WO2021008516A1 - 一种含苯基化合物、其中间体、制备方法及应用 - Google Patents

一种含苯基化合物、其中间体、制备方法及应用 Download PDF

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WO2021008516A1
WO2021008516A1 PCT/CN2020/101842 CN2020101842W WO2021008516A1 WO 2021008516 A1 WO2021008516 A1 WO 2021008516A1 CN 2020101842 W CN2020101842 W CN 2020101842W WO 2021008516 A1 WO2021008516 A1 WO 2021008516A1
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formula
hydrophobic drug
compound
compound represented
drug
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PCT/CN2020/101842
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English (en)
French (fr)
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何军
王哲烽
赵悦竹
杨亚妮
付庆辉
卞玮
赵源
葛晨
章越
益兵
牛明浩
张久惠
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上海现代药物制剂工程研究中心有限公司
上海医药工业研究院
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Priority to JP2022503467A priority Critical patent/JP7282977B2/ja
Priority to EP20840790.8A priority patent/EP4001262A4/en
Priority to US17/627,965 priority patent/US11667604B2/en
Publication of WO2021008516A1 publication Critical patent/WO2021008516A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/17—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/18—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing carboxyl groups bound to the carbon skeleton containing amino groups bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmacy, relates to a drug delivery micellar system, and specifically relates to a phenyl-containing compound, its intermediate, a preparation method and an application.
  • micellar system is one of the simplest colloidal drug delivery systems, which can increase the water solubility of poorly soluble drugs and is a good passive targeting carrier system.
  • Micelles are divided into polymer micelles and small molecule micelles.
  • the polymer micelles solubilize hydrophobic drug molecules into the micelles through the self-assembly of amphiphilic block copolymers in water to extend the blood circulation time and half-life of the drugs.
  • Commonly used are polyethylene glycol-polylactic acid block copolymer, polyvinylpyrrolidone-racemic polylactic acid block copolymer, polyoxyethylene-polyoxystyrene block copolymer and polyoxyethylene-polyoxybutylene block copolymer.
  • Segment copolymers and so on Small molecule micelles are less common. Small molecule micelles are formed when the surfactant concentration is greater than the critical micelle concentration. Surfactants are composed of polar hydrophilic groups and non-polar hydrophobic groups. Compared with other polymer carriers, they have high drug loading and are safe. Good sex.
  • N-(all-trans-retinoyl)-L-cysteine sulfonate and its sodium salt can be used as a small molecule micelle.
  • N-(all-trans-retinoyl)-L-cysteine sulfonate and its sodium salt are combined with cytotoxic compounds such as docetaxel and doxorubicin, it has a synergistic effect: N-(all-trans Formula-retinoyl)-L-cystesulfonate methyl ester and its sodium salt can prepare poorly soluble drugs (such as docetaxel, paclitaxel, etc.) into water-soluble preparations, which can increase drug solubility and enhance pharmacological activity ; It and doxorubicin can be prepared into water-soluble preparations, which can increase the therapeutic window of the drug and improve the therapeutic efficacy.
  • poorly soluble drugs such as docetaxel, paclitaxel, etc.
  • methyl N-(all-trans-retinoyl)-L-cystesulfonate has poor stability and strong hygroscopicity.
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently C 1 -C 6 alkoxy
  • said C 1 -C 6 alkoxy The group is preferably C 1 -C 4 alkoxy, more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, and further Preferably it is a methoxy group.
  • said R 8 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • said R 6 is preferably
  • said C 1- 4 alkoxy group is preferably methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy, isobutoxy or tert-butoxy, more preferably methoxy.
  • said R 7 is preferably C 1-4 alkoxy.
  • said R 1 , R 2 and R 5 are independently C 1 -C 6 alkyl; said R 3 is C 1 -C 6 alkoxy; said R 4 is hydrogen; said R 6 is The R 7 is C 1-4 alkoxy.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof is preferably
  • the present invention also provides a method for preparing the compound represented by formula I, which comprises the following steps: in a polar aprotic solvent, under the action of a base, the compound represented by formula III and the compound represented by formula II
  • the compound can be subjected to the amine transesterification reaction shown below,
  • the technical problem to be solved by the present invention is to overcome the defect of a single type of the existing drug delivery carrier, and provide a phenyl-containing compound, its intermediate, a preparation method and application.
  • the phenyl-containing compound of the present invention has a lower critical micelle concentration (CMC) and good stability.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • R 6 is (Correspondingly, in the pharmaceutically acceptable salt of the compound represented by formula I, R 6 may be );
  • R 7 is -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C 1-4 alkoxy (correspondingly, in the pharmaceutically acceptable salt of the compound represented by formula I, R 7 can be -O - Na + ).
  • the C 1 -C 6 alkyl is preferably It is a C 1 -C 4 alkyl group, more preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and still more preferably a methyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the same as defined above.
  • the polar aprotic solvent may be a conventional polar aprotic solvent for this type of reaction in the field.
  • amide solvents, ether solvents, ketone solvents, and nitriles are particularly preferred.
  • the amide solvent is preferably one or more of N,N-dimethylformamide, hexamethylphosphoramide and N,N-dimethylacetamide, and more preferably N,N-dimethylformamide ⁇ Formamide.
  • the ether solvent is preferably tetrahydrofuran.
  • the ketone solvent is preferably acetone and/or N-methylpyrrolidone.
  • the nitrile solvent is preferably acetonitrile.
  • the sulfoxide solvent is preferably dimethyl sulfoxide.
  • the polar aprotic solvents are preferably amide solvents, ether solvents and nitrile solvents, and more preferably tetrahydrofuran, acetonitrile and N,N-dimethylformamide.
  • the molar concentration of the compound represented by formula III in the polar aprotic solvent may be a conventional molar concentration of this type of reaction in the art, and it is particularly preferably 0.01 in the present invention. ⁇ 0.2 mol/L, more preferably 0.05 to 0.8 mol/L (for example, 0.0625 mol/L).
  • the base can be a conventional base in this type of reaction in the art.
  • the present invention is particularly preferably an organic amine, and further preferably triethylamine, diisopropylethylamine, pyridine, and triethylamine.
  • the molar ratio of the base to the compound represented by formula III can be a conventional molar ratio of this type of reaction in the art, and the present invention is particularly preferably 1.5:1 to 3: 1. More preferably, it is 1.8:1 to 2.5:1 (for example, 2.02:1).
  • the molar ratio of the compound represented by formula II to the compound represented by formula III may be a conventional molar ratio of this type of reaction in the art, and the present invention is particularly preferably 1:1 to 3:1, more preferably 1:1 to 2:1 (for example, 1.5:1).
  • the progress of the reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), and the disappearance of the compound represented by formula III is generally monitored as the end of the reaction.
  • the reaction time of the reaction is preferably 1 to 24 hours, more preferably 4 to 12 hours (for example, 4 hours and 12 hours).
  • the reaction temperature of the reaction may be a conventional reaction temperature of this type of reaction in the art, and room temperature is particularly preferred in the present invention.
  • a post-treatment step may be further included.
  • the post-treatment steps are preferably concentrating, quenching, extracting, re-extracting, washing, filtering and drying the reaction solution.
  • the reagent used for the quenching is preferably water.
  • the reagent used for the extraction is preferably methyl tert-butyl ether.
  • the reagent used for the re-extraction is preferably ethyl acetate.
  • the reagent used for the washing is preferably a saturated sodium chloride solution.
  • the drying temperature is preferably 40°C.
  • the instrument used for the drying is preferably a vacuum drying oven.
  • the method for preparing the compound represented by formula I includes the following steps: combining the polar aprotic solvent, the base and the compound as shown in formula II Mix the compounds shown, and add the compound shown in formula III to react.
  • the present invention also provides a method for preparing the compound represented by formula I, which may further include the following steps: in a polar aprotic solvent, under the action of a base, the compound represented by formula IV and the compound represented by formula The compound shown in V may undergo the condensation reaction shown below,
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
  • the polar aprotic solvent may be a conventional polar aprotic solvent for this type of reaction in the field.
  • the present invention is particularly preferably an ether solvent and/or a nitrile solvent, and preferably an ether solvent
  • the nitrile solvent is more preferably an ether solvent and a nitrile solvent having a volume ratio of 1:2.
  • the ether solvent is preferably tetrahydrofuran.
  • the nitrile solvent is preferably acetonitrile.
  • the polar aprotic solvent is preferably a mixed solvent of tetrahydrofuran and acetonitrile with a volume ratio of 1:2.
  • the molar concentration of the compound represented by formula IV in the polar aprotic solvent can be the molar concentration conventional in this type of reaction in the art, and it is particularly preferably 0.01-1 mol in the present invention. /L, more preferably 0.1 to 0.2 mol/L (for example, 1/6 mol/L).
  • the base can be a conventional base for this type of reaction in the field.
  • the present invention is particularly preferably an organic amine, and more preferably triethylamine, diisopropylethylamine, pyridine, and tri-n-butylamine. And one or more of N-methylmorpholine, more preferably triethylamine.
  • the molar ratio of the base to the compound represented by formula IV can be a conventional molar ratio of this type of reaction in the art, and the molar ratio can be greater than 1:1.
  • the ratio is particularly preferably 1:1 to 3:1, and more preferably 1:1 to 1.5:1 (for example, 1.15:1).
  • the molar ratio of the compound represented by formula V to the compound represented by formula IV may be a conventional molar ratio of this type of reaction in the art, and the molar ratio of the present invention is particularly preferably 1: 1 to 3:1, more preferably 1:1 to 1.5:1 (for example, 1.1:1).
  • the progress of the reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), and the disappearance of the compound represented by formula IV is generally monitored as the end point of the reaction.
  • the reaction time of the reaction is preferably 10 to 60 minutes, more preferably 25 to 35 minutes (for example, 30 minutes).
  • the reaction temperature of the reaction can be the conventional reaction temperature of this type of reaction in the art. In the present invention, it is particularly preferably 0 to -40°C, further preferably -10 to -30°C (for example, -20 °C).
  • the condensation reaction includes the following steps: mixing the polar aprotic solvent, the base and the compound represented by formula IV, and adding the The compound shown in formula V can be reacted.
  • the present invention also provides a compound represented by formula III,
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
  • the compound represented by formula III is preferably
  • the present invention also provides an application of the compound represented by Formula I or a pharmaceutically acceptable salt thereof as a pharmaceutical excipient.
  • the pharmaceutical excipients are preferably drug carriers in the micellar drug delivery system.
  • the drug in the drug carrier is preferably a hydrophobic drug.
  • the hydrophobic drug is preferably docetaxel, doxorubicin or paclitaxel, and more preferably docetaxel.
  • the present invention also provides a hydrophobic drug micelle, which comprises the hydrophobic drug and substance X; the substance X is the compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the mass ratio of the hydrophobic drug to the substance X is preferably 1.25:1 to 3:1.
  • the present invention also provides a method for preparing hydrophobic drug micelles, which includes the following steps:
  • Step 1 Mix the above-mentioned hydrophobic drug, the above-mentioned substance X, and methanol to obtain material A;
  • Step 2 Remove the methanol from the material A, hydrate, filter, and freeze-dry.
  • the mass ratio of the substance X to the hydrophobic drug is preferably 1.25:1 to 3:1.
  • the volume of the methanol can dissolve the hydrophobic drug, and the ratio of the volume of the methanol to the mass of the hydrophobic drug is preferably 1:4 mL/g.
  • step 1 after mixing the hydrophobic drug, the substance X, and methanol, an ultrasonic step may be further included. After the ultrasonic step, the material is obtained A.
  • the method for removing methanol is preferably rotary evaporation and drying.
  • the temperature of the rotary evaporation is preferably 30-50°C (for example, 40°C).
  • the drying temperature is preferably 30-50°C (for example, 40°C).
  • the ratio of the volume of the water for injection used in the hydration to the mass of the hydrophobic drug is preferably 1:10mL/g to 3:10mL/g, more preferably 1:10mL/g , 3:20mL/g, 1:5mL/g, 1:4mL/g or 3:10mL/g.
  • the rotation speed of the hydration can be the conventional hydration rotation speed in the thin film hydration method in the field, and it is particularly preferably 100-200 r/min (for example, 100 r/min) in the present invention.
  • the hydration time can be the conventional hydration time in the film hydration method in the field, and it is particularly preferably 5-20 min (for example, 10 min) in the present invention.
  • the filter used in the filtration is preferably a microporous membrane.
  • the pore size of the microporous filter membrane is preferably 0.22 ⁇ m.
  • the present invention also provides a hydrophobic drug micelle, which is prepared according to the above preparation method; the hydrophobic drug is preferably docetaxel.
  • the present invention also provides an application of docetaxel micelles in the preparation of drugs for the treatment of advanced or metastatic breast cancer that has failed prior chemotherapy, or advanced or metastatic non-small cell lung cancer drugs that use cisplatin-based chemotherapy failure .
  • room temperature refers to 10 to 30°C.
  • hydrophobic drugs refer to drugs that tend to be non-polar, insoluble in water, and easily soluble in neutral and non-polar solutions (such as organic solvents). Hydrophobic drugs include, but are not limited to, docetaxel, doxorubicin, or paclitaxel.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that the phenyl-containing compound provided by the present invention has a low critical micelle concentration (CMC), good dilution resistance, can encapsulate poorly soluble drugs to form small molecule micelles, and has high drug loading. Good stability.
  • CMC critical micelle concentration
  • Figure 1 shows the measurement of carrier CMC value by pyrene fluorescence probe method.
  • HPLC detection conditions Column: Insertsil ODS-SP (4.6 ⁇ 250mm, 5 ⁇ m); Mobile phase: Acetonitrile: Phosphate buffer (43:57); Buffer: 20mmol/L potassium dihydrogen phosphate and dihydrogen phosphate Sodium; flow rate: 1.0 mL/min; column temperature: 40° C.; detection wavelength: 355 nm; injection volume: 10 ⁇ L; retention time of product peak: 21.234 min. HPLC detection results are shown in Table 1.
  • Example 2 The carrier of Example 1 was placed in a solid form in an environment of normal temperature and normal light, normal temperature and dark, 4°C and -18°C, respectively, and tested at 1d, 3d, 7d, 30d, 60d, 90d, 120d. After the remaining amount of the carrier, the remaining amount was determined by HPLC, and the test results are shown in Table 2.
  • the sodium salt of N-(all-trans-retinoyl)-L-cysteine sulfonate is placed in a solid form in the environment of room temperature and light, room temperature and light, 4°C and -18°C (other Under the same conditions as in Example 4), the appearance and remaining amount after 1d, 3d, 7d, and 30d were tested respectively. The remaining amount was determined by HPLC. The test results are shown in Table 5.

Abstract

一种含苯基化合物、其中间体、制备方法及应用。一种如式I所示的化合物或其药学上可接受的盐，其中，R 1、R 2、R 3、R 4和R 5独立地为氢、C 1-C 6烷基、C 1-C 6烷氧基或C（＝O）OR 8；其中R 8为C 1-C 4烷基；R 6为（II）, （II）或（IV）R 7为-OH、-NH 2、-NHCH 3、-N（CH 3）2或C 1-4烷氧基。此类化合物具有较低的临界胶束浓度（CMC），耐稀释性良好，能够包裹难溶性药物形成小分子胶束，载药量高，稳定性好。（I）

Description

一种含苯基化合物、其中间体、制备方法及应用
本申请要求申请日为2019年7月18日的中国专利申请CN2019106503581的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药学领域，涉及给药胶束系统，具体涉及是一种含苯基化合物、其中间体、制备方法及应用。
背景技术
胶束系统是最简单的胶体给药系统之一，可增加难溶性药物的水溶性，是一种良好的被动靶向载体系统。胶束分为聚合物胶束和小分子胶束。聚合物胶束通过两亲性嵌段共聚物在水中的自组装作用，将疏水性药物分子增溶到胶束内部，达到延长药物的血液循环时间及半衰期的作用。常见有聚乙二醇-聚乳酸嵌段共聚物、聚乙烯吡咯烷酮-外消旋聚乳酸嵌段共聚物、聚氧乙烯-聚氧苯乙烯嵌段共聚物和聚氧乙烯-聚氧丁烯嵌段共聚物等。小分子胶束载药较不常见。小分子胶束由表面活性剂浓度大于临界胶束浓度时形成，表面活性剂由极性亲水基团和非极性疏水基团组成，相较于其他聚合物载体，载药量高，安全性好。
CN1668583A中报道了N-(全反式-视黄酰基)-L-半胱磺酸甲酯及其钠盐可作为一种小分子胶束。N-(全反式-视黄酰基)-L-半胱磺酸甲酯及其钠盐与多西他赛、多柔比星等细胞毒性化合物联用时，具有协同作用：N-(全反式-视黄酰基)-L-半胱磺酸甲酯及其钠盐可将溶解度差的药物(例如多西他赛、紫杉醇等)制备成水溶性制剂，能够增大药物溶解度，增强药理活性；其与多柔比星可以制备成水溶性制剂，能够增大该药物的治疗窗，改进治疗功效。
但N-(全反式-视黄酰基)-L-半胱磺酸甲酯存在稳定性差、吸湿性极强、
在本发明一优选实施方案中，当所述的R 1、R 2、R 3、R 4和R 5独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基优选为C 1-C 4烷氧基，进一步优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，更进一步优选为甲氧基。
在本发明一优选实施方案中，所述的R 8优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在本发明一优选实施方案中，所述的R 6优选为
Figure PCTCN2020101842-appb-000001
在本发明一优选实施方案中，当所述的R 7为C 1-4烷氧基时，所述的C 1- 4烷氧基优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，进一步优选为甲氧基。
在本发明一优选实施方案中，所述的R 7优选为C 1-4烷氧基。
在本发明一优选实施方案中，所述的R 1、R 2和R 5独立地为C 1-C 6烷基；所述的R 3为C 1-C 6烷氧基；所述的R 4为氢；所述的R 6为
Figure PCTCN2020101842-appb-000002
所述的R 7为C 1-4烷氧基。
在本发明一优选实施方案中，所述的如式I所示的化合物或其药学上可接受的盐优选为
Figure PCTCN2020101842-appb-000003
Figure PCTCN2020101842-appb-000004
本发明还提供了一种如式I所示的化合物的制备方法，其包括以下步骤：极性非质子溶剂中，在碱的作用下，将如式III所示的化合物和如式II所示的化合物进行如下所示的胺酯交换反应即可，
不能以固体形式储存的缺点，在工业生产与运输都存在问题。
Figure PCTCN2020101842-appb-000005
发明内容
本发明要解决的技术问题是克服现有的给药载体种类单一的缺陷，而提供了一种含苯基化合物、其中间体、制备方法及应用。本发明的含苯基化合物具有较低的临界胶束浓度(CMC)且稳定性好。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种如式I所示的化合物或其药学上可接受的盐，
Figure PCTCN2020101842-appb-000006
其中，R 1、R 2、R 3、R 4和R 5独立地为氢、C 1-C 6烷基、C 1-C 6烷氧基或C(＝O)OR 8；其中R 8为C 1-C 4烷基；
R 6为
Figure PCTCN2020101842-appb-000007
(相应地，如式I所示的化合物的药学上可接受的盐中，R 6可以为
Figure PCTCN2020101842-appb-000008
)；
R 7为-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C 1-4烷氧基(相应地，如式I所示的化合物的药学上可接受的盐中，R 7可以为-O -Na +)。
在本发明一优选实施方案中，当所述的R 1、R 2、R 3、R 4和R 5独立地为C 1-C 6烷基时，所述的C 1-C 6烷基优选为C 1-C 4烷基，进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，更进一步优选为甲基。
Figure PCTCN2020101842-appb-000009
其中，R 1、R 2、R 3、R 4、R 5、R 6和R 7同前所定义。
所述的胺酯交换反应中，所述的极性非质子溶剂可为本领域该类反应常规的极性非质子溶剂，本发明特别优选为酰胺类溶剂、醚类溶剂、酮类溶剂、腈类溶剂和亚砜类溶剂中的一种或多种。所述的酰胺类溶剂优选为N,N-二甲基甲酰胺、六甲基磷酰胺和N,N-二甲基乙酰胺中的一种或多种，进一步优选为N,N-二甲基甲酰胺。所述的醚类溶剂优选为四氢呋喃。所述的酮类溶剂优选为丙酮和/或N-甲基吡咯烷酮。所述的腈类溶剂优选为乙腈。所述的亚砜类溶剂优选为二甲亚砜。所述的极性非质子溶剂优选为酰胺类溶剂、醚类溶剂和腈类溶剂，进一步优选为四氢呋喃、乙腈和N,N-二甲基甲酰胺。
所述的胺酯交换反应中，所述的如式III所示的化合物在所述的极性非质子溶剂中的摩尔浓度可为本领域该类反应常规的摩尔浓度，本发明特别优选为0.01～0.2mol/L，进一步优选为0.05～0.8mol/L(例如0.0625mol/L)。
所述的胺酯交换反应中，所述的碱可为本领域该类反应常规的碱，本发明特别优选为有机胺，进一步优选为三乙胺、二异丙基乙胺、吡啶、三正丁胺和N-甲基吗啉中的一种或多种，更进一步优选三乙胺。
所述的胺酯交换反应中，所述的碱与所述的如式III所示的化合物的摩尔比可为本领域该类反应常规的摩尔比，本发明特别优选为1.5:1～3:1，进一步优选为1.8:1～2.5:1(例如2.02:1)。
所述的胺酯交换反应中，所述的如式II所示的化合物与所述的如式III所示的化合物的摩尔比可为本领域该类反应常规的摩尔比，本发明特别优选为1:1～3:1，进一步优选为1:1～2:1(例如1.5:1)。
所述的胺酯交换反应中，反应进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以监测到如式III所示的化合 物消失作为反应终点。所述的反应的反应时间优选为1～24小时，进一步优选4～12小时(例如4小时和12小时)。
所述的胺酯交换反应中，所述的反应的反应温度可为本领域该类反应常规的反应温度，本发明特别优选为室温。
所述的胺酯交换反应中，所述的反应结束后还可进一步包括后处理步骤。所述的后处理步骤优选为将反应液浓缩、淬灭、萃取、再萃取、洗涤、过滤和干燥。所述的淬灭所用的试剂优选为水。所述的萃取所用的试剂优选为甲基叔丁基醚。所述的再萃取所用的试剂优选为乙酸乙酯。所述的洗涤所用的试剂优选为饱和氯化钠溶液。所述的干燥的温度优选为40℃。所述的干燥所使用的仪器优选为真空干燥箱。
在本发明一优选实施方案中，所述的如式I所示的化合物的制备方法，其包括以下步骤：将所述的极性非质子溶剂，所述的碱和所述的如式II所示的化合物混合，加入所述的如式III所示的化合物反应即可。
本发明还提供了一种如式I所示的化合物的制备方法，其还可进一步包括以下步骤：极性非质子溶剂中，在碱的作用下，将如式IV所示的化合物和如式V所示的化合物进行如下所示的缩合反应即可，
Figure PCTCN2020101842-appb-000010
其中，R 1、R 2、R 3、R 4和R 5同前所定义。
所述的缩合反应中，所述的极性非质子溶剂可为本领域该类反应常规的极性非质子溶剂，本发明特别优选为醚类溶剂和/或腈类溶剂，优选为醚类溶剂和腈类溶剂，进一步优选为体积比为1:2的醚类溶剂和腈类溶剂。所述的醚类溶剂优选为四氢呋喃。所述的腈类溶剂优选为乙腈。所述的极性非质子溶剂优选为体积比为1:2的四氢呋喃和乙腈的混合溶剂。
所述的缩合反应中，所述的如式IV所示的化合物在所述的极性非质子 溶剂中的摩尔浓度可为本领域该类反应常规的摩尔浓度，本发明特别优选为0.01～1mol/L，进一步优选为0.1～0.2mol/L(例如1/6mol/L)。
所述的缩合反应中，所述的碱可为本领域该类反应常规的碱，本发明特别优选为有机胺，进一步优选为三乙胺、二异丙基乙胺、吡啶、三正丁胺和N-甲基吗啉中的一种或多种，更进一步优选三乙胺。
所述的缩合反应中，所述的碱与所述的如式IV所示的化合物的摩尔比可为本领域该类反应常规的摩尔比，所述的摩尔比大于1:1即可，本发明特别优选为1:1～3:1，进一步优选为1:1～1.5:1(例如1.15:1)。
所述的缩合反应中，所述的如式V所示的化合物与所述的如式IV所示的化合物的摩尔比可为本领域该类反应常规的摩尔比，本发明特别优选为1:1～3:1，进一步优选为1:1-1.5:1(例如1.1:1)。
所述的缩合反应中，反应进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以监测到如式IV所示的化合物消失作为反应终点。所述的反应的反应时间优选为10～60分钟，进一步优选25～35分钟(例如30分钟)。
所述的缩合反应中，所述的反应的反应温度可为本领域该类反应常规的反应温度，本发明特别优选为0～-40℃，进一步优选为-10～-30℃(例如-20℃)。
在本发明一优选实施方案中，所述缩合反应，其包括以下步骤：将所述的极性非质子溶剂，所述的碱和所述的如式IV所示的化合物混合，加入所述的如式V所示的化合物反应即可。
本发明还提供了如式III所示的化合物，
Figure PCTCN2020101842-appb-000011
其中，R 1、R 2、R 3、R 4和R 5同前所定义。
在本发明的一优选实施方案中，所述的如式III所示的化合物优选为
Figure PCTCN2020101842-appb-000012
本发明还提供了一种上述如式I所示的化合物或其药学上可接受的盐作为药用辅料的应用。
所述的药用辅料优选为胶束给药系统中的药物载体。所述的药物载体中所述的药物优选为疏水性药物。所述的疏水性药物优选为多西他赛、多柔比星或紫杉醇，进一步优选为多西他赛。
本发明还提供了一种疏水性药物胶束，其包含上述疏水性药物和物质X；所述的物质X为上述如式I所示的化合物或其药学上可接受的盐。
在本发明一优选实施方案中，所述的疏水性药物胶束中，所述的疏水性药物和所述的物质X的质量比优选为1.25:1～3:1。
本发明还提供了一种疏水性药物胶束的制备方法，其包括以下步骤：
步骤1：将上述疏水性药物、上述物质X、和甲醇混合，得物料A；
步骤2：将所述的物料A去除甲醇，水化，过滤，冻干即可。
在本发明一优选实施方案中，所述的疏水性药物胶束的制备方法中，所述的物质X与所述的疏水性药物的质量比优选为1.25:1～3:1。
在本发明一优选实施方案中，所述的甲醇的体积使所述的疏水性药物溶解即可，所述的甲醇的体积和所述的疏水性药物质量比优选为1:4mL/g。
在本发明一优选实施方案中，步骤1中，将所述的疏水性药物、所述的物质X、和甲醇混合后，还可进一步包括超声步骤，所述的超声步骤后得所述的物料A。
在本发明一优选实施方案中，所述的去除甲醇的方式优选为旋转蒸发和干燥。所述的旋转蒸发的温度优选为30～50℃(例如40℃)。所述的干燥的温度优选为30～50℃(例如40℃)。
在本发明一优选实施方案中，所述水化所使用的注射用水体积和所述的 疏水性药物质量比优选为1:10mL/g～3:10mL/g，进一步优选为1:10mL/g、3:20mL/g、1:5mL/g、1:4mL/g或3:10mL/g。
在本发明一优选实施方案中，所述水化的转速可为本领域薄膜水化法中的常规水化转速，本发明特别优选为100～200r/min(例如100r/min)。
在本发明一优选实施方案中，所述水化的时间可为本领域薄膜水化法中的常规水化时间，本发明特别优选为5～20min(例如10min)。
在本发明一优选实施方案中，所述过滤所用的过滤器优选为微孔滤膜。所述的微孔滤膜的孔径优选为0.22μm。
本发明还提供了一种疏水性药物胶束，其按照上述的制备方法制得；所述的疏水性药物优选为多西他赛。
本发明还提供了一种多西他赛胶束在制备治疗先期化疗失败的晚期或转移性乳腺癌、或者使用以顺铂为主的化疗失败的晚期或转移性非小细胞肺癌药物中的应用。
本发明中，室温指10～30℃。
本发明中，疏水性药物是指偏向于非极性的药物，不溶于水，易溶解在中性和非极性溶液(如有机溶剂)。疏水性药物包括但不限于多西他赛、多柔比星或紫杉醇。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供的含苯基化合物，具有较低的临界胶束浓度(CMC)，耐稀释性良好，能够包裹难溶性药物形成小分子胶束，载药量高，稳定性好。
附图说明
图1为芘荧光探针法测定载体CMC值。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
Figure PCTCN2020101842-appb-000013
阿维A酸丁酸酐的制备：在25mL的三口瓶中，室温下，依次加入阿维A酸(0.32g，1mmol)、2mL四氢呋喃、4mL乙腈、0.16mL三乙胺，放入低温冷却槽，机械搅拌，反应体系降温至-20℃时，缓慢加入氯甲酸丁酯(0.14mL，1.1mmol)，加入完毕后，继续反应30min。得阿维A酸丁酸酐反应液。
Figure PCTCN2020101842-appb-000014
载体的制备：在25mL的四口瓶中，室温下，依次加入L-半胱磺酸甲酯(0.33g，1.5mmol)、10mL N,N-二甲基甲酰胺、0.26mL三乙胺，机械搅拌，室温，搅拌至基本溶解后，开始滴加上述的阿维A酸丁酸酐反应液。滴加完毕后，继续反应4h。反应完毕后，旋掉部分反应溶剂，加入20mL水，用甲基叔丁基醚萃取未反应的阿维A酸(20mL×3)，用乙酸乙酯萃取反应产物(20mL×2)。乙酸乙酯相中用饱和氯化钠洗,第二遍析出固体，过滤后将固体放置40℃真空干燥箱烘干，得到410mg淡黄色固体，产品收率84％，纯度99.78％。
钠盐载体的制备：在25mL的四口瓶中，室温下，依次加入L-半胱磺酸甲酯(0.33g，1.5mmol)、10mL N,N-二甲基甲酰胺、0.26mL三乙胺，机械 搅拌，室温，搅拌至基本溶解后，开始滴加上述的阿维A酸丁酸酐反应液。滴加完毕后，继续反应4h。反应完毕后，旋掉部分反应溶剂，加入6ml饱和碳酸氢钠，继续搅拌1h，加入20mL水，用甲基叔丁基醚萃取未反应的阿维A酸(20mL×3)，用乙酸乙酯萃取反应产物(20mL×2)。乙酸乙酯相中用饱和氯化钠洗,第二遍析出固体，过滤后将固体放置40℃真空干燥箱烘干，得到410mg淡黄色固体，产品收率82％，纯度99.64％。
载体：MS(ESI)m/z 490.29(M-H +)； 1H NMR(400MHz,MeOD)δ8.00(s,1H，NH),7.06(dd,J＝14.9,11.5Hz,1H,CH＝CH-),6.72(d,J＝16.3Hz,1H,-CH＝CH-),6.65(s,1H,Ph-H),6.38(d,J＝15.0Hz,1H,-CH＝CH-),6.32–6.19(m,2H,-CH＝CH-),4.58(s,1H,CH),3.80(s,3H,-O-CH 3),3.77(s,3H,C-O-CH 3),3.02(s,1H,CH 2),2.88(s,1H,CH 2),2.33(s,3H,CH 3),2.29(s,3H,CH 3),2.23(s,3H,CH 3),2.12(s,6H,CH 3).
载体：HPLC检测条件：色谱柱：Inertsil ODS-SP(4.6×250mm，5μm)；流动相：乙腈：磷酸缓冲盐(43：57)；缓冲液：20mmol/L的磷酸二氢钾与磷酸氢二钠；流速：1.0mL/min；柱温：40℃；检测波长：355nm；进样体积：10μL；产品峰的保留时间：21.234min，HPLC检测结果具体见表1。
表1载体的HPLC检测结果
Figure PCTCN2020101842-appb-000015
实施例2
Figure PCTCN2020101842-appb-000016
阿维A酸丁酸酐的制备：在50mL的三口瓶中，室温下，依次加入阿维A酸(0.98g，3mmol)、6mL四氢呋喃、12mL乙腈、0.48mL三乙胺，放入低温冷却槽，机械搅拌，反应体系降温至-20℃时，缓慢加入氯甲酸丁酯(0.42mL，3.3mmol)，加入完毕后，继续反应30min。得阿维A酸丁酸酐反应液。
Figure PCTCN2020101842-appb-000017
载体的制备：在100mL的四口瓶中，室温下，依次加入L-半胱磺酸甲酯(0.99g，4.5mmol)、30mL N,N-二甲基甲酰胺、0.78mL三乙胺，机械搅拌，室温，搅拌至基本溶解后，开始滴加上述的阿维A酸丁酸酐反应液。滴加完毕后，继续反应12h。反应完毕后，旋掉部分反应溶剂，加入60mL水，用甲基叔丁基醚萃取未反应的阿维A酸(60mL×3)，用乙酸乙酯萃取反应产物(60mL×3)。乙酸乙酯相中用饱和氯化钠洗,第二遍析出固体，过滤后将固体放置40℃真空干燥箱烘干，得到1.21g淡黄色固体，产品收率82％，纯度99.69％。其MS(ESI)和 1H NMR数据同实施例1的载体。
实施例3芘荧光探针法测定临界胶束浓度(CMC)
配制芘母液1.0mg/mL于丙酮，稀释100倍至0.01mg/mL，移取10μL于1.5mL EP管中，常温下，置于通风处中避光挥干丙酮。加入1mL各浓度的载体溶液(实施例1的载体溶解在纯水中，配置成不同浓度)，振摇平衡6h，荧光分光光度计测定其在I1(373nm)和I3(384nm)处的荧光强度值，以I1/I3对LogC作图，测得CMC为6.5μg/mL。
实施例4载体的稳定性测试
将实施例1的载体以固体形式分别放置于常温常光、常温避光、4℃避光和-18℃避光的环境下，分别测试在放置1d、3d、7d、30d、60d、90d、120d后的载体剩余量，其中剩余量用HPLC测定，测试结果如表2所示。
表2实施例1的载体的稳定性数据
Figure PCTCN2020101842-appb-000018
实施例5薄膜水化法制备多西他赛纳米胶束
称取多西他赛(DTX)、实施例1的载体，用甲醇超声至完全溶解，40℃下以一定转速旋转蒸发5min，除去溶剂甲醇，40℃下真空干燥箱中放置2h，除去残留溶剂，加入注射用水水化，其中水化转速为100r/min，水化时间为10min，0.22μm微孔滤膜(PES)过滤，冷冻干燥，得到纳米胶束冻干制剂，制剂的表征数据如表3所示。
表3不同多西他赛和载体质量比下制剂表征数据
Figure PCTCN2020101842-appb-000019
Figure PCTCN2020101842-appb-000020
实施例5薄膜水化法制备多西他赛纳米胶束
称取DTX 20mg、实施例1的载体30mg，用5mL甲醇超声至完全溶解，40℃下以一定转速旋转蒸发5min，除去溶剂甲醇，40℃下真空干燥箱中放置2h，除去残留溶剂，加入注射用水水化，其中水化转速为100r/min，水化时间为10min，0.22μm微孔滤膜(PES)过滤，冷冻干燥，得到纳米胶束冻干制剂，制剂的表征数据如表4所示。
表4不同注射用水体积下制剂表征数据
Figure PCTCN2020101842-appb-000021
对比实施例1
N-(全反式-视黄酰基)-L-半胱磺酸甲酯的钠盐以固体形式分别放置于常 温常光、常温避光、4℃避光和-18℃避光的环境(其他条件同实施例4)下，分别测试在放置1d、3d、7d、30d后的外观以及剩余量，其中剩余量用HPLC测定，测试结果如表5所示。
表5 N-(全反式-视黄酰基)-L-半胱磺酸甲酯的钠盐的稳定性数据
Figure PCTCN2020101842-appb-000022
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (15)

  1. 一种如式I所示的化合物或其药学上可接受的盐，
    Figure PCTCN2020101842-appb-100001
    其中，R 1、R 2、R 3、R 4和R 5独立地为氢、C 1-C 6烷基、C 1-C 6烷氧基或C(＝O)OR 8；其中R 8为C 1-C 4烷基；
    R 6为
    Figure PCTCN2020101842-appb-100002
    R 7为-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C 1-4烷氧基。
  2. 如权利要求1所述的如式I所示的化合物或其药学上可接受的盐，其特征在于，
    如式I所示的化合物的药学上可接受的盐中，如式I所示的化合物的R 6与离子形成
    Figure PCTCN2020101842-appb-100003
    和/或，如式I所示的化合物的药学上可接受的盐中，如式I所示的化合物的R 7与离子形成-O -Na +；
    和/或，当所述的R 1、R 2、R 3、R 4和R 5独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为C 1-C 4烷基，优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，进一步优选为甲基；
    和/或，当所述的R 1、R 2、R 3、R 4和R 5独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为C 1-C 4烷氧基，优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，进一步优选为甲氧基；
    和/或，所述的R 8为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，当所述的R 7为C 1-4烷氧基时，所述的C 1-4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，优选为甲氧基；
    和/或，所述的R 6为
    Figure PCTCN2020101842-appb-100004
    和/或，所述的R 7为C 1-4烷氧基。
  3. 如权利要求1或2所述的如式I所示的化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物或其药学上可接受的盐为
    Figure PCTCN2020101842-appb-100005
  4. 一种如权利要求1～3任一项所述的如式I所示的化合物的制备方法，其特征在于，其包括以下步骤：极性非质子溶剂中，在碱的作用下，将如式III所示的化合物和如式II所示的化合物进行如下所示的胺酯交换反应即可，
    Figure PCTCN2020101842-appb-100006
  5. 一种如权利要求4所述的如式I所示的化合物的制备方法，其特征在于，其还进一步包括以下步骤：极性非质子溶剂中，在碱的作用下，将如式IV所示的化合物和如式V所示的化合物进行如下所示的缩合反应即可，
    Figure PCTCN2020101842-appb-100007
  6. 一种如式III所示的化合物，
    Figure PCTCN2020101842-appb-100008
    其中，R 1、R 2、R 3、R 4和R 5同权利要求1～3任一项所定义。
  7. 如权利要求6所述的如式III所示的化合物，其特征在于，所述的如式III所示的化合物为
    Figure PCTCN2020101842-appb-100009
  8. 一种如权利要求1～3任一项所述的如式I所示的化合物或其药学上可接受的盐作为药用辅料的应用。
  9. 如权利要求8所述的应用，其特征在于，所述的药用辅料为胶束给药系统中的药物载体；所述的药物载体中所述的药物优选为疏水性药物；所述的疏水性药物优选为多西他赛、多柔比星或紫杉醇，进一步优选为多西他赛。
  10. 一种疏水性药物胶束，其特征在于，其包含如权利要求9所述的疏水性药物和物质X；所述的物质X为如权利要求1～3任一项所述的如式I所示的化合物或其药学上可接受的盐。
  11. 如权利要求10所述的疏水性药物胶束，其特征在于，所述的疏水性药物和所述的物质X的质量比为1.25:1～3:1。
  12. 一种疏水性药物胶束的制备方法，其特征在于，其包括以下步骤：
    步骤1：将如权利要求9所述的疏水性药物、如权利要求10所述的所述的物质X、和甲醇混合，得物料A；
    步骤2：将所述的物料A去除甲醇，水化，过滤，冻干即可。
  13. 如权利要求12所述的疏水性药物胶束的制备方法，其特征在于，
    所述的物质X与所述的疏水性药物的质量比为1.25:1～3:1；
    和/或，所述的甲醇的体积使所述的疏水性药物溶解即可，所述的甲醇的体积和所述的疏水性药物质量比优选为1:4mL/g；
    和/或，步骤1中，将所述的疏水性药物、所述的物质X、和甲醇混合后，还进一步包括超声步骤，所述的超声步骤后得所述的物料A；
    和/或，所述的去除甲醇的方式为旋转蒸发和干燥；所述的旋转蒸发的温度优选为30～50℃；所述的干燥的温度优选为30～50℃；
    和/或，所述水化所使用的注射用水体积和所述的疏水性药物质量比为1:10mL/g～3:10mL/g，优选为1:10mL/g、3:20mL/g、1:5mL/g、1:4mL/g或3:10mL/g；
    和/或，所述水化的转速为100～200r/min；
    和/或，所述水化的时间为5～20min；
    和/或，所述过滤所用的过滤器为微孔滤膜；所述的微孔滤膜的孔径优选为0.22μm。
  14. 一种疏水性药物胶束，其按照权利要求12或13所述的制备方法制得；所述的疏水性药物优选为多西他赛。
  15. 一种如权利要求10、11或14所述的多西他赛胶束在制备治疗先期化疗失败的晚期或转移性乳腺癌、或者使用以顺铂为主的化疗失败的晚期或转移性非小细胞肺癌药物中的应用。
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