WO2002020621A1

WO2002020621A1 - Tetraphenylporphyrin derivatives and compositions comprising the same

Info

Publication number: WO2002020621A1
Application number: PCT/JP2001/007757
Authority: WO
Inventors: Shigenobu Yano; Toyoji Kakuchi; Isamu Kinoshita
Original assignee: San-Ei Gen F.F.I.,Inc.
Priority date: 2000-09-08
Filing date: 2001-09-06
Publication date: 2002-03-14
Also published as: JPWO2002020621A1; JP4312455B2; AU2001284465A1

Abstract

Tetraphenylporphyrin derivatives of the general formula (I) or salts thereof; and use of both as photosensitizer wherein R?1, R2, R3 and R4¿ are each independently a group represented by the formula (II), (III) or (IV) with that proviso that at least one of R1 to R4 is the group represented by the formula (II) and at least one of the others is the group represented by the formula (III).

Description

TECHNICAL FIELD 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). The present invention relates to a composition as a photosensitizer comprising a tetraphenylporphyrin derivative or a salt thereof, which can be used. View &: art

Photodynamic therapy (PDT), 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. As 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.

By the way, 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. However, 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

Accordingly, 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. BRIEF DESCRIPTION OF THE FIGURES

Fig. La is a graph showing the toxicity of the compound A of the present invention to cells not irradiated with light, and Fig. Lb is a graph showing the toxicity of the compound A of the present invention to cells irradiated with light. . BEST MODE FOR CARRYING OUT THE INVENTION

Departure

Wherein R i, R 2, R 3 and R 4 are, independently of one another,

Or

And at least one of Ri R ⁴ is

And at least one of the remaining Ri to R4 is

^ -0 (CH ₂ ) ₉ is a group represented by CH ₃ ]

And a salt thereof is provided.

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.

For example, 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)). .

An example is shown in the following reaction formula.

In this specific example, first, 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). You.

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.

In addition, 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.

(X)

Ob)

In this specific example, first, 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).

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).

Induce this tetraphenylporphyrin compound (X) to maltohexose The compound (XI) is obtained by coupling reaction with the conductor (VI), and then the hydroxy protecting group of the maltohexose moiety is removed to obtain a compound having a maltohexose residue or decyl group. A substituted tetraphenylporphyrin derivative (lb) can be obtained.

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.

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. 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 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 (eg, aluminum, gallium, indium), group 14 (eg, silicon, germanium, tin, lead) and group 15 (arsenic, antimony, bismuth) metals. Among them, 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. In addition, 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.

Therefore, according to the present invention, there is provided a composition as a photosensitizer comprising the tetraphenylporphyrin derivative (I) or a salt thereof.

The 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. Examples of 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.

The tetraphenylporphyrin derivative (I) of the present invention or a salt thereof is administered to a human or animal as a composition in combination with a usual pharmaceutically acceptable additive. The compositions of the present invention may optionally further comprise other medicaments.

The 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.

Pharmaceutically acceptable excipients, although depending on the dosage form, may be those commonly used in the field of medicine.

For example, when forming into tablets, excipients (lactose, starch, crystalline cellulose, etc.), binders (starch solution, carboxymethyl cellulose, etc.), etc. can be added and manufactured according to a conventional method. .

For example, when shaping into an injection or infusion form, it is dissolved in distilled water for injection as a diluent, and a pH adjuster and a buffer (sodium tenoate, sodium acetate, sodium phosphate, etc.) are appropriately added. 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. 07 mg / kg (photofilin), preferably 0.7 mg / kg (photophylline), and 30-0.3 mg / kg HpD (photophylline) for the treatment of tumors. Preferably it is 3 mgZkg HpD (photophylline) or 20-0.2 mg / kg PHE (photophylline), preferably 2 mg / kg PHE (photophyllin).

When the composition of the present invention is administered, 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.

For the treatment of tumors, after administration of a composition containing the tetraphenylporphyrin derivative (I) or a salt thereof, a wavelength around 650 ηm, for example between 630 and 670 nm, is applied to the site to be treated. Is irradiated. Although 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.

Hereinafter, specific production examples of the tetraphenylporphyrin derivative (I) of the present invention will be described with reference to Examples, but the present invention is not limited to these Examples.

The meanings of the abbreviations used in the examples are as follows.

THF: tetrahydrofuran

DMAP: 4-dimethylaminopyridine

DMF: dimethylformamide

TFA: trifluoroacetic acid

DDQ: 2,3-dichloro-5,6-dicyanone 1,4-benzoquinone DMSO: methylsulfoxide Production example 1: icosa-1-O-acetyl-1-α-cyclodextrin

Pyridine (900 mL) was added to a solution of α-cyclodextrin ( _α —CD) (197 g, 202 mmo 1) in acetic anhydride (600 mL), and the mixture was stirred at room temperature for 4 hours. Cold water was added to the solution and stirred overnight. The reaction mixture was acidified with 6 N hydrochloric acid, and then extracted with black hole form. The organic phase was washed with cold water and a saturated aqueous solution of sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The combined extract was evaporated under vacuum to give icosa O-acetyl-α-CD (318 g, 91%). Production Example 2: Icocer O-acetyl-β-D-maltohexanoside icosa-1-acetyl- CK _CD (200 g, 0.12mo1) in anhydrous acetic acid (120 mL), concentrated sulfuric acid (24 mL) And stirred at 60 ° C. for 2.5 hours. The mixture was neutralized by adding a solution of sodium acetate in ethanol (about 40 OmL) at 0 ° C. Azeotropically remove the solvent with toluene After that, the residue was resuspended in toluene. The insoluble solid was filtered off, and the filtrate was evaporated under vacuum. The crude product was purified by silica gel column chromatography, eluting with toluene Zaceton (4Z 1-5 / 2, v / v), recrystallized from ethanol, and a white solid, icosa-1O-acetyl-1D-malto Hexanoside (42.3 g, 20%) was obtained. Production Example 3: Nonade force—O-acetyl-1-1-hydroxy-1] 3-D—maltohexanoside

To a solution of icosa-1-O-acetyl-1D-maltohexanoside (20 g, 10.9 mmol) in THF (20 OmL) was added piperidine (6 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into cold 2N-hydrochloric acid, and then extracted with porcine. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporating the combined extracts, the crude product was purified by silica gel column chromatography eluting with toluene Z acetone (v / v, 4/1) to yield a white solid nonade 1-Hydroxy β-D-maltohexanoside (15.8 g, 81%) was obtained. Production Example 4: Nonade force 0-acetyl-1_triclo mouth imidate j3—D-maltoxanoside

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. Elute the crude product with toluene / acetone (8/3, v / v) The residue was purified by silica gel column chromatography to obtain a white solid, nonaden-O-acetyl-1-trichloroimidate-D-maltoxanoside (11.0 g, 76%).

Elemental analysis: C76Hioo0 ₅ as oNCl _3; Calculated: C 47.22, H 5.22, N 0.73, C1 5.43; Found C 47.94, H 5.24, N 0.85 , C15.85;

FAB MS m / z: 1972.0 (M + K). Production Example 5: Nonade li-O-Acetyl-l-bromopropoxy-D-manoletohexanoside

Nonadeforce 1-Acetyl-1 1-Triclomimidate-1 J3-D-Maltoxanoside (10 g, 5.17 mmo 1) and Molecular Sheep 4 A in anhydrous dichloromethane (100 mL) solution, 3-bromopropanol (4.67 mL, 51.7 mmo 1) was added at _20 ° C under a nitrogen stream. After the reaction mixture was stirred at 120 ° C. for 30 minutes, BF3 · Et20 (0.65 mL, 5.17 mmol 1) was added, and the mixture was stirred for 20 minutes. The reaction was quenched by the addition of pyridine (1 mL). The reaction mixture was poured into cold water and then extracted with dichloromethane. After evaporating the combined extracts, the crude product was purified by silica gel column chromatography, eluting with toluene Z acetone (v / v, 2/1) to yield a white solid nonadeca O-acetyl-1-bromopropoxy. 1] 3-D-Manoletohexanoside (7.5 g, 76%) was obtained.

iH NMR (300 MHz, CDCl ₃ ) δ 5.42 (d, 1H, J = 3.8 Hz, 1VI-H), 5.35 (t, 1H, J = 10 Hz, 3I-H), 5.24-5.43 (m, 11H, III , III, IV, V, VI-, 31, II, III, VI, V, VI-H), 5.07 (t, 1H, J = 10 Hz, 4VI-H), 4.86 (dd, 1H, J = 4.0 Hz, 10.5 Hz, 2 VI-H), 4.80 (dd, 1H, J = 7.9 Hz, 9.3 Hz, 21-H), 4.71-4.76 (m, 4H, 2 II, III, IV, VH), 4.54 ( d, 1H, J = 7.9 Hz, 1I-H), 4.53-4.43 (m, 5H, 6a I, II, III, IV, VH), 4.50 (dd, 1H, J = 3.0 Hz, 12.2 Hz, 6al-H), 4.38 (dd, 1H, J = 3.7 Hz, 12.2 Hz, 6bI-H ), 4.30, 4.28, 4.25, 4.16 (dd (4, 4H, 6b ΙΙ, ΙΠ, ΐν, ν-H), 4.22 (m, 1H, 6aVI-H), 4.07 (dd, 1H, J = 2.3Hz, 9.1Hz, 6bVI-H), 3.93 (m, 1H, 5VI-H), 3.93 (m, 1H, OCH 2), 3.98 (m, 1H, 4I-H), 3.71 (m, 1H, 5I-H) , 3.70 (m, 1H, OCH ₂ ), 3.45 (m, 2H, CH ₂ Br), 2.02 (2H, m, CH ₂ CH ₂ CH ₂ ), 1.98-2.20 (s, 3H (19, COCHs).

Elemental analysis: As CyyHiosOsoBr: Calculated C 48.42, H 5.54, Br 4.14; Observed C 48.42, H 5.54, Br 4.29;

FAB MS m / z: 1909.0 (M ⁺ + H). Production Example 6: Nonadeca O-acetyl-1-1-propoxide-1] 3-D-manoletohexanoside

Nonaden O-acetyl-1-bromopropoxy-1] 3-D-maltohexanoside (4.8 g, 2.5 mmo 1) and NaI (3.7 g, 2

A solution of 5 mmo 1) in 2-butanone (100 mL) was heated under reflux for 20 hours. After cooling to room temperature, the reaction mixture was extracted with chloroform. The combined extracts were evaporated and recrystallized from ethanol to obtain white crystals of nonadeca O-acetyl-1-odepropoxy-131D-maltohexanoside (4.6 g, 95%).

_{lH NMR (500 MHz, CDC1 3} ) δ 5.42 (d, 1H, 1VI-H), 5.35 (t, 1H, 31- H), 5.25- 5.50 (m, 1 1H, 1 II, III, IV, V, VI-, 3 I, II, III, IV, V, VI-H) 5.07 (t, 1H, J = 10 Hz, 4VI-H), 4.87 (dd, 1H, 2VI-H), 4.80 (dd, 1H , 2I-H), 4.71-4.76 (m, 4H, 2 II, III, IV, VH) 4.54 (d, 1H, J = 7.9 Hz, 1I-H), 4.50 (dd, 1H, 6aI-H), 3.71 (m, 1H, 5I-H), 3.60 (1H, m, OCH ₂ ), 3.23 (2H, m, CH ₂ I), 2.02 (2H, m, CH ₂ CH ₂ CH ₂ ), 1.98-2.20 ( s, 3H (19, COCHs).

¹³ C NMR (125 MHz, CDCI3): δ 2.90 (CH ₂ I), 20.60, 20.89 (COCH3),

32.85 (CH2CH2CH), 61.374 (6VI-C), 62.17 (6V-C), 62.35 (6IV-C),

62.47 (6III-C), 62.52 (6II-C), 62.89 (6I-C), 67.95 (4VI-C), 68.97

(OCH2), 69.36 (3VI-C), 70.44 (5VI-C), 72.34 (2I-C), 73.75 (4I-C),

75.30 (31-C), 95.63 (1VI-C), 95.73 (1 II, III, IV, V-C), 100.42 (II-C),

169.48, 169.75, 170.12, 170.43, 170.66 (C = 0).

Elemental analysis: as CyyHiosOsoI: calc C 47.24, H 5.41, I 6.48; found

C 47.11, H 5.30, I 7.45;

FAB MS m / z: 1957.0 (M + + H). Production Example 7: 4-Acetoxybenzaldehyde

Pyridine (5.8 mL) and anhydrous acetic acid (6.8 mL) were added to a solution of 4-hydroxybenzaldehyde (5.87 g, 48.6 mmol) in ethyl acetate (1 O OmL). After stirring at room temperature for 2.5 hours, a catalytic amount of DMAP was added and the mixture was stirred for 30 minutes. The reaction mixture was quenched with 0.5 N-hydrochloric acid and extracted with black form. The combined extracts were washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium dynamite, and then dried over anhydrous magnesium sulfate. After evaporating the extract, the crude product was purified by silica gel column chromatography using hexane / ethyl acetate (5/2, v / v) as eluent to give a white oil of 4-acetate. Xybenzaldehyde (7.80 g, 99%) was obtained.

NMR (300 MHz, CDCI3) δ 9.97 (s, 1Η, CHO), 7.86 (d, 2H, J = 7.32 Hz, Ar-3, 5), 7.24 (s, 2H, J = 7.37 Hz, Ar-2, 6), 2.28 (s, 3H, Ac). Production Example 8: 4-I-decyloxybenzaldehyde To a solution of 4-hydroxybenzaldehyde (5.0 g) in anhydrous DMF (40 mL) was added 1-bromodecane (8.5 mL) and potassium carbonate (6.0 g). After stirring at room temperature for 21 hours, DMF was removed under reduced pressure. The reaction mixture was extracted with black form. 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%).

iH NMR (300 MHz, CDCls) δ 9.87 (s, 1H, CHO), 7.80 (d, 2H, J = 6.53 Hz, Ar-3, 5), 7.00 (s, 2H, J = 6.56 Hz, Ar-2 , 6), 4.04 (m, 2H, CH 2 0), 1.80 (m, 2H, CH2CH2O), 1.45 - 1.27 (m, 14H, -CH 2 -.), 0.88 (s, 3H, CH 3) preparation example 9: 1—Mesityl dipyrrolomethane

A solution of pyrrole (25 mL, 360 mm 01) and mesitylaldehyde (214 g, 14.4 mmol) was purged with argon for 5 minutes. TFA (0.1 mL, 1.44 mmol) was added to this solution. After stirring at room temperature for 1 hour, the reaction mixture was neutralized by adding triethylamine (0.5 mL). About 10 OmL of toluene was added thereto, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solution was filtered and evaporated under vacuum to give a black oil. The oil was further purified by distillation to give a yellow solid. Recrystallization from ethanol / water (Ι, v / v) yielded the title compound as pale yellow crystals (0.8 g, 21%).

iH NMR (300 MHz, CDCI3) δ 2.06 is.6H, 2,6-CH ₃ ), 2.28 is.3H, 4- CH ₃ ), 5.93 (s, 1H, meso-CH), 6.01 (m, 2H, pyr-β), 6.17-6.19 (m, 2H, NH), 6.67 (m, 2H, pyr-j3), 6.87 ( s, 2H, pyr-a), 7.97 (brs, 2H, Ar-3,5). Production Example 10: 5,10-di- (4-decinoleoxy) -1,15,20-g (4-hydroxy) tetraphene Nilporphyrin

Propionic acid (200 mL) of 4-acetoxybenzaldehyde (1.0 g, 1 equivalent), 4-decyloxybenzaldehyde (1.6 g, 1 equivalent) and pyrrole (0.85 mL, 2 equivalents) The solution was heated at reflux for 1 hour. After cooling, the reaction mixture was neutralized with a 0.5 N aqueous solution of sodium hydroxide, and then extracted five times with a mouth-hole form. The organic phase was washed with cold water and saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and the solvent was evaporated. 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.

iH NMR (300 MHz, CDCls) δ 8.94 (d, 2H, J = 4.67 Hz, pyr-j3),

8.84, 8.83 (s, 2H), 8.83 (d, 2H, J = 4.7 Hz, pyr-β), 8.20 (d, 2H, Ar-3, 5), 8.09 (d, 2H, Ar-2, 6) , 7.50 (d, 2H, J = 8.57 Hz, Ar'- 3,5), 7.28 (d, 2H, J = 8.10 Hz, Ar'- 2, 6), 4.24 (m, 4H, CH20), 2.49 ( s, 6H, Ac), 1.98 (m, 4H, CH2CH2O), 1.62-1.25 (m, 28H, -CH2-), 0.91 (t, 6H, CH 3). Production Example 1 1: 5,10-di- (4-decyloxyphenyl) -15,20-bis- [4- [3- (nonadeca-1-acetyl-] 3-D-maltohexanosyl) propoxy ] Phenyl] porphyrin

5,10-Gee (4-decyloxy) -1,20-di- (4-hydroxy) tetraphenylporphyrin (20.7 mg) and potassium carbonate (1 g) in anhydrous DMF (2 OmL) To the middle mixture was added nonadecal O-a-cetyl-l-propoxide-1] 3-D-maltohexanoside (163.5 mg). After stirring at room temperature for 60 hours, DMF was removed under reduced pressure. To this was added about 20 OmL of chloroform-form, and the pore-form phase was washed with 1N-hydrochloric acid, cold water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride. The port-form solution was dried over anhydrous sodium sulfate and filtered. The crude product obtained was purified by cyclic HPLC using THF as eluent to give the title compound (43.3 mg, 45%). _{m NMR (300 MHz, CDC1 3} ) δ 8.80 (d, 2H, J = 4.9 Hz, pyr- β), 8.79 (s, 2H, pyr- β), 8.76 (s, 2H, pyr- β), 8.75 ( d, 2H, J = 5.0 Hz, pyr-β), 8.05 (d, 4H, Ar-3, 5), 8.02 (d, 4H, Ar-2, 6), 7.19 (d, 4H, J = 8.4 Hz , Ar'-3, 5), 7.07 (d, 4H, J = 8.4 Hz, Ar'-2, 6), 8.20 (d, 2H, Ar-3, 5), 8.09 (d, 2H, Ar-2 , 6), 7.50 (d, 2H, J = 8.57 Hz, Ar'-3, 5), 7.28 (d, 2H, J = 8.10 Hz, Ar'-2, 6), 4.24 (m, 4H, CH ₂ . 0), 2.49 (s, 6H, Ac), 1.98 (m, 4H, CH2CH2O), 1.62-1.25 (m, 28H, -CH 2 -), 0.91 (t, 6H, CH 3) example 1: 5 , 10-Di (4-decyloxyphenyl) -15,20 1-bis [4- [3- (jS-D-maltohexanosyl) propoxy] phenyl] porphyrin

5, 10-Gee (4-decyloxyfuel) -15,20-bis [4- [3- (nonadeca O-acetyl-3 / D-maltohexanosyl) [Propoxy] phenyl] porphyrin was deacetylated using sodium methoxide in the same manner as in Production Example 10 to obtain the title compound (yield: 69.3%).

[] 25 _D = + 24.4 ° [α] ²⁵ 365 = + 143.6 ° (0).

iH NMR (300 MHz, DMSO-d ₆ ) δ 8.79 (s 2H pyr- β 8.78 (s 2H pyr- β 8.87 (m 4H, pyr- β 8.10 (m, 16H, Ar-2,3,5,6) , 7.39 (d 2H, J = 8.51Hz, Ar-4), 7.36 (d 2H J = 8.57Hz, Ar-4).

UV (DMSO) 423.5 nm (ε

· M 519.0nm (ε =

^{. 1.2xl0 4 / cm · M 557.0} ε = 9.5xl0 3 / cm · M 596.0nm (ε = 3.5xl0 3 / cm · M 652.0nm (ε = 4.9 <10 3 / cm · M) Production Example 1 2: 5 1 5—Dimesityl 1 10—Acetoxyphenyl- 20 Decyloxyphenylporphyrin

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.

! H NMR (300 MHz, CDCls) δ 8.83 (d 2Η, J = 4.77 Hz, pyr-β 8.80 (d 2H J = 4.79 Hz, pyr- β 8.69 (d 2H J = 4.74 Hz, pyr- β 8.68 (d, 2H, J = 4.77 Hz, pyr-j3), 8.22 (d, 2H, J = 8.46 Hz, ArOAc-2,6), 8.11 (d, 2H, J = 8.55 Hz, ArOdec-2, 6) , 7.48 (d, 2H, J = 8.61 Hz, ArOAc-3,5), 7.28 (s, 4H, Ar), 7.27 (d, 2H, J = 8.77 Hz, ArOdec-3,5), 4.24 (t, 2H, J = 6.50, 6.51, OCH ₂ ), 2.63 (s, 6H, 4-CH ₃ ), 2.48 (s, 3H, OAc), 1.83 (s, 12H, 2, 6-CH ₃ ), 1.18-2.06 (m, 16H, decCH ₂ ), 0.91 (m, 3H, decCHs), -2.63 (s, 2H, NH). Production Example 13: 5,15-dimesityl-1 10-hydroxyphenyl-1 20-dec / reoxyphene / Reporphyrin

A solution of 5,15-dimesityl_10-acetoxyphenyl 20-decyloxyphenylporphyrin (52 mg) in ethanolic hydroxide (100 mL of 95% ethanol containing hydroxide) was refluxed and heated for 1 hour. . After the green solution was acidified with acetic acid and the solvent was evaporated, the residue was washed 2-3 times with cold ethanol to give the title compound as purple crystals (40 g, 80.7%).

_{iH NMR (300 MHz, CDC1 3} ): δ 8.81 (brs, 4H, pyr- β), 8.68 (brs, 4H, pyr-i3), 8.08 (m, 4H, Ar-2,6), 7.27-7.19 ( 8H, m, Ar-3,5), 4.24 (m, 2H, OCH ₂ ), 2.63 (s, 6H, 4-CH ₃ ), 1.83 (s, 12 H, 2,6-CH ₃ ), 1.3- 1.97 (m, 16H, decCH ₂ ), 0.91 (m, 3H, decCHs), -2,62 (s, 2H, NH). Production Example 14: 5, 15-dimesityl-10-decyloxy fueneru 2 0— [4 I [3— (Nonade force O-acetyl- / 3-D-maltohexanosyl) propoxy] phenyl] porphyrin

5, 15-Dimesityl- 10-Hydroxyphenyl 20-decyloxyphenylporphyrin (40 mg, 45.9 mmol) and potassium carbonate (lg) in anhydrous DMF (2 OmL) solution Cetyl-1-odepropoxy-manoletohexanoside (46 mmo 1) was added. After stirring at room temperature for 72 hours, DMF was removed under reduced pressure. To this was added about 20 OmL of chloroform-form, and the pore-form phase was washed with 1N hydrochloric acid, cold water, a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride. The black-mouthed form phase was dried over anhydrous sodium sulfate and filtered. The resulting crude product was purified by circulating HPLC using THF as eluent to give the title compound (59 mg, 85%).

_{iH NMR (300 MHz, CDC1 3} ) δ 8.82 (d, 2Η, J = 4.82 Hz, pyr- β), 8.79 (d, 2H, J = 4.75 Hz, pyr- j3), 8.67 (d, 2H, J = 4.67 Hz, pyr-β), 8.66 (d, 2H, J = 4.70 Hz, pyr-), 8.1 1 (d, 4H, J = 8.46 Hz, ArOCH ₂ -2,6), 7.48 (d, 2H, J = 8.61 Hz, ArOAc-3,5), 7.28 (s, 4H, mes-Ar), 7.23- 7.27 (m, 4H, ArOCH ₂ -3,5), 5.42 (d, 1H, J = 3.8 Hz, IVI -H), 5.35 (t, 1H, J = 10 Hz, 3I-H), 5.24-5.43 (m, 1 IH, III, III, IV, V, VI-, 31, II, III, IV, V, VI-H), 5.07 (t, IH, J = 10 Hz, 4VI-H), 4.86 (dd, 1H, J = 4.0 Hz, 10.5 Hz, 2VI-H), 4,80 (dd, 1H, J = 7.9, 9.3 Hz, 2I-H), 4.71-4.76 (m, 4H, 2II, III, IV, V-H), 4.54 (d, 1H, J = 7.9 Hz, 1I-H), 4.53-4.43 (m , 5H, 6aI, II, III, IV, VH), 4.50 (dd, 1H, J = 3.0 Hz, 12.2 Hz, 6aI-H), 4.38 (dd, 1H, J = 3.7, 12.2 Hz, 6bI-H) , 4.30, 4.28, 4.25, 4.16 (dd (4, 1H, 6bII, III, IV, VH), 4.22 (m, H, 6aVI-H), 4.07 (dd, IH, J = 2.3 Hz, 9. 1 Hz, 6bVI-H), 3,93 (m, IH, 5VI-H), 3.93 (m 1H, OCH2CH2), 3.98 (m , 1H, 4I-H), 3.71 (m, IH, 5I-H), 3.70 (m, IH, OCH 2), 3.45 (m, 2H, CH 2 OAr), 2.02 ( 2H, m, CH ₂ CH ₂ CH ₂ ), 4.24 (t, 2H, J = 6.50, 6.51 Hz, OCH2), 2.63 (s, 6H, 4-CH3), 1.83 (s, 12H, 2, 6-CH _{3), 1.91 - 2.20 (s} , 3H (76H, COCH3), 1.25-2.06 (m, 16H, decCH 2), 0.91 (m, 3H, decCHs), 2.62 (s, 2H, NH). Example 2: 5,15-dimesityl-10-decyloxyphenyl 20- [4- [3-(] 3-D-maltohexanosyl) propoxy] phenyl] ponolephyrin

5, 1 5—dimesityl 1 10—decyloxyphenyl 20— [4-1 [3- (nonadecyl-O-acetyl-β-D-maltohexanosyl) propoxy] phenyl] Deacetylation of porphyrin The title compound was obtained in the same manner as in Production Example 10 using sodium methoxide (yield, 75%).

NMR (300 MHz, DMSO-d ₆ ) δ 8.83 (d, 2Η, J = 5.4 Hz, pyr-β), 8.82 (d, 2H, J = 4.8 Hz, pyr-β), 8.62 (m, 4H, pyr -β), 8.25 (d, 2H, J = 8.4 Hz, Ar-3,5), 8.07 (d, 2H, J = 8.4 Hz, Ar-2,6), 7.36 (d, 2H, J = 8.7 Hz , Ar-3 ', 5 *), 7.34 (s, 4H, Mes-2,6), 7.30 (d, 2H, J = 8.8Hz, Ar-2', 6 '), 3.75-3.77 (4H, OCH _{2), 2.58 (s, 6H} , 4-CH 3), 2.27 (m, 2H, sug-CH 2 -), 1.76-1.85 (m, 12H, 2,6-CH 3), 1.27-1.76 (m, 16H, decCH ₂ ), 0.86 (t, 3H, J = 6.4 Hz, decCHs).

ESI mass: 1901.8461 as C99H128N4O33 (MH) ⁺ , measured

1902.5458.

UV (DMSO): 423.5 nm ( ε = 3.5xl05 / cm · M), 516.5nm (ε = 1.3xl0 4 / cm - M), 553.0nm (ε = 6.6 <10 3 / cm · M), 593.5nm ( ε = 3.7xl0 ³ / cm · M), 650.0nm (ε = 4.4> 10 ³ / cm · M). Test Example 1: Phototoxicity test

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 ゥ in a 96 ゥ 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 μM). The cells to which compound A was added were washed with PBS. After incubation for 20 hours, IO JUL's solution of 3- (4,5-dimethinole-1-thiazolyl) -1,2,5-diphenyl-1H-tetrazolium (MTT) (5 mg / mL) was added. After incubating the cells for an additional 4 hours, viability was determined by measuring the optical density at 540 nm (OD ₅₄₀ ). Panel la) shows the survival ratio (%) of unirradiated cells. The ratio was calculated according to the following formula: Cell survival ratio (%) = {of compound A in the presence OD ₅₄₀ Z Compound A Out of OD _540} X 100. A cell viability of 100% indicates the absence of cytotoxicity. This ratio is considered the cytotoxicity of Compound A. As shown in Fig. La), it was clarified that no cytotoxicity was exhibited in the absence of irradiation even in the presence of the compound A.

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. Cell survival ratio was calculated according to the following formula: cell production presence ratio (%) = [Compound A exists at the OD ₅₄₀ when no OD 540 / irradiated at Compound A exists when irradiated] X 100. As shown in the figure (lb), it was revealed that light irradiation in the presence of Compound A exhibited cytotoxicity. Industrial applicability

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.

Further, the tetraphenylporphyrin derivative or a salt thereof of the present invention can be used as a pressure-sensitive paint.

Claims

The scope of the claims

-. Formula (I)

[Wherein Ri, R2, R3 and R4 are, independently of each other,

Or

And at least one of Ri R ⁴ is

And at least one of the remaining Ri to R ⁴ is

Is a group represented by Or a salt thereof.

2. R 1 force

R 3 force

In a group represented, R2 and R ⁴ are each

2. The tetraphenylporphyrin derivative or a salt thereof according to claim 1, which is a group represented by the formula:

3. The tetraphenylphenylporphyrin derivative or a salt thereof according to claim 1 or 2, wherein the salt is an intramolecular complex salt with a metal.

4. A composition as a photosensitizer comprising the tetraphenylporphyrine derivative or a salt thereof according to any one of claims 1 to 3.

5. The composition according to claim 4, which is used for photodynamic therapy.