Alkylthiosubstituted phtalocyanides, their medicinal forms and method of photodynamic therapy
SUBSTANCE: as photosensibilizers emulsions of alkylthiosubstituted phalocyanides of general formula , where R1=R4=Cl, R2=R3=n-C10H21S, M=Zn or R1=t-C4H9S, R2=R3=R4=H, M=HH or R1=t-C4H9S, R2=R4=H, R3=t-C4H9, M=HH or R1=R3=t-C4H9S, R2=R4=H, M=HH or R1=R2=R3=R4=t-C4H9S, M=HH or R1=R4=Cl, R2=R3=t-C4H9S, M=Zn, in water solution of Proxanol 268 are suggested.
EFFECT: elaboration of highly selective and efficient photosensibilizers for application in photodynamic therapy of tumours.
3 cl, 18 ex, 4 tbl, 9 dwg
The present invention relates to medicine, and more specifically to the photosensitizers for photodynamic therapy (PDT) of tumors and other diseases, medications and method of photodynamic therapy using the prepared dosage forms.
Photodynamic therapy is based on the use of photosensitizers, which have the ability in the system, for example, intravenously, selectively accumulate in the tumor and subsequent light irradiation pathological area to catalyze the formation of cytotoxic agents, in particular singlet oxygen and highly reactive oxygen radicals. The disadvantage commonly used in clinical practice photosensitizers based on derivatives of hematoporphyrin, such as HPD (hematoporphyrin derivative), Fotofrin-2, is the low intensity of the absorption band photoexcitation (625-640 nm) (R.Bonnett. Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem. Soc. Rev., 24(1), 19-33, 1995). 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).
This deficiency is partially removed when using the selected authentication derivatives of phthalocyanines. Known photosensitizer "photosense" based on sulfonated phthalocyanine hydroxylamine, absorbing more far-red region (675 nm) extinction coefficient greater than 105l×mol-1·cm-1due to that its absorption within the operating range of the injected dose becomes comparable with the self-absorption of biological tissue (Eaaaat. New sensitizers for photodynamic therapy. Ross. chem. journal, 42(5), 9-16, 1998). The self absorption desensibilisation tissue remains significant and in the field of absorption "Photosense", which limits the depth effect on the tumor and reduces the energy efficiency of light radiation.
To address the problem of increasing the efficiency of PDT deep tumor tissue razrabatyvalsya photosensitizers with intense absorption in the spectral region of the "therapeutic window" next 700 nm. So, as a photosensitizer for PDT proposed penaltypoints phthalocyanine General formula
where R=H, t-C4H9; M=NN, AlOH, Zn.
The presence of the benzene rings of the phthalocyanine paneltop significantly shifts the long-wavelength absorption band in the red region, which allows the use of these compounds as photosensitizers, feeling twitteling in the near IR region of the spectrum (RF Patent No. 2257898, AC 31/409 (2005). They are the closest analogue proposed in this application of photosensitizers. Also proposed liposomal dosage form of these photosensitizers, which is used when performing photodynamic therapy, which is the composition of a mixture of lipids (lecithin, cholesterol, cardiolipin), a photosensitizer.
The disadvantage of these photosensitizers is the need to use for their solubilization in aqueous solutions of a mixture of expensive and quite unstable lipids of natural origin, which makes it very difficult operation.
In the present invention the task of creating photosensitizers for PDT with intense absorption in the spectral region 710-750 nm and tools based on them in the form of stable aqueous emulsions and method of PDT using these dosage forms.
This task is solved by the fact that as a photosensitizer for photodynamic therapy offers alkylthiophene phthalocyanines containing macroalga as deputies from four to sixteen alkylthio, and the remaining provisions of the hydrogen atoms or chlorine or tert-butylene group, the General formula
|Oboznacheny the connection||R1||R2||R3||R4|
Dosage forms synthesized lipophilic phthalocyanines are water-micellar solutions (emulsion) in nonionic surface-active compound of the class pluronic - proxanol is chosen 268.
The objective of the invention is solved in that a method of photodynamic therapy using as photosensitizers suggested above dosage forms.
The proposed substituted phthalocyanines synthesized according to our developed methods. Bezmetallny phthalocyanines obtained by tetrameristaceae corresponding substituted phthalonitrile in the presence of sodium methylate in environment n hexanol at boiling point. (DecS)8Cl8PcZn and (ButS)8Cl8PcZn obtained by fusing the corresponding substituted phthalonitrile with zinc acetate in the presence of ammonium molybdate or by boiling the corresponding substituted phthalonitrile in pentanol in the presence of zinc acetate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The invention is illustrated by the following examples.
Synthesis of 4,5-bis(decillia)-3,6-dichloropropionitrile. To a suspension of 1.33 g (5.0 mmol) of tetrachloroisophthalonitrile and 2.05 ml (10.0 mmol) of decelerating in 20 ml of DMF was added 1.40 ml (10.0 mmol) of triethylamine. After 1 h the reaction was poured into cold acidified water and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, the solvent is removed and the residue purified column chromatography (adsorbent is silica gel, eluent benzene). Obtain 2.36 g (87.4%) of viscous yellow oil. Found, %: C 62.19; H 7.75; Cl 12.99; N, 4.95; S 12.18. C28H42Cl2N2S2. Calculated, %: C 62.08; H 7.82; Cl 13.09; N, 5.17; S 11.84. IR-spectrum (KBr), νcm-1: 2232 (C≡N). Mass is the range, m/z: 540 [M+;35Cl35Cl]. An NMR spectrum1N [DMSO-d6], δ, M. D.: 0.86 (t, 6N), 1.40-1.54 (m, N), 3.10 (t, 4H). Range13With NMR [DMSO-d6], δ, M. D.: 149.2 (CArS), 139.8 (CAr-Cl), 117.9 (CAr-CN), 114.1 (CN), 37.2 (CH2S), 32.0 (CH2), 29.8 (CH2), 29.6 (CH2), 29.4(CH2), 29.2 (CH2), 28.7 (CH2), 28.5 (CH2), 22.8 (CH2), 14.6 (CH3).
Synthesis of 2,3,9,10,16,17,23,24-octakis(decillia)-1,4,8,11,15,18,22,25-octachloro-cyanine zinc [(DecS)8Cl8PcZn].
Method A. a Mixture of 0,270 g (0.50 mmol) of 4,5-bis(decillia)-3,6-dichloropropionitrile, 0,024 g (0.13 mmol) of zinc acetate and 2-3 mg of ammonium molybdate gradually heated to a temperature of 210°C and maintained for 3 hours the Cooled reaction mass is treated with boiling ethanol and water, the residue is purified column chromatography (adsorbent is silica gel, eluent - dichloromethane) and get 0,056 g (20%) of product as a viscous dark green oil. Found, %: C 60,36; N 7,89; Cl 12,51; N 4,86; S 11,65. C112H168Cl8N8S8Zn. Calculated, %: C 60.27; H 7.59; Cl 12,71; N, 5.02; S 11.49.
Method B. Boil 0,270 g (0.50 mmol) of 4,5-bis(decillia)-3,6-dichloropropionitrile and 0.024 g (0.13 mmol) of zinc acetate in 5 ml of pentanol or hexanol within 2-6 hours After cooling, the complex precipitated from the reaction mixture by ethanol, purified column chromatography (adsorbent is silica gel, eluent - dichloromethane) and get 20-28%of the product, identical obtained by the method of A.
Synthesis of 3-(tert-butylthio)phthalonitrile. To a solution of 3.46 g (20.00 mmol) of 3-nitrophthalonitrile in 30 ml of DMF add 2.48 ml (22.00 mmol) of tert-butylmercaptan and 3.07 ml (22.00 mmol) of triethylamine and stirred for 30 minutes at 50°C. the Reaction was poured into cold acidified water, the precipitation is washed on the filter with water, recrystallized from hexane and obtain 3.13 g (72.5%) of white crystalline substance, TPL 64-65°C (hexane). Found, %: C 67.10; N, 5.52; N, 12.94; S 14.3712H12N2S. Calculated %: 66.67; N, 5.56; N, 12.96; S 14.81. IR-spectrum (KBr), νcm-1: 2236 (C≡N). Mass spectrum, m/z: 216 [M+].
Synthesis of 1,8,15,22-tetrakis(tert-butylthio)phthalocyanine [(ButS)4PcH2]. The mixture 0,225 g (1.040 mmol) of 3-(tert-butylthio)phthalonitrile, 0.023 g (0,426 mmol) of sodium methylate and 2 ml of 1-hexanol boiled for 3 hours After cooling the reaction mixture the product is planted with methanol, precipitated precipitate is filtered off, washed with hot methanol and purified column chromatography (adsorbent - SiO2, eluent benzene). The fraction containing the product is concentrated and diluted with methanol, the precipitated product is filtered, dried in air and get 0.090 g (39,9%) of product. Found, %: C 66.90; H 6.12; N, 12.46; S 14.32. C48H50N8S4. Calculated, %: C 66.48; H 5.81; N, 12.92; S 14.79.
USE the 3.
Synthesis of 5-tert-butyl-3-(tert-butylthio)phthalonitrile. A mixture of 0.86 ml (7,60 mmol) of tert-butylmercaptan and 1.048 g (7.60 mmol) svejeporublennogo potash in 20 ml of DMF is stirred for 30 minutes, then load 1.00 g (of 3.80 mmol) 3-bromo-5-tert-butylphthalocyanine [Mikhalenko SR, Derkacheva V.M., E.A. Lukyanets - AH, 1981, 51(7), 1650] and heated 5 h at 65°C. the Reaction was poured into cold acidified water, the precipitated precipitate is extracted with ethyl acetate, the extract washed with water, dried over anhydrous sodium sulfate and remove the solvent. The oil obtained clobber in hexane, the crystalline product is recrystallized from hexane and obtain 0.64 g (62.5%) of white crystalline substance with TPL 94-95°C (hexane). Found, %: C 70.61; N, 7.52; N, 10.25; S 1.48. C16H20N2S. Calculated, %: C 70.59; N, 7.35; N, 10.29; S 11.76. IR-spectrum (KBr), νcm-1: 2236 (C≡N). Mass spectrum, m/z: 272 [M+].
Synthesis 3,10,17,24-Tetra-tert-butyl-1,8,15,22-tetrakis(tert-butylthio)phthalocyanine [But 4(ButS)4PcH2]. Get analogously to example 2, using as the starting material 0.283 g (1.040 mmol) of 5-tert-butyl-3-(tert-butylthio)phthalonitrile. Get 0.126 g (44.4%) of product. Found, %: C 70.04; N, 7.22; N, 10.04; S 11.24. C64H82N8S4. Calculated, %: C 70.41; N, 7.57; N, 10.27; S 11.75.
Synthesis of 3,5-bis(tert-butylthio)phthalonitrile. 3,5-Bis(tert-butylthio) " FTA " is ontril get analogously to example 1, but instead of tetrachloroisophthalonitrile use of 0.98 g (4.50 mmol) of 3,5-dinitrophenolate [Negrimovskii V.M., Derkacheva V.M., E.A. Lukyanets - AH, 1989, 59(7), 1688] and instead of decelerating use 1.03 ml (9.10 mmol) of tert-butylmercaptan. Obtain 1.15 g (83.9%) of white crystalline substance, TPL 92-93°With (benzene-hexane 1:2). Found, %: C 63.20; N, 6.69; N, 9.07; S 21.04. C16H20N2S2. Calculated, %: C 63.12; H 6.62; N, 9.20; S 21.06. IR-spectrum (KBr), νcm-1: 2226 and 2234 (C≡N). Mass spectrum, m/z: 304 [M+].
Synthesis 1,3,8,10,15,17,22,24-octakis(tert-butylthio)phthalocyanine [(ButS)8PcH2].
Get analogously to example 2, but as the initial substance use 0.316 g (1.040 mmol) 3,5-bis(tert-butylthio)phthalonitrile. Get 0.121 g (38.2%) of product. Found, %: C 63.31; N, 7.17; N, 8.83; S 21.51. C64H82N8S8. Calculated, %: C at 63.01; H 6.78; N, 9.19; S 21.03.
Synthesis of tetrakis(tert-butylthio)phthalonitrile. Tetrakis(tert-butylthio)phthalonitrile get analogously to example 1, but instead of decelerating use 2.26 ml (20.0 mmol) of tert-butylmercaptan and equimolar him a number of triethylamine. Obtain 2.16 g (89.8%) of white crystalline substance, TPL 140-142°C (ethanol). Found, %: 59.86; N, 7.52; N, 5.91; S 26.71. C24H36N2S4. Calculated, %: C 59.95; N, 7.55; N, 5.83; S 26.68. IR-spectrum (KBr), νcm-1: 2228 (C≡N). Mass spectrum, m/z: 480 [M+ ]. An NMR spectrum1H [DMSO-d6], δ, M. D.: 1.25 (s, N), 1.40 (s, N).
Synthesis of hexadecane(tert-butylthio)phthalocyanine [(ButS)16RSN2]. Get analogously to example 2, using as the starting material 0.500 g (1.040 mmol) tetrakis(tert-butylthio)phthalonitrile. Get 0.037 g (7.4%) of product. Found, %: C 60.11; N, 7.75; N, 5.71; S at 26.83. C96H146N8S16. Calculated, %: 59.89; N, 7.64; N, 5.82; S 26.65.
Synthesis of 4,5-bis(tert-butylthio)-3,6-dichloropropionitrile. 4,5-Bis(tert-butylthio)-3,6-dichloropropionitrile get analogously to example 1, but instead of decelerating use 1.13 ml (10.0 mmol) of tert-butylmercaptan. Obtain 1.72 g (92,2%) of white crystalline substance, TPL 146-148°C (ethanol). Found, %: C 51.50; N, 4.92; Cl 18.77; N, 7.54; S 17.31. C16H18Cl2N2S2. Calculated, %: C at 51.47; H 4,86; Cl 18.99; N, 7.50; S 17.18. IR-spectrum (KBr), νcm-1: 2231 (C≡N). Mass spectrum, m/z: 372 [M+]. An NMR spectrum1N [DMSO-d6], δ, M. D.: 1.27-1.36 (m, N) 1.42-1.38 (m, N).
Synthesis of 2,3,9,10,16,17,23,24-octakis(tert-butylthio)-1,4,8,11,15,18,22,25-octachlorostyrene zinc [(ButS)8Cl8PcZn]. Get analogously to example 1, method B, using as the starting material 0.187 g (0.50 mmol) of 4,5-bis(tert-butylthio)-3,6-dichloropropionitrile. Get 0.043 g (22.0%) of product. Found, %: C 49.78; H 4.90; Cl 17.72; N, 7.10; S 16.61. C64H72Cl8N8S8/sub> Zn. Calculated, %: 49.31; H 4.66; Cl 18.19; N, 7.19; S 16.46.
All synthesized phthalocyanines have an intense absorption in the spectral range 710-730 nm, in which the self absorption desencibiliziruuchee tissue close to the minimum (see table 1).
Maxima wavelength bands (ε) and ratios of molar extinction (e) in the electronic absorption spectra of alkyldiethanolamine in organic solvents
|Phthalocyanine||Solvent||λnm (ε×10-5, DM3×hmol-l×cm-l)|
|But 4(ButS)4PcH2||CHCl3||713 (1.24), 682 (1.04)|
|(ButS)4PcH2||CHCl3||715 (0.90), 686 (0.76)|
|(ButS)8PcH2||CHCl3||728 (0.90), 704 (0.75)|
Since the derivatives of alkyldiethanolamine hydrof is BNY, to create medicines for the system, in particular, intravenous injection in the present invention has a water-micellar solutions (emulsion) of these compounds in the presence of surface-active substances of class pluronic - proxanol is chosen 268. The use of a 4% aqueous solution of proxanol is chosen-268 allows you to obtain medicines with a high content of active substance (see tab. 2).
The maximum achievable concentration alkyldiethanolamine in water emulsions 4% proxanol is chosen 268
Receiving water emulsion and the concentration of (ButS)16PcH24% proxanol is chosen 268. Dissolve 7.7 mg ((ButS)16PcH2in 8 ml of chloroform, the sample was diluted 20 times with dimethylformamide (DMF), R is gastronaut electronic absorption spectrum and determine the molar extinction coefficient ε (ButS)16PcH2(PL. 1, Figure 1). To 3 ml of 4% (wt.) solution proxanol is chosen-268 in bidistillate at 65-70°add in a stream of nitrogen prepared above solution (ButS)16PcH2in chloroform. After removal of residual chloroform emulsion is filtered through a membrane filter "Millipore" (0.45 μm), an aliquot was diluted 20 times with DMF, register the electronic absorption spectrum and determine the value of the optical density at the maximum of the long-wave band Dmax. Concentration (ButS)16PcH2in the emulsion is calculated using formula 1:
where CSolthe concentration of the phthalocyanine in the emulsion, mol/l;
Dmax- the optical density at the maximum of the long-wavelength absorption band;
ε - molar extinction coefficient, l/(mol×cm);
l is the thickness of the cuvette, cm;
N is the degree of dilution of aliquots of the emulsion (in this example N=20).
Receiving water emulsion and the concentration (DecS)8Cl8PcZn 4% proxanol is chosen 268. Solution (DecS)8Cl8PcZn (22.3 mg in 20 ml of chloroform) was diluted 10 times with chloroform, register the electronic absorption spectrum thus prepared 5×10-5M solution (DecS)8Cl8PcZn and determine the molar extinction coefficient e (PL. 1, Figure 1). Figure 1 shows the electronic spectra of p is the absorption of alkyldiethanolamine, where the continuous line represents the spectra in organic solvents, and the dashed line is the absorption spectra of the emulsions in 4% proxanol is chosen 268: - (ButS)16RSN2, 2.5×10-5M in DMF)+5% CHCl3l=0.2 cm, 1.13×10-4M 4% proxanol is chosen 268 l=0.05 cm; b - (DecS)8Cl8PcZn, 5×10-5M in CHCl3l=0.1 cm, 1.35×10-4M 4% proxanol is chosen 268 l=0.05 cm; But 4(ButS)4RSN2, 5.0×10-4M in CHCl3l=0.009 cm, 1.28×10-4M 4% proxanol is chosen 268 l=0.1 cm; g (ButS)4RSN2, 4.1×10-4M in CHCl3l=0.02 cm; 1.15×10-4M 4% proxanol is chosen 268 l=0.1 cm; d - (ButS)8PcH2, 5×10-4M in CHCl3l=0.02 cm 3.9×10-4M 4% proxanol is chosen 268 l=0.05 cm; f - (ButS)8Cl8PcZn, 2.5×10-5M in CHCl3l=0.2 cm, 3.2×10-4M 4% proxanol is chosen 268 l=0.02, refer To 5 ml of 4% (wt.) solution proxanol is chosen 268 in bidistillate added at 65-70°and With stirring in a stream of nitrogen above prepared solution (DecS)8Cl8PcZn in chloroform. After removal of residual chloroform emulsion is filtered through a membrane filter "Millipore" (0.45 μm), an aliquot of 0.1 ml extracted with 5 ml chloroform, dried with CaCl2filter register electronic absorption spectrum of the filtrate and determine the value of the optical density at the maximum of the long-wave band DmaxKonz is Tracey (DecS) 8Cl8PcZn in the emulsion is determined by the formula (1), where N=50, using the value of molar extinction coefficient ε long-wavelength strip solution (DecS)8Cl8PcZn in chloroform.
Getting drugs for intravenous ButS)4PcH2But 4(ButS)4PcH2, (ButS)8Cl8PcZn and (ButS)8PcH2in the form of their aqueous emulsions in 4% proxanol is chosen-268 and determination of content of active substances in medicinal products conducted similarly to examples 7, 8.
Investigation of the pharmacokinetics of TRANS-tert-butyldiethanolamine (ButS)16PcH2when administered intravenously in aqueous emulsion in 4% proxanol is chosen 268 at a dose of 2.0 mg/kg To study the pharmacokinetics (ButS)16PcH2using mice breed or Balb F1with Ehrlich tumor (ELD), inoculated intramuscularly for 6 days before injection. The concentration of the photosensitizer in the tumor is determined by means of diffusive scattering percutaneously using a spectrum analyzer "LESA-01-BIOSPEC" (Loshchenov V.B. have been, stratonikos A.A., Volkov, A. I., Prokhorov A.M. Ross. chem. journal, 42(5), 50-53, 1998). The concentration of photosensitizer in normal tissue measured in the contralateral area of the left paw. On the basis of the received data count value index selectivelyyreplaced photosensitizer in the tumor relative to normal tissue and the relative time variation of the concentration of the photosensitizer. Absorption spectra of sensitized by 2 mg/kg (ButS)16PcH2in water emulsion 4% proxanol is chosen 268 tumor (1) and normal tissue (2) within 2 days after the injection are shown in figure 2.
Concentration (ButS)16PcH2in the tumor reaches through the day and remains almost constant within 5 days. In normal tissue concentration (ButS)16PcH2reaches almost immediately after the introduction and significantly (3-4 times) falls within the next 2 days. The dynamics of the selectivity index of accumulation (ButS)16PcH2after intravenous administration at a dose of 2 mg/kg of the aqueous emulsion in 4% proxanol is chosen 268 two mice breed Balb tumours Ehrlich presented in Figure 3.
Pharmacokinetic studies OCTA-3,6-decillia-4,5-octachlorostyrene zinc ((DecS)8Cl8PcZn] when administered intravenously in aqueous emulsion in 4% proxanol is chosen 268 at a dose of 3.0 mg/kg Absorption (DecS)8Cl8PcZn in vivo was investigated in mice F1with inoculated intramuscularly with Ehrlich tumor (ELD). During the first hours after the injection of the emulsion (DecS)8Cl8PcZn dose of 3 mg/kg absorption spectrum in the tumor is a fairly narrow peak with a spectral maximum at a wavelength of 727 nm (figure 4, where 3, 4, 5 - absorption spectra of the tumor, respectively after 1, 4 and 24 hours n the following introduction, 6 - absorption spectrum of the tissue prior to the introduction). To further increase the intensity of this peak is slowing down, when this occurs, the short-wave peak with the spectral absorption maximum at 676 nm, which can be associated with the aggregation of phthalocyanine and its biodegradation in biological tissue.
The study of the accumulation level (DecS)8Cl8PcZn in the tissue by the integral intensity of the main absorption peak at 727 nm showed that the highest accumulation of the photosensitizer in the tumor reached approximately one day after injection and long enough it is held. In normal tissue uptake of photosensitizer for 3-6 days decreases to values that are not experimentally detectable, indicating that it has been almost a complete removal of normal tissue (Figure 5, where 7 and 8 - accumulation (DecS)8Cl8PcZn in Ehrlich tumor and normal tissue, respectively intravenous its emulsion in 4% proxanol is chosen 268 mice BDF1at a dose of 3 mg/kg).
The selectivity of accumulation (DecS)8Cl8PcZn in Ehrlich tumor (ELD) intravenously at a dose of 3 mg/kg compared with normal tissue reaches values ˜8 and ˜17 after 4 h and 24 h after injection, respectively (Fig.6).
Pharmacokinetic studies OCTA-3,5-tert-butyldiethanolamine [(ButS)8PcH2 ] when administered intravenously in aqueous emulsion in 4% solution of proxanol is chosen 268. Absorption spectrum (ButS)8RSN2in biological tissue is a broad band in the range 670-770 nm, showing significant aggregation. Structuring strip slowly, mainly during the first days after the administration of low doses (˜1 mg/kg). With the increase of dose and time after administration dominated by short-wavelength wing of the strip in the area 670-710 nm (Fig.7, where 9, 10, 11 - absorption spectra of sensitized Ehrlich tumor when administered intravenously (ButS)8RSN2at a dose of 4.7 mg/kg after 2, 24 and 120 hours after administration, 12 - absorption spectrum of tumors prior to the introduction). The level and selectivity of accumulation (ButS)8RSN2the tumor is assessed according to the integrated intensity of the bands in the spectral range 702-742 nm. The compound is characterized by an average selectivity of accumulation in the tumor (selectivity index of 2.5-3.5) and slowly eliminated from biological, including normal tissue [Fig, the dynamics of the accumulation level (ButS)8RSN2in Ehrlich tumor (13) and normal tissue (14) when administered intravenously at a dose of 4.7 mg/kg to mice BDF1; Fig.9 - dynamics of the selectivity index of accumulation (ButS)8RSN2in Ehrlich tumor compared to normal tissue, is followed when administered intravenously at a dose of 4.7 mg/kg].
Photodynamic activity in vivo water-proximally emulsions (ButS)16PcH2study in mice with Ehrlich tumor or sarcoma S-37 inoculated subcutaneously on the outer surface of the thigh, lower limbs female mice of lines IAS (Ehrlich tumor) or BDF1(S-37).
Medicines, prepared as described in examples 7-8, injected into the tail vein of animals once on day 6 after inoculation for 4, 24 or 48 h prior to PDT.
Sensitized the tumor is irradiated by the radiation of therapeutic cancer photodynamic therapy ATO-1, equipped with a filter KS-18 and filter SES. Spectral emission maximum at a wavelength of 700 nm, the radiation power density of 220 mW/cm2the density of the light dose of 120 j/cm2. Before irradiation the wool over the tumor removed. The duration of observation of the animals is 20-25 days after treatment.
The performance impact is judged by the change in tumor volume (Von) and the values of inhibition of tumor growth (SRW), calculated by the formulas (2) and (3).
where D1D2and D3three mutually perpendicular tumor size.
In the study of biological activity (ButS)16PcH24% Proxen the Les 268 in doses from 0.1 to 5.0 mg/kg installed, that the analyzed samples of the drug have no cytotoxicity in the absence of light exposure. Irradiation of tumors without the drug also does not suppress the growth of malignant tumors. After a single PDT using (ButS)16PcH2at doses of 0.1; 0.25; 0.5; 1.0 and 5.0 mg/kg for 48 h before irradiation in all cases, the observed high values TRO (57.5-100.0%) for 20-25 days of observation. Comparative data analysis of the effectiveness of PDT (ButS)16PcH2in the tested doses showed a decrease in the values of TRO (20-25%) on 15 and 20 day when reducing the dose to 0.1 mg/kg While conducting irradiation at various times after administration (ButS)16PcH2at doses of 0.1; 0.25 or 0.5 mg/kg no observed significant differences in photodynamic efficiency of the connection PDT through 4; 24 or 48 h after intravenous injection (PL. 3).
Photodynamic activity in vivo water emulsions But 4(ButS)4RSN24% proxanol is chosen 268 studied in mice BDF1with transplantable sarcoma S-37 after the introduction of the drug in doses 0.37, 0.75 and 1.5 mg/kg "Dark" cytotoxicity with the introduction of But 4(ButS)4RSN2in the maximum dose 1.5 mg/kg not observed. If Pro is the introduction photodynamic therapy of tumors sensitized for 24 h before irradiation, in all cases biologically significant inhibition of tumor growth (SRW=56.2-100.0%) for the entire observation period. Identified a direct correlation of antitumor effect of the dose of the photosensitizer. Average values SRW with the introduction of photosensitizer dose of 0.37 mg/kg are 56.2-75.9%; at a dose of 0.75 mg/kg - 72.8-82.3%; at a dose of 1.5 mg/kg - 100.0%, i.e. there is a complete resorption of tumor formation during 20 days of observation (Table 3).
Photodynamic activity in vivo water emulsions (ButS)4PcH24% proxanol is chosen 268 studied in mice BDF1sarcoma S-37 after the introduction of the drug in doses 8.8; 4.0; 1.0; 0.5 and 0.1 mg/kg was Established that the composition (ButS)4PcH2with the introduction of the maximum dose of the drug 8.8 mg/kg does not have "dark" cytotoxicity. During PDT of tumors, sensitized (ButS)4PcH2in doses of 8.8 and 4.0 mg/kg per 24 h before irradiation, marked biologically significant inhibition of tumor growth (SRW=53.5 97.1 per cent) during 20 days of observation. When using the sensitizer in smaller doses (1.0; 0.5; 0.1 mg/kg) significant suppression of tumor growth is not installed (PL. 3).
Photodynamic activity in vivo water emulsions (ButS)8PcH24% proxanol is chosen 268 we studied on the Ah BDF 1sarcoma S-37 after intravenous injection of the compound at doses of 6.0 and 1.0 mg/kg of Emulsion (ButS)8PcH2with the introduction of the drug in the maximum dose of 6.1 mg/kg does not have "dark" cytotoxicity. During PDT of tumors, sensitized (ButS)8PcH2at a dose of 6.0 mg/kg per 24 h before irradiation in all animals in the experimental group showed complete resorption of tumor entities, registered for 20 days of observation. When introducing the compound at a dose of 1.0 mg/kg and conducting photodynamic therapy biologically significant inhibition of tumor growth (SRW=56.6-86.4%) persisted throughout the observation period (Table 3).
Photodynamic activity in vivo water emulsions (DecS)8Cl8PcZn 4% proxanol is chosen 268 studied in mice BDF1sarcoma S-37 after the introduction of the compound in doses 22.0; 5.0 and 1.0 mg/kg is Established that (DecS)8Cl8PcZn in an aqueous solution of 4% proxanol is chosen 268 when administered intravenously at a dose of 5.0 mg/kg in the absence of irradiation does not inhibit the growth of experimental tumors. During PDT of tumors, sensitized (DecS)8Cl8PcZn at a dose of 1.0 mg/kg per 24 h before irradiation biologically significant suppression of tumor growth was observed only on day 10 after treatment (SRW=55.4%). After injection of the photosensitizer in large doses (5.0 and 22.0 mg/kg) therapeutic efficiency is more pronounced (SRW=61.8-75.9%) and is celebrated for 15 days of observation. Reducing the time interval between injection and irradiation from 24 to 4 hours at doses of 5.0 and 1.0 mg/kg leads to a significant increase in therapeutic effect (Table. 3).
Photodynamic activity in vivo water emulsions (ButS)8Cl8PcZn 4% proxanol is chosen 268 studied in mice with sarcoma S-37 after administration of the compound at doses of 3.7, 1.5, and 0.5 mg/kg During PDT of tumors, sensitized (ButS)8Cl8PcZn for 4 h before irradiation, a significant suppression of tumor growth is observed for all doses administered throughout the observation period (20 days Table. 3).
Inhibition of tumor growth when used as photosensitizers for PDT of aqueous emulsions of alkyldiethanolamine 4% proxanol is chosen 268
|The photosensitizer||Dose, mg/kg||The time between introduction and radiation, h||SRW, %|
|10 days||15 days||20 days|
Photodynamic efficacy in vivo water emulsions (DecS)8Cl8PcZn 4% proxanol is chosen in the treatment of tumors of large size has been studied in Ehrlich tumor (ELD). Drug-based (DecS)8Cl8/sub> PcZn enter through 5 days after inoculation of the tumor, when the average tumor volume reaches 0.6-1 cm3and lateral dimensions exceeding 0.8 see Irradiation of the tumor is performed by laser LTD-730/01-BIOSPEC with a wavelength of 732 nm at a power density of 250 mW/cm2.
When a high dose of a photosensitizer (6.0 mg/kg) irradiation of tumors of large size through 18 h after injection causes biologically significant, but an intermediate level of therapeutic effect (SRW=67%). Upon irradiation after 3-4 h after injection and increasing exposure time up to 30 min (dose 450 j/cm2) PDT efficacy increases (SRW=77%). When reducing the dose to 3.0 mg/kg therapeutic effectiveness of the composition increases and reaches high values (SRW=75% and 84% at the dose of 300 j/cm2and 450 j/cm2respectively (Table 4).
Photodynamic activity of the medicinal product based on water emulsions (DecS)8Cl8PcZn in the treatment of tumors Ehrlich large size (0.7-1 cm3)
|Dose FS, mg/kg||The time between introduction and radiation, h||The density of the light dose, j/cm2||SRW, % (number of days after irradiation)|
Thus, the proposed in the present invention alkylthiophene phthalocyanines with intense absorption in the spectral region 710-730 nm represent a new class of efficient photosensitizers near IR region of the spectrum. Drugs based on them in the form of aqueous emulsions can be used for the treatment of a tumor, including deep, PDT.
1. Alkylthiophene phthalocyanines of General formula
where R1=R4=Cl, R2=R3=n-C10H21S, M=Zn;
R1=t-C4H9S, R2=R3=R4=H, M=HH;
R1=t-C4H9S, R2=R4=H, R3=t-C4H9M=NN;
Rl=R3=t-C4H9S, R2=R4=H, M=NN;
R1=R4=Cl, R2=R3=t-C4H9S, M=Zn.
2. Drugs for photodynamic therapy of cancer, representing water-soluble forms of photosensitizers, characterized in that they are water emulsion alkylthiophene phthalocyanines according to claim 1 on the basis of nonionic surfactants - proxanol is chosen 268.
3. With the persons of photodynamic therapy using a photosensitizer based on the derivatives of phthalocyanines, characterized in that the use of the medicinal form of the photosensitizer according to claim 2.
SUBSTANCE: invention concerns a new compound, zinc meso-trans-dihexadecyltetrabenzoporphyrinate .
EFFECT: compound can be applied as a fat-soluble green colorant for solution dyeing of paraffin and polyethylene.
1 cl, 2 ex, 2 dwg
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention proposes an improved method for synthesis of bis-(1-vinylimidazole)-zinc diacetate representing a complex compound of zinc diacetate with 1-vinylimidazole and known as medicinal preparation acizol. Acizol is an effective antidote and antihypoxic agent of the broad spectrum of effect. Method for synthesis of 1-vinylimidazole metal with zinc diacetate of the composition 2:1 involves carrying reaction in the absence of solvent and using available commercial zinc diacetate of the formula Zn(OCOCH3)2 x 2 H2O in the stoichiometric mole ratio 1-vinylimidazole : salt in the range from 2.9:1 to 2:1, and synthesized pure product is isolated by water distilling off or its azeotropic mixture with 1-vinylimidazole. Method provides excluding the dehydration step of parent zinc salt from technological process and to decrease consumption of used reagent 1-vinylimidazole significantly, Invention provides significant reducing energetic and industrial consumptions, simplifying and decreasing cost of process and retaining the quantitative yield of highly pure pharmacopoeia acizol preparation.
EFFECT: improved method of synthesis.
FIELD: luminescent substances, organic chemistry.
SUBSTANCE: invention relates to electroluminescent materials containing organic luminescent substance. Invention describes novel electroluminescent material consisting of injection layer, active luminescent layer based on chelate metal complex, hole-transporting layer and hole-injecting layer. Material comprises metal complexes based on sulfanyl derivatives of 8-aminoquinoline as a luminescent substance, in particular, zinc complexes of 8-(methylsulfanylamino)-quinoline and 8-(3,5-difluorophenylsulfanylamino)-quinoline. Material comprises a mixture of triphenylamine oligomers as a hole-transporting layer. Invention provides creature of electroluminescent material showing the enhanced moisture resistance, enhanced resistance to crystallization and enhanced thermal stability.
EFFECT: improved and valuable properties of material.
4 cl, 5 ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to novel compounds, namely zinc bis-[2-(tosylamino)benzylidene-N-alkyl(aryl, hetaryl)aminates] of the general formula (I): wherein Ts means tosyl; R means (C1-C6)-alkyl with exception isopropyl, (C1-C6)-alkyl-substituted phenyl, (C1-C6)-alkoxy-substituted phenyl with exception para- and ortho-methoxyphenyl, pyridyl, (C1-C6)-alkylpyridyl, or R + R form in common disulfidodialkyl group -(CH2)n-S-S-(CH2)n- wherein n = 1-3, but preferably to zinc bis-[2-(tosylamino)benzylidene-N-alkylidenemercaptoaminates] of the general formula (Ia): Compounds can be used for synthesis of light-radiating organic diode of white and visible light. Fluorescence can be observed in blue region of spectrum with fluorescence bands maximum at 428-496 nm. Quantum yields are 0.2-0.25.
EFFECT: valuable physical properties of compounds.
5 cl, 8 ex
FIELD: medicine, in particular photosensitizing agents for antimicrobial photodynamic therapy.
SUBSTANCE: invention relates to new photosensitizing agents for antimicrobial photodynamic therapy namely cationic phthalocyanines of general formula MPc(CH2X)nCln, wherein Pc is phthalocyanine rest C32H16N8; M is Zn, AlY; n = 6-8; X is Y is Cl, OH, OSO3H. Claimed agents is characterized by wide range of antimicrobial activity. Single complex action of nontoxic in darkness micromolar (up to 2.0 muM) concentration thereof and low dose of red irradiation make it possible to produce high inactivation levels (up to 97-99 %) both gram-negative bacteria and yeast fungi of genus Candida.
EFFECT: improved agents for treatment of various severe complications of inflammation diseases.
3 dwg, 13 ex, 2 tbl
FIELD: medicine, in particular photosensitizing agents for photodynamic therapy.
SUBSTANCE: invention relates to quaternary phthalocyanines of general formula MPc(CH2X)nCln, wherein Pc is phthalocyanine rest C32H16N8; M is Zn, AlY; n = 6-8; X is Y is Cl, OH, OSO3H, useful as photosensitizing agents in photodynamic therapy having high photoinduced activity in vivo and in vitro.
EFFECT: new class of effective photosensitizing agents useful in treatment of various tumors by photodynamic therapy.
1 dwg, 8 ex
FIELD: chemistry, chemical technology.
SUBSTANCE: invention relates to quaternized phthalocyanines and their using for treatment of water against bacterial pollution. Invention describes novel quaternized phthalocyanines representing poly-(trialkylammoniomethyl)-substituted zinc and aluminum phthalocyanines that are sensitizing agents in formation of singlet oxygen by effect of visible light. Also, invention relates to a method for photodisinfection of water by using these quaternized phthalocyanines or their mixtures with dyes of acridine, rhodamine or phenothiazine series and radiation in visible range in the presence of oxygen that provides the effective treatment of water against bacterial pollution.
EFFECT: valuable properties of compounds, improved method of water treatment.
3 cl, 5 tbl, 16 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to the improved method for synthesis of zinc phthalocyanine of high purity degree that can be used as a photosensitizing agent for photodynamic therapy. Method is carried out by interaction of phthalonitrile with zinc salt at heating in the presence of a tertiary amine - N,N-dialkylaniline, N,N-dialkylethanolamine or trialkylamine in an aprotonic dipolar solvent medium, for example, dimethylformamide. Method provides preparing the end product with 97-99% content of the basic substance. Method shows the technological effectiveness as it suggests using inexpensive reagents, small amount of solvent and it doesn't require the complex purifying procedures.
EFFECT: improved method of synthesis.
2 cl, 4 ex
FIELD: production of high temperature superconductors.
SUBSTANCE: invention relates to electrochemical synthesis of metal β-diketonates, in particular acetylacetonates. Synthesis of Cu(II) and Zn(II) acetylacetonates in carried out by electrolysis of acetylacetone solution and base electrolyte in acetonitryl in ratio of (1:10):0.5:100, with electrodes made of metal presenting in produced acetylacetonate, at current density not more mA/cm2 by using pulse current. Pulse time is controlled by pulse forming unit connected in parallel to elecrtolyzer. As base electrolyte preferably lithium perchlorate or lithium chloride is used.
EFFECT: controlled process for production of metal acetylacetonates.
5 cl, 2 ex, 1 dwg
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
FIELD: medicine; pharmacology.
SUBSTANCE: way of obtaining of new derivatives of a chlorophyll with two N, N-dimethylaminomethyl groups is described. The method lies in treatment of chlorine e6 derivative by bis-N, N-dimethylaminomethane in an admixture of butylene oxide with acetic acid at temperature of boiling of a reactionary admixture with the subsequent allocation of target product with column chromatography.
EFFECT: high output of a product and simplicity of technology.
SUBSTANCE: method is performed by the following way: unfiltered culture liquid is acidated to pH 2-2.5, sorb on cationite KU-23/100 in pulsing fluidisated mode with subsequent desorption using elution systems with pH 6.0±0.1, containing sodium citrate 1.5% and carbamide 0.5%. Coproporphyrin III is precipitaled on produced eluate, reducing pH to 3.5±0.1. Produced precipitate is extracted with hydrochloric acid solution, thereafter chromatographic cleaning of extract on molecular sorbent follows. End product is precipitaled on eluate. Then extraction and chromatographic cleaning are repeated, whereupon end product is precipitaled on eluate and transformed into potassium salt.
EFFECT: technology allows for production of water-soluble preparation based unfiltered culture liquid.
FIELD: medicine; pharmacology.
SUBSTANCE: invention refers to pharmacology, namely to production of biologically active compounds, specifically to improved method of chlorine e6 production applied for production of photosensitisers for photodynamic cancer therapy. Method is performed by processing sulphuric acid concentrated spirulina methanolic suspensions followed by filtration, dilution with water, alkali neutralisation by, filtration of settled deposition through celite layer followed with washing in hot water and petroleum-ether, elution with acetone celite, silica gel based chromatography, recrystallisation of mixed chloride methylene- methanol, release of produced alkylpheophorbide and its dilution with acetone, alkali processing, hydrochloric acid neutralisation, a filtration through celite layer, washing in water, aqueous ammonia, lyophilisation, dilution with aqueous alkali, filtration through sephadex layer, neutralisation, centrifugation and lyophilisation.
EFFECT: production of pure product with reagents taken in small amounts.
1 cl, 6 ex
SUBSTANCE: invention concerns a new compound, zinc meso-trans-dihexadecyltetrabenzoporphyrinate .
EFFECT: compound can be applied as a fat-soluble green colorant for solution dyeing of paraffin and polyethylene.
1 cl, 2 ex, 2 dwg
SUBSTANCE: photosensitising agents obtained by reducing a double bond in porphyrinic macrocycle of sulphonated mesotetraphenylporphyrine, preferably disulphonated mesotetraphenylporphyrine, such as TPPS2a. Resulting sulphonated mesotetraphenylchlorines are compounds of formula (I) , (where X stands for -SO3Н; each of n, p, q and r independently stands for 0 or 1; and sum of n, p, q and r is an integer from 1 to 4, preferably at least 2, in particular, 2 or 4), isomers or isomeric mixture. Compounds in accordance with the said invention and pharmaceutically suitable salts thereof have a high extinction coefficient in the region of 630 to 680 nm.
EFFECT: compounds are widely used as photosensitising agents for photochemical internalisation of molecules and photodynamic therapy.
25 cl, 8 ex, 8 dwg
FIELD: chemistry of coordination compounds, chemical technology, medicine.
SUBSTANCE: invention relates to an improved method for synthesis of metallic complexes of chlorophyll (A) derivatives with transient metal ions (Ni2+, Zn2+, Co2+, Cu2+). Method involves boiling the parent ligand with transient metal salt followed by isolation of the end product. Method involves using methylpyropheophorbid (a) or chlorin e6 13-N-methylamide-15,17-dimethylester or 13(2)-hydroxymethlpheiphorbid (a) as a ligand, and acetyl acetonate of the corresponding metal is used as transient metal salt, and boiling is carried out in equimolar amount of reagents for 2-3 h. By alternative variant the method involves boiling the parent ligand with transient metal salt followed by isolation of the end product wherein methylpyropheophorbid (a) or chlorin e6 13-N-methylamide-15,17-dimethyl ester, or 13(2)-hydroxymethylpheophorbid (a) is used as a ligand. Acetyl acetonate of the corresponding metal is used as transient metal salt in 10-fold excess. Acetyl acetonate is added to the reaction mixture by two equal portions followed by boiling for 1-2 min after each addition. Method provides high yield and without using large excess of metal salts. Invention can be used in synthesis of antitumor and antiviral preparations used in medicine.
EFFECT: improved method of synthesis, valuable medicinal properties of complexes.
3 cl, 1 dwg, 8 ex
FIELD: medicine, radiation therapy.
SUBSTANCE: the present innovation refers to radiosensitizers that contain as an active component halogenated derivatives of borated porphyrines that contain a great number of carboranic cells which are selectively accumulated in neoplasms' tissues in the irradiated volume and could be applied in such type of cancer therapy that include but are not restricted with boron-neutron-capturing therapy and photodynamic therapy. The present innovation , also, deals with applying these radiosensitizers for visualization of the tumor and treating the cancer.
EFFECT: higher efficiency.
35 cl, 2 dwg, 8 ex, 7 tbl
FIELD: organic chemistry.
SUBSTANCE: claimed method includes interaction of 1,3-diaminopropane with paraformaldehyde at room temperature for 10-20 min under stirring and recrystallization of condensation product from ethanol or heptane.
EFFECT: method of high yield.
1 dwg, 2 ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to a method for synthesis of e6 chlorine derivatives with two or three amino-groups. The proposed method provides to synthesize chlorines comprising 2 and 3 amino-groups without using activating agent and with high yields that are similar or exceed yields of analogous compounds prepared by using activating agents. In using the proposed methods di- and triaminochlorines can be synthesized selectively from methylpheophorbid (a) directly without isolation of intermediate compounds. Method for synthesis of aminochlorines involves interaction of ester groups of chlorine e6 with ethylenediamine and isolation of the end product wherein pure ethylenediamine is used, chlorine e6 13-N-(2-aminoethylamide)-15,17-dimethyl ester is synthesized in situ from methylpheophorbid (a) and 50-200-fold mole excess of ethylenediamine in chloroform medium at room temperature 15-25°C for 1.5-2.5 h followed by evaporation of chloroform in rotor evaporator under reduced pressure 20-300 mm mercury column and at bath temperature 50°C, not above. Before isolation the reaction mixture is kept in dark at room temperature and after keeping the mixture for 20 h e6 chlorine diamine is isolated as the end product that comprises two amino-groups, and after keeping the mixture for 70 h e6 chlorine triamide is isolated comprising tree amino-groups. The proposed method of synthesis chlorines can be used in synthesis of antitumor and antiviral preparations in medicinal aims.
EFFECT: improved method of synthesis.
FIELD: chemistry of metalloorganic compounds, chemical technology.
SUBSTANCE: invention relates to an improved method for synthesis of octa-4,5-carboxyphthalocyanine cobalt sodium salt, or 2,3,9,10,16,17,23,24-octacarboxylic acid of phthalocyanine cobalt (terephthal) of the formula (I) . Terephthal is a synthetic preparation used in catalytic ("dark") therapy of cancer based on generation of oxygen reactive species in tumor directly by chemical manner and in combination with ascorbic acid being without using the physical effect. Method for preparing octa-4,5-carboxyphthalocyanine cobalt sodium salt involves melting pyromellitic acid dianhydride with cobalt salt in the presence of urea followed by alkaline hydrolysis of prepared octa-4,5-carboxyphthalcyanine cobalt tetraimide. Salt formed after hydrolysis is purified from impurities, in particularly, from oligomeric compounds by column chromatography method on aluminum oxide, following precipitation of octacarboxylic acid, its, its washing out, concentrating and purifying from residual inorganic salts by washing out with distilled water and by neutralization with sodium hydroxide aqueous solution also, treatment with apyrogenic activated carbon, filtration and drying the end substance. Purification of octa-4,5-carboxyphthalocyanine cobalt from residual inorganic salt is carried out preferably by electrodialysis method after its partial neutralization to pH 5.2-5.5 at current density 0.15-0.25 A/dm2, temperature 20-35°C and the concentration 1.5-3.0% followed by complete neutralization to pH 8.7, treatment of obtained octacarboxy-PcCo salt solution with activated carbon, filtration and drying filtrate in a spray drier. Proposed method provides preparing octa-4,5-carbocyphthalocyanine cobalt salt of high purity degree and free of oligomeric compounds and residual chlorides.
EFFECT: improved method of synthesis.
SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.
EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.
41 cl, 8 tbl, 423 ex