WO2018086241A1 - pH敏感的1，4-二取代酞菁锌配合物及其制备方法和在医药上的应用 - Google Patents

pH敏感的1，4-二取代酞菁锌配合物及其制备方法和在医药上的应用 Download PDF

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WO2018086241A1
WO2018086241A1 PCT/CN2017/070293 CN2017070293W WO2018086241A1 WO 2018086241 A1 WO2018086241 A1 WO 2018086241A1 CN 2017070293 W CN2017070293 W CN 2017070293W WO 2018086241 A1 WO2018086241 A1 WO 2018086241A1
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cancer
compound
formula
group
preparation
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French (fr)
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蒋雄杰
黄华静
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深圳市声光动力生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines

Definitions

  • the invention belongs to the field of medicine, relates to zinc phthalocyanine complexes, a preparation method thereof and application thereof in medicine, and discloses the use thereof as a photosensitizer for treating cancer.
  • Photodynamic Therapy also known as Photoradiation Therapy (PRT) or Photochemotherapy
  • PDT Photodynamic Therapy
  • PS Photoradiation Therapy
  • the photosensitizer is injected into the body by intravenous injection (for the skin, it can also be applied to the affected area).
  • the tumor tissue is irradiated with light of a specific wavelength, and the photosensitizer enriched in the tumor tissue is excited by light.
  • Photodynamic therapy can also effectively treat non-cancer diseases such as bacterial infections, oral infections, macular degeneration, arteriosclerosis, traumatic infections, and skin diseases.
  • Photosensitizers can also be used for photodynamic disinfection, most importantly for sterilization of blood and blood derivatives.
  • photodynamic diagnosis using the fluorescent properties of photosensitizers is also an important use of medical photosensitizers.
  • the key to photodynamic therapy lies in photosensitizers, and the photodynamic efficacy depends on the pros and cons of photosensitizers. Based on the potential of photodynamic therapy in the treatment of tumors and other diseases, the scientific community generally believes that photodynamic therapy will become an important medical method in the 21st century.
  • the main photosensitizer used in clinical practice is Porfimer sodium (Photofin), which has been listed in 28 countries and regions such as the Netherlands, Canada, Japan, the United States, France, Germany, and the United Kingdom. China's research on photodynamic therapy (PDT) started later than the United States, Japan and other countries, but the progress is faster. Since the early 1980s, a lot of work has been done to develop photodynamic therapy.
  • Hematoporphyrin Hematoporphyrin
  • SFDA State Food and Drug Administration
  • hypoxic microenvironment in the solid tissue of the tumor results in a lower pH outside the tumor (about 6.5), while the extracellular pH of the normal tissue is about 7.4.
  • the difference in pH between tumor solid tissue and normal tissue provides a new strategy for the design of tumor-targeted drugs.
  • the inventors of the present invention have reported in recent years a number of series of pH-sensitive photosensitive compounds, such as axial amino derivatives substituted silicon phthalocyanine, which affect the photosensitivity by different degrees of ionization of amino groups in different pH environments ( Jiang, X.-J .et.al, Chem.Commun., 2010, 46, 3188-3190); Axial phenyl derivatives replace silicon phthalocyanine, which affects photosensitivity by different degrees of aggregation of phthalocyanine molecules in a pH environment ( Jiang, X.- J. et . al, Chem. Eur. J.
  • the quencher can quench the photoactive activity of the fluoroboron dipyrrole derivative by photoinduced electron transfer (PET) process, but in the micro acid environment, the ketal is hydrolyzed and the ferrocene is supplied with electrons. The group is detached and the photosensitivity of the dipyrrole derivative is restored ( Jiang, X.-J. et. al, Chem. Eur . J. 2016, 22, 8273-8281).
  • these compounds and most of the pH-sensitive drugs reported so far are not tumor cell extracellular micro-acid environment-targeting drugs, because the subcellular tissues of tumor cells and normal cells such as mitochondria and lysosomes are acidic, lysozyme
  • the pH of the body can be as low as 5.
  • These compounds, when taken up by tumor cells and normal cells, can be stimulated by the acid in the subcellular tissue to damage the photosensitizing activity and damage the tumor cells and normal cells.
  • the present invention discloses a series of tumor extracellular microacid environments that target photosensitizing drugs.
  • the structure, synthesis and application of a series of ketal-linked zinc phthalocyanine complexes and cholesterol derivatives are disclosed.
  • Introducing a cholesterol group at the 1,4 position of zinc phthalocyanine, an acid-sensitive ketal bond between zinc phthalocyanine complex and cholesterol, zinc phthalocyanine-cholesterol complex due to the non-polar nature of cholesterol and large steric hindrance The substance is difficult to be taken up by cancer cells and normal cells, but in the micro-acid environment outside the tumor solid tissue, the ketal bond is hydrolyzed, the cholesterol group is shed, and the zinc phthalocyanine hydrolyzed derivative can be taken up by the cancer cells and exhibited.
  • Extremely high photosensitivity they are tumor-specific extracellular micro-acid environments that target photosensitizing drugs.
  • the present invention provides a compound of the formula (I):
  • n 1, 2, 3, or 4;
  • X O or NH;
  • the hydrolysate of the compound of the formula (I) is a compound of the formula (V) having the same structure and similar structure as the compound reported in the literature (Liu, J.-Y., Jiang, X.-J.et. Al., Org. Biomol. Chem., 2008, 6, 4560-4566; Liu, J.-Y., lo, P.-C., Jiang, X.-J., et . al., Dalton Trans. , 2009, 4129-4135), these compounds have high uptake rates in tumor cells and exhibit very high photosensitivity at very low concentrations.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention also provides a process for the preparation of a compound of the formula (I), which comprises:
  • n 1, 2, 3, or 4;
  • X O or NH;
  • the solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform and tetrahydrofuran; the reaction is carried out at a temperature of -5 to 80 ° C;
  • the basic condition is provided by a reagent selected from the group consisting of pyridine, triethylamine, sodium hydride and 4-N,N-lutidine; the molar ratio of the compound of the formula (II) to cholesterol formyl chloride is 1:0.2-2 .
  • the solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform and tetrahydrofuran; the reaction is carried out at a temperature of -5 to 80 ° C;
  • the basic condition is provided by a reagent selected from the group consisting of pyridine, triethylamine, sodium hydride and 4-N,N-lutidine; the molar ratio of the compound of the formula (IV) to the compound of the formula (III) is 1: 0.5 to 5.
  • the compound can also be purified by methods well known to those skilled in the art, such as by distillation, by silica gel column chromatography or by high performance liquid chromatography (HPLC).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a photodynamic drug or a photosensitizing drug.
  • the present invention also relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a medicament comprising the same Use of a composition for the manufacture of a medicament for the treatment of cancer.
  • the cancer described therein is selected from the group consisting of lung cancer, gastric cancer, esophageal cancer, breast cancer, bladder cancer, prostate cancer, pancreatic cancer, cholangiocarcinoma, rectal cancer, colon cancer, skin cancer, head and neck cancer, Eye tumor, uterine cancer and ovarian cancer, excellent breast cancer.
  • the present invention also relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a photodynamic drug or a photosensitizing drug.
  • the present invention also relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is useful for treating cancer.
  • the cancer described therein is selected from the group consisting of lung cancer, gastric cancer, esophageal cancer, breast cancer, bladder cancer, prostate cancer, pancreatic cancer, cholangiocarcinoma, rectal cancer, colon cancer, skin cancer, head and neck cancer, eye tumor, uterine cancer and ovary. Cancer, preferably breast cancer.
  • the present invention also relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and then suitably
  • the light source is illuminated.
  • the suitable light source may be provided by a conventional light source coupled to a suitable filter or by a laser of a particular wavelength, the source having a wavelength in the range of 550 to 900 nm, preferably 620 to 720 nm.
  • the compounds according to the invention may be administered orally, sublingually, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, topically or rectally.
  • the active ingredient may be conventionally used.
  • the pharmaceutically acceptable carriers are mixed together and administered to the animal or human in the form of an administration unit.
  • Suitable administration unit forms include oral forms such as tablets, gel capsules, powders, granules and solutions or suspensions for oral administration, sublingual or buccal administration, parenteral, subcutaneous, intramuscular, intravenous, nasal Internal or intraocular administration forms and rectal administration forms.
  • the main active ingredient is mixed with a pharmaceutically acceptable carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutically acceptable carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets may be coated with sucrose or other suitable materials or treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.
  • a gel capsule preparation is obtained by mixing the active ingredient with a diluent and by pouring the obtained mixture into a soft or hard capsule.
  • Formulations in the form of syrups or elixirs may contain the active ingredient along with sweetening agents, preservatives, and perfuses, and suitable colorants.
  • the powder or granules which may be dispersed in water may contain the active ingredient in admixture with a dispersing agent, a surfactant, a wetting or suspending agent, and a flavoring or sweetening agent.
  • the pharmaceutical composition contains polyoxyethylene castor oil and its derivatives, dimethyl sulfoxide, ethanol, glycerin, N, N-dimethylformamide, polyethylene glycol 300-3000, cyclodextrin, glucose, Tween One or more of polyethylene glycol monostearate.
  • Suppositories are used for rectal administration, which are prepared using a binder that melts at the rectal temperature, for example, cocoa butter or polyethylene glycol.
  • a physiologically compatible dispersing and/or wetting agent is for parenteral, intranasal or intraocular administration.
  • the pharmaceutical composition contains polyoxyethylene castor oil and its derivatives, dimethyl sulfoxide, ethanol, glycerin, N, N-dimethylformamide, polyethylene glycol 300-3000, cyclodextrin, glucose, Tween One or more of polyethylene glycol monostearate.
  • the active ingredient (possibly together with one or more additive carriers) can also be formulated as a microcapsule.
  • the compounds of the invention can be administered at doses between 0.01 mg/day and 5000 mg/day, in a single dose/day manner or in several doses throughout the day, for example, the same dose twice daily. .
  • the daily dose administered is advantageously between 0.1 mg and 200 mg, even more advantageously between 2.5 mg and 50 mg. It may be desirable to use dosages outside of these ranges, as will be appreciated by those skilled in the art.
  • the pharmaceutical composition may also be formulated for external administration. It can be introduced into the usual form of the application type (i.e., especially lotions, foams, gels, dispersants, sprays), the usual forms having excipients, in particular excipients It is able to penetrate the skin in order to improve the properties and accessibility of the active ingredients.
  • these compositions generally further comprise a physiologically acceptable medium, which usually comprises water or a solvent, for example an alcohol, an ether or an ethylene glycol.
  • the composition may further comprise a surfactant, a preservative, a stabilizer, an emulsifier, a thickener, other active ingredients that produce a complementary effect or a possible synergistic effect, trace elements, essential oils, perfumes, colorants, collagen, Chemical or mineral filter.
  • pharmaceutically acceptable is understood to mean that it is used in the preparation of a pharmaceutical composition which is generally safe, non-toxic, biologically or otherwise satisfying needs and said combination Objects can be accepted for use in mammals and humans.
  • a "pharmaceutically acceptable salt” of a compound is understood to mean a salt which is a pharmaceutically acceptable (as defined herein) salt and which possesses the desired pharmacological activity of the parent compound.
  • This salt includes:
  • Acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid , fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, sticky
  • a metal ion such as an alkali metal ion (for example, Na + , K + or Li + ), an alkaline earth metal ion (such as Ca 2+ or Mg 2+ ) or aluminum ion.
  • a salt formed when coordinated with an organic or inorganic base include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • Ts is p-toluenesulfonate.
  • Nuclear Magnetic Resonance Instrument Bruker ARX-300 high resolution high resolution nuclear magnetic resonance instrument.
  • Mass Spectrometry QSTAR Elite tandem quadrupole time-of-flight mass spectrometer.
  • PBS buffer phosphate buffer
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR chemical shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the solvent was determined to be deuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard was tetramethylsilane (TMS).
  • TMS tetramethylsilane
  • s is a single peak
  • bs is a broad single peak
  • d is a doublet
  • t is a triplet
  • qdt is a quartet
  • m is a multiple or a large number of peaks
  • dd is a doublet.
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, and the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm to 0.2 mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4 mm to 0.5 mm.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the temperature of the reaction was room temperature unless otherwise specified.
  • Test case in vitro anti-tumor cell light-sensitive experiment
  • Test article Compound 2 of the present invention
  • hematoporphyrin injection (English name: Hematoporphyrin Injection; trade name: Xibo, produced by Chongqing Huading Modern Biopharmaceutical Co., Ltd.).
  • Test cells human breast cancer cells MCF-7
  • RPMI-1640 complete medium Add 500,000 U of penicillin/streptomycin, 56 mL of fetal bovine serum to 500 mL of RPMI-1640 liquid medium (GIBCO), and mix.
  • MTT solution MTT: 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide, purchased from MP Company, USA
  • concentration is dissolved in PBS solution, sterilized by filtration, and is now ready for use.
  • test sample is formulated into a mother liquor having a concentration of 1 mM in DMSO; 100 ⁇ L of a 1 mg/mL mother liquor is taken during the experiment, and 1.15 mL of 0.5% (w/w) polyoxyethylene castor oil pH 7.4 PBS is added.
  • pH 6.5 PBS buffer formulated into 80 ⁇ g / mL drug solution, and diluted with the corresponding PBS buffer into different concentrations of the drug solution, the pH value of the drug solution is kept unchanged during the dilution process, and the drug solution is cultured immediately after preparation. .
  • the final concentration of DMSO in each drug and negative control group was ⁇ 1%.
  • Xibofen is a 25 mL preparation containing 5 mg of liquid solution at a concentration of 5 mg/mL. Take 100 ⁇ L of 5 mg/mL preparation, add 4.90 mL of pH 7.4 PBS or pH 6.5 PBS buffer, and dilute to different concentrations of the solution with the corresponding PBS buffer. Keep the pH of the solution unchanged during the dilution process. Cell dosing culture is performed immediately.
  • the culture was continued at 37 ° C and 5% CO 2 . hour. After 24 hours, add 5 mg/mL MTT per well, 20 ⁇ L, and incubate for 4 hours at 37 ° C, 5% CO 2 , carefully aspirate the supernatant, add 200 ⁇ L of DMSO to each well, and shake for 10 minutes to form the formed formazan. After the particles were sufficiently dissolved, the absorbance was measured by a microplate reader, and the measurement wavelength was 570 nm, and the reference wavelength was 630 nm.
  • the light source is connected to the insulated water tank by a 200W halogen lamp and a filter larger than 610 nm, and the light dose is 48 J cm -2 .
  • tumor cell growth inhibition rate (%) [(negative control group OD mean - administration group OD mean) / negative control group OD mean value] ⁇ 100%.
  • the calculation of the half-inhibitory concentration IC 50 was determined by logit regression.
  • Solid tumors have a slightly acidic environment, such as lung cancer, stomach cancer, esophageal cancer, breast cancer, bladder cancer, prostate cancer, pancreatic cancer, cholangiocarcinoma, rectal cancer, colon cancer, skin cancer, head and neck.
  • Solid tumors such as cancer, ocular tumor, uterine cancer and ovarian cancer all have a slightly acidic environment, and the compound disclosed in the present patent or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same can be prepared as a photosensitizing drug for treating the above cancer.

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Abstract

本发明涉及pH敏感的缩酮连接的胆固醇-酞菁锌配合物及其制备方法和在医药上的应用。特别地，本发明涉及通式（I）所示的酞菁锌配合物、其制备方法及含有该配合物的药物组合物，以及其作为光敏剂的用途，特别是在治疗癌症中的用途，其中通式（I）中的各取代基与说明书中的定义相同。由于胆固醇基团的存在，该系列化合物很难被肿瘤细胞和正常细胞摄取，但在肿瘤组织细胞外微酸环境下，缩酮发生水解反应，酞菁锌的水解衍生物能很容易被癌细胞摄取，并展现极高的光敏活性，它们可制备成肿瘤细胞外微酸环境靶向光敏药物。

Description

pH敏感的1，4-二取代酞菁锌配合物及其制备方法和在医药上的应用 技术领域
本发明属于医药领域，涉及酞菁锌配合物及其制备方法及其在医药上的应用，本发明公开了其作为光敏剂，用于治疗癌症的用途。
技术背景
光动力治疗(Photodynamic Therapy，简称PDT)，又称光辐射疗法(Photoradiation Therapy，简称PRT)或称光化学疗法(Photochemotherapy)，是一种基于特定化学物质的光化学反应原理的治疗方法。所用的化学物质称为肿瘤化学诊治药物(也称光敏剂，Photosensitizer，简称PS)。PDT疗法过程是通过静脉注射将光敏剂注入体内(对于皮肤也可以将其涂于患处)，经过一定时间后用特定波长的光照射肿瘤组织，富集在肿瘤组织的光敏剂在光的激发下，产生一系列光物理化学反应，产生细胞毒性的活性氧，从而杀死癌细胞破坏肿瘤组织。
1996年被美国FDA批准用于临床，1997年FDA将其列入肿瘤治疗的五类基本方法(手术、放疗、化疗、光动力、生化免疫)之一。和传统的疗法相比，PDT疗法具有创伤很小、毒性低微、选择性好、适用性好、可重复治疗、可姑息治疗、可协同手术提高疗效、可消灭隐性癌病灶、可保护容貌及重要器官功能、治疗时间短等优势。
光动力疗法还可以有效地治疗细菌感染、口腔感染、黄斑变性眼病、动脉硬化、创伤感染以及皮肤病等非癌症疾病。光敏剂还可以用于光动力消毒，最主要的是用于血液和血液衍生物的灭菌消毒。同时，利用光敏剂的荧光性质进行光动力诊断，也是医用光敏剂的一个重要用途。
光动力治疗的关键在于光敏剂，光动力疗效取决于光敏剂的优劣。基于光动力治疗在治疗肿瘤和其他疾病方面的潜力，科学界普遍认为，光动力治疗将成为21世纪的重要医疗方法。现在临床主要应用的光敏剂为卟非姆纳(Porfimer sodium，Photofin)，该药先后在荷兰、加拿大、日本、美国、法国、德国、英国等28个国家和地区上市。我国在光动力治疗(PDT)方面的研究较美国、日本等国起步较迟，但进步较快。20世纪80年代初至今，为发展光动力治疗做了大量工作，与国外报道的成果相比，其深度和广度并无太大差距。重庆华鼎现代生物制药有限责任公司研制、生产用以治疗肿瘤的血卟啉(Hematoporphyrin，喜泊分)，已经由国家食品药品管理局(SFDA)正式批准生产、销售并应用于临床。喜泊分是我国唯一上市的抗癌光敏剂，是国外上市的卟非姆纳类似物，均是血卟啉衍生物，同属于第一代抗癌光敏药物。
尽管卟非姆纳和喜泊分在临床上取得了成功，但其组分复杂，各种成分在光动力损伤中的作用至今也未弄清，占药物总量20％以上的非活性成分不仅不能对病变的靶组织产生有效的光动力损伤作用，反而成为导致正常组织发生光敏反应的祸首。另外第一代光敏药物对肿瘤的靶向作用不强，研究高效、低毒的具有肿瘤靶向性的光敏药物是最近的研究热点。
肿瘤实体组织部位存在的缺氧微环境导致该部位肿瘤细胞外的pH值较低(在6.5左右)，而正常组织细胞外pH值为7.4左右。肿瘤实体组织和正常组织之间的pH值差异为肿瘤靶向药物的设计提供了新的策略。本专利发明人近年报道了多个系列的pH敏感的光敏化合物，比如轴向氨基衍生物取代硅酞菁，通过氨基在不同pH环境下的离子化程度不同影响光敏活性(Jiang，X.-J.et.al，Chem.Commun.，2010，46，3188-3190)；轴向苯基衍生物取代硅酞菁，通过pH环境下酞菁分子的聚集程度不同影响光敏活性(Jiang，X.-J.et.al，Chem.Eur.J.，2010，16，4777-4783)；通过pH敏感的缩酮键连接的氟硼二吡咯衍生物和二茂铁衍生物，由于二茂铁为荧光淬灭剂，可以通过光诱导电子转移(photoinduced electron transfer，PET)过程淬灭氟硼二吡咯衍生物的光敏活性，但在微酸环境下，缩酮发生水解反应，供电子特性的二茂铁基团脱落，二吡咯衍生物的光敏活性得到恢复(Jiang，X.-J.et.al，Chem.Eur.J.2016，22，8273-8281)。但这些化合物和目前报道的大多数pH敏感的药物均不是肿瘤细胞外微酸环境靶向药物，这是由于肿瘤细胞和正常细胞的亚细胞组织如线粒体、溶酶体等均显酸性，溶酶体的pH值更可以低至5。这些化合物在被肿瘤细胞和正常细胞摄取后，可以被亚细胞组织中的酸激发光敏活性，损伤肿瘤细胞和正常细胞。
发明内容
本发明公开了一系列肿瘤细胞外微酸环境靶向光敏药物。公开了一系列缩酮连接的酞菁锌配合物和胆固醇衍生物的结构、合成及应用。在酞菁锌1，4位引入胆固醇基团，酞菁锌配合物和胆固醇之间用酸敏感的缩酮键连接，由于胆固醇的非极性特性和大位阻作用，酞菁锌-胆固醇配合物很难被癌细胞和正常细胞摄取，但在肿瘤实体组织癌细胞外的微酸环境下，缩酮键发生水解反应，胆固醇基团脱落，酞菁锌水解衍生物能被癌细胞摄取并展现极高的光敏活性，它们是肿瘤细胞外微酸环境靶向光敏药物。
本发明提供的一种通式(I)所示的化合物：
其中：n＝1，2，3，或4；X＝O或NH；
Figure PCTCN2017070293-appb-000002
或其药学上可接受的盐。
通式(I)所示的化合物在微酸环境下的水解反应化学式(1)
Figure PCTCN2017070293-appb-000003
通式(I)的所示化合物的水解产物为通式(V)化合物的结构与已有文献报道的化合物结构相同和类似(Liu，J.-Y.，Jiang，X.-J.et.al.，Org.Biomol.Chem.，2008，6，4560-4566；Liu，J.-Y.，lo，P.-C.，Jiang，X.-J.，et.al.，Dalton Trans.，2009，4129-4135)，这些化合物在肿瘤细胞摄取率高，在很低的浓度下展现非常高的光敏活性。
本发明典型的化合物包括，但不限于：
Figure PCTCN2017070293-appb-000004
Figure PCTCN2017070293-appb-000005
或其药学上可接受的盐，其中
Figure PCTCN2017070293-appb-000006
本发明还提供一种制备通式(I)所示的化合物的方法，该方法包括：
Figure PCTCN2017070293-appb-000007
其中：n＝1，2，3，或4；X＝O或NH；
Figure PCTCN2017070293-appb-000008
第1步，所述溶剂选自N，N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃；所述反应在-5～80℃温度下进行；所述碱性条件由选自吡啶、三乙胺、氢化钠和4-N，N-二甲基吡啶等试剂提供；所述通式(II)化合物与胆固醇甲酰氯的摩尔比为1∶0.2～2。
第2步，所述溶剂选自N，N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃；所述反应在-5～80℃温度下进行；所述碱性条件由选自吡啶、三乙胺、氢化钠和4-N，N-二甲基吡啶等试剂提供；所述通式(IV)化合物与通式(III)化合物的摩尔比为1∶0.5～5。
如果有必要，通过本领域技术人员熟知的方法，如通过蒸馏、通过硅胶柱色谱法或者通过高效液相色谱法(HPLC)也可以纯化化合物。
本发明还提供一种药物组合物，其含有治疗有效量的通式(I)所示的化合物或或其药学上可接受的盐，以及药学上可接受的载体、稀释剂或赋形剂。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐，或包含其的药物组合物在制备光动力药物或光敏药物中的用途。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐，或包含其的药物 组合物在制备治疗癌症的药物中的用途。其中所述的癌症选自其中所述的癌症选自肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌，优乳腺癌。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐，或包含其的药物组合物，其用作光动力药物或光敏药物。
本发明还涉及通式(I)所示的化合物或其药学上可接受的盐，或包含其的药物组合物，其用于治疗癌症。其中所述的癌症选自肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌，优选乳腺癌。
本发明还涉及一种治疗癌症的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其药学上可接受的盐，或包含其的药物组合物，然后用适宜的光源照射。所述适宜的光源可以由普通光源连接合适的滤光片来提供或由特定波长的激光来提供，光源的波长范围为550～900nm，优选620～720nm。
根据本发明的化合物可以被口服施用、舌下施用、肠胃外施用、皮下施用、肌内施用、静脉内施用、经皮施用、局部施用或直肠施用。
在本发明的药用化合物中，对于口服施用、舌下施用、肠胃外施用、皮下施用、肌内施用、静脉内施用、经皮施用、局部施用或直肠施用而言，活性成分可以与常规的药用载体混合在一起，以施用单位的形式施用于动物或人类。适合的施用单位形式包含口服形式如片剂、凝胶胶囊剂、粉剂、颗粒剂和口服的溶液剂或混悬剂，舌下或口腔施用形式，肠胃外、皮下、肌内、静脉内、鼻内或眼内施用形式和直肠施用形式。
当固体组合物被制备成片剂形式时，主要活性成分与药用载体如明胶、淀粉、乳糖、硬脂酸镁、滑石、阿拉伯胶等混合。片剂可以采用蔗糖或其他适合的材料包衣或者以如此的方式处理以至于其具有延长的或延迟的活性并且连续释放预定量的活性成分。
通过将活性成分与稀释剂混合并通过将获得的混合物倾倒入软质或硬质胶囊中来获得凝胶胶囊制剂。
糖浆剂或酊剂形式的制剂可以包含活性成分连同甜味剂、防腐剂以及芳香剂和适当的着色剂。
可分散于水中的粉剂或颗粒剂可以包含活性成分，其与分散剂、表面活性剂、润湿剂或悬浮剂以及与矫味剂或甜味剂混合在一起。其药物组合中含有聚氧乙烯蓖麻油及其衍生物、二甲亚砜、乙醇、甘油、N，N-二甲基甲酰胺、聚乙二醇300-3000、环糊精、葡萄糖、吐温、聚乙二醇单硬脂酸酯中的一种或几种。
栓剂用于直肠施用，其采用在直肠温度下熔化的粘合剂，例如，可可脂或聚乙二醇来制备。
水性混悬剂、等渗的生理盐水溶液剂或无菌的且可注射的溶液剂(其包含药 理学上可兼容的分散剂和/或润湿剂)用于肠胃外、鼻内或眼内施用。其药物组合中含有聚氧乙烯蓖麻油及其衍生物、二甲亚砜、乙醇、甘油、N，N-二甲基甲酰胺、聚乙二醇300-3000、环糊精、葡萄糖、吐温、聚乙二醇单硬脂酸酯中的一种或几种。
活性成分(可能与一种或多种添加剂载体一起)也可以被配制成微囊剂。
本发明的化合物能够以介于0.01mg/天和5000mg/天之间的剂量来使用，以单一剂量/天的方式来提供或者以全天内若干剂量的方式来施用，例如，相同剂量每天两次。所施用的日剂量有利地介于0.1mg和200mg之间，甚至更有利地介于2.5mg和50mg之间。使用超出这些范围的剂量可能是需要的，本领域技术人员自身将会意识到这一点。
在本发明的一个特定实施方案中，药物组合物也可以被配制用于外部施用。它可以被引入到该施用类型的常用形式(即，特别是洗剂、泡沫剂、凝胶剂、分散剂、喷雾剂)中，所述常用形式具有赋形剂，所述赋形剂特别地能够穿透皮肤，以便于改善活性成分的性质和可接近性。除了根据本发明的组合物之外，这些组合物通常进一步包含生理上可接受的介质，所述介质通常包含水或溶剂，例如，醇、醚或乙二醇。所述组合物还可以包含表面活性剂、防腐剂、稳定剂、乳化剂、增稠剂、产生互补效果或可能的协同效果的其他活性成分、微量元素、精油、香料、着色剂、胶原蛋白、化学或矿物过滤剂。
定义
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
在本发明中，“药学上可接受的”被理解为是指其用于制备药物组合物，所述组合物一般是安全的，无毒的，在生物学或其他方面满足需要并且所述组合物可以被接受用于兽类和人类药物用途。
在本发明中，化合物的“药学上可接受的盐”被理解为指代下列盐，其是药学上可接受的(如本文所定义的)盐并且其具备预期的母体化合物的药理活性。这种盐包括：
(1)与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐，或与有机酸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、羟萘酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、二苯甲酰基-L-酒石酸、酒石酸、对甲苯磺酸、三甲基乙酸、三氟乙酸等形成的酸加成盐；和
(2)当母体化合物中存在的酸质子被金属离子，例如，碱金属离子(例如，Na+、K+或Li+)，碱土金属离子(如Ca2+或Mg2+)或铝离子代替；或者与有机碱或无机碱配位时形成的盐。可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化 钾、碳酸钠和氢氧化钠。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“Ts”为对甲基苯磺酸基。
具体实施方式
通过阅读下列实施例，本领域技术人员将会更好地理解本发明。这些实施例仅用于解释本发明。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。通式化合物(IV)参考文献方法很容易合成得到(New J.Chem.，2013，37，1746-1752；Org.Biomol.Chem.，2008，6，4560-4566；Dalton Trans.，2009，4129-4135)。
核磁共振仪：Bruker ARX-300型高分辨高分辨核磁共振仪。
质谱：QSTAR Elite串联四级杆飞行时间质谱仪。
MTT检测仪器：Thermo Scientific Multiskan GO全波长酶标仪
PBS缓冲液：磷酸盐缓冲液
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR化学位移(δ)以10-6(ppm)的单位给出。测定溶剂为氘代二甲亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)。使用下列缩写：s为单峰，bs为宽单峰，d为二重峰，t为三重峰，qdt为四重峰，m为多重峰或大量峰，dd为双二重峰等。
薄层层析硅胶板使用青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。
实施例中如无特殊说明，反应中的溶液是指水溶液。
实施例中如无特殊说明，反应的温度为室温。
实施例中的反应进程的监测采用薄层色谱法(TLC)。
实施例1化合物1的合成
Figure PCTCN2017070293-appb-000009
第1步
在冰水浴中，把化合物1-1(1.62g，10mmol)，胆固醇酰氯(2.2g，4.9mmol)和三乙胺(2g，20mmol)加入二氯甲烷(50mL)，继续搅拌反应2小时，停止反应，向反应液中加入水(100mL)，搅拌静置，收集有机相，有机相用无水硫酸钠干燥，减压蒸馏，粗产品用硅胶层析柱分离纯化，洗脱剂为三氯甲烷/甲醇(9∶1)，得到白色固体1-2(1.53g，55％)。MS(ESI)：m/z＝598[M+Na]+。
第2步
在冰水浴中，把化合物1-3(1.27g，1mmol)，1-2(1.55g，2.7mmol)和吡啶(0.8g，10.1mmol)加入三氯甲烷(25mL)，继续搅拌反应2小时，停止反应，向反应液中加入水(120mL)，搅拌静置，收集有机相，有机相用无水硫酸钠干燥，减压蒸馏，粗产品用硅胶层析柱分离纯化，洗脱剂为三氯甲烷/甲醇(20∶1)，得到绿色固体1(1.18g，57％)。1H NMR(300MHz，DMSO-d6)：δ9.33-9.37(m，4H，Pc-Hα)，9.21-9.25(m，2H，Pc-Hα)，8.15-8.20(m，6H，Pc-Hβ)，7.53(s，2H，Pc-Hβ)，5.28-5.37(m，2H，chol-6-CH)，4.82-4.90(m，4H，CH2)，4.35-4.49(m，6H，CH2，chol-3-CH)，3.85-4.10(m，8H，CH2)，3.41-3.75(m，32H，CH2)，1.72-2.35(m，16H，chol)，0.85-1.58(s，76H，chol，CH3)，0.68(s，6H，chol-18-CH3)。MS(ESI)：m/z＝2077[M+H]+。
实施例2化合物2的合成
Figure PCTCN2017070293-appb-000010
第1步
在冰水浴中，把化合物2-1(1.64g，10mmol)，胆固醇酰氯(1.55g，3.5mmol)和吡啶(0.8g，10.1mmol)加入二氯甲烷(25mL)，温度升到室温，继续搅拌反应2小时，停止反应，向反应液中加入水(100mL)，搅拌静置，收集有机相，有机相用无水硫酸钠干燥，减压蒸馏，粗产品用硅胶层析柱分离纯化，洗脱剂为三氯甲烷/甲醇(15∶1)，得到白色固体2-2(1.02g，49％)。MS(ESI)：m/z＝599[M+Na]+。
第2步
在冰水浴中，把化合物2-3(0.7g，0.6mmol)，2-2(1.6g，2.8mmol)加入四氢呋喃(30mL)，缓慢向反应液中加入氢化钠(0.1g，4.2mmol)，继续搅拌反应2小时，缓慢加入2毫升水淬灭反应，向反应液中加入水(100mL)，搅拌静置，收集有机相，有机相用无水硫酸钠干燥，减压蒸馏，粗产品用硅胶层析柱分离纯化，洗脱剂为三氯甲烷/甲醇(20∶1)，得到蓝色固体2(0.25g，22％)。1H NMR(300MHz，DMSO-d6)：δ9.32-9.36(m，4H，Pc-Hα)，9.20-9.25(m，2H，Pc-Hα)，8.12-8.2(m，6H，Pc-Hβ)，7.51(s，2H，Pc-Hβ)，5.30-5.37(m，2H，chol-6-CH)，4.81-4.91(m，4H，CH2)，4.32-4.48(m，10H，CH2，chol-3-CH)，3.85-4.12(m，8H，CH2)，3.41-3.75(m，20H，CH2)，1.70-2.35(m，16H，chol)，0.83-1.57(s，76H，chol，CH3)，0.67(s，6H，chol-18-CH3)。MS(ESI)：m/z＝1992[M]+。
实施例3化合物3的合成
Figure PCTCN2017070293-appb-000011
在冰水浴中，把化合物3-3(0.6g，5.5mmol)，2-2(0.8g，1.4mmo)加入四氢呋喃(30mL)，缓慢向反应液中加入氢化钠(0.1g，4.2mmol)，继续搅拌反应2小时，缓慢加入2毫升水淬灭反应，向反应液中加入水(100mL)，搅拌静置，收集有机相，有机相用无水硫酸钠干燥，减压蒸馏，粗产品用硅胶层析柱分离纯化，洗脱剂为三氯甲烷/甲醇(20∶1)，得到蓝色固体3(0.22g，21％)。1H NMR(300MHz，DMSO-d6)：δ9.35-9.49(m，6H，Pc-Hα)，8.12-8.2(m，6H，Pc-Hβ)，7.58(s，2H，Pc-Hβ)，5.31-5.35(m，2H，chol-6-CH)，4.81-4.98(m，4H，CH2)，4.32-4.56(m，10H，CH2，chol-3-CH)，4.10-4.20(m，4H，CH2)，3.41-3.75(m，12H，CH2)，1.70-2.35(m，16H，chol)，0.80-1.62(s，76H，chol，CH3)，0.66(s，6H，chol-18-CH3)。MS(ESI)：m/z＝1904[M]+。
实施例4化合物4的合成
Figure PCTCN2017070293-appb-000012
在冰水浴中，把化合物4-3(0.7g，0.7mmol)，1-2(1.33g，2.1mmol)和三乙胺(2g，20mmol)加入三氯甲烷(30mL)，继续搅拌反应2小时，停止反应，向反应液中加入水(100mL)，搅拌静置，收集有机相，有机相用无水硫酸钠干燥，减压蒸馏，粗产品用硅胶层析柱分离纯化，洗脱剂为三氯甲烷/甲醇(20∶1)，得到蓝色固体4(0.25g，20％)。1H NMR(300MHz，DMSO-d6)：δ9.33-9.53(m，6H，Pc-Hα)，8.10-8.18(m，6H，Pc-Hβ)，7.58(s，2H，Pc-Hβ)，5.36-5.40(m，2H，chol-6-CH)，4.73-4.80(m，4H，CH2)，4.38-4.60(m，2H，chol-3-CH)，3.35-3.85(m，20H，CH2)，1.73-2.40(m，16H，chol)，0.84-1.65(s，76H，chol，CH3)，0.68(s，6H，chol-18-CH3)。MS(ESI)：m/z＝1813[M+H]+。
测试例：体外抗肿瘤细胞光敏实验
供试品：本发明化合物2
阳性对照品：血卟啉注射液(英文名：Hematoporphyrin Injection；商品名：喜泊分，重庆市华鼎现代生物制药有限责任公司生产)。
测试细胞：人乳腺癌细胞MCF-7
主要试剂：1)RPMI-1640完全培养液：于500mL RPMI-1640液体培养液(GIBCO公司)中加入青霉素/链霉素10万U，胎牛血清56mL，混匀。2)MTT溶液(MTT：3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐，购于美国MP公司)：将粉状MTT以5mg/mL的浓度溶于PBS溶液，过滤灭菌，现配现用。
实验方法：
1)供试品配制方法：将供试品用DMSO配成浓度为1mM的母液；实验时取100μL1mg/mL的母液，加入1.15mL 0.5％(w/w)聚氧乙烯蓖麻油pH 7.4PBS和pH 6.5PBS缓冲液，配制成80μg/mL药液，并用相对应的PBS缓冲液稀释成不同浓度的药液，稀释过程中保持药液pH值不变，药液配制后马上进行细胞加药培养。各药物和阴性对照组中DMSO的终浓度是≤1％。喜泊芬为5mL液体溶液含25mg制剂，浓度5mg/mL。取100μL 5mg/mL的制剂，加入4.90mLpH 7.4PBS或pH 6.5PBS缓冲液，并用相对应的PBS缓冲液稀释成不同浓度的药液，稀释过程中保持药液pH值不变，药液配制后马上进行细胞加药培养。
2)选用对数生长期的贴壁肿瘤细胞，用胰酶消化后，用含10％胎牛血清的RPMI 1640培养基配成适合浓度的细胞悬液，接种在96孔培养板中。每孔接种100μL，每加完一排将细胞悬液摇一下，加完细胞后轻轻水平转动培养板使细胞均匀地分散在皿孔表面，96孔板周围一圈孔加入无菌PBS，37℃，5％CO2培养24小时。然后分别加入不同浓度的受试药物、阳性药物、溶剂和培养液各100μL，每组3个平行孔。混匀后分为光照和避光两组，均在加药共培养2小时后，弃去培养基，重新加入不含供试品的培养基置37℃、5％CO2条件下继续培养24小时。24小时后，每孔加入5mg/mL MTT，20μL，37℃、5％CO2条件下孵育4小时后，仔细吸弃上清液，每孔加入200μL DMSO，振荡10分钟，使形成的甲臜颗粒充分溶解后，酶标仪检测吸光值，测定波长570nm，参考波长630nm。光源通过200W的卤素灯连接隔热水槽加大于610nm的滤光片提供，光剂量为48J cm-2。
3)药物对肿瘤细胞生长的抑制率的计算方法：肿瘤细胞生长抑制率(％)＝[(阴性对照组OD均值-给药组OD均值)/阴性对照组OD均值]×100％。半数抑制浓度IC50的计算，采用logit回归法测定。
实验结果：
表1化合物2和喜泊分在照光时人乳腺癌细胞MCF-7的IC50(ng/mL)值
光敏药物 细胞pH 7.4药液培养 细胞pH 6.5药液培养
化合物2 ＞8000 95
喜泊分 3800 4100
实验结果显示，在避光环境下，所有测试的化合物在浓度高达5000ng/mL时，没有显示细胞毒性，但在照光情况下喜泊分在pH 6.5和pH 7.4时对人乳腺癌细胞MCF-7的半致死浓度IC50值相差不大，在3800-4100ng/mL之间。但化合物2在pH 7.4的药液培养细胞时，浓度高达8000ng/mL，在照光时完全没有光敏活性，但化合物2在pH 6.5的药液进行培养细胞时，展现非常高的光敏活性，IC50值为95ng/mL，展现非常明显的肿瘤细胞外微酸环境靶向性。
目前已知，几乎所有的实体肿瘤都存在微酸环境，如肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌等实体肿瘤均存在微酸环境，本专利公开的化合物或其药学上可接受的盐，或包含其的药物组合物均可以制备成光敏药物治疗上述癌症。
以上所述仅为本发明的实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (8)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2017070293-appb-100001
    其中：n＝1,2,3,或4；X＝O或NH；R＝
    Figure PCTCN2017070293-appb-100002
    或其药学上可接受的盐。
  2. 根据权利要求1所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2017070293-appb-100003
    Figure PCTCN2017070293-appb-100004
    其中R＝
    Figure PCTCN2017070293-appb-100005
  3. 一种制备根据权利要求1所述的通式(I)所示的化合物的方法，该方法包括：
    Figure PCTCN2017070293-appb-100006
    其中：n＝1,2,3,或4；X＝O或NH；R＝
    Figure PCTCN2017070293-appb-100007
    第1步，在有机溶剂中，在碱性环境下，含有缩醛键的通式(II)化合物与胆固醇甲酰氯反应得到通式(III)化合物；
    第2步，在有机溶剂中，在碱性条件下，酞菁锌衍生物通式(IV)化合物与通式(III)化合物反应，得到通式(I)化合物；
  4. 根据权利要求3所述的方法，其中：
    第1步，所述溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃；所述反应在-5～80℃温度下进行；所述碱性条件由选自吡啶、三乙胺、氢化钠和4-N,N-二甲基吡啶等试剂提供；所述通式(II)化合物与胆固醇甲酰氯的摩尔比为1:0.2～2。
    第2步，所述溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、三氯甲烷和四氢呋喃；所述反应在-5～80℃温度下进行；所述碱性条件由选自吡啶、三乙胺、氢化钠和4-N,N-二甲基吡啶等试剂提供；所述通式(IV)化合物与通式(III)化合物的摩尔比为1:0.5～5。
  5. 一种药物组合物，其含有治疗有效量的根据权利要求1～2中任意一项所述的通式(I)所示的化合物以及药学上可接受的载体、稀释剂或赋形剂。
  6. 根据权利要求1～2中任意一项所述的通式(I)所示的化合物或根据权利要求5所述的药物组合物在制备光动力药物或光敏药物中的用途。
  7. 根据权利要求1～2中任意一项所述的通式(I)所示的化合物或根据权利要求5所述的药物组合物在制备治疗癌症的药物中的用途。
  8. 根据权利要求7所述的用途，其中所述的癌症选自肺癌、胃癌、食管癌、乳腺癌、膀胱癌、前列腺癌、胰腺癌、胆管癌、直肠癌、结肠癌、皮肤癌、头颈部癌症、眼肿瘤、子宫癌和卵巢癌，优选乳腺癌。
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