WO2018086241A1 - Complexe de coordination de phtalocyanine de zinc 1,4-disubstitué sensible au ph, sa méthode de préparation et son application en médecine - Google Patents

Complexe de coordination de phtalocyanine de zinc 1,4-disubstitué sensible au ph, sa méthode de préparation et son application en médecine 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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PCT/CN2017/070293
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English (en)
Chinese (zh)
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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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Publication of WO2018086241A1 publication Critical patent/WO2018086241A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un complexe de coordination de phtalocyanine du cholestérol-zinc lié au cétal sensible au pH et sa méthode de préparation et son application en médecine. En particulier, la présente invention concerne le complexe de coordination de phtalocyanine de zinc représenté dans une formule générale (I), sa méthode de préparation, une composition pharmaceutique contenant le complexe de coordination, et leur utilisation en tant que photosensibilisant, en particulier pour le traitement de cancers, tous les substituants dans la formule générale (I) ayant la même définition que celles dans la description. Comme les radicaux de cholestérol existent, la série de composés est difficile pour les cellules tumorales et les cellules normales à assimiler, toutefois, dans un environnement sous-acide externe de cellules de tissu tumoral, une réaction d'hydrolyse de cétal se produit, et des dérivés d'hydrolyse de phtalocyanine de zinc peuvent être facilement pris en charge par des cellules cancéreuses et présentent une activité photosensible extrêmement élevée. Les complexes de coordination de phtalocyanine de zinc peuvent être préparés dans un environnement sous-acide externe de cellule tumorale cible de la médecine photosensible.
PCT/CN2017/070293 2016-11-11 2017-01-05 Complexe de coordination de phtalocyanine de zinc 1,4-disubstitué sensible au ph, sa méthode de préparation et son application en médecine WO2018086241A1 (fr)

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CN201611039671.4A CN106749478B (zh) 2016-11-11 2016-11-11 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
CN201611039671.4 2016-11-11

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WO2019056374A1 (fr) * 2017-09-25 2019-03-28 深圳市声光动力生物医药科技有限公司 Complexe de subphtalocyanine de bore-géfitinib sensible à l'acide, son procédé de préparation et son utilisation médicale
CN107629063B (zh) * 2017-09-25 2019-03-19 深圳市声光动力生物医药科技有限公司 酸敏感的酞菁锌-吉非替尼配合物及其制备方法和在医药上的应用
CN110628049B (zh) * 2019-10-22 2022-04-12 西华师范大学 一种光响应抗菌的自修复胶原凝胶及其制备方法
CN114621309B (zh) * 2022-03-03 2023-03-21 宁德师范学院 酞菁铵盐类液晶超分子抗静电材料、中间体、制备及应用

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CN102250101A (zh) * 2011-08-08 2011-11-23 福州大学 二-α-喹啉-低聚乙二醇酞菁锌及其制备方法
CN103755714B (zh) * 2014-01-27 2015-12-02 福州大学 一种酞菁-水滑石复合物及其制备方法和应用
CN105418643B (zh) * 2015-12-22 2017-10-20 福州大学 一种双边生物素‑酞菁锌轭合物及其制备和应用
CN105585571B (zh) * 2016-03-10 2018-08-17 福州大学 一种周边单取代的酞菁锌配合物及其阿霉素偶联物

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