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WO2019056375A1 - Complexe de phtalocyanine de silicium à substitution géfitinib axiale sensible aux acides, son procédé de préparation et son utilisation médicale - Google Patents

Complexe de phtalocyanine de silicium à substitution géfitinib axiale sensible aux acides, son procédé de préparation et son utilisation médicale Download PDF

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Publication number
WO2019056375A1
WO2019056375A1 PCT/CN2017/103187 CN2017103187W WO2019056375A1 WO 2019056375 A1 WO2019056375 A1 WO 2019056375A1 CN 2017103187 W CN2017103187 W CN 2017103187W WO 2019056375 A1 WO2019056375 A1 WO 2019056375A1
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WO
WIPO (PCT)
Prior art keywords
cancer
gefitinib
compound
acid
preparation
Prior art date
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Ceased
Application number
PCT/CN2017/103187
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English (en)
Chinese (zh)
Inventor
蒋雄杰
黄华静
梁艳红
刘瑶
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Sono-Photodynamic Bio-Med Technology Ltd
Original Assignee
Shenzhen Sono-Photodynamic Bio-Med Technology Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Shenzhen Sono-Photodynamic Bio-Med Technology Ltd filed Critical Shenzhen Sono-Photodynamic Bio-Med Technology Ltd
Priority to PCT/CN2017/103187 priority Critical patent/WO2019056375A1/fr
Publication of WO2019056375A1 publication Critical patent/WO2019056375A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the invention belongs to the field of medicine, relates to a silicon phthalocyanine-gefitinib complex and a preparation method thereof and application thereof in medicine, and the invention discloses the use thereof as a photodynamic therapy-chemotherapy dual therapeutic drug 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 has been successfully applied to 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 Treatment of ovarian cancer.
  • EGFR epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • Gefitinib is an EGFR tyrosine kinase inhibitor that is a targeted drug for the treatment of tumors. It was first marketed in Japan in 2002 and was approved as a third-line monotherapy for advanced non-small cell lung cancer in the United States and Australia in May 2003. Formally launched in China in 2005, it has been used for clinical treatment of locally advanced or metastatic non-small cell lung cancer.
  • hypoxic microenvironment present in the solid tissue of the tumor results in a lower pH outside the tumor cell at that site (at 6.5 or so), while the normal tissue extracellular pH 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 present invention discloses a series of silicon phthalocyanine-gefitinib complexes linked by micro-acid environmentally sensitive bonds outside the tumor tissue.
  • the complex In the normal tissue environment, due to the interaction between the silicon phthalocyanine group and the gefitinib group, the complex has low cytotoxicity, but in the extracellular micro-acid environment of the tumor tissue, it can be released at the same time by hydrolysis.
  • the photosensitive active phthalocyanine silicon fragment and the high EGFR tyrosine kinase inhibitory activity of the gefitinib derivative fragments can be prepared as a dual-targeted anti-cancer drug for tumor cell extracellular micro-acid environment and EGFR tyrosine kinase dual targeting.
  • the invention discloses a series of micro acid environment sensitive ketal-linked silicon phthalocyanine-gefitinib complexes, a preparation method thereof and application in medicine.
  • the present invention relates to a silicon phthalocyanine-gefitinib complex represented by the general formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a photosensitizer, particularly in the treatment Use in cancer.
  • the complex In the normal tissue environment, due to the interaction between the silicon phthalocyanine group and the gefitinib group, the complex has low cytotoxicity, but in the extracellular micro-acid environment of the tumor tissue, the ketal is hydrolyzed and hydrolyzed.
  • the product silicon phthalocyanine fragments exhibit extremely high photosensitivity, while the other hydrolysate gefitinib derivative acts as an epidermal growth factor receptor (EGFR) tyrosinase inhibitor, inhibiting tumor growth.
  • EGFR epidermal growth factor receptor
  • They can be prepared as a dual-targeted anti-cancer drug for tumor cell extracellular micro-acid environment and EGFR tyrosine kinase dual targeting.
  • the present invention provides a compound of the formula (I):
  • n 1, 2, 3, or 4;
  • n 1, 2, 3, or 4;
  • the structure of formula (I) is stable under normal tissue extracellular pH of 7.4. Due to the interaction of the phthalocyanine silicon group and the gefitinib group, such compounds have lower cytotoxicity.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention also provides a process for the preparation of the compound of the formula (I), the reaction equation being as follows, but not limited to the following methods:
  • n 1, 2, 3, or 4;
  • the organic 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 at least one agent selected from the group consisting of pyridine, triethylamine, sodium hydride and 4-N,N-lutidine; the molar ratio of the material a to p-toluenesulfonyl chloride is 1: 0.2 to 2.
  • the solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, ethanol, and methanol; the reaction is carried out at a temperature of 30 to 120 ° C; and the basic condition is selected from the group consisting of pyridine Providing at least one of triethylamine, potassium carbonate, and sodium carbonate; the molar ratio of the intermediate a to the material b is 1:0.3-3.
  • the material b reference method is easily synthesized from gefitinib (Tetrhedron Letters, 46(43), 7381-7384).
  • the organic 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 60 ° C;
  • the basic condition is provided by at least one agent selected from the group consisting of pyridine, triethylamine, sodium hydride and 4-N,N-lutidine; the molar ratio of the intermediate c to the compound of the formula (IV) is 1 : 0.5 to 2.
  • the solvent is selected from the group consisting of toluene and xylene; and the reaction is carried out at a temperature of 80 to 160 ° C;
  • the basic condition is provided by a reagent selected from the group consisting of pyridine, triethylamine, sodium hydride and 4-N,N-dimethylpyridine; the molar ratio of the dichlorosilicon phthalocyanine to the compound of the formula (V) is 1: 0.5 to 10.
  • 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 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 medicament 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, uterine and ovarian 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.
  • 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 600 to 750 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.
  • a powder or granule which can be dispersed in water may contain an active ingredient, which is dispersed with a surfactant, and is surface active An agent, wetting or suspending agent, and mixed with 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.
  • An aqueous suspension, an isotonic physiological saline solution or a sterile and injectable solution comprising a pharmacologically compatible dispersant and/or wetting agent for parenteral, intranasal or intraocular administration Apply.
  • 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.
  • TsCl is p-toluenesulfonyl chloride.
  • the experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the raw material or the manufacturer of the commodity.
  • Reagents without specific source are routine reagents purchased from the market.
  • the material b reference method is easily synthesized from gefitinib (Tetrhedron Letters, 46(43), 7381-7384).
  • NMR instrument Bruker ARX-300/Bruker ARX-400 high resolution high resolution nuclear magnetic resonance instrument.
  • Mass Spectrometry QSTAR Elite tandem quadrupole time-of-flight mass spectrometer.
  • MTT test instrument Thermo Scientific Multiskan GO full wavelength microplate reader.
  • 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 ) or deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • 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 Example 2 In vitro anti-tumor cell photosensitivity test
  • Test sample compound 2, compound 4 and compound of formula (III) of the present invention
  • Test cells human lung cancer cell PC9
  • DMEM complete medium Add 500,000 U of penicillin/streptomycin, 56 mL of fetal bovine serum to 500 mL DMEM liquid medium (GIBCO), and mix.
  • MTT solution MTT: 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide, purchased from MP Company, USA: 5 mg/mL of powdered MTT The concentration is dissolved in PBS solution, sterilized by filtration, and is now ready for use.
  • the test sample was formulated into a mother liquor at a concentration of 1 mM in DMSO; 100 ⁇ L of 1 mg/mL mother liquor was taken during the experiment, and 1.15 mL of 0.5% (w/w) polyoxyethylene castor oil pH 7.4 PBS and pH 6.5 PBS buffer were added to prepare the test solution.
  • the solution was made into 80 ⁇ g/mL, and diluted with different PBS buffers into different concentrations of the drug solution.
  • the pH value of the drug solution was kept unchanged during the dilution process. After the drug solution was prepared, it was allowed to stand at room temperature for 24 hours, and then subjected to cell dosing culture.
  • the final concentration of DMSO in each drug and negative control group was ⁇ 1%.
  • Adherent tumor cells in logarithmic growth phase were selected and digested with trypsin, and mixed with DMEM medium containing 10% fetal bovine serum to prepare a suitable concentration of cell suspension, inoculated in 96-well culture plate at 37 ° C, 5% Incubate for 24 hours under CO 2 conditions. Then, 100 ⁇ L of each test drug, solvent and culture solution of different concentrations were added, respectively, and 3 parallel holes per group. After mixing, it was divided into two groups: light and dark. After co-cultivation for 2 hours, the medium was discarded, and the medium containing no test sample was added again. The culture was continued at 37 ° C and 5% CO 2 . hour.
  • 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] x 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un complexe de phtalocyanine de silicium à substitution géfitinib axiale à liaison cétal et sensible à l'environnement légèrement acide, ainsi que son procédé de préparation et son utilisation médicale. En particulier, la présente invention concerne un complexe de phtalocyanine de silicium-géfitinib tel que représenté dans la formule générale (I), son procédé de préparation et une composition pharmaceutique contenant le complexe, ainsi que son utilisation comme photosensibilisant, en particulier son utilisation dans le traitement des cancers, la définition de chaque substituant dans la formule générale (I) étant la même que celle donnée dans la description. Dans un environnement de tissu normal, en raison de l'interaction du groupe phtalocyanine de silicium et du groupe géfitinib, le complexe présente une cytotoxicité moindre. Cependant, dans l'environnement extracellulaire légèrement acide du tissu tumoral, les cétals s'hydrolysent et les fragments de l'hydrolysat, c'est-à-dire la phtalocyanine de silicium, présentent une activité photosensible extrêmement élevée, pendant qu'un autre hydrolysat, c'est-à-dire un dérivé géfitinib, peut être utilisé comme inhibiteur du récepteur du facteur de croissance épidermique (EGFR) tyrosinase pour inhiber la croissance tumorale. Les complexes peuvent être préparés sous forme de médicaments anticancéreux à double efficacité thérapeutique photodynamique et chimiothérapeutique, ciblant tant l'environnement extracellulaire tumoral légèrement acide que l'EGFR tyrosine kinase.
PCT/CN2017/103187 2017-09-25 2017-09-25 Complexe de phtalocyanine de silicium à substitution géfitinib axiale sensible aux acides, son procédé de préparation et son utilisation médicale Ceased WO2019056375A1 (fr)

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PCT/CN2017/103187 WO2019056375A1 (fr) 2017-09-25 2017-09-25 Complexe de phtalocyanine de silicium à substitution géfitinib axiale sensible aux acides, son procédé de préparation et son utilisation médicale

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Cited By (1)

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CN111057063A (zh) * 2019-12-19 2020-04-24 福州大学 一种用于急性淋巴细胞白血病的靶向光动力治疗的酞菁衍生物及其制备方法

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CN103626781A (zh) * 2013-12-12 2014-03-12 福州大学 一种靶向抗癌分子吉非替尼酞菁轭合物及其制备和应用
CN106565763A (zh) * 2016-11-11 2017-04-19 深圳市声光动力生物医药科技有限公司 pH敏感的轴向取代硅酞菁配合物及其制备方法和在医药上的应用

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CN1583762A (zh) * 2004-06-11 2005-02-23 福州大学 新的轴向取代酞菁配合物、它的制备及其在光动力治疗中的应用
CN1861603A (zh) * 2006-06-21 2006-11-15 福州大学 酞菁硅配合物及其复合物以及它们的制备和应用
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111057063A (zh) * 2019-12-19 2020-04-24 福州大学 一种用于急性淋巴细胞白血病的靶向光动力治疗的酞菁衍生物及其制备方法
CN111057063B (zh) * 2019-12-19 2022-06-14 福州大学 一种用于急性淋巴细胞白血病的靶向光动力治疗的酞菁衍生物及其制备方法

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