WO2002020621A1 - Derives de tetraphenylporphyrine et compositions renfermant ces derniers - Google Patents

Derives de tetraphenylporphyrine et compositions renfermant ces derniers Download PDF

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Publication number
WO2002020621A1
WO2002020621A1 PCT/JP2001/007757 JP0107757W WO0220621A1 WO 2002020621 A1 WO2002020621 A1 WO 2002020621A1 JP 0107757 W JP0107757 W JP 0107757W WO 0220621 A1 WO0220621 A1 WO 0220621A1
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Prior art keywords
salt
tetraphenylporphyrin
derivative
pyr
group
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PCT/JP2001/007757
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English (en)
Japanese (ja)
Inventor
Shigenobu Yano
Toyoji Kakuchi
Isamu Kinoshita
Original Assignee
San-Ei Gen F.F.I.,Inc.
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Application filed by San-Ei Gen F.F.I.,Inc. filed Critical San-Ei Gen F.F.I.,Inc.
Priority to AU2001284465A priority Critical patent/AU2001284465A1/en
Priority to JP2002525240A priority patent/JP4312455B2/ja
Publication of WO2002020621A1 publication Critical patent/WO2002020621A1/fr

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    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to tetraphenylporphyrin derivatives and compositions comprising the same.
  • the present invention relates to a tetraphenylporphyrin derivative, and in particular, to a tetraphenylporphyrin derivative or a salt thereof substituted with a maltohexose residue and a decyl group, and a photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • the present invention relates to a composition as a photosensitizer comprising a tetraphenylporphyrin derivative or a salt thereof, which can be used.
  • Photodynamic therapy in which a photosensitizer having a specific affinity for S-severe cells is administered to a patient in advance and then irradiated with laser light of various wavelengths to treat cancer, It is receiving attention as one of the non-invasive treatments for cancer.
  • a photosensitizer that can be used in such PDT therapy various derivatives having a porphyrin skeleton are known, and some of them are actually used clinically.
  • desirable photosensitizers that can be used for PDT therapy include hydrophilicity, high selectivity for tumor cells, harmlessness to cells in the dark, good tissue permeability, and low cost. It is required that the extinction coefficient in the long wavelength region that can use a suitable laser light device be large.
  • the porphyrin derivatives proposed so far have problems such as side effects caused by hydrophobicity and small absorption coefficient of excitation light in a long wavelength region with high tissue permeability. Hope to develop excellent photosensitizer It is rare. Disclosure of the invention
  • the present inventors have conducted intensive studies to develop a better photosensitizer, and have found that maltohexose residues for imparting hydrophilicity and cell affinity and affinity for cell walls are increased.
  • the present inventors have found that a tetraphenylporphyrin derivative having a decyl group has an excellent cell killing effect by light in a long wavelength region, and completed the present invention.
  • Fig. La is a graph showing the toxicity of the compound A of the present invention to cells not irradiated with light
  • Fig. Lb is a graph showing the toxicity of the compound A of the present invention to cells irradiated with light.
  • R i, R 2, R 3 and R 4 are, independently of one another, Or
  • ⁇ -0 (CH 2 ) 9 is a group represented by CH 3 ]
  • Examples of preferred specific compounds of the tetraphenylporphyrin derivative (I) according to the present invention are as follows.
  • the tetraphenylporphyrin derivative (I) of the present invention can be produced by the method described below or a method analogous thereto.
  • a tetraphenylporphyrin derivative (la) substituted with a maltohexose residue and a decyl group is a benzaldehyde derivative in which the hydroxy group on the benzene ring is protected with an appropriate protecting group, and the hydroxy group on the benzene ring is It can be obtained by reacting a benzaldehyde derivative substituted with a decyl group, pyrrole, according to the method of Ad 1er et al. (J. Org. Chem., 32, 476 (1967)). .
  • a tetraphenylporphyrin derivative (IV) is obtained by reacting pyrrole with two kinds of benzaldehyde derivatives (II) and (III) in a suitable organic solvent such as propionic acid.
  • the hydroxy-protecting group on the benzene ring is removed from the tetrafluoroporphyrin derivative (IV) obtained above in the presence of a base such as sodium methoxide to give a tetraphenylporphyrin compound (V).
  • This tetraphenylporphyrin compound (V) is subjected to a coupling reaction with a maltohexose derivative (VI) to obtain a compound (VII), and then the hydroxy protecting group of the maltohexose moiety is eliminated to thereby remove the hydroxy protecting group.
  • a tetraphenylporphyrin derivative (la) substituted with a maltohexose residue and a decyl group can be obtained.
  • tetraphenylporphyrin derivatives (lb) substituted with a maltohexose residue and a decyl group are a benzaldehyde derivative in which the hydroxy group on the benzene ring is protected by an appropriate protecting group, and a Benzaldehyde derivatives in which the xy group is substituted with a decyl group, 1-mesityl dipyrromethane, were prepared according to the method of Lindsey et al. (J. Org. Chem., 64, 1391 (1999) and 64, 2864 ( 1999)). An example of this is shown in the following reaction formula.
  • 1-mesityl dipyrrolomethane (VIII) and two kinds of benzaldehyde derivatives (II) and (III) are mixed with trifluoroacetic acid in a suitable organic solvent, for example, an inert solvent such as anhydrous dichloromethane. And then treated with 2,3-dichloro-1,5-dicyano-1,4-benzoquinone to obtain a tetraphenylporphyrin compound (IX).
  • a suitable organic solvent for example, an inert solvent such as anhydrous dichloromethane.
  • the hydroxyprotecting group on the benzene ring is removed from the obtained tetraphenylporphyrin compound (IX) in the presence of a base such as potassium hydroxide to obtain a tetraphenylporphyrin compound (X).
  • Examples of the salt of the tetrafluoroporphyrin derivative (I) of the present invention include a salt formed with an acid or a base, and an intramolecular 'complex salt with a metal.
  • the salt formed with an acid or a base can be formed by treating the tetraphenylporphyrin derivative (I) obtained as described above with an appropriate acid or base.
  • Examples of the acid or base used to form the salt include mineral acids such as hydrochloric acid, hydrogen bromide, nitric acid, and sulfuric acid; organic acids such as toluene sulfonic acid and benzene sulfonic acid; alkali metals or alkaline earth metals ( For example, sodium, potassium, calcium or magnesium) hydroxides, carbonates or bicarbonates, or organic bases such as ammonium, trimethinoleamine, and triethylamine.
  • mineral acids such as hydrochloric acid, hydrogen bromide, nitric acid, and sulfuric acid
  • organic acids such as toluene sulfonic acid and benzene sulfonic acid
  • alkali metals or alkaline earth metals For example, sodium, potassium, calcium or magnesium hydroxides, carbonates or bicarbonates, or organic bases such as ammonium, trimethinoleamine, and triethylamine.
  • Metals that form intramolecular complex salts include alkali metals (eg, lithium, sodium, potassium, rubidium, cesium), alkaline earth metals (eg, magnesium, canoledium, barium, strontium) and periodic table of elements.
  • alkali metals eg, lithium, sodium, potassium, rubidium, cesium
  • alkaline earth metals eg, magnesium, canoledium, barium, strontium
  • Group 3 eg, scandium, lanthanum, yttrium), lanthanoids (eg, europium, praseodymium, ytterbium), Group 4 (eg, titanium), Group 5 (eg, vanadium), Group 6 (eg, Chromium, molybdenum, tungsten), Group 7 (eg, manganese, rhenium), Group 8 (eg, iron, ruthenium, osmium), Group 9 (eg, cobalt, rhodium, iridium).
  • Group 3 eg, scandium, lanthanum, yttrium
  • lanthanoids eg, europium, praseodymium, ytterbium
  • Group 4 eg, titanium
  • Group 5 eg, vanadium
  • Group 6 eg, Chromium, molybdenum, tungsten
  • Group 7 eg, manganese, rhenium
  • Group 8 eg, iron,
  • Group 10 eg, For example, nickel, palladium, platinum
  • the first Group 1 e.g., copper, silver, gold
  • Group 1 2 e.g., zinc, force Domiumu, mercury
  • the first 3 Group e.g, aluminum, gallium, indium
  • group 14 e.g, silicon, germanium, tin, lead
  • group 15 arsenic, antimony, bismuth
  • metals of Group 10 and Group 12 of the Periodic Table of the Elements are preferred, and zinc and platinum are most preferred.
  • An intramolecular complex salt with a metal can be formed by the reaction of a tetraphenylporphyrin derivative (I) with a metal halide, a metal acetate, a metal hydroxide or a metal perchlorate.
  • the tetraphenylporphyrin derivative (I) and a salt thereof according to the present invention have improved hydrophilicity and lipophilicity by the introduction of a maltohexose residue and a decyl group, and have a function of tumor cell recognition by maltose residue. Selectivity for is expected. Furthermore, the tetrafluoroporphyrin derivative (I) of the present invention and its salt are not toxic to cells in some places, have good cell tissue permeability, and have a cell killing effect by light irradiation in a long wavelength region. Therefore, it is useful as a photosensitizer in PDT therapy.
  • the porphyrin skeleton accumulated in tumor cells emits a characteristic red fluorescence when excited by light in the Q band (approximately 650 nm). Therefore, the tetraphenylporphyrin derivative (I) and its salt are It is also expected to be applied to photodynamic diagnosis (PDD) to diagnose the presence or location of cancer lesions.
  • PDD photodynamic diagnosis
  • composition as a photosensitizer comprising the tetraphenylporphyrin derivative (I) or a salt thereof.
  • composition comprising the tetraphenylporphyrin derivative (I) or a salt thereof of the present invention can be used for diagnosis and treatment of cancer and tumor.
  • cancer tumors include stomach cancer, intestinal cancer, lung cancer, breast cancer, uterine cancer, esophageal cancer, ovarian cancer, renal cancer, pharyngeal cancer, sarcoma, liver cancer, bladder cancer, maxillary cancer, bile duct cancer, tongue Cancer, cerebral tumor, skin cancer, malignant goiter, prostate cancer, parotid gland cancer, Hodgkin's disease, multiple myeloma, kidney cancer, leukemia and malignant lymphoma It is.
  • compositions of the present invention may optionally further comprise other medicaments.
  • compositions of the present invention are administered orally or parenterally, such as by intravenous or intramuscular injection. Orally, it is administered in the form of tablets, pills, powders, granules, fine granules, capsules, solutions, suspensions, emulsions, and the like. It is administered parenterally in the form of injections, drops, suppositories, ointments, plasters, patches, aerosols and the like.
  • compositions although depending on the dosage form, may be those commonly used in the field of medicine.
  • excipients lactose, starch, crystalline cellulose, etc.
  • binders starch solution, carboxymethyl cellulose, etc.
  • a pH adjuster and a buffer sodium tenoate, sodium acetate, sodium phosphate, etc.
  • the mixture can be added to produce an injection or drip for intravenous, intramuscular, subcutaneous, intradermal, or intraperitoneal use in a conventional manner.
  • the injection or infusion is preferably sterilized and isotonic with blood.
  • the administration amount of the tetraphenylporphyrin derivative (I) or a salt thereof according to the present invention is 7 to 0 for the diagnosis of B-severe ulcer as the amount of the tetraphenylporphyrin derivative (I) or a salt thereof.
  • it is 3 mgZkg HpD (photophylline) or 20-0.2 mg / kg PHE (photophylline), preferably 2 mg / kg PHE (photophyllin).
  • the tetraphe-noreporphyrin derivative (I) of the present invention or a salt thereof is selectively distributed to tumor cells after a certain period of time. Then, for the diagnosis of J tumor, the site to be examined is irradiated with light having a wavelength between 360 and 760 nm.
  • the irradiation source is not limited, but a halogen lamp is preferable because it can emit light in a wide wavelength range.
  • the tetraphenylporphyrin derivative (I) or a salt thereof distributed in the heavy tumor cells emits fluorescence by the light having the above-mentioned wavelength, and the localization and presence or absence of tumor cells can be diagnosed.
  • a wavelength around 650 ⁇ m, for example between 630 and 670 nm is applied to the site to be treated. Is irradiated.
  • the irradiation source is not limited, it is desirable to select and use a source that selectively emits a strong light beam in a desired wavelength range.
  • the irradiation source may be a semiconductor laser, such as a gallium-aluminum-arsenic, gallium-aluminum-arsenic, gallium-aluminum or near-infrared laser using gallium-aluminum-phosphorus, which emits a laser beam.
  • Gas lasers such as light-emitting diodes and krypton ion lasers include dye lasers using styrene, oxazine and xanthene.
  • the irradiation intensity of the light beam is, specifically, 10 to 500 mW / cm2, preferably 160 to 500 mW / cm2.
  • the irradiation frequency of the light beam may be one or more times a day, for example, 1 to 100 times Z days, preferably 1 to 10 times Z days.
  • the combination of the number of administrations of the composition of the present invention and the number of irradiations of light is sufficient to significantly reduce tumors. Just do it.
  • Nonadeforce O-acetyl_1-hydroxy-1-j3-D-maltohexanoside (13.5 g, 7.5 mmol) in anhydrous dichloromethane (15 OmL) was added to potassium carbonate (10.3 g, 75 mmol). 1) and CC 13 CN (11.2 mL, 0.1 lmo 1) were added, and the mixture was stirred at room temperature for 15 hours. The potassium carbonate was removed by filtration using Celite, and the filtrate was evaporated under vacuum.
  • the black-mouthed form phase was washed with 2N-hydrochloric acid, ice water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate.
  • the extract was evaporated and the resulting crude product was purified by silica gel column chromatography using hexane / ethyl acetate (4Zl, v / v) as eluent to give 4-decyloxybenzaldehyde (9.13 g, 85%).
  • the crude product was purified by column chromatography on silica gel 6 ON using hexane / ethyl acetate (20/1 to 8/1, v / v) as the gradient eluent to give 5,10-di (4-decyloxy).
  • One 5,20-di- (4-acetoxy) tetraphenylporphyrin (100.lmg, 3.1%) was obtained.
  • the obtained product was stirred at room temperature in a methanol solution of sodium methoxide (1% by weight) to obtain the title compound as a purple solid.
  • example 1 5 , 10-Di (4-decyloxyphenyl) -15,20 1-bis [4- [3- (jS-D-maltohexanosyl) propoxy] phenyl] porphyrin
  • 1-mesityl dipyrromethane (264.4 mg, 1.0 mmo 1) 4-acetoxybenzaldehyde (82.2 mg, 0.5 mmol and 4-decyloxybenzaldehyde in dichloromethane (100 m L), purged with argon for 5 minutes, added TFA (0.13 ml 1.78 mmol) and stirred for 30 minutes DDQ (380 mg) was added to the reaction mixture and stirred for an additional hour After neutralization with triethylamine (0.5 mL), the mixed solvent was filtered and removed under vacuum The residue was purified by silica gel chromatography using dichloromethane hexane (3Z2, v / v) as eluent. The resulting crude product was further purified by circulating HP LC using THF as eluent to give the title compound (80 mg 17.5%) as a purple solid.
  • Test Example 1 Phototoxicity test
  • Compound A 5,10-di (4-decyloxyphenyl) 1 1 5,20-bis [4- [3- (j3-D-maltohexanosyl) propoxy] phenyl] porphyrin (hereinafter “Compound A”) Cytotoxicity was determined by the healing method using the MTT assay (Carmichal, J., WGDeGraff, AFGazdar, JDMinna and JBMitchell, Cancer Res., 1987, 47, 936-942). The cell viability was evaluated.
  • HeLa cells (1 x 10 4 cells / well) were placed in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) at 37 ⁇ in a 96 ⁇ 1 well plate under 5% CO 2. Incubated for 24 hours. After washing with phosphate buffered saline (PBS), cells were incubated with serum-free DMEM for 2 hours in the presence of Compound A (5 or 10 ⁇ M). The cells to which compound A was added were washed with PBS.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • HeLa cells (1 ⁇ 10 4 cells / well) were treated in the same manner as Kamiyoshi.
  • the cells to which compound A was added were irradiated for 8 minutes with a 500 W halogen lamp equipped with a filter that cuts wavelengths shorter than 500 nm. After incubation for 24 hours, viability was measured by MTT assay.
  • the figure (lb) shows the cell survival ratio (%) after irradiation.
  • the tetraphenylporphyrin derivative or a salt thereof of the present invention has enhanced hydrophilicity and lipophilicity by introducing a maltohexose residue and a decyl group, and has selectivity for tumor cells by cell recognition by maltose residue. There is expected. Furthermore, the tetraphenylporphyrin derivative or a salt thereof of the present invention has no cell toxicity in the dark and has a cell killing effect by irradiation with light in a long wavelength region having good cell tissue permeability. Therefore, PDT therapy is useful as a photosensitizer in PDD.
  • tetraphenylporphyrin derivative or a salt thereof of the present invention can be used as a pressure-sensitive paint.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne des dérivés de tetraphénylporphyrine représentés par la formule générale (I), dans laquelle R?1, R2, R3 et R4¿ représentent chacun indépendament un groupe représenté par la formule générale (II), (III) ou (IV), à condition que R1 et/ou R4 soit le groupe représenté par la formule générale (II) et qu'au moins un des autres groupes soit le groupe représenté par la formule générale (III). L'invention concerne également des sels de ces dérivés, ainsi que l'utilisation de ces dérivés et de ces sels comme agents photosensibilisants.
PCT/JP2001/007757 2000-09-08 2001-09-06 Derives de tetraphenylporphyrine et compositions renfermant ces derniers WO2002020621A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001284465A AU2001284465A1 (en) 2000-09-08 2001-09-06 Tetraphenylporphyrin derivatives and compositions comprising the same
JP2002525240A JP4312455B2 (ja) 2000-09-08 2001-09-06 テトラフェニルポルフィリン誘導体およびそれからなる組成物

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JP2000273650 2000-09-08
JP2000-273650 2000-09-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8748037B2 (en) 2011-12-20 2014-06-10 Samsung Electronics Co., Ltd. Cathode and electrochemical device including cathode
JP2014528918A (ja) * 2011-07-22 2014-10-30 バイオリテック ファーマ マーケティング リミテッド 抗菌性光線力学療法のための、糖−置換ジヒドロキシ−クロリン及びβ−官能化クロリン
US8906562B2 (en) 2011-12-20 2014-12-09 Samsung Electronics Co., Ltd. Polymeric compound, oxygen permeable membrane, oxygen permeable composite, electrochemical device

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05112593A (ja) * 1991-10-21 1993-05-07 Honen Corp 新規なテトラフエニルポルフイン配糖体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05112593A (ja) * 1991-10-21 1993-05-07 Honen Corp 新規なテトラフエニルポルフイン配糖体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014528918A (ja) * 2011-07-22 2014-10-30 バイオリテック ファーマ マーケティング リミテッド 抗菌性光線力学療法のための、糖−置換ジヒドロキシ−クロリン及びβ−官能化クロリン
US8748037B2 (en) 2011-12-20 2014-06-10 Samsung Electronics Co., Ltd. Cathode and electrochemical device including cathode
US8906562B2 (en) 2011-12-20 2014-12-09 Samsung Electronics Co., Ltd. Polymeric compound, oxygen permeable membrane, oxygen permeable composite, electrochemical device

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AU2001284465A1 (en) 2002-03-22
JP4312455B2 (ja) 2009-08-12

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