RU2633371C1 - 10-(5-iodine vanillyl-5,15-bis(pentaflutorphenyl)corrole, showing properties of potential sensibilizer for photodynamic therapy of antibacterial infections and oncological diseases - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to the preparation of a new corrole, in particular 10-(5-iodine vanillyl)-5,15-bis(pentafluorophenyl)corrole, which can be used as a sensibilizer for photodynamic therapy of infectious and oncological diseases.

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EFFECT: increased efficiency of treatment.

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Description

The invention relates to the chemical industry, in particular to the production of a new ligand of corroles, in particular 10- (5-iodoanilyl) -5,15-bis (pentafluorophenyl) corroles, which can be used to create a photosensitizer based on it for photodynamic therapy of infectious and oncological diseases.

Corroles are tetrapyrrole macroheterocyclic compounds that occupy an intermediate position in structure between porphyrins and corrins [Erben, Ch. Metallocorroles: molecular structure, spectroscopy and electronic states. / Ch. Erben, S. Will, KM Kadish // In: The porphyrin handbook. - Ed. by Kadish KM, Smith KM, Guilard R. - Academic Press. - New York. - 2000. - V. 2. - P. 235-300]. Synthetic methods described in the literature [Gryko, DT Refined methods for the synthesis of meso-substituted A ₃ - and trans-A ₂ B-corroles. / DT Gryko, B. Koszarna // Org. Biomol. Chem. - 2003. -V. l. - P. 350-357] make it possible to obtain meso-substituted corroles of various structures, both with identical (A ₃ types) and with different (A ₂ B types) meso substituents, including various electronic nature. Asymmetric A ₂ B-type corroles and their extended analogs can exhibit high quantum fluorescence yields and act as efficient singlet oxygen generators [Flamigni, L. Photoactive corrole-based arrays. / L. Flamigni, DT Gryko // Chem. Soc. Rev. - 2009. - V. 38. - P. 1635-1646; Shi, L. The heavy atom effect on photocleavage of DNA by mono-hydroxyl halogenated corroles. / L. Shi, HY Liu, LP Si, KM Peng, LL You, H. Wang, L. Zhang, LN Ji, CK Chang, HF Jiang // Chinese Chem. Lett. - 2010. - V. 21. - P. 373-375], which allows us to consider them as potential agents for photodynamic therapy of infectious and oncological diseases.

The closest structural analogue of the claimed compound is 10- (2-hydroxy-5-iodophenyl) -5,15-bis (pentafluorophenyl) corrol [You, L.L. Photophysical properties of the corrole photosensitizers. / L.L. You, H. Shen, L. Shi, G.L. Zhang, H.Y. Liu, H. Wang, L.N. Ji // Sci. China Phys. Mech Astron - 2010. - V. 53. -N. 8 - P. 1491-1496] above. This compound has a pronounced ability to generate singlet oxygen in non-aqueous media by reducing the quantum yield of fluorescence, which allows us to consider it as a potential effective means for PDT.

The main disadvantage of this compound is the high cost of 2-hydroxy-5-iodobenzaldehyde and its low stability, which greatly complicates and increases the cost of obtaining corrole.

The technical result of the invention consists in the creation of a new corrol from substances stable at room temperature, having one of the highest quantum yields of singlet oxygen in a non-aqueous medium, at a low cost of the resulting preparation and the possibility of varying its amphiphilicity by further chemical modification.

The technical result is achieved by the synthesis of 10- (5-iodoanilyl) -5,15-bis (pentafluorophenyl) corrole of the formula:

,

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showing the properties of a potential sensitizer for photodynamic therapy of antibacterial infections and cancer.

The structure of the claimed compounds is proved by methods of electron spectroscopy, ¹ H-NMR and mass spectrometry MALDI.

ESP: λ _max (CHCl ₃ ) (logε) / nm 412 (5.18), 426 (pl), 526 (pl), 565 (4.38), 613 (4.17), 655 (pl); λ _max (DMF) (logε) / nm 425 (5.19), 441 (5.16), 589 (4.24), 628 (4.67).

^{1 1} NMR (CDCl ₃ , 500 MHz), δ, ppm (J, Hz). 9.15 d (2H, H ² , H ¹⁸ , J 4.2), 8.76 dd (4H, H ^7-8 , H ^12-13 , J 17.2 and 7.7), 8.60 d (2H, H ³ , H ¹⁷ , J 4.3), 8.16 and 7.69 both with (1H, 10-meso-Ph), 4.04 s (3H, 10-meso-Ph-OCH ₃ ), 1.28 s (1H, 10-meso-Ph-OH).

Mass spectrum, m / z: 877.92 (100%) [M] ⁺ , 878.93 (56%) [MN] ⁺ .

This invention allows to obtain the following advantages:

- use starting materials with high availability and stability;

- vary amphiphilism due to the modification of both the hydroxy and methoxy groups, which can be converted to the hydroxy group in the 5-iodovaniline residue;

- achieve a lower cost of the drug.

To implement the method, the following substances are used:

1. Chloroform TU 2631-001-29483781-04 rev. No. 1, 2

2. Methanol GOST 6995-77

3. Dichloromethane TU 6-09-2662-77 rev. No. 1, 2, 3

4. Petroleum ether TU 2631-074-44493179-01

5. Pyrrole CAS 109-97-7

6. Hydrochloric acid (conc.) GOST 3118-77 (ST SEV 4276-83)

7. n-Chloranil CAS 118-75-2

8. Pentafluorobenzaldehyde CAS 653-37-2

9. Vanillin CAS 121-33-5

10. Iodine GOST 4159-79

11. Potassium iodide GOST 4232-74

12. Sodium bicarbonate GOST 2156-76

13. Sodium carbonate GOST 83-79

14. Trifluoroacetic acid TU 6-09-3877-80

15. Silica gel for column chromatography CAS 7631-86-9 or Cat No. 1.07734.9999.

The invention is illustrated by drawings, where:

FIG. 1 - Mass spectrum of 5- (pentafluorophenyl) dipyrrolylmethane,

FIG. 2 - Mass spectrum of 5-iodwaniline,

FIG. 3 - Mass spectrum 10- (5-iodoanilyl) -5.15-

bis (pentafluorophenyl) corrole,

FIG. 4 - ¹ H NMR spectrum of 5- (pentafluorophenyl) dipyrrolylmethane,

FIG. 5 - ¹ H NMR spectrum of 5-iodo-vanillin,

FIG. 6 - ¹ H NMR spectrum of 10- (5-iodonanilyl) -5,15-bis (pentafluorophenyl) corrole,

FIG. 7 - Electronic absorption spectrum of 10- (5-iodonanilyl) -5,15-bis (pentafluorophenyl) corrole in 1 - chloroform, 2 - DMF, 3-10% aq. ethanol with the addition of 1% surfactant.

The claimed compound is prepared as follows.

Step 1. Synthesis of 5- (pentafluorophenyl) dipyrrolylmethane.

2 ml (16.2 mmol) of pentafluorobenzaldehyde are dissolved in 50 ml of freshly distilled pyrrole. 0.12 ml (1.62 mmol) of trifluoroacetic acid was added to the mixture. The reaction mass is stirred for 0.5 h at room temperature, then diluted with 150 ml of chloroform and washed on a separatory funnel with water, an aqueous solution of sodium carbonate (5.72 g of Na ₂ CO ₃ ⋅ 10H ₂ O in 400 ml of water) and four times with water to obtain a pH of ~ 7. The organic layer is separated. By distillation on a rotary evaporator, chloroform is partially distilled off; during subsequent solvent distillation under vacuum, a mixture of chloroform and pyrrole is distilled off, and a brown gum is left in the reaction flask. The resin is dissolved in 120 ml of methanol, and with the subsequent addition of water, the formation of a whitish precipitate of dipyrrolylmethane is observed, which is filtered off and dried. For additional purification, a solution of the reprecipitated product in methanol is treated with activated carbon at room temperature for 5-10 minutes, after which the carbon is filtered off and re-precipitation is carried out by adding water. The product thus purified forms pale pink needle crystals.

Yield: 2.01 g (40%). Nuclear Magnetic Resonance Spectrum ^l H (CDCl ₃ , 500 MHz), δ, ppm 8.19 br.s (2Н, NH ^l , NH ¹¹ ), 6.76 s (2Н, Η ² , Н ¹⁰ ), 6.20-6.18 m (2Н, Н ³ , Н ⁹ ), 6.05 br.s (2Н, Η ⁴ , H ⁸ ). Mass spectrum, m / z: 311.05 (100%) [M ₁ ] ⁺ , 312.06 (90%) [M ₂ ] ⁺ , 313.05 (74%) [M ₃ ] ⁺ (isotopic effect).

Stage 2. Synthesis of 5-iodwaniline.

10 g of potassium iodide and 5 g of sodium bicarbonate are dissolved in 200 ml of water. To the resulting solution, 7.51 g (0.05 mol) of vanillin are added with stirring. Then, 12.66 g (0.05 mol) of crystalline iodine is slowly added in small portions to the formed suspension. The total synthesis time is 2 hours. Already by the middle of the reaction, the formation of a precipitate of 5-iodvaniline is observed, and the solution is colored intense brown due to an excess of iodine. The cream-colored 5-iodwaniline precipitate was separated from the solution using a Schott filter, washed five times with water and dried in an oven at 50 ° C to constant weight.

Yield: 10.17 g (74%). ¹ Ή NMR spectrum (CDC1 ₃ , 500 MHz), δ, ppm 9.79 s (1H, 3-СОН), 7.84 and 7.40 both with (1Н, Η ² , Н ⁴ ), 3.99 s (3Н, 1-ОСН ₃ ), 3.20 - 2.20 under m (1Н, 6-ОН). Mass spectrum, m / z: 279.05 (100%) [MH] ⁺ .

Stage 3. Synthesis of 10- (5-iodoanilyl) -5,15-bis (pentafluorophenyl) corrole.

153.1 mg (0.48 mmol) of 5- (pentafluorophenyl) dipyrrolylmethane and 68.2 mg (0.24 mmol) of 5-iodvaniline are dissolved in 24 ml of methanol, then a solution of 1.2 ml of concentrated hydrochloric acid is added to the reaction mixture in 24 ml of water. In this case, the formation of a pink precipitate is observed. The reaction mass is stirred for 1 h at room temperature, followed by extraction with 20 ml of chloroform, separation of the organic layer and washing it three times with water. The resulting solution in CHCl _{3 was} diluted with 100 ml of chloroform. Then, 177.4 mg (0.72 mmol) of n-chloranil (2,3,5,6-tetrachloro-1,4-benzoquinone) was added to the solution, and the reaction mixture was boiled for 1 hour. After that, the reaction mixture was evaporated and subjected to silica gel column chromatography using chloroform as an eluent. Most of the corrolet remains in the first fraction, however, it is rechromatographed to isolate the pure product. Repeat chromatography was carried out on silica gel using a mixture of dichloromethane - petroleum ether (1: 1 vol., Then 3: 1 vol.) As eluent. The violet zone immediately following the very first yellow zone is 10- (5-iodvanilyl) -5,15-bis (pentafluorophenyl) corrol. The solution of this zone is collected and evaporated; the product is reprecipitated from dichloromethane with petroleum ether.

Yield: 56 mg (26%). ESP: λ _max (CHCl ₃ ) (logε) / nm 412 (5.18), 426 (pl), 526 (pl), 565 (4.38), 613 (4.17), 655 (pl); λ _max (DMF) (logε) / nm 425 (5.19), 441 (5.16), 589 (4.24), 628 (4.67). ¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ, ppm (J, Hz). 9.15 d (2H, H ² , H ¹⁸ , J 4.2), 8.76 dd (4H, H ^7-8 , ^H12-13 , J 17.2 and 7.7), 8.60 d (2H, H ³ , H ¹⁷ , J 4.3 ), 8.16 and 7.69 both with (1H, 10-meso-Ph), 4.04 s (3H, 10-meso-Ph-OCH ₃ ), 1.28 s (1H, 10-meso-Ph-OH) · Mass spectrum, m / z: 877.92 (100%) [M] ⁺ , 878.93 (56%) [MH] ⁺ .

The possibility of using the claimed compound as a potential photosensitizer is illustrated by a photophysical parameter - the lifetime of singlet oxygen (Δτ) and its quantum yield (ϕ _Δ ). Determination of the photophysical characteristics of 10- (5-iodonanilyl) -5,15-bis (pentafluorophenyl) corrole in benzene was carried out by the combined photooxidation of tetracene and corrole in benzene in the presence of molecular oxygen when the process was initiated by light from an OVS-1 illuminator with a KGM 9- halogen lamp 70. The solutions were irradiated in a rectangular quartz glass cuvette (1 × 1 cm) using a combination of a KS-10 glass filter with a short-wavelength transmission limit at 610 nm and a lens condenser. In accordance with the experimental conditions, exciting light was absorbed in the region of the long-wavelength maximum of corrole. In this case, the maximum optical density in the most bathochromic bands of the visible absorption spectrum of tetracene and corrol was about 1. Oxidation was controlled by a decrease in the intensity of their absorption. Electronic absorption spectra and photooxidation kinetics were measured on a SPECORD-M40 spectrophotometer (Carl Zeiss, GDR).

The quantum yield ¹ O ₂ (ϕ _Δ ) was determined by the relative method. When using Pd-mesoporphyrin-IX dimethyl ether (ϕ _Δ ^et = 1) as a reference standard, it was found that upon excitation of a solution of 10- (5-iodvanilyl) -5,15-bis (pentafluorophenyl) corrole in the region of its UV absorption 337.1 nm) ϕ _Δ is 0.75 in benzene. The value of the quantum yield ¹ O _{2 of the} resulting corrole is almost the same as that of the prototype, however, is significantly higher than for photosensitizers currently used for medical purposes, for which the value ϕ _Δ ranges from 0.4-0.6 [Bonnett R. Chemical aspects of photodynamic therapy. VHC Publ .: London, 2000.285 p.].

Claims (2)

10- (5-iodonanilyl) -5,15-bis (pentafluorophenyl) corrol of the formula

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