Tetraazachlorines as photosensibilizators for photodynamic therapy

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to photosensitizing agents used in photodynamic therapy of neoplasm and some other diseases. Invention describes tetraazachlorines of the general formula: wherein R1R2 mean -C6H4; R3 = R4 = R5 mean -CH3; M means HH (H2TBTAC); R1R2 means 1,2-C10H6; R3 = R4 = R5 mean -CH3; M means Zn(Zn-1,2-TNTAC); R1 = R2 mean -C6H5; R3 = R4 = R5 mean -CH3; M means HH (H2TACPh6); R1 = R3 mean hydrogen atom (H); R2 =R4 mean -C6H5; R5R5 mean -CH2N(CH3)CH2; M means HH (H2PyrTACPh4); R1R2 mean 4-C(CH3)3C6H3; R3 = R4 mean hydrogen atom (H); R5R5 mean -CH2N(CH3)CH2; M means HH (H2TBtTACPyrN-Me) used as photosensitizing agents in the near IR-region of spectrum for carrying out the photodynamic therapy. These photosensitizing agents possess the intensive absorption in spectral region 710-750 nm and can be used in treatment of deep tumor tissues by the photodynamic therapy method.

EFFECT: valuable medicinal properties of compounds.

1 cl, 4 ex

 

The present invention relates to medicine and, more specifically, to photosensitizers for photodynamic therapy (PDT) of tumors and other diseases.

Photodynamic therapy is based on the use of drugs, photosensitizers, which have the ability when introduced into the body to accumulate mainly in the tumor. At the next light, for example laser, irradiation of pathological part of photosensitizer molecules catalyze the formation of cytotoxic agents, in particular singlet oxygen that destroys the tumor cells.

The disadvantage commonly used in clinical practice photosensitizers based on derivatives of hematoporphyrin, such as HPD (hematoporphyrin derivative, Photofrin-2, is the low intensity of the absorption band photoexcitation (625-640 nm). Significant intrinsic absorption of biological tissues in this spectral region causes a low penetration of radiation and complicates the treatment of tumors of large size (R. Bonnett. Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem. Soc. Rev., 24(1), 19-33, 1995). In this respect, the advantage are the photosensitizers based chlorines (dihydroporphyrin), more intense long-wavelength absorption band which is shifted to the red compared with porphyrins. Among them should be noted the ü water-soluble mono-L-especillay e 6u(drugs NPe6, MACE) and other various forms of chlorin e6in particular domestic products "Photoditazine", "Radachlorin", as well as synthetic chlorins - 5,10,15,20-tetrakis(m-hydroxyphenyl)chlorin (], m-THPC, foscan) and derivatives benzoporphyrin (benzoporphyrin monocerata, ring (A) with maximum absorption at 690 nm. However, these compounds are difficult to access, the same extinction coefficient as a rule, small.

Very promising photosensitizers are derivatives of phthalocyanine, tetrabenzoate similar to porphyrins. Thus, the photosensitizer "photosense" based on sulfonated phthalocyanine hydroxylamine, absorbing at 675 nm with an extinction coefficient greater than 105l×mol-1·cm-1(Eaaaat. New sensitizers for photodynamic therapy. Ross. chem. journal, 42(5), 9-16, 1998), approved for clinical use in Russia for the treatment of several cancers in different locations. However, in the field of absorption "Photosense" the self absorption desensibilisation tissue remains significant. It is known that it is a minimum only at wavelengths greater than 700 nm, in the field of so-called "therapeutic window". In addition, the lack of "Photosense" is long-term retention in the skin that requires careful sobl the Denia patients in day length. "Photosense" is the closest analogue proposed in this application of photosensitizers.

In the present invention the task of creating photosensitizers for PDT with intense absorption in the spectral region 710-750 nm. This task is solved by the fact that as a photosensitizer for photodynamic therapy offers new connections derivatives tetrasaccharide - General formula

where R1R2=C6H4, R3=R4=R5=CH3M=NN(H2TBTAC);

R1R2=1,2-C10H6; R3=R4=R5=CH3, M=Zn(Zn-1,2-TNTAC);

R1=R2=C6H5; R3=R4=R5=CH3M=NN (H2TACPh6);

R1=R3=N, R2=R4=C6H5, R5R5=CH2N(CH3)CH2M=NN (H2PyrTACPh4);

R1R2=4-C(CH3)3With6H3, R3=R4=N, R5R5=CH2N(CH3)CH2M=NN (H2TBtTACPyrBN-Me).

for example, tetramethylcyclotetrasiloxane (H2TWTAS), tetramethylene-1,2-oil-tetrazolium zinc (Zn-1,2-TNTAC), tetramethylcyclotetrasiloxane (H2TACPh6), N-methylpyrrolidine-[3,4-b]tetraphenylarsonium (H2PyrTACPh4), N-methylpyrrolidine-[3,4-b]three-(4'-Proc. of the so-butyl)benzoheterocycles (H 2TBtTACPyrN-IU).

The proposed derivatives tetrasaccharide synthesized according to our developed methods. Tetramethylcyclotetrasiloxane (H2TWTAS) and hexaphenyldisilane (H2TACPh6) obtained by condensation of a mixture of tetramethylcyclobutane with the corresponding 1,2-dinitrile in dimethylaminoethanol in the presence of dimethylaminoethyl lithium, and three-1,2-kattoterassin zinc (Zn-1,2-TNTAC) - similar condensation in high-boiling organic solvents in the presence of zinc chloride [RF Patent №2188200, class C 07 D 487/22 (2002). BI No. 24 (2002)]. N-Methylpyrrolidine[3,4-b]tetraphenylarsonium (H2PyrTACPh4) and three-(4'-tert.-butyl)benzoheterocycles (H2TVtACPyrN-Me) obtained by analogy with tetraarylporphyrins (Silva A.M.G, Tome AC., Neves G.P.M.S., Silva A.M.S, Cavaleiro J.A.S., II J.Chem. Soc. Chem. Commun., 1999, R) by the reaction of 1,3-cycloaddition of the corresponding tetraazaporphyrin with isometamidium, generated in situ from N-methylglycine and paraform. All the synthesized tetrasaccharide insoluble in water and used in the form of emulsions in aqueous 4% solution of Cremophor EL and proxanol is chosen 268 (table 1, drawing).

The present invention is illustrated by the following examples.

EXAMPLE 1. Synthesis of N-methylpyrrolidine[3,4-b]tetraphenylethylene (H2PyrTACPh4). Heated with stirring a solution of 50 mg, 0.08 mmol) tetraphenylporphine in 5 ml of o-dichlorobenzene to 100° In an argon atmosphere and added 14 mg (0.16 mmol) of sarcosine and 12 mg (0.4 mmol) of paraform. Next, the reaction mixture is heated to 150°C and maintained at this temperature for 1.5 hours Then cooled reaction mass chromatographic on silica gel with chloroform. The second fraction (a mixture of chlorine and usabacterial) re chromatographic on aluminium oxide toluene. Collect crimson faction and after removal of the solvent receive 15 mg (27.5%) H2PyrTACPh4. Mass spectrum, m/z: 675 (M+). ESP, λmax(ratio of intensities), chloroform: 711 (1.0), 656 square (0.39), 547 (0.49), 358 (1.02), 333 (0.99).

Likewise, a three-(4'-tert.-butyl)betteradapted obtained N-methylpyrrolidine-[3,4-b]three-(4'-tert.-butyl)benzoheterocycles (H2TBtTACPyrN-Me).

EXAMPLE 2. Synthesis of tetramethylcyclotetrasiloxane (H2TACPh6). Dissolve 0.01 g (14 mmol) of lithium when heated in 20 ml of dimethylaminoethanol, cooled to room temperature. Add a mixture of 0.82 g (3.6 mmol) of diphenylacetonitrile and 0.49 g (3.6 mmol) of tetramethylcyclobutane slowly heated with stirring to a boil and continue boiling for 4 hours. Then the reaction mixture is cooled, diluted with 100 ml of water, precipitated precipitate is filtered off, washed successively with hot water, 50% aqueous ethanol, air-dried. The residue is triturated, e is stragiht ethanol to remove impurities, then chlorobenzene. Chlorbenzol extract evaporated in vacuum and chromatographic on silica gel with chloroform, collecting crimson faction. Get 0.025 g (3.8%) H2TACPh6. Found, %: C 78.45; H 5.66; N, 12.76. C56H44N8H2O. Calculated, %: C 79.41; N, 5.47; N, 13.23. Mass spectrum, m/z: 829.2 (M+). The electronic absorption spectrum. λmaxnm (lg ε), chloroform: 727 (4.63), PL. (3.85), PL. (3.69), 557 (4.10), 488 (3.57), 371 (4.32), 336 (4.33).

EXAMPLE 3. Determination of phototoxicity N-methylpyrrolidine[3,4-b]tetraphenylethylene besmearing (H2PyrTACPh4) in vitro.

Testing was carried out on cell cultures epidermoid carcinoma of the hypopharynx person Ner. Cells subcultured at a concentration of 40×103cells/ml in the wells of 96-hole tablet ("Costar, USA) in the environment of NEEDLE-MEM containing 7% fetal calf serum. After 24 hours (early logarithmic growth phase culture) made substance in serial dilutions, incubated the cells for 2-5 hours and perform the irradiation with a halogen lamp (500 W using a filter KS-13 (λ≥640 nm). The power density was 13.6-15.0 mW/cm2. Estimated light dose in all experiments was 10 j/cm2. The control were: 1) cells that were not exposed to processing dye, solvent and radiation, 2) cells, powerhouseselect without prior incubation with the dye, 3) cells incubated with dye without subsequent exposure, 4) cells treated with 4% Cremophor followed by radiation.

The results of determination of phototoxicity are shown in table 2.

EXAMPLE 4. The definition of photodynamic activity of aqueous emulsions of tetrasaccharides in vivo.

Solid ascitic form of Ehrlich carcinoma (MA) were inoculated subcutaneously on the outer surface of the lower extremity female mice of line CBA. Was used for implantation of diluted ascitic fluid (˜2.2×106tumor cells obtained from a mouse donor on day 7 of tumor growth.

Sample tetrasaccharide 4% Cremophor EL or proxanol is chosen 268 filtered through a membrane filter of 0.22 μm and animals were injected intravenously (tail vein) once on day 6 of tumor growth at 48, 24 and 0.5 hours before PDT.

Sensitized the tumor was irradiated with therapeutic apparatus for photodynamic cancer therapy ATO-1 and filters CS-18 with maximum transmittance at a wavelength of 700 nm and SES for filtering the ultraviolet part of the spectrum. The radiation power density of 250 mW/cm2the density dose of 300 j/cm2. Before irradiation the wool over the tumor was removed. The duration of observation of the animals was 25 days after treatment.

Efficacy was assessed by the change of the of Yama tumor (V op) and the values of inhibition of tumor growth (SRW), calculated by the formulas (2) and (3):

where D1D2and D3three mutually perpendicular diameters of the tumor.

In the study of photodynamic activity in vivo water emulsions H2PyrTACPh44% Cremophor in mice with tumor P-388 irradiation was performed at 30 minutes after injection using the apparatus of ATO-1 with filters KC-10 and SES. The radiation power density of 300 mW/cm2a light dose of 270 j/cm2.

The results of the photodynamic activity are summarized in tables 3-5.

Emulsion H2PyrTACPh44% Cremophor (H2PyrTACPh4-CrEL) has photoinduced activity on the culture of human tumor cells (table 2). In the standard screening conditions IR50when radiation is on average 1-33 μm (culture NER) and 1.63 μm (culture A), "dark" toxicity at this concentration range is missing. Varying the time of incubation and irradiation conditions allows us to conclude that close to the maximum effective concentration of H2PyrTACPh4in the cells to thetsa to 2 hours and phototoxicity in this period primarily due to intracellular photosensitizer. A similar emulsion Zn-1,2-TNTAC has a relatively low photoinduced activity: the value of IR50he was equal to 31.0 μm (culture NER).

Photodynamic activity in vivo water emulsions H2PyrTACPh4studied in mice with solid ascitic form of Ehrlich carcinoma (MA). H2PyrTACPh4in an aqueous solution of 4% Cremophor EL (in doses of 0.1-6.0 mg/kg) and 4% of proxanol is chosen 268 (in doses of 1.0-7.0 mg/kg) did not suppress tumor growth in the absence of light exposure, i.e. did not have the "dark" cytotoxicity (table 3). During PDT after 48 and 24 hours after intravenous injection of N2PyrTACPh4at doses of 1.0, 3.0 and 6.0 mg/kg there was marked antitumor effect throughout the observation (SRW=52.2-92.3%). During the session, irradiation within 0.5 hour after administration of the photosensitizer at a dose of 1.0 mg/kg therapeutic effect was recorded for 25 days of observation (SRW=61.9-65.1), and at a dose of 0.5 mg/kg only on the 15th day after PDT (61.8%).

A solution of H2PyrTACPh44% proxanol is chosen 268 showed high photodynamic activity against experimental MA at the doses of 3.5 and 7.0 mg/kg 24 hours prior to photodynamic therapy is the inhibition of tumor growth was achieved 91.8-100% (table 3). At lower doses (1.0 and 0.5 mg/kg) biologically significant suppression of tumor growth was observed under irradiation through 0.5 the Asa after injection and was 52.6-70.0% 15-25 day of observation. Comparison of the photodynamic activity of H2PyrTACPh4in Cremophor EL and proxanol is chosen 268 revealed no significant differences (table 3).

Water emulsion H2TACPh6H2TBTAC and H2TBtTACPyrN-Me4% proxanol is chosen 268 in similar conditions also did not have the "dark" toxicity and showed pronounced activity during the session, PDT 2 hours after injection (table 4). It should be noted the high activity of N2TWTAS providing high value TRO at low doses (up to 0.35 mg/kg).

We have also studied the photodynamic activity in vivo water emulsions H2PyrTACPh44% Cremophor in mice with tumor P-388. PDT with H2PyrTACPh4-CrEL has led to the development of a characteristic of tissue reactions - swelling with subsequent formation of necrotic scab in all animals between 8 and 9 days after irradiation. PDT with H2PyrTACPh4-CrEL led to a significant suppression of tumor growth of P-388 in all periods of observation and increase the lifespan of animal (table 4). therapeutic effect of PDT higher dose of photosensitizer 1.0 mg/kg than at the dose of 0.5 mg/kg: TRO exceeded 80% at the dose of 1.0 mg/kg and 70% at the dose of 0.5 mg/kg; UPI at the dose of 1.0 mg/kg was 42.9%, at a dose of 0.5 mg/kg - 24.9%.

Thus, the proposed in the present invention derivatives of tetrasaccharide with intense absorption in the spectra the General area 710-750 nm represent a new class of efficient photosensitizers near IR region of the spectrum, which can be used for treatment by PDT deep tumor tissue.

Tetrasaccharide General formula

where R1R2=C6H4, R3=R4=R5=CH3M=NN (N2TWTAS);

R1R2=1,2-C10H6; R3=R4=R5=CH3, M=Zn(Zn-1,2-TNTAC);

R1=R2=C6H5; R3=R4=R5=CH3M=NN (H2TACPh6);

R1=R3=H, R2=R4=C6H5, R5R5=CH2N(CH3)CH2M=NN (H2PyrTACPh4);

R1R2=4-C(CH3)3C6H3, R3=R4=N, R5R5=CH2N(CH3)CH2M=NN (H2TBtTACPyrN-Me).

as photosensitizers for photodynamic therapy.



 

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