Potent conjugates and hydrophilic cross-linking agents (linkers)

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or (I'): Z-X1-(-CH2-CH2-O-)n-Yp-D (I), D-Yp-(-CH2-CH2-O-)n-X1-Z (l'), where: Z is a reactive carboxylic ether selected from a group consisting of N-succinimidyl, N-sulphosuccinimidyl, N-phthalimidyl, N-sulphophthalimidyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-sulpho-4-nitrophenyl, 3-carboxy-4-nitrophenyl and a trifluorophenyl ester, or haloacetamide; D is maytansinoid; X is an aliphatic structural unit; Y is an aliphatic structural unit linked to the maytansinoid through a thioether bond; where said aliphatic structural unit, represented by X or Y, is a simple or branched alkyl group with 1-20 carbon atoms in the chain, a cyclic alkyl group having 3-10 carbon atoms, a simple or branched alkenyl group, having 2-15 carbon atoms in the chain or a simple or branched alkynyl group, having 2-15 carbon atoms in the chain; 1 equals 0 or 1; p equals 0 or 1; and n is an integer from 1 to 2000. The invention also relates to a conjugate of a cell-binding agent, and cytotoxic maytansinoid, where the cell-binding agent is an antibody.

EFFECT: obtaining compounds and conjugates, as well as pharmaceutical compositions based thereon, which can be used in medicine to treat tumours, autoimmune diseases, graft rejection, graft-versus-host disease, viral infections and parasitic infections.

20 cl, 38 dwg, 10 ex

 

The text descriptions are given in facsimile form.

1. The connection is of the formula (1) or (1'):


where Z is a reactive carboxylic ester selected from the group consisting of N-Succinimidyl, N-sulfosuccinimidyl, N-phthalimide, N-sulfofluoride, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-sulfo-4-nitrophenyl, 3-carboxy-4-nitrophenyl and complex ester triterpene or haloacetic;
D represents maytansinoid;
X represents an aliphatic structural unit;
Y represents an aliphatic structural unit attached to maytansinoid through a thioester linkage;
where specified aliphatic structural unit represented by X or Y is a simple or branched alkyl group having 1-20 carbon atoms in the chain, a cyclic alkyl group having 3-10 carbon atoms, simple or branched alkenylphenol group having 2-15 carbon atoms in the chain or simple or branched alkenylphenol group having 2-15 carbon atoms in the chain;
1 represents 0 or 1;
p represents 0 or 1; and
n is an integer from 1 to 2000.

2. Conjugate agent that communicates with the cell and cytotoxic maytansinoid formula (2) or (2'):


where ST represents the agent that communicates with the cell and is what I antibody;
D represents maytansinoid;
X represents an aliphatic structural unit that is attached to the agent that communicates with the cell through an amide linkage;
Y represents an aliphatic structural unit attached to maytansinoid through a thioester linkage;
where specified aliphatic structural unit represented by X or Y is a simple or branched alkyl group having 1-20 carbon atoms in the chain, a cyclic alkyl group having 3-10 carbon atoms, simple or branched alkenylphenol group having 2-15 carbon atoms in the chain or simple or branched alkenylphenol group having 2-15 carbon atoms in the chain;
1 represents 0 or 1;
p represents 0 or 1; and
m is an integer from 2 to 15; and
n is an integer from 1 to 2000.

3. The conjugate according to claim 2, wherein said agent that communicates with the cell, is a single-chain antibody, antibody fragment that preferentially binds to cell-targeted monoclonal antibody, single-chain monoclonal antibody, monoclonal antibody, bespecifically antibody fragment that specifically binds to a cell-target.

4. The conjugate according to claim 2, wherein said agent that communicates with the cell, is monoclonal the Noah antibody with a modified surface, single-chain monoclonal antibody with a modified surface or fragment monoclonal antibodies with a modified surface, which preferably communicates with the cell-target.

5. The conjugate according to claim 2, wherein said agent that communicates with the cell, is humanitariannet monoclonal antibody, humanitariannet single-chain monoclonal antibody, or fragment gumanitarnogo monoclonal antibody that preferentially binds to the cell-target.

6. The conjugate according to claim 2, in which the indicated antibody is a chimeric antibody, a fragment of a chimeric antibody, a domain of the antibody or fragment of the domain of the antibody.

7. The conjugate according to claim 2, in which the indicated antibody is a MY9, anti-B4, C or antibody that binds to an antigen selected from the group consisting of Arcam, CD2, CD3, CD4, CD5, CD6, CD11, CD19, CD20, CD22, CD26. CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, receptors EphA, EphB receptors, EGFR, EGFRvIII, HER2, HER3,, mesothelin, Cripto protein, integrin, alphabets, alphabet and alphabet.

8. The conjugate according to claim 2, in which the indicated antibody is humanitariannet, the human antibody or antibody with a modified surface, which are selected from A-b, B4, S, N901, DS6, receptor EphA2, CD38, IGF-IR, CNTO 95,-B4, trastuzumab, pertuzumab, butusually, dibromobutane or RIT is ximba.

9. The conjugate according to claim 2, wherein said agent that communicates with the cell, binds to the cell-target which is selected from tumor cells; cells infected with virus, cells infected with microorganisms, cells infected with parasites, autoimmune cells, activated cells, myeloid cells, activated T cells, b cells, or melanocytes; cells expressing one or more of the following: IGF-IR, CanAg, EGFR, MUC1, MUC16, VEGF, TF, MY9, anti-B4, Ersam, CD2, CD3, CD4, CD5, CD6, CD11, CD11a, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD70, CD79, CD105, CD138, receptors EphA, EphB receptor, EGFRvIII, HER2/neu, HER3,, mesothelin, Cripto protein, integrin alphavbeta3, the integrin alphabets, integrin alphavbeta6, Aro and antigens S; or cells expressing the receptor for insulin-like growth factor, receptor, epidermal growth factor and receptor folate.

10. The conjugate according to claim 9, in which the tumor cells are cells that are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cell cancer, small-cell lung cancer cells and cancer cells of the testes.

11. The compound that is represented by a formula selected from the following:



;
,
where n is an integer from 1 to 2000; R represents H, q=1 or R represents a CH3and q=2.

12. The conjugate is represented by a formula selected from:
;
;
;
;
,
where n is an integer from 1 to 2000; m is an integer from 2 to 15; mAb is a monoclonal antibody; R is a H, q=1 or R represents a CH3a q=2.

13. The compound according to claim 1 or 11, where n is an integer from 1 to 14.

14. The connection indicated in paragraph 13, where n is an integer from 1 to 4.

15. The conjugate according to any one of claim 2 to 10 and 12, where n is an integer from 1 to 14.

16. The conjugate according to clause 15, where n is an integer from 1 to 4.

17. Pharmaceutical composition for treating tumors, autoimmune diseases, graft rejections, reactions, graft versus host, viral infections and parasitic infections that are sensitive to the pharmaceutical compositions containing an effective amount of the conjugate maytansinoid agent that communicates with the cell according to claim 2, 12, 15, or 16, or its pharmaceutically acceptable salt, or MES, and a pharmaceutically acceptable carrier, aslavital or exipient.

18. A method of treating tumors, autoimmune diseases, graft rejections, reactions, graft versus host, viral infections and parasitic infections that are sensitive to treatment by the above method, which comprises parenteral administration to the needy in this patient an effective dose of the conjugate according to claim 2, 12, 15, or 16.

19. The method according to p, which indicated the tumor is selected from one or more cancers of the lung, blood, plasma, breast, colon, prostate, kidney, pancreas, brain, bones, ovaries, testes and organs of the lymphatic system.

20. The method according to p, in which the tumor expresses one or more of the following: IGF-IR, FOLR1, CanAg, EGFR, EphA2, MUC1, MUC16, VEGF, TF, MY9, anti-B4, EpCAM, CD2, CDS, CD4, CD5, CD6, CD11, CD11a, CD18, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD70, CD79, CD105, CD138, EphA, EphB, EGFRvIII, HER2/neu, HER3,mesothelin, Cripto protein, integrin, alphabets, integrin alphavbeta5the integrin alphavbeta6, Aro and antigens C.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.

EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).

53 cl, 502 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to products of oxidative decomposition of atorvastatin calcium, specifically to 4-[6-(4-fluorophenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoylhexahydro-1,2-dioxa- 5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid, phenylamide 4-(4-fluorophenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid and 4-[1b-(4-fluorophenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoylhexahydro-1,2-dioxa-5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid. The invention also relates synthesis methods thereof, based on oxidation of an atorvastatin salt.

EFFECT: disclosed are products of oxidative decomposition of an atorvastatin salt, which can be used to identify impurities or a product of decomposition of an atorvastatin salt in accordance with approved analytical procedures.

15 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to D-proline derivatives of formula I or IA wherein R1 and R2 are independently lower alcoxy, lower alkenyloxy, hydroxy, -OCH(CH3)OC(O)-lower alkyl or -OCH2C(O)N(R3)N(R4), with the proviso, that only one from R1 and R2 represent hydroxy; R3 and R4 are independently hydrogen, lower alkyl? Lower alkenyl, or cycloalkyl; or R1 and R2 together with carbon atom to which they are attached form linkage group X, wherein X represents -O(CH2)nCH=CH(CH2)nO- or -O(CH2)mO-; n = 1, 2 or 3; m = 4-8.

EFFECT: new prodrugs.

14 cl, 1 tbl, 25(29) ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to derivatives of general formula I , wherein R1, R2 and R3 are independently H or C1-C4-alkyl; Ar is condensed thiophene or pyridine ring optionally substituted with one or more substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkyloxy(C1-C4)-alkyl, CF3, halogen, nitro, cyano, NR4R5 NR4COR6 and CONR4R5 (R4 and R5 are independently H or C1-C4-alkyl; or R4 and R5 together with adjacent nitrogen atom form 5- or 6-membered saturated heterocyclic ring; R6 is C1-C4-alkyl): A is residue of 4-7-membered saturated heterocyclic ring optionally containing nictogen atom and optiomally substituted with 1-3 substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, hydroxyl, halogen, and alkoxy; and pharmaceutical composition based on the same; with the proviso, that compound of formula I wherein A represents condensed [3,2-f]pyridine ring; each R1, R2 and R3 represents H, and A represents (CH2)3. Also described are application of abovementioned derivatives, pharmaceutical composition enhancing of synaptic response mediated with AMPA receptors in CNS based on the same, and method for treatment of neurological diseases or mental disorders.

EFFECT: new compounds with value biological properties.

7 cl, 1 tbl, 12 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives of the following structures (I) and (II) wherein X represents NH or O; R represents H or C1-6alkyl; R1 represents a structure specified in wherein R1' means a substitution in n-, o- or m-positions by one or more substitutes from halogen, -OCF3, -CF3 or -OCH3; R2 represents -(CH2)1;2-piperid-4-yl or substituted -(CH2)1,2-piperid-4-yl, substituted by C1-6alkyl or C(O)cyclopropyl; or R2 represents -(CH2)n-cyclohexyl wherein n means 0 or 1, wherein -(CH2)n-cyclohexyl is optionally substituted by one or more substitutes specified in halogen, oxo, cyano, amino, alkylamino, alkyl, alkoxy, hydroxyalkyl, morpholinyl, -NReC(=O)Rf, -S(=O)2NH2, -NReS(=O)2Rf, wherein Rf and Re are identical or different and independently represent hydrogen, alkyl or morpholinylalkyl. The invention also refers to a composition possessing activity inhibiting Pim-1 kinase activity.

EFFECT: there are produced new compounds and composition on their basis which can find application in medicine for treating cancer expressing Pim-1 kinase.

13 cl, 5 dwg, 9 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 4-[3-(4-cyclopropanecarbonyl-piperazin-1-carbonyl)-4-fluor-benzyl]-2H-phthalazin-1-one in the form of a crystalline form L having characteristic peaks on an X-ray powder diffraction pattern presented in the patent claim, to methods for preparing the form L, pharmaceutical formulation containing the form L, and versions of using the form L and formulations containing the form L.

EFFECT: preparing the new crystalline form of the above compound which possesses poly-(ADP)polymerase (PARP) inhibitory activity The form L contains no solvent impurities that enables more accurate dosage of the active compound when treating the patient.

17 cl, 4 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and hematology, and may be used in treating the patients with refractory and recurrent clinical course of Hodgkin's lymphoma. For this purpose, 24 hours before the leucopheresis procedure, a granulocyte colony-stimulating factor is administered to the patient. That is followed by the leucopheresis procedure with using MCS "Haemonetics" blood separator, and the prepared leukapack is divided on 4 portions. The leukapack portions are collected in sterile containers and incubated for 180 minutes at temperature 37°C: portions 1 and 3 with recombinant interleukin-2 5 thousand IU/ml, portions 2 and 4 with interferon-α-2b 10 thousand IU/ml. That is followed by the intravenous, drop-by-drop reinfusions of the leukapack before a course of the polychemotherapy: portions 1 and 2 on the day of the leucopheresis procedure, portions 3 and 4 of the laukapack are kept in a fridge at temperature 0 to 8°C for 24 hours and then incubated with immune preparations in the specified mode and administered to the patient. After the course of the polychemotherapy has been completed, the leucopheresis procedure is conducted again. The above therapy is prescribed for cycles 4 and 6 of the polychemotherapy used for refractory Hodgkin lymphoma and for cycles 2 and 4 cycles of the polychemotherapy used for recurrent Hodgkin's lymphoma, regardless of a response to therapy.

EFFECT: method enables the effective therapy of the given pathology ensured by activation of the proper anti-tumour response.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacy and medicine, and concerns using the pyridopyrazine derivatives for preparing a drug for treating or preventing the physiological and/or pathophysiological conditions associated withPI3K kinase inhibition in mammals.

EFFECT: invention provides high clinical effectiveness.

7 cl, 4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology and can be used in treatment of gall bladder cancer with metastases into liver. Essence of method lies in the following: 1-st course of regional chemotherapy is carried out on the 14-th day after operative intervention. Under conditions of procedure room 20 ml of autoblood were sampled from patient and incubated with gemzar in amount 1000 mg/m2 for 30 minutes at temperature 37.5°C. Chamber of infusion system was punctured with Gruber's needle and preparation is introduced. On the second day introduction of oxalyplatin on 5% glucose solution was introduced in amount 100 mg/m2. Courses of regional autohemochemotherapy were repeated every 14 days.

EFFECT: method provides possibility of carrying out chemotherapeutic treatment in earlier terms of postoperative period, as well as realisation of direct impact on remaining tumour cells and focuses of metastatic affection, in addition method application makes it possible to reduce amount of applied anti-tumour medications and minimise their side toxic manifestations, achieve maximal concentration of chemical preparations in regional blood flow.

1 ex

FIELD: medicine.

SUBSTANCE: what is presented is a nucleic acid construct for treating tumours comprising at least two open reading frames that include sequences encoding a cytotoxic or cytostatic gene product, in particular diphtheria toxin functionally related to various tumour-specific promoters: H19-specific promoter, IGF-II P3 or P4 promoter. What is described is a eukaryotic expression vector comprising the above nucleic acid construct, and methods of treating and inhibiting the tumour development in a human subject by administering the nucleic acid construct under the invention.

EFFECT: invention can find further application in therapy of cancer.

33 cl, 12 ex, 40 dwg

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a therapeutic and/or preventive agent for cancer pain which may be administered to the patient for a long time from the earliest to the last stage instead of conventional non-opioid or opioid analgesics in a daily dose for adults from 50 to 600 mg. As an active ingredient, the agent comprises a compound of formula (I) or its acceptable salt thereof (particularly, (R)-(-)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoic acid or (version) a combination with an opioid analgesic. What is presented is the use of the compound of formula (I) or a salt thereof to prepare the above agent in a daily dose of 50 to 600 mg (version - a combination with the opioid analgesic) and a related method of treating (versions). What is shown is relieving pain under action of the compound of formula (I) not related with the effect of tumour regression.

EFFECT: compound causes no serious side effects normally caused by the non-opioid and opioid analgesics.

18 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to immunology and represents a method for preparing a concentrated immunoglobulin preparation for subcutaneous administration involving the purification of Cohn fraction II of human plasma protein contaminants from unstable protein impurities and lipids by fractionation in aqueous solutions, the adsorption of pyrogens by aluminium hydroxide, the solvent/detergent preparation by a mixture of tributyl phosphate and sodium cholate, the removal of virus-inactivating reactants, the neutralisation of pyrogens in the presence of salts, the stabilisation by glycine, wherein the solvent and detergent are removed by depth filtration and ultrafiltration with multiple change of the solvent in the ultrafiltration, in a combination of the concentration of the immunoglobulin solution and he preparation release from the fractionation agent and salts thereof.

EFFECT: invention provides higher quality of the preparation ensured by additional neutralisation of pyrogens and the highest possible removal of the solvent/detergent impurities by aqueous solution in the ultrafiltration.

3 cl, 2 ex, 1 tbl

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