Photoinitiator process of destruction of malignant cells in living organisms
(57) Abstract:The invention relates to methods of destruction of malignant cells in living organisms and can be used for the treatment of solid tumors, for programmed cell death in biological and medical research, for photodynamic therapy of cancer. The aim of the invention is to increase the efficiency of the process of destruction of malignant cells in living organisms. The technical effect is achieved by using as photoinitiator photolysis of malignant cells in living organisms tidimensional dye of the formula
(X = CH3C6H4SO-3). The proposed photoinitiator polymethine has a number of advantages compared with the known photoinitiators. Due to the positive charge of the polymethine selectively accumulates in cancer cells, effectively inhibits the growth of solid tumors in mice and destroys the malignant cells in vitro. At lower doses of irradiation efficiency 1.5-4.0 times higher than the efficiency of known photoinitiator of cryptocyanine that it is important for the treatment of deep-lying cells in the tumor. 1 Il., table 2. The invention relates to spooley, for programmed cell death in biological and medical research, for photodynamic therapy of cancer.Known application of porphines, such as Photofrin II as photoinitiator destruction of cells under the action of red light. The most likely mechanisms of photodynamic porphines as other dyes, consider their vodoprivredna education or singlet oxygen mechanism of type I or radicals (the mechanism of type II). Mechanisms of type I and II lead to the accumulation in the cells of active forms of oxygen, photomodification uses of cell membranes, disruption of the functioning of the cells and, ultimately, to cell death. Porfiry are not sufficiently effective, their use requires very large therapeutic doses. So, a 50% survival rate of mice with melanoma is achieved by the application of Photofrin II in a dose of 10 mg of dye per 1 kg of body weight of the mouse with a total dose of 500 j/cm2light with a wavelength of 630 nm.It is also known application as photoinitiator photolysis cell phtalocyanine dyes. Chloroaluminium phthalocyanine sulfonate is the most effective dye from this class: concentration 1,310-5mol/l (11-12 mg/kg) of annih works assumed what phthalocyanines act as exogenous sensitizers, and the mechanisms of type I and II are not met. However, in further work, this assumption was not confirmed and received evidence that phthalocyanines initiate photolysis cells by the mechanism of type I formation of singlet oxygen. Phthalocyanines are not widely used in photodynamic therapy, which may be due to their lack of efficiency and difficulties in their synthesis and purification.It is also known the use of cyanine dyes of the formula
< / BR>as photoinitiator photolysis cell. Cyanine dyes have certain advantages in comparison with the previous dyes: they are selective on - cableways in malignant cells and kept them in longer than in healthy cells, due to increased membrane potential of malignant cells. Therefore, cyanine dyes are promising photoinitiators selective photolysis of malignant cells in tumors. For example, merocyanine-540 shown that cyanine dyes are photoinitiator radical-chain oxidation of lipids. The destruction of 90% of malignant cells in their presence usually p is the cure. Of these dyes are the most famous cryptocyanine (R1=R2= C2H5), which inhibits the development of tumors in mice the repetition of the procedure of injection of the dye, followed by irradiation of the tumor. The mechanism of photodynamic action of cryptocyanine is photoinitiator oxidative processes, leading to the accumulation in the cell products that inhibit oxido-reductase that leads to the subsequent slow death of malignant cells 
The data show that the effectiveness of the known dyes used for PDT is insufficient. The aim of the invention is to increase the efficiency of the process of destruction of malignant cells in living organisms.This effect is achieved by using as photoinitiator photolysis of malignant cells in living organisms tidimensional dye of the formula
< / BR>The compound of formula (I) is used as a spectral sensitizer silver halide photographic emulsions to spectrum 650-790 nm with a maximum sensitization at 745-750 nm 
Get the compound (I) interaction of the Quaternary salt of 2-methyl-3-ethyl-5-methoxy-6-met the Ave ethyl ester p-toluene-sulfonic acids with subsequent condensation of the resulting compounds of the formula
< / BR>with the Quaternary salt of 2-methyl-3-ethyl-5-methoxy-6-methylthiotetrazole formula (II) in the presence of triethylamine in an environment of pyridine at boiling or in the environment of dimethylacetamide at a temperature of 150-155o
Compound I (polymethine) available, utilized in industrial production at the pilot plant Kazan "Tasma".Application polymethine as photoinitiator photolysis of malignant cells in living organisms can significantly improve the efficiency of photolysis at lower doses compared with analogue cryptocyanine. Cells injected with polymethines with its concentrations of 1-4 mg/kg and irradiated with light with wave lengths 660-760 nm to dose 10-130 j/cm2.The following examples illustrate the invention but do not restrict it.Example 1. From the abdominal cavity of the mouse syringe is taken 0.1 ml of ascitic fluid containing tumor cells R, bred buffer Hanks solution to a concentration of 1106cells/ml In the resulting cell suspension R add polymethine to the concentration of 510-6mol/l and incubated for 30 min to saturate the cells polymethines. Then 1 ml of cells leave for control in the dark, and another 1 ml of cell irradiation of Idenix of N cells after irradiation was measured by bromide staining by ethidium and fluorescenceactivated. To determine the effectiveness of polymethine towards cryptocyanine perform the same procedure, but instead of polymethine use cryptocyanine. The effectiveness of polymethine E is defined as the value of E=N1/N0where N1and N0the number of damaged cells when used as photoinitiator polymethine and cryptocyanine respectively. Measurement of N1and N0give N1=12% N0=5% E=2,4 (PL.1). Thus, at the dose of 10 j/cm2the effectiveness of polymethine 2.4 times higher than that of cryptocyanine.Example 2. Perform analogously to example 1, but with the difference that the irradiation dose of 30 j/cm2. Measurement of N1and N0give N1=16% N0=4% E=4,0 (PL.1). Thus, at the dose of 30 j/cm2the effectiveness of polymethine 4 times higher than cryptocyanine.Example 3. Perform analogously to example 1, but with the difference that the radiation dose is 60 j/cm2. Measurement of N1and N0give N1=21% N0=14% and E=1,5 (PL. 1). This shows that at a dose of 60 j/cm2the effectiveness of polymethine 1.5 times higher than cryptocyanine.Example 4. From the abdominal cavity of the mouse syringe is taken 0.1 ml of ascitic fluid containing about the suspension of cells L1210 add polymethine to the concentration of 510-6mol/l and incubated for 10-30 min to saturate the cells polymethines. Then 1 ml of cells leave for control in the dark, and another 1 ml of cells irradiated at room temperature by light with wavelengths 660-760 nm to dose of 130 j/cm2. On painting fluorescenceactivated observed damage 100% of the cells and in the control of 5% of the cells.Example 5. Receipt of L1210 cells with the addition of polymethine and their irradiation performed analogously to example 4 with the difference that the cell suspension is diluted with saline to a concentration of 2107cells/ml, and the training is conducted to a dose of 60 j/cm2. Irradiated cell suspension injected intraperitoneally healthy mice hybrids C57/DBA 0.2 ml of suspension per mouse, and monitor the development in mice lymphoid leukemia L1210. As the death of mice determine the time t100, t60and t40life expectancy 100% 60% and 40% of mice, respectively, from the onset of the disease. All three values of t100, t60and t40exceed 120 days (table.2), indicating complete destruction of L1210 cells in their photolysis in vitro using as photoinitiator polymethine.Examples 6-10. Perform analogously to example 5, but at other concentrations, F. the data table.2, photolysis in vitro in the presence 510-7mol/l of photoinitiator significantly increases the lifespan of mice, and the effectiveness of the proposed photoinitiator polymethine significantly higher than known photoinitiator of cryptocyanine at lower doses.Increased the effectiveness of the proposed photoinitiator at lower doses is important for the destruction of deep-lying cells in solid tumors who receive a smaller dose of radiation than cells in the surface layers of the tumor.Example 11. From the abdominal cavity of the mouse is taken 0.1-0.5 ml of ascitic fluid containing tumor cells R, bred it with a saline solution so that 0.1 ml of the suspension contained 1,5105cells R and injected with 0.1 ml of the resulting suspension mice-hybrids S/TWO subcutaneously in the shoulder area of the forelimb for the development of solid tumors. The average mass growing tumor determine its weighting after opening mice. On the 5th day of tumor development begin conducting photodynamic therapy, which is as follows: mice injected polymethine intraperitoneally at the rate of 1 mg photoinitiator on 1 kg of body weight of the mouse and leave the mice in the dark for 1 day for on the to a dose of 80 j/cm2under General anesthesia for fixing the mouse.Data on the development of the tumor before and after photodynamic therapy is shown in the drawing.As follows from the drawing, already a single use of photodynamic therapy with the proposed photoinitiation polymethine stops the growth of solid tumor R mice-hybrids S/TWO. Pathologic-anatomic analysis also shows the complete cessation of sprouting blood vessels in the tumor, indicating a high efficiency of the proposed photoinitiator.Example 12. Is comparative and is similar to example 11, but without using polymethine. The data obtained is shown in the drawing and show that without the use of polymethine rapid tumor growth, leading to death of the mice.Polymethine were injected intraperitoneally (1 mg/kg) per day before irradiation with red light. Radiation treatment of the tumor was performed once daily for 40 min under General anesthesia for fixing the mouse. Date procedures in the drawing indicated by the arrow. Point on the 11th day are average (20 mice per point), other individual.Thus, the proposed photoinitiator polymethine has Radome accumulates in malignant cells and keep them longer than in healthy cells, due to increased membrane potential of malignant cells, which is important for selective photolysis of malignant cells. Polymethine effectively inhibits the growth of solid tumors in mice and destroys the malignant cells in vitro. At lower doses of irradiation efficiency 1.5-4.0 times higher than the efficiency of known photoinitiator of cryptocyanine that it is important for the treatment of deep-lying cells in the tumor. Finally, polymethine is available compound utilized in industrial production. Application tidimensional dye of the formula
< / BR>as photoinitiator process of destruction of malignant cells in living organisms.
FIELD: organic chemistry, biochemistry.
SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.
EFFECT: new epothilones capable of cell growth inhibiting.
19 cl, 39 ex
FIELD: medicine, gastroenterology, pharmacy.
SUBSTANCE: invention relates to a solid composition eliciting with an anti-ulcer activity and to a method for its preparing. Pharmaceutical composition consists of a core containing famotidine as an active component and starch, aerosil, stearic acid salt as accessory inert substances wherein a core is covered by polymeric envelope. Core comprises glucose and stearic acid as an accessory inert substance and magnesium stearate as a stearic acid salt. Polymeric envelope comprises oxypropylmethylcellulose, propylene glycol, castor oil, talc and titanium dioxide taken in the definite ratio of all components in the composition. Method for preparing pharmaceutical composition involves preparing raw, mixing therapeutically effective amount of famotidine with glucose and starch, moistening the mixture with starch paste, granulation, drying wetted granulate, repeated granulation, powdering dry granules, tableting and applying polymeric envelope containing oxypropylmethylcellulose on prepared cores with addition of titanium dioxide, propylene glycol, castor oil and talc. Invention provides enhancement of degradability, solubility and stability in storing.
EFFECT: improved method for preparing, valuable pharmaceutical properties of composition.
3 cl, 1 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.
EFFECT: valuable medicinal and biochemical properties of azoles.
27 cl, 8 tbl
FIELD: medicine, therapy, gastroenterology.
SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.
EFFECT: improved therapy method.
4 tbl, 2 ex
FIELD: medicine, endocrinology.
SUBSTANCE: invention relates to treatment of diabetes mellitus in mammals. Invention proposes applying inhibitors of enzyme dipeptidyl peptidase IV as an active component in manufacturing a medicinal agent, and in a method for treatment of diabetes mellitus. Invention provides enhancing the functional activity of insulin-producing cells in animal and differentiation of epithelial cells of the pancreas.
EFFECT: improved method for insulin producing and diabetes treatment.
20 cl, 5 dwg, 2 tbl, 2 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.
EFFECT: improved and valuable properties of composition.
10 cl, 4 tbl, 14 ex
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.
EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.
12 cl, 2 dwg, 32 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.
EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.
22 cl, 8 tbl, 453 ex
SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.
EFFECT: enhanced effectiveness of treatment.
6 cl, 11 dwg, 2 tbl
FIELD: organic chemistry.
SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.
EFFECT: polymorphous crystalline forms of high stability.
12 cl, 1 tbl, 13 dwg, 5 ex