WO2017162108A1 - 一种柱芳烃类复合物、其制备方法、药物组合物和用途 - Google Patents

一种柱芳烃类复合物、其制备方法、药物组合物和用途 Download PDF

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WO2017162108A1
WO2017162108A1 PCT/CN2017/077130 CN2017077130W WO2017162108A1 WO 2017162108 A1 WO2017162108 A1 WO 2017162108A1 CN 2017077130 W CN2017077130 W CN 2017077130W WO 2017162108 A1 WO2017162108 A1 WO 2017162108A1
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cancer
cells
complex
drug
group
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French (fr)
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孟庆斌
李春举
李斌
孟昭
董华进
贾学顺
刘克良
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中国人民解放军军事医学科学院毒物药物研究所
上海大学
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Publication of WO2017162108A1 publication Critical patent/WO2017162108A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Definitions

  • the invention belongs to the technical field of medicine and relates to a column aromatic hydrocarbon composite, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the column aromatic hydrocarbon complex refers to a complex formed of a derivative of a column aromatic hydrocarbon and a drug.
  • the drug is an antitumor drug.
  • Nitrogen mustard is the earliest anticancer drug for clinical use and has outstanding curative effect. It is mainly used for the treatment of malignant lymphoma. It also has certain curative effect on ovarian cancer, breast cancer and prostate cancer. Its anti-tumor mechanism is due to the presence of highly active double
  • the chloroethylamine alkylating agent enters the body and forms a highly active ethyleneimine ion by intramolecular ring formation, thereby rapidly binding to a nucleophilic group such as a protein nucleic acid for alkylation.
  • Nitrogen mustard is a representative of alkylating agents, has a highly active nature, is unstable in the body, and acts rapidly into the body.
  • Oxaliplatin is the third-generation platinum antitumor drug after cisplatin and carboplatin. It is a stable, water-soluble platinum alkylating agent and is the first effective for colon cancer and in vitro and in vivo. Platinum antitumor drugs with broad-spectrum anti-tumor activity also have effects on cisplatin-resistant tumor cells.
  • Supramolecular chemistry is a new application of supramolecular chemistry in the field of pharmacy.
  • the field is developing rapidly and has a wide range of research. It is a dynamic and emerging interdisciplinary subject and is gradually becoming a relatively independent research field.
  • Head A supramolecular complex drug in which two or more molecules have been formed by intermolecular supramolecular action has been used in the clinic.
  • Supramolecular chemical drugs have good safety, low toxicity, less adverse reactions, high bioavailability, strong drug targeting, low multidrug resistance, good biocompatibility, high efficacy and low development cost, cycle Short-term and many other advantages have attracted much attention.
  • Supramolecular chemistry has great potential and prospects.
  • water-soluble supramolecular macrocyclic hosts eg, crown ethers, cyclodextrins, calixarenes, cucurbiturils, etc.
  • water-soluble supramolecular macrocyclic hosts eg, crown ethers, cyclodextrins, calixarenes, cucurbiturils, etc.
  • macrocyclic host molecules such as crown ether, cyclodextrin, calixarene, cucurbituril and the like in the aqueous phase have been reported.
  • cyclodextrin and its derivatives are widely used as carriers of drugs for encapsulating drug molecules to improve the solubility and stability of drugs, and to adjust the drug release rate, thereby improving the bioavailability of drugs in vivo.
  • Listed drugs currently using cyclodextrin as a carrier or additive include itraconazole, cisapride, mitomycin, piroxicam, dexamethasone, nitroglycerin, alprostadil, and the like.
  • Supramolecular chemistry is developing rapidly, and scientists have been working on the development of new supramolecular chemistry subjects.
  • column aromatic hydrocarbons have a more rigid skeleton and a properly sized cavity structure than other macrocyclic host molecules, they are suspected to be highly toxic due to their multiple benzene ring structures. Further, at present, there have been reports on some column aromatic hydrocarbon derivatives, such as the compounds represented by the following formulas 1 to 5.
  • the inventors have obtained in-depth research and creative labor to prepare a complex of a column aromatic derivative and a drug molecule.
  • the present inventors have surprisingly found that this type of complex can better improve the bioavailability of the drug in vivo, and can be prepared into an injection preparation and an oral dosage form, thereby improving the drug efficacy, reducing the toxic side effects of the drug, and the water solubility of the complex. Good stability.
  • the following invention is thus provided:
  • One aspect of the invention relates to a complex formed from a drug and a column aromatic derivative; preferably, the complex is formed by intermolecular supramolecular action of a drug and a column aromatic derivative.
  • the complex wherein the drug is an antitumor drug; preferably, nitrogen mustard, cisplatin, carboplatin or oxaliplatin.
  • the complex wherein the column aromatic derivative is as shown in Formula I below,
  • n 5, 6, 7, 8, 9, or 10;
  • R is selected from Formula II, Formula III or Formula IV below, and the two Rs are the same;
  • M + is an ammonium ion, a sodium ion or a potassium ion, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • Y is an amino group, an aldehyde group, a hydroxyl group, a thiol group, an acid group, a quaternary ammonium salt or a pyridinium salt, and b is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • c is 1, 2, 3, 4 or 5.
  • n is a positive integer at least equal to five. n is less than 5 and is difficult to form a loop, and the tension is too large. No more than 10 has been reported so far.
  • the one-pot synthesis of all-ethyl substituted column aromatic hydrocarbons using 1,4-diethoxy as a raw material can separate 5-10 membered rings, but the 7,8,9,10-membered ring yields are very low (Jun-Li Hou, Chem. Commun., 2012, 48, 10999-11001).
  • the 8, 9, and 10 element ring structure is two cavities with a folded structure, and the cavity is smaller with respect to the 5, 6, and 7-membered rings, thus limiting its research).
  • n is equal to 5 or 6 having a suitably sized cavity structure, similar to the cyclodextrin cavity structure; on the other hand, the yield of n equal to 5 or 6 is relatively high.
  • the complex wherein the column aromatic hydrocarbon is selected from the group consisting of the following compounds 1-5:
  • the compound 1 is the following compound 6,
  • the compound 6 is a fully carboxylated water-soluble column [6] arene (CP6A) having a structure of the following formula V:
  • the column aromatic hydrocarbon derivative of the present invention is preferably a water-soluble column aromatic hydrocarbon derivative, wherein a fully carboxylated water-soluble column [5] arene, a water-soluble column [6] arene are preferred, and a fully carboxylated water-soluble solution is preferred.
  • the column [6] arene is the best choice.
  • the columnar arene complex is a complex of a water soluble column aromatic derivative and nitrogen mustard or oxaliplatin.
  • FIG. 1A A schematic diagram of the structure of the nitrogen mustard/CP6A complex is shown in Figure 1A.
  • Figure 1B A schematic diagram of the structure of oxaliplatin/CP6A composite is shown in Figure 1B.
  • the complex is for use in preventing and/or treating a tumor; preferably, the tumor is selected from the group consisting of lung cancer, liver cancer, bladder cancer, gastric cancer, ovarian cancer, breast cancer, prostate cancer , malignant lymphoma, colon cancer and sarcoma.
  • the column aromatic hydrocarbon or its derivative contains a plurality of benzene ring structures, and its host-guest recognition is different from cyclodextrin and cucurbituril.
  • the cyclodextrin, cucurbituril and drug complexes rely on intra-ring hydrophobic interaction.
  • the use of a column aromatic hydrocarbon or a derivative thereof as a carrier in combination with a drug has a function of -CH--- ⁇ , a cation--- ⁇ , etc. in the Chinese patent publication CN104922688A, cyclodextrin and oxaliplatin.
  • the complex does not give its Ka value, and the 1 H-NMR chemical shift of its complex shows that the interaction between them is very weak, whereas the complex of the column aromatic derivative and oxaliplatin in the present invention It has a strong effect, and the 1 H-NMR chemical shift of oxaliplatin in the composite changes greatly, and the Ka value is further determined to be (3.25 ⁇ 0.36) ⁇ 10 3 M -1 compared to the invention patent CN104922688A.
  • the column aromatic hydrocarbon derivative and the oxaliplatin complex of the invention have a stronger effect, so that the drug has a better sustained release effect, and the bioavailability of the drug can be greatly improved.
  • the CP6A/nitrogen mustard and CP6A/oxaliplatin complexes formed by the present invention were all confirmed by 1 H-NMR host-object 1:1 (as in Example 1 and Example 2). Without limiting the theory, nitrogen mustard and oxaliplatin can be inserted into the cavity of CP6A. Due to the shielding effect, the hydrogen on nitrogen mustard and oxaliplatin shifts to the high field, and the peak shape widens or even disappears.
  • nitrogen mustard is extremely unstable in aqueous solution, and enters the body rapidly, and stays in the blood for only 0.5-1 min, 90% disappears from blood within 1 min, and 50% is metabolite within 24 hours. discharge.
  • the nitrogen mustard/CP6A complex of the present invention enhances the stability of nitrogen mustard molecules.
  • the present invention utilizes its hydrochloride structure.
  • the nitrogen in the nitrogen mustard hydrochloride has a positive charge and a plurality of structures of -CH 2 which can pass through the host-guest-C---H--- The supramolecular interactions of ⁇ , ionic- ⁇ and -C---H---Cl intercalated into the cavity of CP6A to form a strongly bonded supramolecular complex.
  • the invention particularly relates to a composite of a water soluble column [6] arene and oxaliplatin.
  • the oxaliplatin drug of the present invention may have a -CH 2 structure in the molecule of cyclohexanediamine which may also form a -C---H--- ⁇ super in the benzene ring in CP6A.
  • the cycloheximide part of oxaliplatin is inserted into the cavity of CP6A to form a supramolecular complex, which can enhance the action time of the drug in the body.
  • oxaliplatin is relatively stable in aqueous solution, but upon entering the body, it rapidly hydrolyzes into DNA to form intrachain and interchain crosslinks to inhibit DNA synthesis.
  • Cell experiments demonstrate that the present invention is capable of reducing compound 50 values IC, also shows a prolonged duration of action of drugs.
  • Another aspect of the invention relates to a method of preparing the composite of any of the inventions, comprising the steps of:
  • the steps include the following steps:
  • the steps include the following steps:
  • the above-mentioned column aromatic hydrocarbon derivative is the above-mentioned compound 6.
  • the preparation method wherein the molar ratio of the column aromatic derivative to the drug is from 0.1 to 10; preferably from 0.5 to 5 or from 0.8 to 1.5; more preferably 1.
  • the preparation method wherein the benign solvent is selected from the group consisting of water, a buffer solution (eg, a phosphate buffer solution, a carbonate buffer solution, etc.), methanol, ethanol, isopropanol, or a mixture thereof .
  • a buffer solution eg, a phosphate buffer solution, a carbonate buffer solution, etc.
  • methanol e.g., ethanol, isopropanol, or a mixture thereof .
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the complex of any of the invention, and optionally a pharmaceutically acceptable adjuvant, such as a carrier or excipient.
  • the pharmaceutical compositions of the invention contain from 0.1% to 90% by weight of the complex.
  • Pharmaceutical compositions can be prepared according to methods known in the art.
  • the complex can be combined with one or more solid or liquid pharmaceutical excipients to provide a suitable form of administration or dosage form for human use.
  • the complex of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • a unit dosage form which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • Formulations such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powders Wait. It may be a general preparation, a sustained release preparation, a controlled release preparation, and various microparticle delivery systems.
  • various excipients known in the art can be widely used.
  • carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • wetting agent and binder such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, gum arabic, gelatin paste, sodium carboxymethyl cellulose , shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, etc.
  • disintegrating agents such as dried starch, alginates, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxyethylene, Sorbitol fatty acid ester, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.
  • disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.
  • absorption promotion Agents such as quaternary ammonium salts, sodium lauryl sulfate, and the like
  • lubricants such as talc, silica,
  • the tablet can also be further coated Tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • various carriers known in the art can be widely used.
  • the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, and the like.
  • the complex is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule.
  • the complex may also be formulated as a microcapsule, suspended in an aqueous medium to form a suspension, or incorporated into a hard capsule or used as an injection.
  • an injection preparation such as a solution, an emulsion, a lyophilized powder injection and a suspension
  • all diluents conventionally used in the art for example, water, ethanol, polyethylene glycol, 1, 3 may be used.
  • diluents conventionally used in the art for example, water, ethanol, polyethylene glycol, 1, 3 may be used.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional solubilizer, a buffer, a pH adjuster or the like may be added.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the dosage of the complex of the present invention depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight and individual response of the patient or animal, the particular drug used, the route of administration and the number of doses administered. Wait.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms.
  • composition as used herein is intended to include a product comprising specified amounts of each of the specified ingredients, as well as any product that results, directly or indirectly, from the specified combination of the specified ingredients.
  • each active ingredient (drug or complex) in the pharmaceutical compositions of the present invention can be varied so that the amount of active ingredient is effective to achieve the desired therapeutic response to the particular patient, composition, and mode of administration.
  • the dosage level will be selected based on the activity of the particular drug or complex, the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated.
  • the dose of the complex begins at a level below that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved.
  • a further aspect of the invention relates to the use of a complex of the invention in the manufacture of a medicament selected from the group consisting of:
  • a drug for treating and/or preventing tumors, especially malignant tumors is a drug for treating and/or preventing tumors, especially malignant tumors
  • the tumor is selected from the group consisting of lung cancer, liver cancer, bladder cancer, gastric cancer, ovarian cancer, breast cancer, prostate cancer, malignant lymphoma, colon cancer and sarcoma;
  • the tumor cells are selected from the group consisting of lung cancer cells, liver cancer cells, bladder cancer cells, gastric cancer cells, ovarian cancer cells, breast cancer cells, prostate cancer cells, malignant lymphoma cells, colon cancer cells, and sarcoma cells.
  • the sarcoma is selected from the group consisting of angiosarcoma, lymphangisarcoma, lymphosarcoma, liposarcoma, chondrosarcoma, and osteosarcoma.
  • the sarcoma cells are selected from the group consisting of angiosarcoma cells, lymphangiosarcoma cells, lymphosarcoma cells, liposarcoma cells, chondrosarcoma cells, and osteosarcoma cells.
  • a further aspect of the invention relates to a method of inhibiting tumor cells in vivo or in vitro comprising the step of using an effective amount of a complex of the invention; preferably, the tumor cells are selected from the group consisting of lung cancer cells, liver cancer cells, bladder cancer cells , gastric cancer cells, ovarian cancer cells, breast cancer cells, prostate cancer cells, malignant lymphoma cells, colon cancer cells, and sarcoma cells.
  • the method is for non-therapeutic purposes.
  • a further aspect of the invention relates to a method of preventing and/or treating a tumor, in particular a malignant tumor, comprising the step of administering to the subject an effective amount of a complex of the invention; preferably, the tumor is selected from the group consisting of lung cancer, liver cancer, Bladder cancer, gastric cancer, ovarian cancer, breast cancer, prostate cancer, malignant lymphoma, colon cancer and sarcoma.
  • a therapeutically and/or prophylactically effective amount of a complex of the invention may be applied in pure form, or the complex may comprise a compound of interest and one or more drugs
  • the pharmaceutical composition that can receive the excipient is administered. It will be appreciated, however, that the total daily usage of the complexes and compositions of the present invention must be determined by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the specific complex or drug activity employed; Composition; patient's age, weight, general health, Gender and diet; time of administration, route of administration and excretion rate of the particular complex employed; duration of treatment; drugs used in combination with or concurrent with the particular complex employed; and similar factors well known in the medical arts.
  • the dosage of the complex begins at a level below that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved.
  • the dosage of the complex of the invention for use in mammals, particularly humans may range from 0.001 to 1000 mg/kg body weight per day, for example between 0.01 and 100 mg/kg body weight per day, for example between 0.01 and 10 mg per kg body weight. /day.
  • nitrogen mustard has obvious local stimulating effect, it is easy to cause tissue necrosis, so it can only be administered by injection, including intravenous injection, arterial injection, subcutaneous injection, intradermal injection and intraluminal injection.
  • the route of administration of the complex involving oxaliplatin and CP6A in the present invention is preferably an intravenous drip.
  • intermolecular supramolecular action refers to interactions between molecules, such as van der Waals forces, hydrogen bonds, hydrophobic interactions, electrostatic interactions, ⁇ - ⁇ stacking, and the like, or a plurality thereof. Intermolecular supramolecular interaction is the basis of supramolecular chemistry research.
  • molecular recognition is the interaction between two or more molecules by non-covalent bonding.
  • the process of molecular recognition is actually the process by which molecules interact under each other through the synergistic action of intermolecular forces. This actually reveals three important components of the principle of molecular recognition.
  • Specific conditions refer to the state in which molecules depend on pre-organization to achieve complementarity.
  • Intermolecular interaction force refers to the existence between molecules. Non-covalent interactions, while “synergy” emphasizes that molecules need to rely on macrocyclic or chelation effects to produce consistent effects between interactions. Complementarity and pre-organization are two key principles that determine molecular recognition.
  • the former determines the selectivity of the recognition process and the latter determines the bonding ability of the recognition process.
  • the complementarity of substrate and receptor includes the complementarity of spatial structure and spatial electrical properties. Spatial complementarity was first described by Fisher's "lock-key" relationship. Pre-organization refers to the better the organization of the receptor and substrate molecules to accommodate the substrate in the receptor before recognition, and the lower the solvating power, the better the recognition effect and the more stable the complex formed. Molecular recognition relies on supramolecular action.
  • the term "effective amount” refers to a dose that can achieve a treatment, prevention, alleviation, and/or alleviation of a disease or condition described herein in a subject.
  • disease and/or condition refers to a physical state of the subject that is in accordance with the present invention. Related to the disease and/or condition.
  • subject can refer to a patient or other animal that receives the pharmaceutical composition of the invention to treat, prevent, ameliorate and/or alleviate the disease or condition of the invention, particularly a mammal, such as a human, a dog, a monkey, or a cow. , horses, etc.
  • the complex of the invention improves the bioavailability of the drug (especially, can effectively inhibit tumor), is simple to prepare, has mild reaction conditions, and is suitable for industrial production, especially for injection preparation of nitrogen mustard and oxalib. Improve drug stability and anti-tumor activity, making the drug more medicinal.
  • Figure 1 Schematic diagram of the structure of nitrogen mustard / CP6A complex.
  • Figure 1B is a schematic view showing the structure of oxaliplatin/CP6A complex.
  • Figure 2 Relative cell viability of lung cancer cell A549, liver cancer cell HepG2 and human breast cancer cell MCF-7 at different CP6A concentrations.
  • Figure 3 Relative cell viability of normal hepatocytes 3T3 at different CP6A concentrations.
  • Figure 4 1 H-NMR spectrum of CP6A and nitrogen mustard; (a) CP6A; (b) CP6A + nitrogen mustard; (c) nitrogen mustard; D 2 O, 5 mM.
  • Figure 5 1 H-NMR spectrum of CP6A and oxaliplatin; (a) CP6A; (b) CP6A + oxaliplatin; (c) oxaliplatin; D 2 O, 5 mM.
  • Figure 6 Figure 6A, Evaluation of the inhibitory activity of the CP6A/NM complex on tumor cell MCF-7 cells.
  • Figure 6B Evaluation of the inhibitory activity of the CP6A/NM complex on tumor cell HepG2 cells.
  • NM represents nitrogen mustard.
  • CP6A (M is an ammonium ion), prepared in accordance with J. Am. Chem. SOC. 2012, 134, 13248-13251.
  • Lung cancer cell A549, hepatoma cell HepG2, human breast cancer cell MCF-7 and normal hepatocyte 3T3 were all provided by Peking Union Cell Bank.
  • 3T3, A549, MCF-7 were all used in DMEM medium (containing 10% FBS, 1% penicillin/streptomycin), HepG2 was used in MEM medium (containing 10% FBS, 1% penicillin/streptomycin) at 5% CO 2 , culture at 37 ° C constant temperature, CP6A dissolved in PBS to prepare a solution
  • Collect logarithmic growth cells (A549, MCF-7, HepG-2 cells), adjust the cell suspension concentration, inoculate the cell suspension in 96-well plates, and plate the cells to adjust the density to about 10000/well.
  • 100 ⁇ L of the cell suspension was incubated at 5% CO 2 at 37 ° C for 24 h. The cells were observed to adhere to the microscope.
  • 10 ⁇ L of CP6A was added to the plate, and the concentrations of CP6A were 3.2 mM, 1.6 mM, 0.8 mM, respectively. 0.4 mM, 0.2 mM, 0.1 mM.
  • the logarithmic growth of 3T3 cells was collected, the cell suspension concentration was adjusted, the cell suspension was seeded in a 96-well plate, and the cells were plated to a density of about 10,000/well, 100 ⁇ L of cell suspension per well, at 5% CO 2 . Incubate at 37 ° C for 24 h, and observe the growth of cells adherent under the microscope. 10 ⁇ L of CP6A was added to the plate at a concentration of 2.9 mM, 0.74 mM, 0.15 mM, 0.03 mM, 0.003 mM, 0.0003 mM, respectively.
  • Example 3 Evaluation of inhibition of tumor cells by CP6A/nitrogen mustard complex
  • Human breast cancer cells MCF-7 and liver cancer cells HepG2 were provided by the Peking Union Cell Bank.
  • the inhibitory effect of CP6A/nitrogen mustard complex on human breast cancer cell line MCF-7 and hepatoma cell line HepG2 was evaluated by MTT assay.
  • the nitrogen mustard drug was used as the control group, and the toxicity was measured 48 h after cell administration.
  • MCF-7 logarithmic growth cells
  • MCF-7 logarithmic growth cells
  • inoculate the cell suspension in 96-well plates and plate the cells to adjust the density to about 10,000.
  • /well 100 ⁇ L of cell suspension per well, incubate at 5% CO 2 , 37 ° C for 24 h, microscopically observed cell adhesion growth, add 10 ⁇ L of prepared aqueous solution of nitrogen mustard hydrochloride or contain Column hexaacetate of ammonium mustard hydrochloride (prepared in Example 1) (molar ratio 1:1), wherein 0 mM, 0.01 mM, 0.1 mM, 0.2 mM, 0.4 mM, 0.6 mM were calculated according to the nitrogen mustard concentration, respectively.
  • Example 4 Evaluation of inhibition of tumor cells by CP6A/oxaliplatin complex
  • Lung cancer cells A549, liver cancer cells HepG2, T24 cells (bladder cancer cells), NCI cells (lung cancer cells), MGC-803 cells (gastric cancer cells), and BEL-7404 cells (hepatoma cells) were all supplied by the Peking Union Cell Bank.
  • MTT assay was used to evaluate the inhibitory effect of CP6A/oxaliplatin complex on lung cancer cell A549, liver cancer cell HepG2, bladder cancer T24, lung cancer NCI, gastric cancer MGC-803, liver cancer BEL-7404, and the drug oxaliplatin alone.
  • the toxicity was measured 48 hours after administration of the cells.
  • each cell For each cell, collect the cells growing in log phase, adjust the cell suspension concentration, inoculate the cell suspension in a 96-well plate, and plate the cells to adjust the density to about 10000/well, 100 ⁇ L of cell suspension per well. Incubate at 5% CO 2 at 37 ° C for 24 h. The cells were observed to adhere to the growth of the cells. 10 ⁇ L of the prepared aqueous solution of oxaliplatin or ammonium hexaacetate containing oxaliplatin was added to the plate.
  • Example 2 (molar ratio is 1:1), wherein each of the oxaliplatin concentrations are 0 mg/ml, 25 mg/ml, 50 mg/ml, 100 mg/ml, 200 mg/ml, and 400 mg/ml, respectively.
  • Five replicate wells were set in parallel, and only PBS was added as a blank control. A blank group was set as a control. After gently shaking for 5 minutes on a shaker, the plate was placed in an incubator for cultivation. After 48 hours, the plate was taken out, 10 ⁇ l of MTT (5 mg/mL) solution was added to each well under aseptic conditions, and the culture was continued for 4 hours, the culture was terminated, and the culture solution in the well was carefully aspirated.
  • MTT 5 mg/mL
  • Example 5 Evaluation of tumor suppressive effect by NM/CP6A
  • NM/CP6A The previous Example 1 produced a CP6A/nitrogen mustard complex.
  • S180 tumor cells purchased from the Concord Cell Bank.
  • S180 tumor cells were implanted into Kunming mice by intraperitoneal injection, 1 ⁇ 10 7 cells/only.
  • Kunming mice implanted with S180 tumor cells were randomly divided into 4 groups of 12 animals each, grouped and administered as follows:
  • Negative control group normal saline
  • Positive control group NM (nitrogen mustard), the total dose is 4mg/kg;
  • the specific administration dose is shown in Table 4 below.
  • mice were sacrificed to dissect the tumor and weighed.
  • the NM/CP6A complex has higher antitumor activity in vivo.
  • OX/CP6A CP6A/oxaliplatin complex prepared in the previous Example 2.
  • S180 tumor cells purchased from the Peking Union Cell Bank.
  • S180 tumor cells were implanted into Kunming mice by intraperitoneal injection, 1 ⁇ 10 7 cells/only.
  • Kunming mice implanted with S180 tumor cells were randomly divided into 4 groups of 12 animals each, grouped and administered as follows:
  • Negative control group normal saline
  • the specific administration dose is shown in Table 6 below.
  • mice were sacrificed to dissect the tumor and weighed.

Abstract

一种式I所示的柱芳烃类复合物，其制备方法、药物组合物及其用途。该复合物提高了药物的稳定性，增强了药物对肿瘤细胞的抑制作用。

Description

一种柱芳烃类复合物、其制备方法、药物组合物和用途 技术领域
本发明属于医药技术领域，涉及一种柱芳烃类复合物、其制备方法、药物组合物和用途。具体地，所述柱芳烃类复合物是指柱芳烃的衍生物与药物形成的复合物。具体地，所述药物为抗肿瘤药物。
背景技术
随着药物化学的不断发展，越来越多的新药被研发出来，并且已上市，然而一些药物因溶解度差、口服吸收差、生物相容性差等问题，导致了药物的生物利用度低。
氮芥药物是最早用于临床并取得突出疗效的抗肿瘤药物，主要用于恶性淋巴瘤的治疗，对卵巢癌、乳腺癌、前列腺癌等也有一定疗效，其抗肿瘤机制是由于存在高度活泼双氯乙胺烷化剂，进入体内后，通过分子内成环作用，形成高度活泼的乙烯亚胺离子，从而迅速结合蛋白质核酸等亲核基团进行烷基化作用。氮芥是烷基化剂的代表，具有高度活泼的性质，在体内及其不稳定，进入体内作用迅速。随着药物化学的发展，新药研发进程变得缓慢，因此老药新用的倡导受到人们的关注。氮芥作为经典的老的抗肿瘤药，逐渐被限制使用(原因包括氮芥极其不稳定、副作用也比较大等)，而本发明人没有检索到任何报道关于增强氮芥药效的报道。
奥沙利铂是继顺铂、卡铂之后的第三代铂类抗肿瘤药物，它作为一种稳定的、水溶性铂类烷化剂，是第一个明显对结肠癌有效及在体内外均有广谱抗肿瘤活性的铂类抗肿瘤药物，对耐顺铂的肿瘤细胞亦有作用。
氮芥和奥沙利铂结构如下：
Figure PCTCN2017077130-appb-000001
超分子化学药物是超分子化学在药学领域的新应用。该领域发展迅速，研究范围广，是一个充满活力的新兴交叉学科，并正在逐渐变成一个相对独立的研究领域。目 前已有许多两个或两个以上分子通过分子间超分子作用形成的超分子复合物药物应用于临床。超分子化学药物具有良好的安全性、低毒性、不良反应少、生物利用度高、药物靶向性强、多药耐药性小、生物相容性好、高疗效以及其开发成本低、周期短等诸多优点而备受关注。超分子化学药物具有很大的发展潜力和前景。
利用水溶性超分子大环主体(例如冠醚、环糊精、杯芳烃、葫芦脲等)在水溶液中基于分子识别来包结药物分子最为普遍。随着超分子化学的不断发展，几代大环主体分子如冠醚、环糊精、杯芳烃、葫芦脲等在水相中的分子识别研究已被报道。
其中环糊精及其衍生物作为药物的载体用于包结药物分子来提高药物的溶解性、稳定性、调节药物释放速率，从而提高药物在体内的生物利用度的研究最为广泛很多。目前利用环糊精作为载体或添加剂的以上市药物包括伊曲康唑、西沙比利、丝裂霉素、吡罗昔康、地塞米松、硝化甘油、前列地尔等。超分子化学发展很快，科学家一直致力于研究开发新的超分子化学主体。
柱芳烃作为继冠醚、环糊精、葫芦脲、杯芳烃后新一代超分子大环主体，于2008年由日本化学家Ogoshi在美国化学会志(J.AM.CHEM.SOC.2008，130，5022-5023)首次报道其合成。由对苯二酚或对苯二酚醚通过亚甲基桥在苯环的对位连接而成的一类环状低聚物，柱芳烃在空间结构上是圆柱状而非锥式构象的杯芳烃，其具有更刚性的骨架。然而，尽管柱芳烃相比其他大环主体分子具有更刚性骨架、大小合适的空腔结构，也因其含多个苯环结构，人们怀疑其有较大的毒性。另外，目前，已经有关于一些柱芳烃衍生物的报道，如下面的式1-式5所示的化合物。
Figure PCTCN2017077130-appb-000002
Figure PCTCN2017077130-appb-000003
然而，基于柱芳烃衍生物包结药物分子从而提高药物生物利用度、稳定性或者溶解性的工作至今未见报道。
发明内容
本发明人经过深入的研究和创造性的劳动，制备得到了柱芳烃衍生物和药物分子的复合物。本发明人惊奇地发现，该类型复合物可以较好地提高药物在体内的生物利用度，且可以制成注射制剂以及口服剂型，提高药效，降低药物的毒副作用，复合物的水溶性和稳定性良好。由此提供了下述发明：
本发明的一个方面涉及一种复合物，其由药物和柱芳烃衍生物形成；优选地，所述复合物通过药物和柱芳烃衍生物的分子间超分子作用形成。
在本发明的一些实施方式中，所述的复合物，其中，所述药物为抗肿瘤药物；优选地，为氮芥、顺铂、卡铂或奥沙利铂。
在本发明的一些实施方式中，所述的复合物，其中，所述柱芳烃衍生物如下面的式I所示，
Figure PCTCN2017077130-appb-000004
Figure PCTCN2017077130-appb-000005
其中，
n为5、6、7、8、9或10；
R选自下面的式II、式III或者式IV，并且两个R是相同的；
Figure PCTCN2017077130-appb-000006
式II中，M+为铵根离子、钠离子或钾离子，a为1、2、3、4、5、6、7、8、9或10；
Figure PCTCN2017077130-appb-000007
式III中，Y为氨基、醛基、羟基、胍基、酸基、季铵盐或吡啶盐，b为1、2、3、4、5、6、7、8、9或10。
Figure PCTCN2017077130-appb-000008
式IV中，c为1、2、3、4或5。
不拘于理论的限制，n为至少等于5的正整数。n小于5难以成环，张力太大。目前没有报道过n大于10的。利用1，4-二乙氧基为原料一锅法合成全乙基取代的柱芳烃，可以分离出5-10元环，但是7、8、9、10元环产率非常低(Jun-Li Hou，Chem.Commun.，2012，48，10999-11001)。另外，8、9、10元环结构是具有折叠结构的两个空腔，空腔相对于5、6、7元环更小，因此也限制了对其研究)。不拘于理论的限制，一方面，n等于5或6具有大小合适的空腔结构，和环糊精空腔结构类似；另一方面，n等于5或6的产率相对较高。
在本发明的一些实施方式中，所述的复合物，其中，所述柱芳烃选自下面的化合物1-5：
Figure PCTCN2017077130-appb-000009
优选地，所述化合物1为如下的化合物6，
Figure PCTCN2017077130-appb-000010
在本发明中，化合物6即全羧基化的水溶性柱[6]芳烃(CP6A)，其结构如下面的式V：
Figure PCTCN2017077130-appb-000011
本发明所述的柱芳烃衍生物优选为水溶性的柱芳烃衍生物，其中以全羧基化的水溶性柱[5]芳烃、水溶性柱[6]芳烃为较优选择，全羧基化的水溶性柱[6]芳烃为最优选择。
在本发明一个特别优选的实施方式中，所述的柱芳烃复合物为水溶性的柱芳烃衍生物和氮芥或奥沙利铂形成的复合物。
氮芥/CP6A复合物的结构示意图如图1A所示。奥沙利铂/CP6A复合物结构示意图如图1B所示。
在本发明的一个实施方案中，所述的复合物，其用于预防和/或治疗肿瘤；优选地，所述肿瘤选自肺癌、肝癌、膀胱癌、胃癌、卵巢癌、乳腺癌、前列腺癌、恶性淋巴瘤、结肠癌和肉瘤。
不拘于理论的限制，柱芳烃或其衍生物含有多个苯环结构，其主客体识别作用不同于环糊精和葫芦脲，环糊精、葫芦脲和药物的复合依靠的是环内疏水作用，然而使用柱芳烃或其衍生物作为载体与药物复合作用除了疏水作用外还有-C-H---π，阳离子---π等，中国专利公开CN104922688A中，环糊精和奥沙利铂的复合物并没有得到其Ka值大小，从其复合物的1H-NMR化学位移就可看出它们之间的相互作用非常弱，然而本发明中柱芳烃衍生物和奥沙利铂的复合物，具有很强的作用，复合物中奥沙利铂的1H-NMR化学位移变化很大，而且进一步求得其Ka值为(3.25±0.36)×103M-1，相比发明专利CN104922688A，本发明柱芳烃衍生物和奥沙利铂复合物具有更强的作用，因此对于药物具有更好的缓释效果，可以大大提高药物的生物利用度。
本发明形成的CP6A/氮芥和CP6A/奥沙利铂复合物均通过1H-NMR的主客体1∶1得到证明(如实施例1和实施例2)。不拘于理论的限制，由于氮芥和奥沙利铂可以穿插进入CP6A的空腔，由于屏蔽效应，氮芥和奥沙利铂上的氢均明显向高场移动，峰型加宽甚至消失。
本领域技术人员知悉，氮芥在水溶液中极不稳定，进入体内作用迅速，在血中停留的时间只有0.5-1min，90％在1min内由血中消失，24小时内50％以代谢物形式排出。令人惊奇的是，本发明的氮芥/CP6A复合物可以增强氮芥分子的稳定性。不拘于理论的限制，本发明利用其盐酸盐结构，氮芥盐酸盐中氮带有正电荷，又有多个-CH2的结构，可以通过主客体-C---H---π、离子-π以及-C---H---Cl超分子作用穿插进入CP6A空腔内形成强键合的超分子复合物。
本发明具体还涉及水溶性的柱[6]芳烃和奥沙利铂形成的复合物。不拘于理论的限制，本发明涉及的奥沙利铂药物，其分子中的环己二胺中的-CH2结构也可以与CP6A中的苯环形成-C---H---π超分子作用，使奥沙利铂中的环己二胺部分穿插进入CP6A的空腔来形成超分子复合物，可以增强药物在体内的作用时间。本领域技术人员知悉，奥沙利铂虽然在水溶液中比较稳定，但是一旦进入体内会迅速水解作用于DNA形成链内和链间交联从而抑制DNA的合成。本发明的细胞实验证明了复合物能够降低IC50值，也说明延长了药物的作用时间。
本发明的另一方面涉及制备本发明中任一项所述的复合物的方法，包括下述步骤：
将一定摩尔比例的药物和柱芳烃衍生物混合物直接溶解在良性溶剂中混合均匀，然后冷冻干燥或减压真空干燥，得到复合物(制得复合物的颜色为棕黄色固体)；
优选地，包括下述步骤：
将一定摩尔比例的氮芥和柱芳烃衍生物的混合物直接溶解在良性溶剂中混合均匀，然后在10分钟以内将混合物的溶液冷冻干燥或减压真空干燥即可；
或者
优选地，包括下述步骤：
将一定摩尔比例的奥沙利铂和柱芳烃衍生物的混合物直接溶解在良性溶剂中30℃ -60℃(优选为40℃-60℃)超声震荡一段时间(优选为10-20min)，至奥沙利铂完全溶解，然后将混合物的溶液冷冻干燥或减压真空干燥即可；
优选地，上述柱芳烃衍生物为上述的化合物6。
在本发明的一些实施方式中，所述的制备方法，其中，所述柱芳烃衍生物与药物的摩尔比值为0.1-10；优选为0.5-5或0.8-1.5；更优选为1。
在本发明的一些实施方式中，所述的制备方法，其中，所述良性溶剂选自水、缓冲溶液(例如磷酸缓冲溶液、碳酸缓冲溶液等)、甲醇、乙醇、异丙醇或者它们的混合物。
本发明的再一方面涉及一种药物组合物，其包含本发明中任一项所述的复合物，以及任选的药学上可接受的辅料，例如载体或赋形剂。
通常本发明药物组合物含有0.1-90重量％的复合物。药物组合物可根据本领域已知的方法制备。用于此目的时，如果需要，可将复合物与一种或多种固体或液体药物辅料结合，制成可作为人用的适当的施用形式或剂量形式。
本发明的复合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。给药剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种辅料。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣 片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将给药单元制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将给药单元制成胶囊，将复合物与上述的各种载体混合，并将由此得到的混合物置于硬的明明胶囊或软胶囊中。也可将复合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。为了将给药单元制成注射用制剂，如溶液剂、乳剂、冻干粉针剂和混悬剂，可以使用本领域常用的所有稀释剂，例如，水、乙醇、聚乙二醇、1，3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
本发明复合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重及个体反应，所用的具体药物，给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品，以及直接或间接从指定量的各指定成分的组合产生的任何产品。
可改变本发明药物组合物中各活性成分(药物或者复合物)的实际剂量水平，以便使活性成分的量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体药物或者复合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是，本领域的做法是，复合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。
本发明的再一方面涉及本发明的复合物在制备选自如下的药物中的用途：
治疗和/或预防肿瘤特别是恶性肿瘤的药物，
抑制肿瘤细胞的药物，或者
治疗和/或预防癌性胸膜炎、心包积液或腹腔积液的药物；
优选地，所述肿瘤选自肺癌、肝癌、膀胱癌、胃癌、卵巢癌、乳腺癌、前列腺癌、恶性淋巴瘤、结肠癌和肉瘤；
优选地，所述肿瘤细胞选自肺癌细胞、肝癌细胞、膀胱癌细胞、胃癌细胞、卵巢癌细胞、乳腺癌细胞、前列腺癌细胞、恶性淋巴瘤细胞、结肠癌细胞和肉瘤细胞。
在本发明的一些实施方式中，所述肉瘤选自血管肉瘤、淋巴管肉瘤、淋巴肉瘤、脂肪肉瘤、软骨肉瘤以及骨肉瘤。
在本发明的一些实施方式中，所述肉瘤细胞选自血管肉瘤细胞、淋巴管肉瘤细胞、淋巴肉瘤细胞、脂肪肉瘤细胞、软骨肉瘤细胞以及骨肉瘤细胞。
本发明的再一方面涉及一种在体内或者体外抑制肿瘤细胞的方法，包括使用有效量的本发明的复合物的步骤；优选地，所述肿瘤细胞选自肺癌细胞、肝癌细胞、膀胱癌细胞、胃癌细胞、卵巢癌细胞、乳腺癌细胞、前列腺癌细胞、恶性淋巴瘤细胞、结肠癌细胞和肉瘤细胞。在本发明的一个实施方案中，所述方法是非治疗目的的。
本发明的再一方面涉及一种预防和/或治疗肿瘤特别是恶性肿瘤的方法，包括给予受试者有效量的本发明的复合物的步骤；优选地，所述肿瘤选自肺癌、肝癌、膀胱癌、胃癌、卵巢癌、乳腺癌、前列腺癌、恶性淋巴瘤、结肠癌和肉瘤。
当用于上述治疗和/或预防时，治疗和/或预防有效量的一种本发明复合物可以以纯形式应用，或者，所述复合物可以以含有该目的复合物与一种或多种药物可接受辅料的药物组合物给药。但应认识到，本发明复合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体复合物或者药物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、 性别和饮食；所采用的具体复合物的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体复合物组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，复合物的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。一般说来，本发明复合物用于哺乳动物特别是人的剂量可以介于0.001-1000mg/kg体重/天，例如介于0.01-100mg/kg体重/天，例如介于0.01-10mg/kg体重/天。
由于氮芥具有明显的局部刺激作用，易引起组织坏死，因此仅供注射给药，包括静脉注射、动脉注射、皮下注射、皮内注射及腔内注射等途径。
在本发明中涉及奥沙利铂和CP6A的复合物给药途径优选为静脉滴注。
本发明中，
术语“分子间超分子作用”或者“超分子作用”指的是分子之间的相互作用，例如范德华力、氢键、疏水作用、静电作用、π-π堆积等，或者其中的多种。分子间超分子作用是超分子化学研究的基础。
术语“分子识别”是两个或以上的分子之间通过非共价键结合相互作用。分子识别的过程实际上是分子在特定的条件下通过分子间作用力的协同作用达到相互结合的过程。这其实也揭示了分子识别原理中的三个重要的组成部分，“特定的条件”即是指分子要依靠预组织达到互补的状态，“分子间相互作用力”即是指存在于分子之间非共价相互作用，而“协同作用”则是强调了分子需要依靠大环效应或者螯合效应使得各种相互作用之间产生一致的效果。互补性及预组织是决定分子识别的两个关键原则。前者决定识别过程的选择性，后者决定识别过程的键合能力。底物与受体的互补性包括空间结构及空间电学特性的互补性。空间互补性最早由Fisher的“锁-钥匙”关系所描述。预组织是指受体与底物分子在识别之前将受体中容纳底物的环境组织得愈好，其溶剂化能力愈低，则它们的识别效果愈佳，形成的络合物愈稳定。分子识别依靠的是超分子作用。
术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
术语“疾病和/或病症”是指所述受试者的一种身体状态，该身体状态与本发明所 述疾病和/或病症有关。
术语“受试者”可以指患者或者其它接受本发明药物组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。
发明的有益效果
本发明的复合物提高了药物的生物利用度(特别是能够有效地抑制肿瘤)，其制备简单、反应条件温和，适用于工业化生产，特别是可用于制备氮芥和奥沙利伯的注射剂型，提高药物稳定性以及抗肿瘤活性，使得药物更有药用价值。
附图说明
图1：图1A，氮芥/CP6A复合物结构示意图。图1B，奥沙利铂/CP6A复合物结构示意图。
图2：不同CP6A浓度下肺癌细胞A549、肝癌细胞HepG2和人乳腺癌细胞MCF-7的相对细胞存活率。
图3：不同CP6A浓度下正常肝细胞3T3的相对细胞存活率。
图4：CP6A和氮芥作用的1H-NMR图谱；其中(a)CP6A；(b)CP6A+氮芥；(c)氮芥；D2O，5mM。
图5：CP6A和奥沙利铂作用的1H-NMR图谱；其中(a)CP6A；(b)CP6A+奥沙利铂；(c)奥沙利铂；D2O，5mM。
图6：图6A，CP6A/NM复合物对肿瘤细胞MCF-7细胞抑制活性评价。图6B，CP6A/NM复合物对肿瘤细胞HepG2细胞抑制活性评价。NM表示氮芥。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
试验例1：CP6A的细胞毒性试验
1.实验样品
CP6A(M为铵根离子)，参考J.Am.Chem.SOC.2012，134，13248-13251制备。
肺癌细胞A549、肝癌细胞HepG2、人乳腺癌细胞MCF-7和正常肝细胞3T3：均由北京协和细胞库提供。
2.实验方法
MTT法：
3T3、A549、MCF-7均用DMEM培养基(含有10％FBS，1％青霉素/链霉素)，HepG2用MEM培养基(含有10％FBS，1％青霉素/链霉素)在5％CO2，37℃恒温下培养，CP6A溶于PBS制备成溶液
收集对数期生长的细胞(A549，MCF-7、HepG-2细胞)，调整细胞悬液浓度，将细胞悬浮液接种于96孔板，铺板使待测细胞调密度至约10000/孔，每孔100μL细胞悬液，在5％CO2，37℃恒温下孵育24h，显微镜下观察可见细胞贴壁生长，向培养板中加入10μL CP6A，其中CP6A浓度分别为3.2mM，1.6mM，0.8mM，0.4mM，0.2mM，0.1mM。每5个孔加10μL同样浓度的CP6A，最后的5个孔加PBS作为空白对照。在摇床上轻摇5min后，将培养板放置于5％CO2，37℃恒温培养箱中培养。48小时后，取出培养板，无菌条件下每孔加入10μl的MTT(5mg/mL)溶液，继续培养4h，终止培养，小心吸去孔内的培养液。接着每孔加入100μl DMSO，放置于摇床下低速震荡10min以使紫色结晶物充分的溶解。在全自动酶标仪490nm处检测各孔的吸光值。
收集对数期生长的3T3细胞，调整细胞悬液浓度，将细胞悬浮液接种于96孔板，铺板使待测细胞调密度至约10000/孔，每孔100μL细胞悬液，在5％CO2，37℃恒温下孵育24h，显微镜下观察可见细胞贴壁生长。向培养板中加入10μL CP6A，CP6A浓度分别为2.9mM，0.74mM，0.15mM，0.03mM，0.003mM，0.0003mM。每5个孔加10μL同样浓度的CP6A，最后的5个孔加PBS作为空白对照。在摇床上轻摇5min后，将培养板放置于5％CO2，37℃恒温培养箱中培养。48小时后，取出培养板，无菌条件下每孔加入10μl的MTT(5mg/mL)溶液，继续培养4h，终止培养，小心吸去孔内的培养液。 接着每孔加入100μl DMSO，放置于摇床下低速震荡10min以使紫色结晶物充分的溶解。在全自动酶标仪490nm处检测各孔的吸光值。
3.实验结果
如下面的图2和图3所示。
结果表明，CP6A对A549、HepG2、MCF-7三种肿瘤细胞无抑制能力，对正常肝细胞3T3在高浓度下具有轻微的毒性。可见，水溶性的柱芳烃衍生物具有非常低的毒性。
实施例1：CP6A/氮芥复合物的制备及表征
CP6A/氮芥复合物的制备及表征：
准确称取20mg氮芥(购自北京伊诺凯有限公司)(0.105mmol)和171mg CP6A(M为铵根离子，制备方法可参考J.Am.Chem.SOC.2012，134，13248-13251)(0.105mmol)混合溶于5mL水中待其充分均匀混合，然后在10分钟以内将混合物的溶液进行真空冷冻干燥，得到氮芥/CP6A的复合物。复合物的1H-NMR以及单独主体CP6A和单独药物氮芥在D2O的1H-NMR如图4，氮芥在复合物中化学位移变化值如下面的表1：
表1
Figure PCTCN2017077130-appb-000012
由表1、图4可以明显看出，当氮芥药物被CP6A包结后，其化学位移值发生明显的变化，Ha、Hb和Hc质子峰明显变宽，基本消失不见，移向高场。其化学位移变化值分别为Δδ(a)＝-1.527、Δδ(b)＝-1.859、Δδ(c)＝-1.717，这表明氮芥进入了CP6A的空腔受到苯环的屏蔽作用，使得氮芥的核磁信号峰向高场移动。峰型变宽基本消失，说明其由于完全处在CP6A主体分子的空腔内屏蔽了核磁信号而导致，Hb和Hc的化学位移变化最大也说明其位置刚好处在CP6A空腔的中心位置，受到屏蔽效应最大。结果表明氮芥进入了CP6A的空腔内。
实施例2：CP6A/奥沙利铂复合物的制备及表征
准确称取20mg奥沙利铂(0.05mmol)(购自北京伊诺凯有限公司)和82mg CP6A(0.05mmol)混合一起溶于10mL水中混合均匀，40℃-60℃下超声震荡20-30min使药物完全溶解并均匀混合，混合液真空下冷冻干燥即可得到CP6A/奥沙利铂复合物。复合物的1H-NMR以及单独主体CP6A和单独奥沙利铂药物在D2O的1H-NMR如图5，奥沙利铂在复合物中的化学位移变化值如下面的表2：
表2
Figure PCTCN2017077130-appb-000013
由表2、图5可以明显看出，奥沙利铂和CP6A形成复合物后，其化学位移值发生明显的变化，Ha，a’、Hb，b’和Hc质子峰明显变宽，接近消失，移向高场。其化学位移变化值如表2所示，这表奥沙利铂分子中的环己烷部分作为头部，与苯环形成-C---H---π超分子作用穿插进入了CP6A的空腔受到苯环的屏蔽作用，使得其核磁信号峰向高场移动。这一结果表明奥沙利铂穿插进入了CP6A的空腔内。
而且进一步求得CP6A和奥沙利铂的键合常数(3.25±0.36)×103M-1。
实施例3：CP6A/氮芥复合物对肿瘤细胞抑制作用评价
1.实验样品
CP6A/氮芥复合物：实施例1制得。
人乳腺癌细胞MCF-7和肝癌细胞HepG2：均由北京协和细胞库提供。
2.实验方法
采用MTT法评价了CP6A/氮芥复合物对人乳腺癌细胞MCF-7和肝癌细胞HepG2的抑制作用，以单独氮芥药物作为对照组，细胞给药后48h测其毒性。
对于每一种细胞，收集对数期生长的细胞(MCF-7、HepG-2细胞)，调整细胞悬液浓度，将细胞悬浮液接种于96孔板，铺板使待测细胞调密度至约10000/孔，每孔100μL细胞悬液，在5％CO2，37℃恒温下孵育24h，显微镜下观察可见细胞贴壁生长，向培养板中加入10μL制备好的氮芥盐酸盐的水溶液或者含有氮芥盐酸盐的柱六乙酸铵(实施例1制备)(摩尔比为1∶1)，其中按照氮芥浓度计算分别均为0mM、0.01mM、0.1mM、0.2mM、0.4mM、0.6mM、0.8mM、1mM，每种浓度平行设置5个复孔，其中最后1孔只加PBS作为空白对照。并设空白组作为对照。在摇床上轻摇5min后，将培养板放置于培养箱中培养。48小时后，取出培养板，无菌条件下每孔加入10μl的MTT(5mg/mL)溶液，继续培养4h，终止培养，小心吸去孔内的培养液。接着每孔加入100μl DMSO，放置于摇床下低速震荡10min以使紫色结晶物充分的溶解。在全自动酶标仪490nm处检测各孔的吸光值。
3.实验结果
如图6A和图6B所示。
结果表明，CP6A包结药物氮芥(NM)后相比单独的氮芥药物而言明显提高药物的抗肿瘤细胞活性。
实施例4：CP6A/奥沙利铂复合物对肿瘤细胞抑制作用评价
1.实验样品
CP6A/奥沙利铂复合物：实施例2所制备。
肺癌细胞A549、肝癌细胞HepG2、T24细胞(膀胱癌细胞)、NCI细胞(肺癌细胞)、MGC-803细胞(胃癌细胞)、以及BEL-7404细胞(肝癌细胞)：均由北京协和细胞库提供。
2.实验方法
实验采用MTT法评价了CP6A/奥沙利铂复合物对肺癌细胞A549、肝癌细胞HepG2、膀胱癌T24、肺癌NCI、胃癌MGC-803、肝癌BEL-7404的抑制作用，以单独药物奥沙利铂作为对照组，细胞给药后48h测其毒性。
对于每一种细胞，收集对数期生长的细胞，调整细胞悬液浓度，将细胞悬浮液接种于96孔板，铺板使待测细胞调密度至约10000/孔，每孔100μL细胞悬液，在5％CO2， 37℃恒温下孵育24h，显微镜下观察可见细胞贴壁生长，向培养板中加入10μL制备好的奥沙利铂的水溶液或者含有奥沙利铂的柱六乙酸铵(实施例2制备)(摩尔比为1∶1)，其中，按照奥沙利铂浓度计算分别均为0mg/ml、25mg/ml、50mg/ml、100mg/ml、200mg/ml、400mg/ml，每种浓度平行设置5个复孔，最后只加PBS作为空白对照。并设空白组作为对照。在摇床上轻摇5min后，将培养板放置于培养箱中培养。48小时后，取出培养板，无菌条件下每孔加入10μl的MTT(5mg/mL)溶液，继续培养4h，终止培养，小心吸去孔内的培养液。接着每孔加入100μl DMSO，放置于摇床下低速震荡10min以使紫色结晶物充分的溶解。在全自动酶标仪490nm处检测各孔的吸光值。
3.实验结果
见下面的表3。
表3
Figure PCTCN2017077130-appb-000014
结果表明，奥沙利铂和CP6A形成复合物后可以明显提高药物对多种肿瘤细胞的抑制作用。
实施例5：NM/CP6A对肿瘤抑制作用评价
1.实验样品
NM/CP6A：前面实施例1制得CP6A/氮芥复合物。
S180肿瘤细胞：购自协和细胞库。
昆明小鼠：购自北京维通利华实验动物技术有限公司。
2.实验方法
将S180肿瘤细胞通过腹腔注射方式植入昆明小鼠，1×107个细胞/只。
将植入S180肿瘤细胞的昆明小鼠随机分成4组，每组12只，分组和给药如下：
阴性对照组：生理盐水；
阳性对照组：为NM(氮芥)，总剂量为4mg/kg；
高剂量实验组：NM/CP6A，4mg/kg，以NM的量计算；
低剂量实验组：NM/CP6A，1mg/kg，以NM的量计算。
分别在植入S180肿瘤细胞后的第1、3、5、7天，由尾静脉给药。
具体给药剂量如下面的表4所示。
表4：各组中每只小鼠的给药剂量
Figure PCTCN2017077130-appb-000015
实验过程中，每次给药前称量小鼠体重变化。实验结束后，杀死小鼠解剖出肿瘤并称重。
3.实验结果
如下面的表5所示。
表5：给小鼠静脉注射NM/CP6A对S-180肿瘤的抑制作用
Figure PCTCN2017077130-appb-000016
Figure PCTCN2017077130-appb-000017
结果显示，阳性对照4mg/kg的NM组肿瘤重量(1.13±0.45g)比4mg/kg的NM/CP6A实验组肿瘤重量(0.66±0.34g)高71％，说明相比同等剂量的阳性对照NM，NM/CP6A复合物具有更高的体内抗肿瘤活性。
实施例6：OX/CP6A对肿瘤抑制作用评价
1.实验样品
OX/CP6A：前面实施例2所制备CP6A/奥沙利铂复合物。
S180肿瘤细胞：购自北京协和细胞库。
昆明小鼠：购自北京维通利华实验动物技术有限公司。
2.实验方法
将S180肿瘤细胞通过腹腔注射方式植入昆明小鼠，1×107个细胞/只。
将植入S180肿瘤细胞的昆明小鼠随机分成4组，每组12只，分组和给药如下：
阴性对照组：生理盐水；
阳性对照组：为OX(奥沙利铂)，总剂量为35mg/kg；
高剂量实验组：OX/CP6A，35mg/kg，以OX的量计算；
低剂量实验组：OX/CP6A，15mg/kg，以OX的量计算。
分别在植入S180肿瘤细胞后的第1、3、5、7天，由尾静脉给药。
具体给药剂量如下面的表6所示。
表6：各组中每只小鼠的给药剂量
Figure PCTCN2017077130-appb-000018
实验过程中，每次给药前称量小鼠体重变化，实验结束后，杀死小鼠解剖出肿瘤并且称重。
3.实验结果
如下面的表7所示。
表7：给小鼠静脉注射OX/CP6A对S-180肿瘤的抑制作用
Figure PCTCN2017077130-appb-000019
结果显示，阳性对照OX组的肿瘤重量(0.85±0.24g)比35mg/kg的OX/CP6A实验组肿瘤重量(0.48±0.24g)高77％，说明相比同等剂量的阳性对照OX，OX/CP6A复合物具有更高的体内抗肿瘤活性。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (12)

  1. 一种复合物，其由药物和柱芳烃衍生物形成；优选地，所述复合物通过药物和柱芳烃衍生物的分子间超分子作用形成。
  2. 根据权利要求1所述的复合物，其中，所述药物为抗肿瘤药物；优选地，为氮芥、顺铂、卡铂或奥沙利铂。
  3. 根据权利要求1所述的复合物，其中，所述柱芳烃衍生物如下面的式I所示，
    Figure PCTCN2017077130-appb-100001
    其中，
    n为5、6、7、8、9或10；
    R选自下面的式II、式III或者式IV，并且两个R是相同的；
    Figure PCTCN2017077130-appb-100002
    式II中，M+为铵根离子、钠离子或钾离子，a为1、2、3、4、5、6、7、8、9或10；
    Figure PCTCN2017077130-appb-100003
    式III中，Y为氨基、醛基、羟基、胍基、酸基、季铵盐或吡啶盐，b为1、2、3、4、5、6、7、8、9或10。
    Figure PCTCN2017077130-appb-100004
    式IV中，c为1、2、3、4或5。
  4. 根据权利要求1至3中任一权利要求所述的复合物，其中，所述柱芳烃选自下面的化合物1-5：
    Figure PCTCN2017077130-appb-100005
    优选地，所述化合物1为如下的化合物6，
    Figure PCTCN2017077130-appb-100006
  5. 制备权利要求1至4中任一权利要求所述的复合物的方法，包括下述步骤：
    将一定摩尔比例的药物和柱芳烃衍生物混合物直接溶解在良性溶剂中混合均匀，然后冷冻干燥或减压真空干燥，得到复合物；
    优选地，包括下述步骤：
    将一定摩尔比例的氮芥和柱芳烃衍生物的混合物直接溶解在良性溶剂中混合均匀，然后在10分钟以内将混合物的溶液冷冻干燥或减压真空干燥即可；
    或者
    优选地，包括下述步骤：
    将一定摩尔比例的奥沙利铂和柱芳烃衍生物的混合物直接溶解在良性溶剂中30℃-60℃(优选为40℃-60℃)超声震荡一段时间(优选为10-20min)，至奥沙利铂完全溶解，然后将混合物的溶液冷冻干燥或减压真空干燥即可；
    优选地，上述柱芳烃衍生物为如下的化合物6，
    Figure PCTCN2017077130-appb-100007
    Figure PCTCN2017077130-appb-100008
  6. 根据权利要求5所述的制备方法，其中，所述柱芳烃衍生物与药物的摩尔比值为0.1-10；优选为0.5-5或0.8-1.5；更优选为1。
  7. 根据权利要求6所述的制备方法，其中，所述良性溶剂选自水、缓冲溶液、甲醇、乙醇、异丙醇或者它们的混合物。
  8. 一种药物组合物，其包含权利要求1至4中任一权利要求所述的复合物，以及任选的药学上可接受的辅料。
  9. 权利要求1至4中任一权利要求所述的复合物在制备选自如下的药物中的用途：
    治疗和/或预防肿瘤的药物，
    抑制肿瘤细胞的药物，或者
    治疗和/或预防癌性胸膜炎、心包积液或腹腔积液的药物；
    优选地，所述肿瘤选自肺癌、肝癌、膀胱癌、胃癌、卵巢癌、乳腺癌、前列腺癌、恶性淋巴瘤、结肠癌和肉瘤；
    优选地，所述肿瘤细胞选自肺癌细胞、肝癌细胞、膀胱癌细胞、胃癌细胞、卵巢癌细胞、乳腺癌细胞、前列腺癌细胞、恶性淋巴瘤细胞、结肠癌细胞和肉瘤细胞。
  10. 一种在体内或者体外抑制肿瘤细胞的方法，包括使用有效量的权利要求1至4中任一权利要求所述的复合物的步骤；优选地，所述肿瘤细胞选自肺癌细胞、肝癌细胞、膀胱癌细胞、胃癌细胞、卵巢癌细胞、乳腺癌细胞、前列腺癌细胞、恶性淋巴瘤细胞、结肠癌细胞和肉瘤细胞。
  11. 一种预防和/或治疗肿瘤特别是恶性肿瘤的方法，包括给予受试者有效量的权利要求1至4中任一权利要求所述的复合物的步骤；优选地，所述肿瘤选自肺癌、肝癌、膀胱癌、胃癌、卵巢癌、乳腺癌、前列腺癌、恶性淋巴瘤、结肠癌和肉瘤。
  12. 根据权利要求1至4中任一权利要求所述的复合物，其用于预防和/或治疗肿瘤；优选地，所述肿瘤选自肺癌、肝癌、膀胱癌、胃癌、卵巢癌、乳腺癌、前列腺癌、恶性淋巴瘤、结肠癌和肉瘤。
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