Oncologic sensibiliser which contains glucosamine, glucosamine derivatives or their salts
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine and pharmacology and represents oncologic sensibiliser, which contains compound, selected from glucosamine, glucosamine derivative, represented by formula 2.
EFFECT: reduction of chemoresistance of cancer cells.
4 cl, 4 ex, 3 dwg
The technical field to which the invention relates
The present invention relates to a cancer sensitizer containing glucosamine, a derivative of glucosamine or their salts, and more specifically to the use of glucosamine, a derivative of glucosamine or their salts as a cancer sensitizer, which can make cancer cells sensitive to anticancer agents and to reduce the resistance of cancer cells to anticancer agents, thereby increasing therapeutic effect of anticancer agents.
The level of technology
Despite their large number, anticancer agents have been developed so far, can heal completely only a few types of cancer. The reason why most cancers cannot be cured completely, is that the cancer is resistant to anti-cancer agents, or that the tumor is reduced in size in the early stages of chemotherapy, but become resistant to anticancer agents during chemotherapy or after it. For effective treatment of cancer using anti-cancer agents, therefore, must be overcome chemoresistance, i.e. the resistance of cancer cells to the chemicals.
Glucosamine is a major component of chitin, a structural polysaccharide that is found in most of the quantities in the exoskeletons of crustaceans, such as sea shell crabs and shrimp, and is safe for the body. Thus, attempts have been made use of glucosamine in cosmetic compositions (patent application Korea No. 10-2005-7014642 and for development of therapeutic drugs against arthritis (patent application Korea No. 10-2005-009182 and 10-2004-0057849). However, in the present invention is first described that, when anti-cancer agents are introduced together with glucosamine, increased susceptibility of cancer cells to anticancer agents and thus glucosamine can be used as a cancer sensitizer.
Leading to the present invention, intensive and thorough research in the field of effective chemotherapy, performed by the authors of the present invention, resulted in the discovery of what is glucosamine or its derivatives may reduce chemoresistant cancer cells.
Description of the invention
For this reason, the aim of the present invention is the establishment of a cancer sensitizer containing glucosamine, its derivative or its salt.
Another objective of the present invention is a method of destruction of chemoresistant cancer cells, including the introduction of glucosamine, a derivative of glucosamine or their salts.
In addition, the present invention which is to provide a composition for inhibiting chemoresistant cancer cells, contains glucosamine, a derivative of glucosamine or its salt in combination with a pharmaceutically acceptable carrier.
In addition, another purpose of this invention is to provide an anticancer composition, which can inhibit chemoresistant cancer cells containing composition for lowering chemoresistance and at least one anticancer agent.
Brief description of drawings
The above and other objectives, features and other advantages of the present invention will be understood more clearly from the following further detailed description, taken in conjunction with the attached drawings, on which:
Figure 1 is a graph showing the cytotoxicity of the anticancer agent on chemoresistant cell line MCF/DOX in the presence of glucosamine;
Figure 2 is a graph showing the cytotoxicity of the anticancer agent on chemoresistant cell line MDA231 in the presence of glucosamine; and
Figure 3 shows the effect of glucosamine on the activity of NF-ΚB and degradation of I-κBα in cells MCF7/DOX and MDA231.
The best way of carrying out the invention
In accordance with one of its aspects the present invention relates to a cancer sensitizer containing glucosamine, a derivative of glucosamine or its salt.
As here used, the term is h "cancer sensitization", as expected, has the same meaning as "chemical sensitization", including the impact of chemotherapy to improve or enhance the cytotoxicity of anticancer agents on cancer cells in the presence rather than absence of a cancer sensitizer, i.e. the effect of lowering the resistance of cancer cells to chemical agents, such as chemoresistance, using a cancer sensitizer to enhance therapeutic effects of anticancer agents. In the present invention glucosamine glucosamine or derivative function, making the cancer cells sensitive to anticancer agents, and reduce the resistance of cancer cells to anticancer agents, thereby increasing therapeutic effect of anticancer agents. For this reason, the term "cancer sensitization" is used here as having a value equivalent to "chemical sensitization".
The term "chemoresistance", as here used, means that the anti-cancer drug, when injected, can't destroy cancer cells or can regulate cancer cells only to a small extent, mainly because of the resistance of cancer cells to chemical medicines. In General, the term "resistance to chemical drug substances is am", as expected, means that when patients, cancer patients treated with anticancer drugs, therapeutic effects of no, or therapeutic effect of anti-cancer drugs, although it is high in the early stages of chemotherapy, increasingly attenuated with continued treatment. In this field it is well known that therapeutic effects of anticancer drugs gradually decreases with the increase of the number of introductions. Chemoresistance attributed to the emergence of resistant to medicines cells.
Glucosamine is a major component of chitin, a structural polysaccharide found in large quantities in the exoskeletons of crustaceans, such as shells of marine crabs and shrimp. Together with chitin chitosan is a main structural component of the exoskeleton. Chitin is a polymer consisting of 2-acetamido-2-deoxy-β-D-glucose (N-acetylglucosamine), and chitosan is a poly(β-(1,4)-glucosamine), a polysaccharide, which can be obtained by deacetylation of chitin. Glucosamine has a structure represented by the following further chemical formula 1.
Chemical formula 1
As used here, the term "produced in the water-glucosamine", as expected, refers to the glucosamine with acyl or alkyl residue, replacement of the hydrogen of the hydroxyl group, as represented by the following further chemical formula 2.
Chemical formula 2
where R represents a C2-C18 acyl or C1-C5 alkyl straight or branched chain. Preferably, R is selected from acyl group consisting of acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, Laurila, tridecanol, myristyl, pentadecanol, Palmitoyl, Margarita and stearyl, or from alkyl groups comprising methyl, ethyl, propyl, butyl, penttila, isopropyl, isobutyl and sec-butyl.
As described above, the introduction of hydrophobic groups in the group of alcohols glucosamine in positions 1, 3, 4, and 6 without change in the amine group, which is assumed to be responsible for the physiological activity of glucosamine, results derived glucosamine, which are well decomposed in a natural way, are non-toxic, well adsorb heavy metals and are strong inhibitors for bacteria, at the same time keeping their own physiological activity.
Found that, when an anti-cancer agent is injected in combination with glucosamine, cancer cells that are on the show chemoresistance, induced that they were subjected to apoptosis in two times more often than when he introduces himself, as seen in figures 1 and 2. These results demonstrate that glucosamine and its derivatives carry out cancer sensitization.
Incomprehensible essentially the mechanism of cancer sensitization of glucosamine and its derivatives presumably attributed to the inhibitory activity against the enzyme or enzymes that play a critical role in the exacerbation of cancer. That is, it is assumed that glucosamine or its derivatives inhibit the enzymatic activity responsible for the malignancy of a cancer, reducing the factors that play a role in chemoresistance, thereby making the cancer cells susceptible to anticancer drugs.
Not imposed specific limitations on the type of cancer for which glucosamine or derivative of glucosamine can be used as a cancer sensitizer. That is glucosamine or a derivative of glucosamine can be effectively used for the treatment of cancer regardless of the type of cancer. For this reason, the type of cancer, which can be used a composition comprising an anticancer drug and glucosamine or its derivative or salt in accordance with the present invention, depends on protivorechu the CSOs medicines. For example, glucosamine, a derivative of glucosamine or their salts can be used as a cancer sensitizer in combination with cisplatin for the treatment of testicular cancer, ovarian cancer, lung cancer, head and neck cancer, tumors of the cervical spinal cord, neuroblastoma, osteosarcoma, and the like in combination with doxorubicin for the treatment of breast cancer, endometrial cancer, head and neck cancer, Ewing sarcoma, osteosarcoma, leukemia and the like in combination with etoposide for the treatment of lung cancer, testicle cancer, osteosarcoma, leukemia, neuroblastoma, and the like.
In the composition of the present invention glucosamine glucosamine or derivative may be in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts, useful in the present invention include sulfates, hydrochlorate, acetates, citrates and maleate glucosamine or derivative of glucosamine, but without limitation. Preferred are sulfate glucosamine or derivative of glucosamine.
In an additional embodiment of the present invention the composition may further contain an antioxidant to maintain the stability of the pharmaceutically acceptable salts of glucosamine or derivative of glucosamine and to prevent oxidation of the amino group or the pharmaceutically priemlemaya metal, preferably sodium or potassium and glucosamine or derivative of glucosamine.
In accordance with another aspect of the present invention relates to pharmaceutical compositions for the inhibition of chemoresistance (increase chemical sensitization), which contains glucosamine, a derivative of glucosamine or its salt and a pharmaceutically acceptable carrier. This composition may be prepared with a carrier in the form of dosage forms. Examples of oral dosage forms suitable for pharmaceutical compositions of the present invention include tablets, lozenges, pellets, water or emulsifiable suspension, powder, granules, emulsions, hard or soft capsules, syrups and elixirs, but without limitation. Suitable for preparation of tablets or capsules pharmaceutical compositions in accordance with the present invention comprise a binder, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin, an excipient such as dicalcium phosphate, baking powder, such as corn starch or starch of sweet potato, and a lubricating substance, such as magnesium stearate, calcium stearate, sodium stearyl fumarate or waxes of polyethylene glycol, by themselves or in combination. For capsules liquid media, such as a lipid, can complement what Ino be used in addition to the above compounds.
For refererlog introduction pharmaceutical composition comprising glucosamine or derivative of glucosamine in accordance with the present invention can be prepared by injection for intravenous or intramuscular route of administration, suppositories or aerosols inhaled through the respiratory tract, such as aerosols. Preparations for injection can be obtained by dissolving or suspension of glucosamine or its derivative with a stabilizer or buffer in water and packaging solution or suspension in a standard single ampoules or vials. Suppositories, usually made of a base for suppository, such as cocoa butter or other glycerides, or therapeutic laxative, which dilute the active substance, i.e. glucosamine or its derivative. For sprays, such as aerosol propellant for spraying dispersed in water concentrate or wettable powder can be used in combination with the additive.
In accordance with an additional aspect of the present invention relates to an anticancer composition containing an anti-cancer agent and a pharmaceutical composition. The term "anticancer agent" or "anti-cancer drug", as used here, is intended for reference chemicals, the cat is PoE can destroy cancer cells. Most anticancer agents or drugs play a critical role in blocking and replication, transcription and/or translation of the DNA in cancer cells. View anticancer agent or drug that can be used in the compositions of the present invention is not in any way limited. Anti-cancer agents or treatments can be selected by standard considerations, such as type of cancer cells, the absorption rate of a drug (the period of time of treatment and method of administration), the position and size of tumors and the like. For example, anticancer agents suitable for use in the present invention, can be an agent for alkylation of DNA, such as mechlorethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustin (CCNU), streptozotocin, busulfan, thiotepa, cisplatin and carboplatin. Anticancer antibiotics are also used in the present invention, such as dactinomycin (actinomycin D), doxorubicin, mitoxantrone, plicamycin, mitomycin and bleomycin C. Examples of plant alkaloids as anticancer agents or drugs suitable for use in the present invention include vincristine, vinblastine, paclitaxel, docetaxel, etoposide, is iniposed, topotecan and irinotecan. However, anti-cancer agents or treatments, suitable for use in the present invention are not limited to the above compounds.
In accordance with another aspect of the present invention relates to a method of increasing the sensitivity of cancer cells to anticancer drugs through the introduction of a cancer sensitizer containing glucosamine, a derivative of glucosamine or its salt.
The term "introduction", as used here, is intended to mention the introduction of the cancer sensitizer of the present invention to patients with cancer in an appropriate way. Insofar as he leads the cancer sensitizer to the desired tissue, may be adopted any method of administration. For example, the introduction of the cancer sensitizer may be used for oral, intraperitoneal, intravenous, intramuscular, percutaneous, subcutaneous, intranasal, intrapulmonary, rectal, intrathecal and/or an intradural ways, but is not limited to this. Cancer sensitizer in accordance with the present invention may be administered simultaneously with the anti-cancer agent or drug or separately from it. In the latter case, cancer sensibilized the R can be entered at set intervals of time before or after administration of an anticancer agent. Preferably, the cancer sensitizer can be entered after anticancer agents. Cancer sensitizer of the present invention may be administered once a day, or two, or three times a day at set intervals.
When considering various factors, including types of cancer, methods of administration, therapeutic effects and chemical sensitization, cancer sensitizer or anticancer composition in accordance with the present invention can be administered accordingly.
A better understanding of the present invention may be obtained through the following examples which are given for illustration, but should not be construed as limitations of the present invention.
Example 1: Preparation of cells resistant to anticancer drug, and their culture
Line of breast cancer cells human MDA-231 (resistant to doxorubicin) purchased from ATCC. MCF-7/DOX (resistant to doxorubicin) obtained from the Dr. Kenneth H. Cowan (University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA). These lines of support cells in media supplemented with 10% fetal calf serum (Gibco BRL), 1 mm sodium pyruvate (Gibco BRL) and 100 units/ml penicillin-streptomycin (Gibco BRL) at 37°C in a humid atmosphere with 5% CO2and subcultured every two or three days.
Example 2: Analysis of citato is lichnosti
Analysis using MTT carried out by colorimetric analysis when restoring a yellow salt of tetrazole to purple formazan in the mitochondria of viable cells. Cells were seeded at a population of 1×105cells/well in 24-hole plates. After incubation for 24 hours, the cells exhibit for doxorubicin. This anticancer agent is administered at a dose of 90 μm for MCF 7/DOX and 5 μm for MDA 231. The control not treated with doxorubicin. On the day of analysis the culture medium in each well is replaced with fresh medium containing MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) (Sigma) at a concentration of 0.5 mg per ml, followed by incubation for an additional 4 hours. After removal of the medium add 500 ál of DMSO to each well, and the crystals formazan dissolved using an orbital shaker. Cell survival is presented as a percentage of the treatment group relative to the control. These experiments are carried out for three samples and repeat at least three times. For each experiment is the average of three independent experiments and standard deviations.
Example 3: Effect of glucosamine on the sensitivity to anticancer agent
Analysis using MTT carried out to investigate whether increases whether glucosamine susceptibility of breast cancer cells the anti-cancer agents. Cell line MCF 7/DOX and MDA 231 are both resistant to anticancer agents, is treated with doxorubicin and glucosamine (1,0-10 mm) for 24 hours.
Controls not treated with glucosamine, while doxorubicin is administered at concentrations of 5 μm for MDA-MB 231 and at concentrations of 90 μm for MCF-7/DOX.
As measured by analysis using MTT, almost all of MCF 7 and MDA 468, they are both susceptible to anti-cancer agent, perish, while apoptosis occurs in approximately 50% of cell lines resistant to anti-cancer agents. When processing glucosamine cell line MCF 7/DOX and MDA 231 become two times (more than twice = two times) more sensitive to doxorubicin than without treatment with glucosamine.
Example 4: Effect of glucosamine on the activity of NF-κB and I-κBα
Cell line MCF7/DOX and MDA231 cultured in media supplemented with 10% fetal calf serum (Gibco BRL), 1 mm sodium pyruvate (Gibco BRL) and 100 units/ml penicillin-streptomycin (Gibco BRL) at 37°C in a humid atmosphere with 5% CO2. Vector pNF-κB-SEAP transferout in cells. After 24 hours of transliterowany cells cultured in the presence or in the absence of glucosamine (represented GM, 5 mm) for 24 hours. Culture of cells subjected to analysis of SEAP, and cells after harvestore subjected to analysis of β-galactosidase. The values obtained during the analysis of SEAP, correcter the Ute for efficiency transliterowany using plasmids pGAL (1 µg). The activity of β-galactosidase is measured to correct the activity of SEAP. The SEAP analysis is carried out in accordance with the procedure described by the manufacturer (BD Biosciences Clontech, Co.). As found, MCF7/DOX and MDA231 have a high percentage of expression TG 2. The results of this analysis are shown in Figa. These experiments carried out on three samples and repeat at least three times. Values for each experiment represent the average from three independent experiments and standard deviations.
Glucosamine analyze its impact on the degradation of I-κBα. For this, cells MCF7/DOX and MDA231 cultured for 1 hour and fractions of the cytoplasm harvested for Western blotting against I-κBα. The results of the Western blot shown in the top panel Figv. Western blotting determined quantitatively using a densitometer, and the results are shown in the bottom panel in figure 3B. For each of the values are the average of three independent experiments and standard deviations.
The introduction of glucosamine, as is clear from the data in figures 3, causes cancer cell line human breast (MDA-231, MCF-7/DOX) to reduce the activity of NF-κB and increase the level of I-κBα, and it shows that chemoresistant cell line susceptible respond to anticancer agents at the moment of death, when glucosamine induces a decrease in the asset the spine of NF-κB (figures 2 and 3).
As described previously, glucosamine, a naturally occurring, harmless material, or a derivative of glucosamine can be used as a cancer sensitizer, which makes cancer cells highly susceptible to anticancer agents without providing specific side effects, in contrast to conventional chemical sensitizers.
Although preferred embodiments of the present invention is described for illustrative purposes, the experts in this field will recognize that various modifications, additions and substitutions, without deviating from the scope and spirit of the present invention, as described in the accompanying claims.
1. Cancer sensitizer containing compound selected from glucosamine, a derivative of glucosamine, represented by the following formula 2:
or their salts, where the cancer sensitizer inhibits chemoresistant cancer cells, and
where R represents an acyl group having 2-18 carbon atoms, or alkyl group with straight or branched chain having 1-5 carbon atoms.
2. Composition for inhibiting chemoresistance containing compound selected from glucosamine, a derivative of glucosamine, presents trail of the overall formula 2:
or their salts, and pharmaceutically acceptable carrier, and where R is an acyl group having 2-18 carbon atoms, or alkyl group with straight or branched chain having 1-5 carbon atoms.
3. Anticancer composition comprising the composition according to claim 2 and an anti-cancer agent, where an anti-cancer agent selected from the group consisting of mechlorethamine, hlorambuzila, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustina (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubitsina, mitoxantrone, plicamycin, mitomycin, bleomycin, vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and irinotecan.
4. Method of reducing chemoresistance, including the introduction of a cancer sensitizer according to claim 1 or a composition according to claim 2.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine, namely to oncology, and can be used for determining efficiency of treatment of uterine body cancer. Method includes determination of cortisol and tetrahydro-11-deoxycortisol level in day urine 1.5-2 weeks after finishing treatment. Coefficient of ratio of tetrahydro-11-deoxycortisol to cortisol is determined; if ratio value is lower than two, duration of recurrence-free period 5 or more years is predicted, and if ratio is higher than two - development of recurrence in the nearest two years.
EFFECT: application of invention makes it possible to select the most efficient preventive therapeutic impact and eliminate additional toxic action of chemical medications.
SUBSTANCE: invention relates to peptides which induce cytotoxic T-cells of general formula ,
where X is a tyrosine residue or methionine residue; each of Y and Z is a single bond; R1 is a hydrogen atom; R2 is a hydroxyl; R3 is hydrogen, amino, C1-6alkylcarbonylamino substituted with 1-2 substitutes selected from a group comprising carboxy and amino; R4 is a carboxy or a group of formula , where W is an amino acid residue; m equals 1 and n equals an integer from 0 to 1, provided that when n equals 0, R3 is hydrogen; pharmaceutically acceptable salts thereof, and use thereof in cancer immunotherapy.
EFFECT: more effective use of the compounds.
17 cl, 9 dwg, 2 tbl, 7 ex
SUBSTANCE: invention relates to derivatives with anticancer activity of formulae:
, , , , ,
R2', R3', R4', R5' and R6' are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9; Y is selected from O and S; X is selected from F, Cl and Br; R8 and R9 are selected from (CH2)nCH3; R2, R3, R4 and R5 are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9, or R3 and R4 together form -Y(CH2)nY-; R1 and R1' are selected from H, Li+, Na+, K+, N+R8R9R10R11 or benzyl, where R10 and R11 are selected from H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, where n and m are integers from 0 to 4, q is an integer from 1 to 4.
EFFECT: obtaining novel compounds with anticancer activity.
37 cl, 3 dwg, 10 ex, 2 tbl
SUBSTANCE: disclosed agent is a xanthine derivative of formula 1
, where R1 denotes CH3, R2 denotes CH3; R3 denotes halogens: F,Cl, Br, I; R4 denotes hydrogen; R1 denotes CH3, R2 denotes CH3; R3 denotes hydrogen, halogens: F, Cl, Br, I; R4 denotes CH2COOH; R1 denotes hydrogen, R2 denotes CH3; R3 denotes halogens: F, Cl, Br, I; R4 denotes CH3. The preferred compounds of the said agent are 8-chlorotheophylline, 8-bromotheophylline and theophylline-7-acetate. The invention also relates to a method of slowing down proliferation of tumour cells and a method of inducing differentiation in mouse melanoma B16-F10 cells. Each of the methods involves addition of an effective amount of the said agent in an effective amount, preferably in amount of 1 mM.
EFFECT: improved properties of the derivatives.
8 cl, 4 tbl, 12 dwg
SUBSTANCE: invention relates to sulphamate derivatives of benzothiophene of formula or
where R1, R2, R3, m and n assume values given in the claim.
EFFECT: possibility of use in treating oestrogen-dependent diseases.
38 cl, 63 ex, 10 tbl
SUBSTANCE: invention relates to novel compounds of the formula I
, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.
EFFECT: novel compounds which can be used in medicine are obtained and described.
38 cl, 43 ex, 2 tbl
SUBSTANCE: invention relates to novel benzimidazole derivatives of formula
and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.
EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.
30 cl, 379 ex
SUBSTANCE: invention relates to heterocyclic compounds of formula I
, where Y denotes -(C=O)-, X denotes -N(R10)-, A denotes -C(A1)(A2)-, B denotes O, S, -(C=O)- or is characterised by formula
, where D denotes N or CR10, and where the remaining substitutes are described in the claim. Compounds of formula I, as well as composition based on said compounds can inhibit the bcl-2 family proteins.
EFFECT: possibility of using said compounds and compositions in treating or modulating disorders associated with hyper-proliferation, such as cancer.
20 cl, 17 ex
SUBSTANCE: invention relates to novel compounds - arylamidrazone derivatives of formula ,
where R1 is a C2-C8 alkyl group or a C2-C8 alkoxy group, which can be substituted with a halogen or a C1-C8 alkoxy group; a 5-7-member aromatic heterocycle containing 1 or 2 oxygen, nitrogen or sulphur atoms, or phenyl, which can be substituted with a halogen, a C1-C8 alkyl group, a haloC1-C8alkyl group or a C1-C8alkoxy group; or NR4R5; R2 and R3 are identical or different, and each is a hydrogen atom, a halogen atom, a halogenC1-C8alkyl group, a C1-C8alkyl group, a C2-C6alkynyl group, a C1-C8alkoxy group, a cyano group, a C2-C6alkanoyl group or a C1-C8alkylsulphonyl group; A is a benzene, pyridine, quinoline or isoquinoline ring; D is a single bond or methylene; m assumes values from 1 to 3 and n assumes values from 1 to 5, having antagonistic effect on S1P3 receptors, as well as to medicinal agents and pharmaceutical compositions containing such compounds as an active ingredient.
EFFECT: improved properties.
13 cl, 161 ex, 19 tbl
SUBSTANCE: invention refers to medicine, oncology, and can be used for treating rectal cancer. That is ensured by an intramuscular introduction of ingaron 500000-1000000 IU ml for 5-10 days to a patient once a day. It is followed with an irradiation procedure in a dynamic dose fractionation mode. The first three coarse irradiation fractions are combined with carboplatin 300-450 mg/m2. Daily during the whole irradiation course, xeloda 500-1500 mg/m2 is introduced as a radio sensitiser.
EFFECT: method allows achieving the manifested regress of a primary tumour, increasing a life span ensured by lower frequency of remote metastases and recurrences, well tolerable by the patients and promotes improving life quality in the inoperable cases.
SUBSTANCE: invention refers to medicine, namely to surgical dentistry and maxillofacial surgery, and aims at treating alveolitis. After local anaesthesia, pharmacological treatment and curettage, an alveolar socket is 2/3 filled with a mixture of the osteoplastic material 'Bialgin' of granule size 1 mm and 30 % lincomycin hydrochloride gel in ratio 1:2, covered with the biologically resorbed membrane 'Collost' and a trapezoid mucoperiosteal flap cut out of a transitory fold of a cheek with its base turned to a buccal wall of the socket so that edges of the flap overlap membrane by 2 mm.
EFFECT: method allows to prevent development of inflammatory complications, atrophy of an alveolar process, to reduce convalescence of patients.
SUBSTANCE: invention relates to pharmacology and medicine. Pharmaceutical composition for reduction of excess sugar levels in blood of type 2 diabetes mellitus patients, containing at least one cyanogenic glycoside from bitter almond kernels as active ingredient.
EFFECT: invention provides for use of natural source in composition for reduction of sugar in blood.
4 cl, 7 ex, 2 tbl, 2 dwg
SUBSTANCE: given invention refers to medicine and concerns a combination for treating an oncological disease, containing as an active ingredient, at least one immunostimulating drug of general formula and one or more chemotherapeutic agents chosen from the group consisting of alkylating agents including carboplatin, cisplatin and oxaliplatin, cytostatic agents chosen from cyclophosphamide and its derivatives, and antimetabolites chosen from fluorouracila and its derivatives, and to a method of treating oncological conditions.
EFFECT: invention provides higher clinical effectiveness.
18 cl, 8 dwg, 5 tbl, 5 ex
SUBSTANCE: for complex treatment of perinatal pointed condylomatosis in outpatient and polyclinic conditions during 10 days peroral introduction of iodantipyrin in dose 200 mg 3 times a day is carried out. Three days after beginning of iodantipyrin introduction bipolar diathermia of perinatal condylomes is performed to healthy tissues, electrodes being applied step-by-step in zigzag order on condyloma circumference. After that in region of operation applied are bandages with solution, containing 200 mg of iodantipyrin and 20 mg of licopid in 200 ml of physiologic solution, or with celandine sap. Bandages are alternated every other day during 14 days.
EFFECT: reduction of disease recurrence, reduces terms of post-operation wound healing and temporary disability.
1 ex, 1 dwg
FIELD: food industry.
SUBSTANCE: invention relates to chemical and pharmaceutical industry and concerns production of sweeteners containing stevioside. Stevioside is mixed with lactose, sodium carboxy-methylcellulose and leucine and produced in form of tabs by direct pressing on rotary tablet press.
EFFECT: obtained tabs of food sweetener have improved stability while storaging.
4 ex, 7 tbl
SUBSTANCE: invention concerns medical products and covers applications of O- and S-glycosides 5-hydroxy-1,4-naphthoquinone (judlone) derivatives of formula 1 as an agent that stimulates human leukaemia cell apoptosis. Disclosed compounds selectively stimulate human leukemia cell apoptosis as comparrf with a prototype juglone without affecting normal cells of human immune system (neutrophils).
EFFECT: invention allows extending range of products selectively stimulating leukaemia cell apoptosis.
4 cl, 13 dwg, 5 tbl, 14 ex
SUBSTANCE: invention relates to the new hem-difluoridated compound of the formula: where R1 represents a group, containing alkyl chain or amino group; R2 represents hydrogen atom, either free or protected functional group of alcohol; R3 represents a group CH2OH, CH2-OGP, where GP respresents protecting group such as alkyl, benzyl (Vp), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetate (Ac); Y, Y', Y" represent independent groups OR, where R represents H, benzyl, Ac, TMS, TBDMS, TBDPS that are used for producing antitumor, antiviral, hypoglycemic and anti-flammatory medicine and compounds for immunology and cosmetology, or glyco peptide analogs of antifreeze molecules. The invention refers particularly also to the new hem-difluoridated compound of the general formula: and to the method of producing new hem-difluoridated compound of the formula: .
EFFECT: compounds possess increased effectiveness.
7 cl, 8 ex, 24 dwg
SUBSTANCE: for treating patients suffering from chronic brucellosis, therapeutic complex includes an antibiotic, as well as Licopid and Tamerite. The preparations are introduced in therapeutic doses.
EFFECT: choice of specific preparations from the group of immunomodulators and antioxidants for specific infections provides long remission and prevention of unfavourable outcome of brucellosis.
3 ex, 3 tbl, 1 dwg
SUBSTANCE: invention relates to medicine, in particular to gastroenterology and cardiology and concerns method of objectifying indications for choosing treatment of patients with ulcer disease (UD) in combination with artery hypertension (AH). For this purpose in accordance with WHO/ISAH classification of 1999, degree of AH and risk of development of cardio-vascular complications (RDCVC) is determined for patients. Patients with UD in combination with AH of I degree and RDCVC of 1-4 degree, as well as patients with UD with AH of II degree and RDCVC of 2 degree undergo traditional anti-ulcer and conventional hypertension therapy. Patients with UD and AH of II degree and RDCVC of 3-4 degree and patients with UD and AH of III degree and RDCVC of 4 degree are examined for presence of immune disorders, intestine disbacteriosis, depressive disorders, sympaticotonia, metabolic syndrome. If said disorders are found immunomodulators, antidepressants, vegetotropic medications are administered and metabolic syndrome therapy is performed, as hypotensive medications ACE inhibitors are introduced. Patients with UD with AH of III degree and RDCVC of 4 degree are administered combined therapy with ACE inhibitors and pulse slowing calcium antagonists, excluding preparations with make QT interval longer.
EFFECT: method ensures individualised treatment of said category of patients taking into account unfavourable development of ulcerous process depending on expression of systemic microcirculation disorders, determined by AH and RDCVC degree, which allows to influence different links of pathologic process fully and prevent development of complications.
8 tbl, 2 ex
SUBSTANCE: invention concerns a pharmaceutical industry, in particular to an agent for improvement of functions of a pancreas. A medical product for improvement of pancreas functions, which contains certain bond. A medical product for improvement of pancreas functions, which contains an extract of a plant of Liliaceae family or its fraction, containing certain bond as an active ingredient. A foodstuff or a drink for improvement of functions of a pancreas which contains certain bond. A foodstuff or a drink for improvement of functions of a pancreas which contains an extract of a plant of family Liliaceae or its fraction containing certain bond as an active ingredient. Application of certain bond, or the extract containing specified bond for manufacture of a medical product for improvement of functions of a pancreas. Method of improvement of functions of a pancreas which includes introduction of certain bond, or the extract containing specified bond, to the subject which functions of a pancreas should be improved.
EFFECT: above described medical product, foodstuff or a drink effectively improve pancreas function.
17 cl, 4 dwg, 3 tbl, 7 ex
FIELD: medicine, therapeutic stomatology.
SUBSTANCE: method involves administration of the medicinal composition into parodontal pockets that is prepared ex tempore and comprising 2 parts of porous hydroxyapatite ceramic with granules size 0.3-0.5 mm, 1 part of zinc oxide powder with addition of 30% solution of lincomycin. Also, method involves coating with fluorolacquer for 12-24 h with treatment course by 6-8 procedures for every day. Method provides effective treatment, prolongation of stable clinical remission being without surgery operation. Invention can be used in treatment of parodontitis of middle severity degree.
EFFECT: improved method of treatment.
7 dwg, 3 ex