - ethylenediamine - succinic acid 0.25g. 0.25 g of the above intermediate product was dissolved in 15 mL of dimethyl sulfoxide, added with 0.3 g of CDI, activated for 1 h, added with 0.10 g of GPC and 0.3 g of DBU, reacted at room temperature for 24 h, precipitated in cold ether, and separated by column chromatography to obtain bis(Besar Rotine-ethylenediaminesuccinic acid-ethylenediaminesuccinic acid) phosphorylcholine 0.14g. ¹ HNMR (500MHz, CD ₃ OD:CDCl ₃ 1:1): 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.

Example 32:

Synthesis of immediate-release biscisplatin compound phosphatidylcholine (see Figure 32 for the synthetic route)

Dissolve 0.4g of cis-dichloro-diamine platinum compound A in 20mL of chloroform, add 0.3g of triethylamine and 0.3g of triphosgene, react at room temperature for 2h, remove the solvent by rotary evaporation, dissolve the solid in 50mL of DMSO, add triphosgene Add 0.3 g of ethylamine, add 0.3 g of dithiodiethylene glycol succinic acid monoester, react at room temperature for 24 hours, and purify the obtained reaction solution by column chromatography to obtain 0.23 g of intermediate product B. 0.23g of intermediate product B was dissolved in 15mL of DMSO, added CDI0.2g, activated for 1 hour, added GPC0.1g and DBU0.2g, reacted at room temperature for 24 hours, precipitated in cold ether, and separated by column chromatography to obtain compound C0.12g. Released biscisplatin compound phosphatidylcholine. [M+H] ⁺ m/z, 1673.24.

Example 33:

Synthesis of Bis(bortezomib-dihydrocaffeic acid-dithiodiethylene glycol ester-succinyl)phosphatidylcholine

Dissolve 1 g of 3-(3,4-dihydroxyphenyl) propionic acid (dihydrocaffeic acid) in 30 mL of DMSO, add 0.8 g of CDI, activate for 40 minutes, add 0.6 g of dithiodiethylene glycol succinic acid monoester, DBU0.8g was reacted at room temperature for 12h, and the product was separated by column chromatography to obtain 0.81g of 3-(3,4-dihydroxyphenyl)propionic acid-dithiodiethylene glycol ester-succinic acid monoester. The product was dissolved in 30mL DMSO, activated by adding CDI0.5g for 30 minutes, then added 0.3g glycerol phosphatidylcholine and DBU0.5g, and reacted at room temperature for 24h; precipitated in cold ether, washed with dilute hydrochloric acid, and the reaction solution was purified by column chromatography , to obtain the intermediate product bis(dihydrocaffeic acid-dithiodiethylene glycol ester-succinyl)phosphorylcholine 0.41g. This intermediate product is dissolved in DMSO and is prepared into a 0.2M solution, adding the same volume of bortezomib DMSO solution with a concentration of 0.2M, leaving it at room temperature for 1 hour, and then separating out in ether to obtain the product bis(bortezomib-dihydrocoffee Acid-dithiodiethylene glycol ester-succinyl)phosphatidylcholine 0.46g.

Example 34:

Preparation of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine liposomes

Take 1 mmol of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine of Example 1, add 20 mL of chloroform, and evaporate the solvent at 60 ° C; add 20 mL of PBS ( pH=7.4) Film was formed at 60°C and filtered with a 200nm filter to obtain a bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome nanoparticle solution. The particle size analysis results are shown in Figure 33, with an average particle size of 270nm. Cryo-TEM (200KvTecnaiG ² F20 field emission cryo-TEM, accelerating voltage 200 kV, magnification 29000 times, camera is FEIEagle4kX4k camera) to measure the morphology of liposome nanoparticles, as shown in Figure 34, showing clear multi-lamellar lipids body fine structure.

Example 35:

Preparation of bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate)phosphatidylcholine liposomes

1 mmol of bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine obtained in Example 2 was added to 20 mL of chloroform, and the solvent was evaporated to dryness at 60°C; 20 mL of PBS ( pH = 7.4) Form a film at 60°C, filter with a 200nm filter to obtain a bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine liposome nanoparticle solution. The particle size analysis results showed that the average particle size was 175nm. The bis(paclitaxel-7-carbonate-dithiodiethylene glycol-adipate) phosphatidylcholine liposome nanoparticle solution was lyophilized to obtain powdery nanoparticle.

Example 36:

Preparation of bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine liposomes

1 mmol of bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine obtained in Example 3 was added to 20 mL of chloroform, and the solvent was evaporated to dryness at 60°C; Add 20 mL of PBS (pH=7.4) to form a membrane at 60°C, and filter with a 200 nm filter to obtain bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes Nanoparticle solution. The particle size analysis results showed that the average particle size was 165nm.

Example 37:

Preparation of bis(doxorubicin-N-carbamate-dithiodiethylene glycol-succinate-GFLG) phosphatidylcholine liposomes

0.3 mmol of bis(doxorubicin-N-carbamate-dithiodiethylene glycol-succinate-GFLG) phosphatidylcholine obtained in Example 5 was added to 10 ml of chloroform, and rotary evaporation at 60°C Dry solvent; add 10ml PBS (pH=7.4) to form a film at 60°C to obtain bis(doxorubicin-N-carbamate-dithiodiethylene glycol-succinate-GFLG) phosphatidylcholine liposomes Nanoparticle solution. The particle size analysis results showed that the average particle size was 154nm.

Example 38:

Preparation of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine-N-polyethylene glycol-N-folate liposomes

0.3mmol of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylethanolamine-N-polyethylene glycol-N-folate compound obtained in Example 27, added trichloro Methane 10ml, 60°C rotary evaporated to dryness; Add 10ml PBS (pH=7.4) 60°C to form a film to obtain bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylethanolamine- N-polyethylene glycol-N-folate liposomal nanoparticle solution. The particle size analysis results showed that the average particle size was 240nm.

Example 39:

Preparation of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine liposome B

Get two (camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine 0.1mmol of embodiment 1, distearoylphosphatidylcholine DSPC0.4mmol, add trichloro 10ml of methane, 60°C rotary evaporation to dry the solvent; add 10ml of PBS (pH=7.4) at 60°C to form a film to obtain bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine Liposome B Nanoparticle Solution. Particle size analysis showed an average particle size of 180 nm.

Example 40:

Preparation of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine liposome C

Get two (camptothecin-20-carbonic acid ester-dithiodiethylene glycol-succinate) phosphatidylcholine 0.1mmol of embodiment 1, distearoylphosphatidylcholine DSPC0.3mmol, distearyl Acylphosphatidylethanolamine-polyethylene glycol DSPE-PEG-folic acid (polyethylene glycol molecular weight 2000) 0.1mmol, add 10ml of chloroform, evaporate the solvent at 60°C; add 10ml of PBS (pH7.4) at 60°C to form a film, A bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome C nanoparticle solution was obtained. Particle size analysis showed that the average particle size was 620nm. Freeze-dry to obtain bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome C powder nanoparticles.

Example 41:

Sn1-camptothecin-20-carbonate-dithiodiethylene glycol-succinate-Sn2-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate-glycerophosphatidylcholine Preparation of liposomes

Sn1-camptothecin-20-carbonic acid ester-dithiodiethylene glycol-succinate-Sn2-paclitaxel-7-carbonic acid ester-dithiodiethylene glycol-adipate obtained by embodiment 6 -Glycerol phosphatidylcholine 0.5mmol, add 20mL of chloroform, and evaporate the solvent at 60°C; add 20mL of PBS (pH7.4) at 60°C to form a film, and filter with a 200nm filter to obtain Sn1-camptothecin-20-carbonate -Dithiodiethylene glycol-succinate-Sn2-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate-glycerol phosphatidylcholine liposome nanoparticle solution. The particle size analysis results showed that the average particle size was 192nm. Sn1-camptothecin-20-carbonate-dithiodiethylene glycol-succinate-Sn2-paclitaxel-7-carbonate-dithiodiethylene glycol-adipate-glycerophosphatidylcholine The alkaline liposome nanoparticle solution was freeze-dried to obtain powdery nanoparticles.

Example 42:

In vitro degradation test of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes

Sample: the two (camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine prepared in Example 1 is dissolved in an appropriate amount of PBS solution and is formulated with a concentration of 0.1mmol solution; implementation The 0.1mmol bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome nanoparticle 10mL PBS solution prepared in example 34; the 0.1mmol bis( Camptothecin-20-succinic acid) phosphatidylcholine liposome nanoparticles 10mL PBS solution.

The above samples were divided into 2 parts, one of which was added with glutathione (GSH) in PBS buffer 0.5mL (GSH concentration 50mmol), and the other was added with PBS buffer, placed in an incubator at 37°C and incubated with high-efficiency Detection of camptothecin content by liquid chromatography (Agilent1100LC, Zorbax reversed-phase C18 column, 150×4.6mm, 5μm, injection volume 20μL, column temperature 25℃, detection wavelength λ=254nm; gradient elution: 2-90% buffer B/A, flow rate 1.0 mL/min, buffer A: 0.1% TFA in deionized water, buffer B: 0.1% TFA in acetonitrile).

The results showed that: the PBS solution of GSH-treated bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine released the original drug of camptothecin after 0.5 hours reaching the total 95% of the amount, the former drug of camptothecin released after 1 hour reaches 100% of the total amount; the bis(camptothecin-20-carbonic acid ester-dithiodiethylene glycol-succinate) phospholipid of GSH The former drug of camptothecin released by acetylcholine liposome solution reached 75% of the total amount after 0.5 hour, and the former drug of camptothecin released after 1 hour reached 100% of the total amount; (Camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine liposome solution and bis(camptothecin-20-carbonate-dithiodiethylene glycol- Succinate) phosphatidylcholine PBS solution did not detect the original drug of camptothecin after 3 hours; GSH-treated bis(camptothecin-20-succinic acid) phosphatidylcholine liposome solution and GSH-treated The bis(camptothecin-20-succinic acid) phosphatidylcholine liposome solution did not detect the original drug of camptothecin after 3 hours.

Obviously, bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate)phosphatidylcholine liposomes, bis(camptothecin-20-carbonate-dithiodiethylene glycol Alcohol-succinate) phosphatidylcholine compounds have GSH sensitivity, under the action of GSH, the bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) The sulfur bond is broken, and the carbonyl group of the carbonate bond is attacked by the broken terminal sulfhydryl group, thereby rapidly releasing the original drug of camptothecin. And bis (camptothecin-20-succinic acid) phosphatidylcholine liposomes cannot be degraded by GSH, so it is difficult to release the former drug of camptothecin quickly.

Example 43:

In vitro degradation test of bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes

Sample: the bis (gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine prepared in Example 3 was dissolved in an appropriate amount of PBS solution to prepare a solution with a concentration of 0.1 mmol 0.1mmol two (gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome nanoparticles 10mL PBS solution prepared in embodiment 36; Prepared in comparative example 3 An appropriate amount of bis(gemcitabine-4-N-succinic acid) phosphatidylcholine was dissolved in 10 mL of PBS solution to obtain a solution with a concentration of 0.1 mmol.

The above samples were divided into 2 parts, one of which was added with glutathione (GSH) in PBS buffer 0.5mL (GSH concentration 50mmol), and the other was added with PBS buffer, placed in an incubator at 37°C and incubated with high-efficiency Gemcitabine content was detected by liquid chromatography (Agilent1100LC, Zorbax reversed-phase C18 column, 150×4.6mm, 5μm, injection volume 20μL, column temperature 25°C, detection wavelength λ=254nm; gradient elution: 2-90% buffer B/ A, flow rate 1.0 mL/min, buffer A: 0.1% TFA in deionized water, buffer B: 0.1% TFA in acetonitrile).

The results showed that: the PBS solution of GSH-treated bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine released the original drug of gemcitabine after 0.5 hours reaching the total 100% of the amount; GSH-treated bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome solution released gemcitabine after 0.5 hours The drug reaches 85% of the total amount, and after 1 hour, the original drug of gemcitabine is released to reach 100% of the total amount; the double (gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) without GSH treatment ester) phosphatidylcholine liposome solution and bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) phosphatidylcholine PBS solution did not detect gemcitabine after 3 hours Original drug;

The PBS solution of GSH-treated bis(gemcitabine-4-N-succinic acid)phosphatidylcholine and the PBS solution of bis(gemcitabine-4-N-succinic acid)phosphatidylcholine without GSH treatment were both The original gemcitabine was not detected.

Apparently, bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate)phosphatidylcholine liposomes, bis(gemcitabine-4-N-carbamate-dithio Diethylene glycol-succinate) phosphatidylcholine compound has GSH sensitivity, under the action of GSH, bis(gemcitabine-4-N-carbamate-dithiodiethylene glycol-succinate) The disulfide bond of phosphatidylcholine is broken, and the carbonyl group of the carbamate bond is attacked by the broken terminal sulfhydryl group, thereby rapidly releasing the original drug of gemcitabine. And double (gemcitabine-4-N-succinic acid) phosphatidylcholine cannot be degraded by GSH, it is difficult to release the original drug of gemcitabine.

Pharmacological experiment

Experimental example 44:

MTT Corporation Cancer Cell Killing Test: Antitumor Activity of Bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes

MCF-7 human breast cancer cells were inoculated in a 96-well culture plate at an inoculation amount of 8×10 ³ cells/well, and after culturing in a 5% CO ₂ , 37°C incubator for 24 hours, each well was added with different concentrations of the bismuth of Example 34. (camptothecin-20-carbonic acid ester-dithiodiethylene glycol-succinate) phosphatidylcholine liposome solution, two (camptothecin-20-succinic acid) phosphatidylcholine prepared in comparative example 2 Alkaline liposome solution, contrast camptothecin drug solution (camptothecin is dissolved in normal saline, solubilized with DMSO) each 100 μ L, make the drug final concentration of final screening be respectively 1, 2, 5, 10, 20 μ g/mL, After continuing to cultivate for 24 hours, add 50 μL MTT and incubate for 4 hours, discard the medium, add 150 μL DMSO, shake well on a plate shaker, read the plate with a microplate reader at 495 nm, and calculate the cell inhibition rate according to the measured absorbance value. Data are presented as mean ± SD (n=6).

The results show that, for tumor cells, the lethality of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes is higher than that of the original drug of contrast camptothecin and the control Bis(camptothecin-20-succinate)phosphatidylcholine liposomes, the former showing excellent antitumor activity. Wherein the IC50 of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome is about 3.5 micrograms/ml, contrast bis(camptothecin-20-succinate Acid) The IC50 of phosphatidylcholine liposome is about 6 micrograms/ml, and the IC50 of the original drug of camptothecin is about 12 micrograms/ml.

Experiment 45:

In vivo toxicity test of drug phospholipid liposome in mice

Animals: ICR mice, male, 18-22 g, purchased from Weitong Lihua Experimental Animal Technology Co., Ltd.

The result (table 2) of the in vivo toxicity test of the double (camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome of embodiment 34 shows that its maximum tolerance The dose is greater than 850mg/kg, indicating that its toxicity is far less than that of the original drug of camptothecin.

Table 2 In vivo toxicity test results in mice

Experimental example 46:

In Vivo Efficacy and Toxicity Experiments

In vivo efficacy and toxicity of bis(camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes

Preparation of nude mouse model: collect cultured HepG2 cell suspension at a concentration of 1×10 ⁷ cells/ml, and inoculate 0.1 ml of each nude mouse subcutaneously in the right armpit. Grouping and administration: The diameter of the transplanted tumor in nude mice was measured with a vernier caliper, and the animals were randomly divided into groups when the tumor grew to 75 mm ³ . At the same time, the nude mice in each group started to be administered. For the dosage regimen, see Group and Dosage Scheme. The antitumor effect of the test samples was dynamically observed by measuring the tumor diameter. The formula for calculating the tumor volume (TV) is: TV=1/2×a×b ² (Formula 3-2), where a and b represent the length and width, respectively.

Groups and administration regimen: blank group: normal saline, intravenous injection, once every three days, with a volume of 0.2ml, for 3 consecutive weeks.

Control group: camptothecin was dissolved in normal saline (a small amount of DMSO for dissolution, and the dosage was 10 mg/kg), and injected intravenously, once every three days, with a volume of 0.2 ml, for 3 consecutive weeks.

Drug group: two (camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposome solution of embodiment 34 (dosage is equivalent to camptothecin 10mg/kg ), intravenous injection, once every three days, with a volume of 0.2ml, for 3 consecutive weeks. During this period, body weight changes were measured.

The results of antitumor activity and body weight change are shown in Figure 35. From the perspective of antitumor activity (Figure 35a), bis (camptothecin-20-carbonate-dithiodiethylene glycol-succinate) phosphatidylcholine liposomes of the present invention have a good tumor growth inhibitory effect. effect, and the animal body weight did not decrease (Fig. 35b), showing no toxicity.

The foregoing embodiments are only preferred implementations of the present invention. It should be pointed out that those skilled in the art can make several improvements and equivalent replacements without departing from the principle of the present invention. Technical solutions requiring improvement and equivalent replacement all fall within the 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.