The method of producing crystals of hydrochloride dihydrate ondansetron reduced size

 

(57) Abstract:

The inventive obtaining crystals of hydrochloride dihydrate ondansetron reduced size by desolvatation of the latter, obtained by crystallization from a mixture of an aqueous solvent by drying at a temperature below 40° C and at atmospheric or reduced pressure, equal to 200 mm cs. or less, followed by rehydration with obtaining a product which is 100 wt.% crystals have a size of less than 250 μm and not less than 80 wt% of the crystals have a size less than 63 μm

 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a new method for preparing 1-(9H-carbazole-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amine}-2-propanol of the formula (I):

and its pharmaceutical salts of acids addition. Method involves interaction of secondary amine of the formula (V):

with epichlorohydrine and synthesized chlorine-containing compound of the formula (VI):

reacts with 4-hydroxy-9H-carbazole of the formula:

and synthesized benzyl-carvedilol of the formula (VIII):

is debenzylated by the catalytic hydrogenation reaction. If necessary, the synthesized compound is subjected for reaction with inorganic or organic acid for preparing its pharmaceutically acceptable salt of acid addition.

EFFECT: improved preparing method.

8 ex

FIELD: pharmaceuticals, in particular composition for treatment or prophylaxis of heart diseases.

SUBSTANCE: invention relates to pharmaceutically acceptable composition containing crystalline form IV of (±)-1-(4-carbazolyloxy)-3-[2-(2-methoxyphenoxy)ethylamine]-2-propanol hemihydrate (carvediol) having melt temperature of 94-96°C or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carrier and/or adjuvant having no surfactant properties, which has melt temperature 120°C or lower and is selected from polyethylene glycol and/or isomalt; and/or nonionic surfactant such as polyoxyethylene and polyoxypropylene copolymer. Claimed composition is obtained by melting of crystalline form of (±)-1-(4-carbazolyloxy)-3-[2-(2-methoxyphenoxy)ethylamine]-2-propanol (carvediol) having melt temperature of 123-126°C or 114-115°C or pharmaceutically acceptable salts thereof in abovementioned adjuvant and/or nonionic surfactant followed by fast cooling and addition of pharmaceutically acceptable carrier.

EFFECT: new pharmaceutical composition for treatment or prophylaxis of heart diseases.

15 cl, 7 dwg, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of tetrahydrocarbazole of the formula (I): wherein n = 0, 1 or 2; X represents -NH or oxygen atom (O); each R is a similar or different radical and chosen independently from group consisting of halogen atom, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group; each R1 is a similar or different radical and chosen independently from group consisting of halogen, halogenalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl, -OR2, -R10OR2, -R10C(O)R2, -C(O)R2, -CO2R2, -R10CO2R2, -R10SO2R2, -S(O)mR2, cyano- or nitro-group and wherein each m means 2 independently; each R10 is a similar or different radical and chosen independently from alkylene; each p and q is chosen independently from 0, 1, 2, 3, 4 or 5; each R2 is a similar or different radical and chosen independently from group consisting of hydrogen atom (H), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R10-cycloalkyl and -R10OH; ring A represents phenyl, naphthyl or heteroaryl wherein heteroaryl represents monocyclic 5-7-membered aromatic ring or condensed bicyclic aromatic ring system consisting of two such aromatic rings that comprise one or two nitrogen atoms and/or sulfur atoms, and to their pharmaceutically acceptable salts, solvates, esters and amides. Compounds of the formula (I) possess effect against disorders caused by HPV-infection and useful in treatment of human papilloma. Also, invention relates to a pharmaceutical composition based on compounds of the formula (I) and its using in preparing drugs for their using in treatment and prophylactic of states or disorders caused by HPV-infection.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: chemistry.

SUBSTANCE: invention refers to the methods for preparation of X-ray amorphous carvedilol [(+)-1-(9H-carbazole-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amine}propane-2-ol] modification and can be used in pharmaceutical industry. Method involves the evaporation of carvedilol parent drug in vacuum device at temperature 80-200oC, residual pressure 5 - 5×10-4 Torr in a inert gas flow fed with the rate from 10 to 100 ml/min with following condensation at -196 - +25oC. The process results in obtaining of powder of X-ray amorphous carvedilol [(±)-1-(9H-carbazole-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amine}propane-2-ol] modification with particle size less than 5 mcm.

EFFECT: enhancing of bioactivity.

7 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of common formula IC1: , where A represents cyano; B represents hydrogen; R1, R2, R3 and R4 independently represent hydrogen; alkyl; halogen or nitro; R5 and R6 independently represent hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heteroarylalkyl; alkenyl; carboxyalkyl; cyanoalkyl; diphenylalkyl; aryl, arylalkoxyaryl, arylalkyl, arylalkylaryl, arylcarbonylaryl or aryloxyaryl, or R5 and R6, together with atom of nitrogen, to which they are connected, create heterocyclic ring system; or to salts of such compound; at the same time "heteroaryl" used separately or in combination, is related to mono-, bi- or tricyclic aromatic ring system, which contains up to 14 atoms included in ring, in which at least one ring contains at least one heteroatom, independently chosen from nitrogen, oxygen or sulfur, besides specified heteroaryl group may be unsubstituted or substituted with one to three substituents, independently selected from alkyl and alkoxy; "diphenylalkyl" is related to alkyl group, where each of two atoms of hydrogen is substituted with unsubstituted phenyl group; "aryl" is related to carbocyclic group, selected from group, which consists of phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, antryl, phenantryl, fluorenyl, indanyl, 2,3-dihydrobenzo[1,4]dioxynyl and benzo[1,3]dioxolyl group, besides specified aryl group may be unnecessarily substituted with functional groups in number from one to three, which are separately and independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, cyano, halogen, halogenlkoxy, halogenalkyl and nitro groups, where in certain specific cases, if aryl group represents condensed system from several rings, in which not all the rings are aromatic, one of carbon atoms of which is not included into aromatic ring may be in oxidised condition, and according fragment of ring -CH2- will be substituted by fragment-C(O); "arylalkoxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkoxygroup, where aryl group is unsubstituted; "arylalkyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via alkyl group, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "aryloxy", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via oxygen bridge, where aryl group may be unsubstituted or substituted with 1-3 substituents, independently selected from group, which consists of halogen; "arylcarbonyl", used separately or in combination, is related to aryl group, which is connected to initial molecular fragment via carbonyl group, where aryl group is unsubstituted; "heterocyclic ring system", used separately or in combination, is related to monocyclic, bicyclic or polycyclic ring system, which contains up to 15 atoms included into ring, at least one of which represents heteroatom, independently selected from nitrogen, oxygen or sulfur, besides specified ring system may be saturated, partially unsaturated, unsaturated or aromatic, where specified heterocyclic fragment may be unnecessarily substituted with one or more substituents, every of which separately and independently is selected from group made of halogen and halogenalkyl, excluding the following compounds: {3-[(E)-2-cyano-2-(4-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-m-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(3-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-phenylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-benzylcarbamoyl-2-cyanovinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-o-tolylcarbamoylvinyl)indole-1-yl]acetic acid; [3-((E)-2-cyano-2-t-tolylcarbamoylvinyl)indole-1-yl]acetic acid; (3-[(E)-2-(4-bromophenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-ethylphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2~cyano-2-(4- ethoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; [3-((E)-2-cyano-2-isopropylcarbamoylvinyl)indole-1-yl]acetic acid; {3-[(E)-2-cyano-2-(3-etoxyphenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-[[2-(1H-indole-3-yl)ethyl]amino]-3-oxo-1-propenyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-chlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-3-(4-methyl-piperidine-1-yl)-3-oxopropenyl]indole-1-yl}acetic acid; {3-[(E)-2-(3-chloro-4-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(3-phenylpropylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2,3-dichlorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-(5-chloro-2-methylphenylcarbamoyl)-2-cyanovinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(4-methoxybenzylcarbamoyl)vinyl]indole-1-yl}acetic acid; {3-[(E)-2-cyano-2-(2-fluorophenylcarbamoyl)vinyl]indole-1-yl}acetic acid; and {3-[(E)-2-cyano-3-oxo-3-(4-phenyl-piperazine-1-yl)propenyl]indole-1-yl}acetic acid. Invention is also related to pharmaceutical composition, and also to application of compounds of clause 1.

EFFECT: production of biologically active compounds, which have activity of antagonist coupled with G-protein of chemoattractant receptor of molecules homologue released by Th2-cells.

11 cl, 156 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising 2,3,4,9-tetrahydro-1H-carbazoles of formula I

,

where R1, R2, R3 and R4 independently denote hydrogen, alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl or formyl, R5 denotes hydrogen, alkyl or -CF3, R6 denotes alkoxy, arylalkoxy, selected from benzyloxy and 1-phenylethoxy, or -NR7R8, R7 and R8 independently denote hydrogen, alkyl, cyanoalkyl, alkenyl, where alkenyl is ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl or 5-hexenyl; aryl, where aryl is a phenyl or naphthyl radical, where said radicals can optionally be monosubstituted with a halogen, alkyl, alkoxy, -CF3, -OCF3, phenylalkyl or phenylcarbonyl; or disubstituted with a substitute independently selected from halogen, alkoxy and phenyl; arylalkyl, where arylalkyl is phenylalkyl, where the alkyl group can optionally be substituted with phenyl; phenylalkyl, where the phenyl ring can optionally be substituted with methylenedioxy; phenylalkyl which is disubstituted with a halogen; phenylalkyl which is monosubstituted with a halogen, -CF3, -OCHF2, alkyl or alkylsulfanyl; or naphthylalkyl; phenylcarbonyl; cycloalkyl, where cycloalkyl is a cyclopentyl or cyclohexyl radical, where said radicals can optionally be substituted with a condensed benzene ring; pyridylalkyl; thienylalkyl; or R7 and R8 together with a nitrogen atom to which they are bonded form a heterocyclic 5-, 6-, 7- or 8-member ring system containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, wherein said cyclic system can optionally be substituted with (1) one or two condensed benzene rings, where the benzene rings are unsubstituted or substituted with one or two substitutes independently selected from a group comprising C1-C4alkyl, C1-C4alkoxy, halogen, -CF3 and -OCF3; (2) unsubstituted phenyl ring, (3) mono- or disubstituted phenyl ring, where the substitutes are independently selected from a group comprising halogen, C1-C4alkyl, C1-C4alkoxy, -CF3 and -OCF3; or (4) phenylalkyl, where the alkyl group is substituted with phenyl; where the term "alkyl", separately or in any combination, denotes a saturated straight or branched hydrocarbon chain containing 1-7 carbon atoms; where the said alkyl group is unsubstituted unless stated otherwise; or to pharmaceutically acceptable salts thereof. Invention also relates to a pharmaceutical composition and to use of compounds in claim 1.

EFFECT: obtaining novel biologically active compounds having CRTH2 receptor antagonist activity.

13 cl, 5 tbl

FIELD: chemistry.

SUBSTANCE: use of compounds of formula (I): where: X denotes >CR1R2 or, when R6 denotes H, X denotes >SO2; Y denotes >CR1R2; Z denotes >C=O, >CH2, single bond; R1 denotes H, R2 denotes H, -COOH, -OH; or R1 and R2 together denote =O, ethylenedioxy or hydroxyimino group; R3 denotes H, lower alkyl group; R4 denotes two H, =O, hydroxyimino group; R5 denotes H, lower alkyl group, halogen; R6 denotes H, lower alkoxy, COOH; R7 and R8 are identical or different from each other and each denotes H, lower alkyl, halogen; and pharmaceutically acceptable salts thereof and esters for preparing a medicinal agent.

EFFECT: agent having neuroprotective action against hypoxia.

2 tbl, 24 ex, 13 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing high-optical purity chiral carvediol of formula I, involving reaction of an amine compound of formula 4 with a chiral glycidol compound of formula 5 to obtain a compound of formula 6 by opening the ring of formula 5 under the effect of the formula 4 compound and then in situ intramolecular cyclisation to obtain a compound of formula 6; removing the protective group for the hydroxy group of the formula 6 compound to obtain a compound of formula 2; reaction of the compound of formula 2 with a halogenating agent, sulphonylation agent or Mitsunobu reagent to activate the hydroxyl group of the formula 2 compound, with a subsequent nucleophilic substitution reaction with 9H-4-hydroxycarbazole to obtain a compound of formula 7; and removing the protection from the obtained compound of formula 7 in the presence of an inorganic base to obtain the desired chiral carvediol of formula 1; Formula 1 , Formula 2 , Formula 4 , Formula 5 , Formula 6 , Formula 7 , where * denotes a chiral centre, X denotes oxygen or sulphur, Y denotes a leaving group, and R1 denotes a protective group for the hydroxy group.

EFFECT: method does not require a complex purification method, does not cause deterioration of optical purity.

4 cl, 5 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formulae (I) and (II) and their pharmaceutically acceptable salts and esters wherein each Z1, Z2 and Z3 is chosen from series of (C1-C6)-alkoxy-group, -CH2OCH3 and -CH2OCH2CH3, or one Z1, Z2 or Z3 means hydrogen atom, and each of two others is chosen independently from series (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH2R1, -CH2-morpholino, -OR2, -OCH2CF3, -OCH(CH3)CH2OH and -COOQ wherein Q is chosen from series hydrogen atom and (C1-C6)-alkyl, or one of Z1, Z2 or Z3 means hydrogen atom, and two others in common with carbon atoms and in combination with bonds between them and benzene cycle to which they are bound for a cycle chosen from 5- and 6-membered unsaturated cycles and 5- and 6-membered saturated cycles that comprise at least one oxygen atom as heteroatom, and wherein R1 is chosen from series -F, -OCH3, -N(CH3)2 and unsaturated 5-membered cycles comprising at least one nitrogen or oxygen atom as heteroatom, and wherein R2 means 3-6-membered saturated cycle, and each Y1 and Y2 is chosen independently from series -Cl, -Br, -NO2, -C≡N and -C≡CH, and their pharmaceutically acceptable salts and esters and wherein Z4 is chosen from series (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -OH, -SCH3, -CF3, -NO2, -COOQ2, -N(CH3)2, -OCH2-phenyl, -Cl, -Br, -F, -OCH2COQ1, saturated 5- and 6-membered cycles comprising at least one heteroatom wherein heteroatom is chosen from nitrogen (N) and oxygen (O) atom, and wherein Q1 is chosen from series, -OH, -NH2 and -O(C1-C6)-alkyl; Q2 is chosen from series hydrogen atom and (C1-C6)-alkyl; Y1 and Y2 are chosen independently from series -Cl, -Br, -NO2, -C≡N and -C≡CH under condition that if both Y1 and Y2 means -Cl then Z4 doesn't means -Cl, and if both Y1 and Y2 mean -NO2 then Z4 doesn't mean -NO2, and if both Y1 and Y2 mean -CN then Z4 doesn't mean -CN. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to MDM2. Invention provides synthesis of novel biologically active compounds and preparing pharmaceutical compositions based on thereof possessing inhibitory activity with respect to MDM2.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

14 cl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds have selective cyclooxygenase-2 inhibitor properties and can be used to treat inflammatory diseases. The diseases can be selected from: articular syndrome with rheumatism and acute gout, rheumatoid arthritis, psoriatic arthritis, osteoarthrosis, radiculitis, in inflammatory processes of ligaments, tendons, ischias, lumbago, menstrual pain or inflammation, associated with inflammations caused by sunburn, skin damage by ultraviolet light, different forms of cancerous diseases of the skin. In formula 1 R is C1-C3 alkyl or an amino group, R' is hydrogen or C1-C3 alkyl, Ar is optionally substituted with a halogen, C1-C3 alkyl, C1-C3 alkoxy group or CF3 aryl; or a 5- or 6-member hetaryl containing one nitrogen, oxygen or sulphur atom in the ring. The invention also relates to a method of producing said compounds. The method includes reaction of a compound of general formula 3 with a substituted ethylenediamine of general formula 4, followed by reaction of the compound of general formula 5: with a compound of general formula 6 to form a compound 1.1, or with a compound of general formula 7 to form a compound 1.2 through an intermediate step of removing the protective group in the compound of general formula 8 according to the scheme where R and R' assume values given above.

EFFECT: high efficiency of using the compounds.

13 cl, 2 tbl, 1 dwg, 40 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted 1-pyridyl-2-azolyl-1-(2-phenylethenyl)ethan-1-ols having general formula I:

where Py denotes 2-, 3-, or 4-pyridyl, Z nitrogen atom or CH group, and R1 and R2, independently from each other, are hydrogen or halogen atom, or trifluoromethyl group. Claimed compounds are applied as agricultural, industrial, medical, or veterinarian fungicides for controlling harmful fungi.

EFFECT: enhanced fungi control efficiency.

2 cl, 3 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of 4-(heteroarylmethyl)halo-1-(2H)-phthalazinones, particularly 4-(4-pyridylmethyl)-1-(2H)-phthalazinone. Claimed method includes interaction between substituted phthalidyl-3-triphenylphosphonium and aldehyde of formula Ar-CHO, wherein Ar is pyridine, pyrazine, or pyrimidine, in presence of base followed by reaction with hydrazine hydrate optionally under acidic conditions.

EFFECT: environmental friendly and safe method.

4 cl, 1 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing (R)-5-(2-benzenesulfonylethyl)-3-N-methylpyrrolidine-2-ylmethyl)-1H-indole of the formula (I): or its pharmaceutically acceptable salt. Method involves hydrolysis of compound of the formula (II): that is prepared by catalytic reduction of compound of the formula (III): . The claimed method excludes formation of dimer in the end product used in medicine.

EFFECT: improved method for preparing.

18 cl, 3 sch, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

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