Macrocyclic compounds as trk kinase inhibitors
SUBSTANCE: invention relates to compound of formula I or its pharmaceutically acceptable salts, which are inhibitors of Trk kinases and are useful for treating pain, malignant oncological disease, inflammation, neurodegenerative diseases and Trypanasoma Crusi infections. Invention also describes versions of methods of producing compound of formula I. In Formula I (I) ring A is selected from A-1, A-2, A-3, having structure , where wavy line marked 1 indicates connection point of ring A to ring B, and wavy line marked 2 indicates point of connection ring A to W; X is N or CH; Y is H or F; R1 is H or halogen; ring B is selected from rings B-1 and B-2, having structure , where wavy line marked 3 indicates point of connection to ring A, and wavy line marked 4 indicates point of connection to pyrazolo[1,5-a]pyrimidine ring of formula I; W is O, NH or CH2, wherein, when ring A is A-2, then W is CH2; m is 0, 1 or 2; D is carbon, R2 and R2a independently represent H, F, (1-3C)alkyl or OH (provided that R2 and R2a are not simultaneously OH), and R3 and R3a are independently H or (1-3C)alkyl, or (D) is carbon or nitrogen, R2 and R3 are absent, and R2a and R3a together with atoms to which they are bonded, form 5-6-member heteroaryl ring containing 1-2 heteroatoms ring; Z is *-NR4aC(=O)-, *-ONHC(=O)-, *-NR4bCH2- or *-OC(=O)-, where asterix indicates connection point of Z to containing carbon R3; R4a is H or (1-6C)alkyl; R4b is H, (1-6C)alkyl, ((1-6C)alkyl)C(O)-, HOCH2C(O)-, ((1-6 C)alkyl) sulfonyl, HO2CCH2- or ((1-6C)alkyl)NH(CO)-; and R-5 and R6 independently represent H, halogen, OH or (1-6C)alkyl.
EFFECT: useful for treating pain, malignant oncological disease, inflammation, neurodegenerative diseases and Trypanasoma Crusi infections.
73 cl, 1 tbl, 45 ex
SUBSTANCE: invention relates to a method of producing 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11.8.0.01,10.02,7.014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones (IIa-d), which includes reacting 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones (Ia-d) with 3,4-dihydro-2H-pyran in a medium of an inert aprotic solvent, followed by separation of the end products. In general formula (I) Ar=Ph (a, d), C6H4Br-4 (b), C6H4OMe-4 (c), R=H (a-c), Cl (d).
EFFECT: obtaining 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11,8,0,01,10,02,7,014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones.
2 cl, 1 tbl, 5 ex
SUBSTANCE: invention relates to 7R-substituted tris[1,2,5]oxadiazolo[3,4-b:3',4'-d:3",4"-f]-azepine derivatives of general formula (1) , where R denotes H, an NH2 group, an alkyl substitute: methyl, a substituted alkyl substitute: 2-hydroxyethyl, benzyl, furfuryl, tetrahydrofurfuryl, homoveratryl. The compounds are obtained by reacting 3,4-bis(4-nitrofurazan-3-yl)furazan with a compound, respectively selected from: ammonia, hydrazine, a compound containing a primary amine group: methylamine, 2-hydroxyethylamine, benzylamine, furfurylamine, tetrahydrofurfurylamine, homoveratrylamine. The technical result is 7R-substituted tris[1,2,5]oxadiazolo[3,4-b:3',4'-d:3",4"-f]-azepine derivatives, which are suitable as a component of explosive compounds, solid rocket propellants and energy compounds for different purposes, used at high temperatures.
EFFECT: high output.
2 cl, 1 dwg, 9 ex
SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).
EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.
48 cl, 7 dwg, 7 tbl, 15 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to conjugates of Disorazol with cell adhesion molecules, such as peptides, proteins, hormones, blood proteins, and methods for preparing conjugates.
EFFECT: conjugates of Disorazol may be used as drug preparations for treating various tumours.
19 cl, 17 dwg, 2 tbl, 17 ex
SUBSTANCE: invention relates to novel crystalline polymorphous forms of the rifaximin antibiotic (INN) known as rifaximin δ and rifaximin ε. The invention also relates to a method for synthesis of such polymorphs, which is realised through hot dissolution of crude rifaximin in ethanol and crystallisation of the product, which is induced by adding water at temperature of approximately 50°C and is carried out for approximately 4-36 hours, with subsequent drying at controlled conditions until attaining given content of water in the end product. Novel polymorphs have properties which enable to control rifaximin absorption when used as an antibiotic. The invention also relates to pharmaceutical compositions containing the novel polymorphous forms of rifaximin.
EFFECT: obtaining novel polymorphous forms of rifaximin.
20 cl, 2 tbl, 3 ex, 2 dwg
SUBSTANCE: new crystal form II N-benzoilstaurosporin is described, as well as pharmaceutical composition containing it, inhibiting protein kinase C; ways of obtaining crystalline form of compounds, and the use of crystal form of II N-benzoilstaurosporin for treatment neoplastic diseases. Crystalline form of II N-benzoilstaurosporin is a stable form of N-benzoilstaurosporin with low hygroscopicity.
EFFECT: suitability in pharmaceutical compositions.
21 cl, 2 tbl, 4 dwg, 16 ex
SUBSTANCE: invention refers to a compound of the formula , where R1 and R2 are different independent groups and are selected from the group consisting of OR3 and N (R3') (R3"); or R1 and R2 are different groups connected through a single bond and selected from the group consisting of O and NR3; R3, R3', and R3" are independently selected from the group consisting of H, phenyl, substituted phenyl, where substituents are independently selected from the group consisting of C1-C6 alkyl, halogen; R4 and R4': (a) independently selected from the group consisting of H, OH, a group of the formula ; R5, R6, and R7 are independently selected from the group consisting of OCH3; R8 and R9 are joined by (i) a single bond and represent CH2 or (ii) double bond and are CH; R15 are selected from the group consisting of C=O; n is equal to 2. The invention also refers to method for obtaining these compounds.
EFFECT: obtaining new compounds which can be used in medicine as neurodefensive and neurogenerative, antiproliferative and anti-inflammatory drugs.
43 cl, 7 tbl, 13 ex
SUBSTANCE: regioselective synthesis of complex rapamycin 42-ether (CCI-779) involves: (a) acylation of 31-silyl rapamycin ether by compound of formula HOOC.CR7R8R9 or its combined anhydride, where: R7 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, -(CR12R13)fOR10, -CF3, -F or -CO2R10; R10 is hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, triphenylmethyl, benzyl, alcoxymethyl with 2-7 carbon atoms, chloroethyl or tetrahydropyranyl; R8 and R9 together form X; X is 2-phenyl-1,3,2-dioxaborinane-5-yl or 2-phenyl-1,3,2-dioxaborinane-4-yl, where phenyl can be optionally substituted; R12 and R13 each is independently hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-7 carbon atoms, alkinyl with 2-7 carbon atoms, trifluormethyl or -F; and f=0-6; to obtain 42-ether boronate of 31-silyl rapamycin ether; (b) selective hydrolysis of 42-ether boronate of 31-silyl rapamycin ether in moderately acid environment to obtain rapamycin 42-ether boronate; and (c) diol treatment of rapamycin 42-etherboronate to obtain complex rapamycine 42-ether. Invention also claims new intermediate products applicable in this method.
EFFECT: application as antitumour medication.
48 cl, 3 ex
FIELD: organic chemistry, biochemistry.
SUBSTANCE: invention relates to some new macroheterocyclic compounds that can act as selective inhibitors of kinase or double kinase. Invention describes compounds of the following formulae: formula (Ia1), formula (Ib1), formula (If1), formula (Ii1), and formula (Ij1) wherein values R2, R4 and R5 are chosen by the dependent manner as given in the invention claim. Invention provides preparing new compounds possessing valuable biological properties.
EFFECT: valuable biological properties of compounds.
5 cl, 3 tbl, 22 ex
SUBSTANCE: invention relates to a novel chemical substance - 4,10-bis((±)-5-benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane The invention also relates to a method of its obtaining, which consists in the acylation of 2,6,8,12-tetraacetyl-2,4,6,8,10,12- hexaazatetracyclo [5,5,0,03,11,05,9]dodecane by chloranhydride 5-benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.
EFFECT: novel compound, which has analgetic activity, is obtained.
2 cl, 1 tbl, 2 ex
SUBSTANCE: invention relates to nickel complex of 5,10,15,20-tetrakis [3',5'-di(2"-methylbutyloxy)phenyl]-porphin of formula
EFFECT: invention makes it possible to obtain nickel complex, demonstrating property of stationary phase for gas chromatography.
SUBSTANCE: invention relates to method of obtaining 2,6-dialkyl-hexahydro-1H,5H-2,3a,4a,6,7a,8a-hexaazacyclopenta [def]fluorene -4,8-dions of general formula (1): where Alkyl=t-Bu; i-Pr, cyclo-C6H11, consisting in interaction of N,N-bis(methoxymethyl)alkylamines of general formula Alkyl-N(CH2OMe)2 (where Alkyl =said above) with glycoluryl in presence of catalyst samarium chloride crystallohydrate SmCl3·6H2O with molar ratio Alkyl-N(CH2OMe)2:glycoluryl:SmCl3·6H2O=20:10:(0,3-0,7) at temperature 60°C and atmospheric pressure in mixture of solvents CHCl3 - EtOH (1:2, volume) for 4-8 h.
EFFECT: obtaining compound with high selectivity.
1 tbl, 1 ex
SUBSTANCE: invention relates to amino amides in the bacteriochlorophyll a series, having the general formula: where n=2, 4, 8, 10, having photo-induced anti-tumour activity, and to a method for production thereof by reacting methyl ether of bacteriopheophorbide a with a diaminoalkane of formula NH2(CH2)nNH2, where n=2, 4, 8, 10, in pyridine.
EFFECT: obtaining highly efficient photosensitisers, amino amides in the bacteriochlorophyll a series based on bacteriochlorin e, having high photo-induced anti-tumour activity.
2 cl, 4 dwg, 11 ex
SUBSTANCE: invention relates to chemistry and chemical technology, namely to synthesis of modified silicagels, containing molecules of substituted phthalocyanines covalently bound with them, and their application for water photoremediation. Method of water photoremediation with application of radiation of visible range in presence of oxygen and heterogenic sensibiliser of general formula: , where R=H is either SPh; X is anion; n=4-8; M=Zn, AlL, GaL, SiLz; L=Cl, OH; M=1-4.
EFFECT: invention makes it possible to carry out efficient purification of water from bacteriological contamination.
2 cl, 3 tbl, 11 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to a photosensitiser for photodynamic therapy. What is declared is methyl ester 13,17-bis(N-methyl-N,N-diethylammonioethylamide) chlorine e6 ditosylate as a photosensitiser having formula: .
EFFECT: compound is stable, possesses high photobactericidal activity in vitro and high photodynamic effectiveness.
4 dwg, 2 tbl, 9 ex
SUBSTANCE: claimed is method of obtaining photosensibiliser, which consists in the following: 3-pyridylcarboxaldehide is condensed with pyrrole in mixture propionic acid-propionic anhydride with their ratio 3-4:1-2 in boiling for 80-100 min. product of condensation is reduced with p-toluenesulfonylhydrazide in pyridine medium in presence of potassium carbonate with its 30-35-fold excess and 5-10% quinoline at temperature 85-95°C for 4-5 hours. After that, obtained product is N-methylated in dimethylformamide in boiling for 50-65 min, precipitated with benzene, filtered and dried. Also claimed is photosensibiliser, obtained in accordance with claimed method, which contains 5,10,15,20-tetrakis(N-methyl-3'-pyridyl)chlorine in quantity 15-25% and 5,10,15,20-tetrakis(N-methyl-3'-pyrydyl)bacteriochlorine in quantity 75-85%.
EFFECT: increase of target product output, reduction of tumour growth rate and dissemination, prevention of tumout tissue necrotisation, complete and uniform saturation of tumour tissue with medication.
3 cl, 1 dwg, 1 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to methods for producing bacteriochlorines presented by formulas (I), (III), wherein the radical values X1-X8, R1-R8, Y, R' are specified in cl. 1, 2 of the patient claim, for a photodynamic therapy (PDT) of hyperproliferative tissues, such as tumours, hyperproliferative blood vessels and other PDT-responding diseases or anomalies.
EFFECT: higher effectiveness of the method.
2 cl, 22 dwg, 21 ex
SUBSTANCE: invention relates to novel substituted metal phthalocyanines, particularly to cobalt or copper tetra-(4-tert-butyl-5-nitro)phthalocyanine (I) which exhibits a polymer material dye property.
EFFECT: metal complexes of tetra-(4-tert-butyl-5-nitro)phthalocyanine (I) widen the colour gamma of metal complexes of tetra-4-tert-butylphthalocyanines with a similar structure to light-blue and blue when dyeing polymer materials.
6 dwg, 3 ex
SUBSTANCE: invention relates to organic chemistry, particularly to chemistry of natural compounds and production of methyl pheophorbide (a), which is meant for synthesis of porphyrins and chlorins for photodynamic therapy purposes. The disclosed method of producing methyl pheophorbide (a) is realised as follows: extracting chlorophyll (a) from Spirulina Platensis microalgae and demetallisation thereof by treating with concentrated acetic acid while exposing the reaction mass to ultrasound at frequency 25-30 kHz for 2.0-2.5 hours at temperature of 45-50°C. The formed pheophytin (a) is then extracted by precipitation with water, after which it is methylated in a medium of tetrahydrofuran in the presence of sulphuric acid at 50-55°C for 1.0-1.5 hours; the end product is extracted by precipitation with water and purified by twofold precipitation from methylene chloride into ethanol.
EFFECT: invention significantly reduces physiological and environmental hazard of the process due to the 55-60-fold reduction of the amount of toxic methanol used, 4-5-fold reduction of the duration of the process and twofold increase in output of the product.
1 tbl, 1 ex
SUBSTANCE: invention relates to improved method of obtaining pyridine compounds (AA),(BB) and (CC) of respective formulas:
said compounds possess inhibiting action with respect to HIV-integrase. method consists in carrying out the following stages: P-1) bromination of compound of formula (I-I) with obtaining bromine-compound of formula (II-II)
where value R represents -CHO, -CH(OH)2, -CH(OH)(OR4), -CH(OH)-CH2OH or -CH(OR5)(OR6); P1 represents benzyl; P3 represents H or protective group of carboxyl; R4 represents lower alkyl; R5 and R6 independently represent lower alkyl or R5 and R6 can represent alkyl and be connected with formation of 5-, 6- or 7-member ring, P-2) formation of side chain of 2,4-di-fluorophenyl-CH2-NH-C(O)- with application of reagents 2,4-di-fluorophenyl-CH2-NH2 and carbon monoxide, stage of formation of Q ring by means of respective amine, selected from 3-amino-butan-1-ol, 2-amino-propan-1-ol and 2-pyrrolidinyl methylamine, and stage of debenzylation with obtaining compound of formula (AA), (BB) or (CC), where said stage P-2 is carried out after formation of Q ring.
EFFECT: method makes it possible to simplify obtaining target compounds due to carrying out regioselective bromination at the first stage.
6 cl, 3 ex, 7 dwg