Derivatives of n-desacetylthiocolchicine and pharmaceutical compositions comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of N-desacetylthiocolchicine of the formula (I):

wherein n represents a whole number from 0 to 8; Y represents group CH2 or if n = 1 then can mean group NH also. These compounds elicit an anti-proliferative activity. Also, invention describes pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of derivatives.

4 cl, 1 tbl, 4 ex

 

This invention relates to derivatives of N-diacetylhydrazine or their isosteres formula (I)

where:

n represents an integer from 0 to 8;

Y is CH2group or, if n is 1, can also be a NH group.

Colchicine and thiocolchicine are known to prevent the growth of connections that can destabilize the microchannels due to interaction with tubulin.

Colchicine currently used in the treatment of gout and related inflammatory diseases, but its application is limited to the acute phase because of its superior gastrointestinal toxicity.

Studied a large number of derivatives of colchicine and thiocolchicine from the point of view of their potential use as anticancer drugs, but research attempts have so far been unsuccessful due to the very limited therapeutic indices such compounds.

Only one derivative of colchicine, demecolcine, used in the past in the clinic for the treatment of leukemia, but with poor success.

Found that the compounds of formula (I) exert an antiproliferative effect, in particular, in cells expressing the phenotype of MRD (resistance to many drugs), with an approximate activity against sensitive cells to activity resistant cleto is equal to 1:1.

Compounds of the invention actually have a strong antimitoticheskoy activity and are characterized by a favorable therapeutic index, which makes them suitable for therapeutic treatment of various forms of tumors, and degenerative rheumatoid arthritis, a disease characterized by excessive proliferation and abnormal leukocyte migration.

The compound (I) has cytotoxicity comparable to that of the most effective anticancer drugs, at the same time having a much wider range of actions, in particular, against cells that are resistant to known drugs.

The compound (I), where Y is CH2receive by reaction of N-diacetylhydrazine with reactive derivatives of dicarboxylic acids in dry solvents. Examples of suitable reactive derivatives of dicarboxylic acids are the anhydrides, reactive anhydrides or esters, in particular diesters of N-hydroxyethanoic acid obtained by the reaction of the specified acid with N-hydroxysuccinimide. The reaction is preferably carried out in solvents, such as ethyl ether, dioxane or tetrahydrofuran, in the presence of a base, such as triethylamine.

On the other hand, the compound (I), where Y is NH and n is 1, can be obtained reactie the N-diacetylhydrazine with N-hydroxysuccinimide in the presence of amines and condensing agents, such as dicyclohexylcarbodiimide (DCGK), in a suitable aprotic solvent, preferably chlorinated hydrocarbons (methylene chloride, chloroform). These compounds can also be obtained as by-products from the reaction between N-hydroxysuccinimide the diesters of dicarboxylic acids and N-diacetylhydrazine.

The activity of these compounds was evaluated on a wide range of resistant tumor cells expressing the phenotype of MRD; these compounds, in particular, has shown activity in a variety of sensitive (cell) lines bowel expressing MRD.

The following table includes examples of the activity of these two compounds, in comparison with the biological activity of thiocolchicine and Taxol, taken as comparative compounds.

Cytotoxic activity was evaluated according ..Alley and others, Cfncer Research, 48, 589-601, 1998.

The above data indicate a high cytotoxic activity of the compounds of the invention with respect to both cell lines and different resistance of cell lines to various anticancer drugs.

Thus, the compounds of the invention are applicable for the treatment of proliferative pathologies and, in particular, tumors of various organs, rheumatoid arthritis or other degenerative pathologies, which shows antiproliferative and anti-inflammatory action.

For this purpose, the compound (I) is administered in the form of pharmaceutical compositions suitable for oral, parenteral, subcutaneous or intradermal injection. Doses of the compounds (I) are in the range from 1 to 100 mg/m2square body, depending on route of administration. The compounds are preferably administered orally.

Examples of compositions include capsules, tablets, capsules, creams, solutions, granulates.

The following examples illustrate in more detail the invention.

EXAMPLE 1

Obtaining the compounds (I), where Y is CH2and n is equal to 2 (Thiokol 39)

100 mg of N-diacetylhydrazine (malves=373 g/mol, a 0.27 mmole) dissolved in 6 ml of dioxane at room temperature in a nitrogen atmosphere. Added 46 mg enabled the adipic acid in the form of N-hydroxysuccinimide diapir (malves=340 g/mol, is 0.135 mmole) and 40 ml of dry triethylamine (malves=101 g/mol, d=0,726 g/ml of 0.27 mmole). The mixture is stirred at room temperature under nitrogen atmosphere for 48 hours (TLC control: l3:Meon=95:5). The solvent is evaporated and the product emit flash chromatography on silica (eluent: l3:Meon=75:1).

Yield: 85%

EXAMPLE 2

Obtaining the compound (I), where Y is NH and n is equal to 1 (Thiokol 54)

A solution of 1 g of diacetylhydrazine in 40 ml of dry CH2CL2combine with 154 mg of N-hydroxysuccinimide, 276 mg DCGK and 476 μl of diisopropylethylamine. The mixture is refluxed under nitrogen for at least 2 days. The progress of the reaction is controlled TLC (CH2Cl2-EtOH=95/5). The mixture is concentrated to small volume and the residue extracted with ethyl acetate. The product is left to crystallize, then purified flash chromatography (eluent AcOEt-hexane 7/3 or CH2Cl2-EtOH=95/5). Receive 500 mg of product.

1H-NMR (DMSO-d6-300 MHz): 8,80 d; 7,82 Sirs; 7,75-7,60; 7,37; 7,18; 6,59% 4,66 m; to 4.52 DD; 3,96 with CNM

13C-NMR (CDCl3): 182,5; 181,9; 172,2; 158,0; 175,5; 157,1; 153,8; 153,7; 153; 152,3; 151,3; 151,2; 141,6; 141,5; 139,4; 139,3; 135,5; 135,5 d, 134,8; 134,7; 129,0; 128,4 (d).

Mass spectrum (m/z) 866,4 [(M+Na)+]

EXAMPLE 3

Obtaining the compounds (1)where Y represents CH2and n = 6 (Thiokol 33)

200 mg of N-diacetylhydrazine (mol. weight 373 g/mol, 0.54 mmole) was dissolved in 12 ml of dry dioxane etc the room temperature in nitrogen atmosphere. Add to 91.8 mg activated sabatinovka acid in the form of N-hydroxysuccinimide diapir (malves=396 g/mol, a 0.27 mmole) and 75 μl of dry triethylamine (malves=101 g/mol, d=0,726 g/ml, 0.54 mmole). The mixture is stirred at room temperature under nitrogen atmosphere for 48 hours (TLC control: l3:Meon=95:5), then after 20 hours, heated to 50°and the solvent evaporated. The crude reaction product is purified flash chromatography on silica (eluent: l3:Meon=40:1)to give 30 mg of the mixture of target compound (Rf:=0.3) and the compound of example 2.

EXAMPLE 4

Obtaining the compound (I), where Y is CH2and n is 0 (Thiokol 43)

Method And

190 mg of N-diacetylhydrazine (malves=373 g/mol, 0,512 mmole) dissolved in 6 ml of dry dioxane at room temperature in a nitrogen atmosphere. Add 80 mg of activated succinic acid in the form of N-hydroxysuccinimide diapir (malves=312 g/mol, 0,256 mmole) and 70 μl of dry triethylamine (malves=101 g/mol, d=0,726 g/ml, 0,512 mmole). The mixture is stirred at room temperature under nitrogen atmosphere for 48 hours (TLC control: l3:Meon=95:5). The solvent is evaporated, the residue is extracted AcOEt to remove residual N-diacetylhydrazine and triethylamine (insoluble product).

Exit 45%

Method In

100 mg of N-deazetil-N-succinyl-thiocolchicine (malves=473 g/mol, of 0.21 mmole) is dissolved in 8 ml of dry CH 2CL2at room temperature in a nitrogen atmosphere. Added 93 mg THIEF [hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)-phosphonium (malves=442,3 g/mol, of 0.21 mmole) and 60 μl of dry triethylamine (malves=101 g/mol, d=0,726 g/ml, at 0.42 mmole). After 10 minutes, 80 mg of N-diacetylhydrazine (malves=101 g/mol, d=0,726 g/ml, at 0.42 mmole) was added to the mixture, which was stirred at room temperature for 48 hours (TLC control: CHCl3:MeOH=95:5), the solvent evaporated and the residue extracted AcOEt to remove residual N-diacetylhydrazine and triethylamine (insoluble product).

Yield: 45%

1. The compounds of formula (I)

where: n represents an integer from 0 to 8;

Y is CH2group or, if n is 1, can also be a NH group.

2. Compounds according to claim 1, where Y is CH2.

3. Compounds according to claim 1, where Y represents NH.

4. Pharmaceutical composition having anti-proliferative activity containing a compound according to claims 1-3.



 

Same patents:

The invention relates to novel 1,3-disubstituted the ureas of General formula I, having the ability to inhibit the action of the enzyme acyl-COA: cholesterol-acyltransferase, which is responsible for the catalysis of intracellular esterification of cholesterol, and method of production thereof

The invention relates to new derivatives of colchicine that has antiproliferative, antineoplastic, anti-inflammatory and relaxing muscle activity, processes for their preparation and the pharmaceutical ready preparative forms

The invention relates to new derivatives of colchicine with antiproliferative, antitumor and anti-inflammatory activities, methods for their preparation and the pharmaceutical compositions

FIELD: medicine, oncology.

SUBSTANCE: the method deals with applying chemopreparations incubated with autolymph and radiation therapy. Lymph taken out of patient's thoracic duct should be centrifuged for 30 min at 2200 rot./min, lymphatic plasma should be taken and frozen at -40 C, lymphatic formic elements should be incubated in a thermostat at 37 C for 1 h together with chemopreparations by a certain scheme to be reinfused for a patient intravenously by drops according to the given scheme. Then, 2 wk later, one should perform therapy with a split course of distance gammatherapy at single focal dosage (SFD) of 4 Gy. At the first stage one should apply per 2 Gy twice daily at 4-5-h-long interval 5 times weekly, at achieving focal dosage of 28 Gy it is necessary to have a week-long interval. Then radiation therapy should be continued but SFD of 4 Gy should be applied at once. One should fulfill 3 fractions of irradiation per a week, there are 6 fractions during the second stage, totally. Total focal dosage (TFD) per the whole course of irradiation corresponds to 52 Gy. About 4 wk after radiation therapy one should defrost lymphatic plasma to incubate it with the same chemopreparations in a thermostat at 37 C for 1 h to be then reinfused for a patient intravenously by drops. The method enables to decrease tumor volume and tumor process metastasing without any operative interference.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, oncourology.

SUBSTANCE: the present innovation deals with treating locally spread tumor diseases of urinary bladder due to applying either chemo- and/or radiation therapy. Moreover, one should intravenously once inject by drops autologous mesenchymal stem cells (AMSC) at the quantity of 1 mln cells/kg patient's body weight. Moreover, in case of chemotherapy AMSC should be injected during the period before the 20-th d after the last injection of chemopreparation, in case of radiation therapy - 12-15 d against the day of irradiation. In case of chemoradiation therapy AMSC should be injected after chemotherapy before the course of radiation therapy. This method enables to carry out chemoradiation therapy in patients with severe accompanying diseases that prevent such a therapy, and prevent the development of general toxic complications of chemoradiation therapy and medicinal and radiation-caused cystitis.

EFFECT: higher efficiency of therapy.

3 ex, 2 tbl

FIELD: medicine, oncology.

SUBSTANCE: in pre-operational period patient's lymph taken out of thoracic duct should be centrifuged for 30 min at 2200 rot./min, lymphatic plasma should be taken and frozen, lymphatic formic elements should be incubated with chemopreparations in a thermostat at 37 C for 1 h to be reinfused for a patient intravenously, by drops, by performing 5 such procedures. In 2 wk one should conduct operative interference, 4 wk after operation lymphatic plasma should be defrosted to incubate it with chemopreparations in a thermostat at 37 C for 1 h to be reinfused for a patient intravenously, by drops, by performing 4 such procedures. The method provides increased anti-tumor activity of chemopreparations, activation of antioxidant factors in the cells of immunocompetent system and, also, inspecific stimulation of immunity in patients with antigens of defrosted and chemopreparation-treated lymphatic plasma.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising benzamide derivative represented by the formula (1)

or its pharmaceutically acceptable salt and one or more substances taken among D-mannitol, carboxymethylstarch sodium, hydroxypropylcellulose, magnesium stearate, partially gelatinized starch, hydroxypropylmethylcellulose, dimethylacetamide, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrocarbonate, potassium hydrocarbonate, sodium hydroxide, sodium hydrogen phosphate, ammonium, monosubstituted sodium fumarate, sodium dehydroacetate, sodium erythorbate, trisubstituted sodium citrate and amine. The composition elicits the enhanced stability.

EFFECT: improved and valuable pharmaceutical properties of composition.

5 cl, 8 tbl, 6 ex

Medicinal agent // 2257200

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent eliciting with the anti-tumor and immunomodulating effect. Agent comprises tetramethyl, pentamethyl or hexamethyl derivative of tri-p-aminotriphenylchloromethane or their mixture with dextrin. Agent elicits enhanced activity and reduced adverse effect.

EFFECT: valuable medicinal properties of agent.

13 cl, 1 tbl, 11 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention relates to a method for treatment of pathology or disorder taken among inflammatory diseases. Method involves using the simultaneous, separating or distributed by time at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2. Also, invention relates to the composition comprising at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2 for using in the method for treatment of pathology or disorder taken among inflammatory diseases.

EFFECT: improved method for treatment.

21 cl, 4 ex

FIELD: medical engineering.

SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.

EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.

3 cl

FIELD: medicine, oncology, chemical-pharmaceutical industry and technology, pharmacy.

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EFFECT: improved for making tablet, valuable medicinal properties of tablet.

7 cl, 4 ex

Substituted indoles // 2255087

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to new substituted indoles of the formula (I): and/or stereoisometic form of compound of the formula (I) and/or physiologically acceptable salt of compound of the formula (I) wherein R3 means residue of the formula (II): wherein D means -C(O)-; R7 means hydrogen atom (H) or -(C1-C4)-alkyl; R8 means (a) typical residue of amino acid among the group: phenylalanine or homophenylalanine wherein phenyl residue is unsubstituted or substituted with halogen atom; or (b) -(C1-C4)-alkyl wherein alkyl is a linear or branched and (b) 1) mono- or multi-substituted independently of one another with pyrrole residue wherein this residue is unsubstituted or substituted with halogen atom; (b) 2) mono- or bi-substituted independently with residue -S(O)x-R10 wherein x = 0, 1 or 2, or (b) 3) mono- or bi-substituted independently of one another -N(R10)2 wherein R10 means (a) hydrogen atom (H); (b) means -(C1-C6)-alkyl wherein alkyl is unsubstituted or substituted with halogen atom from 1 to 3 times; (c) phenyl wherein phenyl is substituted or substituted with halogen atom from 1 to 3 times; in the case (R10)2 residues R10 have values independently of one another (a), (b), (c); Z means (a) residue of heterocycles group comprising benzothiadizine, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, oxadiazolone, triazole being heterocycles are unsubstituted or substituted with -NH2=, =O, alkoxycarbonyl or aminocarbonyl from 1 to 3 times, or (b) means -C(O)-R11 wherein R11 means 1. -O-R10 or 2. -N(R10)2; R9 means (a) hydrogen atom (H); (b) means (C1-C6)-alkyl wherein alkyl is unbranched or branched and substituted with phenyl or =O independently of one another from 1 to 3 times; (c) phenyl wherein phenyl is unsubstituted or substituted with halogen atom; R1, R2 and R4 mean hydrogen atom (H); R5 means hydrogen atom (H); R6 means (a) phenyl wherein phenyl is unsubstituted or substituted with -NH2; (b) pyridine, or (c) pyrimidine being pyridine or pyrimidine is unsubstituted or substituted with groups -NH2, -NH-CH3. Compounds of the formula (I) are specific inhibitors of IkB kinase.

EFFECT: valuable biochemical properties of compounds.

3 cl, 3 tbl, 29 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the solid medicinal formulation comprising chondroitin sulfate. The proposed medicinal formulation comprises 250 mg of chondroitin sulfate as an active component, filling agent, binding agent, antifriction substances and can comprise a solubilizing agent additionally. Pharmaceutical composition is made as a tablet. Invention provides development of the preparation for oral administration with the less amount of active substance and with indices satisfying requirements of the State Pharmacopoeia.

EFFECT: improved and valuable properties of formulation.

8 cl, 16 tbl, 39 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

EFFECT: improved method for preparing and treatment, valuable medicinal properties of compounds.

13 cl, 88 ex

FIELD: medicine.

SUBSTANCE: method involves applying napkin impregnated with medicament to an injured articulation area. The medicament contains hydrocortisone acetate in the amount of 0.4mg/cm2, dimexide - 1.4 mg/cm2 and sodium alginate - 4.1 mg/cm2. The napkins are applied to internal and external side of the articulation for 6 days, changing them in three days.

EFFECT: accelerated treatment course.

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.

EFFECT: higher efficiency of application.

11 cl, 2 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

Up!
ConnectionIC50nm
 MCF7MCF7-ADRrMCF7-ADRr/MCF7
Thiokol 39 (example 1)12433, 58
Thiokol 43 (example 4)21361,71
Thiokol 54 (example 2)2,62,81,07
Thiocolchicine0,0240020000