Novel pyridone derivatives, having mch antagonist activity, and medicinal agent containing said compounds

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I),

, where groups and radicals R1, R2 independently denote H, C1-8-alkyl or C3-7-cycloalkyl, where the alkyl or cycloalkyl group can be mono- or poly-substituted with identical or different groups R11; or R2 denotes a -CH2- or -CH2-CH2- bridge which is bonded with a group Y, and R1 is as defined above, or denotes a group selected from C1-4-alkyl-CO-, C1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO- or (C1-4-alkyl)2N-CO-, where the alkyl groups can be mono- or polyfluorinated; or R1 and R2 form an alkylene bridge such that R1R2N- denotes a group selected from: azetidine, pyrrolidine, piperdine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine, in which the free amino group is substituted with R13, piperidin-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxy iminopiperidin-1-yl and 4-hydroxy iminopiperidin-1-yl. Wherein, when R1 and R2 form an alkylene bridge, one or more H atoms in the alkylene bridge can be substituted with identical or different groups R14, and X denotes a C1-3-alkylene bridge which can contain one, two or three identical or different C1-3-alkyl substitutes; and Y denotes a group of subformula selected from: and , where the group can be mono-substituted with a substitute R20; Z denotes -CH2-CH2- or -C(=O)-CH2-; U, V both denote CH, one of groups U, V denotes N, and the other of U, V denotes CH, where CH can be substituted with L; and L independently denotes halogen, cyano or C1-3-alkyl; and k equals 0, 1 or 2; W is selected from a group consisting of -CH2-O- and -O-CH2-; B is selected from a group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thiophenyl and thiazolyl; each of which can be mono- or poly-substituted with identical or different substitutes R20; radicals R11, R13, R14, R20 assume values given in claim 1. The invention also relates to a pharmaceutical composition containing at least one compound of formula I and having action on MCH receptor.

EFFECT: disclosed pharmaceutical compositions are useful in treating metabolic disorders or eating disorders, especially obesity, bulimia, anorexia, hyperphagia and diabetes.

 

The text descriptions are given in facsimile form.

1. Compounds of General formula I:

where R1, R2independently of one another denote H, C1-8-alkyl Il is C 3-7-cycloalkyl, and alkyl or cycloalkyl group may be mono - or polyamidine identical or different groups R11;
or
R2denotes-CH2- or-CH2-CH2the bridge, which is linked to the group Y, and R1is as defined above or denotes a group selected from C1-4-alkyl-CO -,1-4-alkyl-O-CO-, (C1-4-alkyl)NH-CO - or (C1-4alkyl)2N-CO-, where the alkyl groups may be mono - or polyfluorinated; or
R1and R2form Allenby bridge such that R1R2N denotes a group selected from: azetidine, pyrrolidine, piperidine, ASEAN, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydropyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine in which the free aminogroup substituted R13, piperidine-4-one, morpholine, thiomorpholine, 4-C1-4-alkoxycyanobiphenyl-1-yl and 4-hydroxylaminopurine-1-yl; and when R1and R2form Allenby bridge, Allenova bridge one or more atoms N can be substituted by identical or different groups R14and
X denotes a1-3-Allenby bridge, which may include one, two or three identical or different With1-4-alkyl substituents; and Y denotes a group of podhorany chosen from:
and;
where the group may be monosubstituted by a substituent R20;
Z represents-CH2-CH2- or-C(=O)-CH2-;
U, V both represent CH, or one of the groups U, V denotes N, and the other of U, V denotes SN, where SN can be replaced by L; and
L independently of one another denotes halogen, cyano or1-3-alkyl; and k represents 0, 1 or 2;
W is selected from the group consisting of-CH2-O - and-O-CH2-;
In selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furil, thiophenyl and thiazolyl; each of which may be mono - or polyamidine identical or different substituents R20;
R11denotes halogen, C1-6-alkyl, R15-O-, R15-O-CO, R15-CO-O -, cyano, R16R17N-, R18R19N-CO - or3-7-cycloalkyl, and in the above-described groups of one or more C atoms can be replaced independently of one another by substituents selected from F;
R13has one of the meanings indicated for R17or represents formyl; R14denotes halogen, cyano, C1-6-alkyl, R15-O-, R15-O-CO-, R15-CO-, R15CO-O-, R16R17N-, HCO-NR15-, R18R19N-CO-, R18R19N-CO-NH-, R15-O-C1-3-alkyl, R15-What-CO-C 1-3-alkyl-, R15-SO2-NH-, R15-SO2-N(C1-3-alkyl)-, R15-O-CO-NH-C1-3-alkyl-, R15-SO2-NH-C1-3-alkyl-, R15-CO-C1-3-alkyl-, R15-CO-O-C1-3-alkyl-, R16R17N-C1-3-alkyl-, R18R19N-CO-C1-3-alkyl-,
R15denotes H, C1-4-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkyl,
R16denotes H, C1-4-alkyl, C3-7-cycloalkyl, ω-hydroxy-C2-3-alkyl, ω-(C1-4-alkoxy)-C2-3-alkyl, amino-C2-6-alkyl, C1-4-alkylamino-C2-6-alkyl, di-(C1-4-alkyl)amino-C2-6-alkyl,
R17has one of the meanings indicated for R16or denotes a1-4-alkylsulphonyl,1-4-alkoxycarbonyl;
R18, R19independently of one another denote H or C1-6-alkyl, where R18, R19may be associated with the formation With3-6-alkalinous bridge;
R20denotes halogen, hydroxy, cyano, nitro, C1-6-alkyl, hydroxy-C1-3-alkyl or C1-4-alkoxy; and
moreover, in the above-described groups and radicals, especially in L, W, X, Z, R11, R13-R20in each case one or more C atoms may additionally be mono - or polyamidine F, and/or in each case one or two atoms independently of one another may additionally be vozneseny CL or Br, and/or in each case one or more phenyl rings optionally may include independently of one another one, two or three substituent selected from the group F, Cl, Br, I, cyano, C1-4-alkyl, C1-4-alkoxy, diformate, trifloromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, acetylamino, aminocarbonyl, deformedarse, triptoreline, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl - and di-(C1-3-alkyl)amino-C1-3-alkyl, and/or can be monogamist nitro, and their salts.

2. Compounds according to claim 1, characterized in that the group R1, R2independently from each other selected from the group consisting of H, C1-4-alkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-4-alkyl, C3-7-cycloalkyl, hydroxy-C3-7-cycloalkyl, dihydroxy-C3-6-alkyl, C1-4-Alexi-C2-3-alkyl, hydroxy-C1-4-alkoxy-C2-3-alkyl, C1-4-alkoxy - C1-4-alkoxy-C2-3-alkyl, and alkyl, cycloalkyl or cycloalkenyl groups can be optionally mono - or tizamidine hydroxy and/or hydroxy-C1-3-alkyl, and/or mono - or polyamidine F or C1-3-alkyl, and/or monogamist CF3, Br, CL or CN.

3. Compounds according to claim 1, wherein R1and R2together with the N atom to which they are bound form a heterocyclic group, which is selected from the following values: azetidin, pyrrolidine, piperidine, piperazine in which the free aminogroup substituted R13and morpholine; and one or more atom of N can be substituted by identical or different groups R14and the group R13, R14are as defined in claim 1.

4. Compounds according to claim 1, characterized in that Podgornoe selected from the group consisting of:

,,
where R1denotes H, C1-4-alkyl or C1-4-alkylsulphonyl, and the alkyl group may be mono - or polyfluorinated, L1 is defined as R20and kl denotes 0 or 1.

5. Compounds according to claim 1, characterized in that X represents-CH2-, -CH2-CH2- or-CH2-CH2-CH2- bridge group, where one or two hydrogen atoms may be substituted by the same or different C1-3-alkyl groups.

6. Compounds according to claim 1, characterized in that the group Y denotes
;
where the group may be monosubstituted by a substituent R20.

7. Compounds according to claim 1, characterized in that the group Z represents-C(=O)-CH2-.

8. Compounds according to claim 1, characterized in that the groups which W represents-O-CH 2-.

9. Compounds according to claim 1, characterized in that the group selected from the group consisting of phenyl and pyridyl, where this group may be mono - or polyamidine identical or different substituents R20.

10. Compounds according to claim 1, in the form of their physiologically acceptable salts.

11. Pharmaceutical composition having antagonistic activity against receptor sit-containing compound according to one or more of claims 1 to 9, or its salt, optionally together with one or more inert carriers and/or diluents.

12. A compound selected from the group consisting of:
5-Benzyloxy-2-{2-[4-(3-hydroxy-3-methylpyrrolidine-1-ylmethyl)phenyl]-2-oxoethyl}-2H-pyridazin-3-one,
5-Benzyloxy-2-{2-[4-((R)-3-hydroxypyrrolidine-1-ylmethyl)phenyl]-2-oxoethyl}-2H-pyridazin-3-one,
5-Benzyloxy-2-{2-[4-(4-hydroxypiperidine-1-ylmethyl)phenyl]-2-oxoethyl}-2H-pyridazin-3-one,
5-(5-Chloropyridin-2-ylethoxy)-2-[2-oxo-2-(4-piperidine-1-ylmethylene)ethyl]-2H-pyridazin-3-one,
6-Benzyloxy-3-{2-[4-(4-hydroxy-4-methylpiperidin-1-ylmethyl)phenyl]-2-oxoethyl}-3H-pyrimidine-4-one,
5-Benzyloxy-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinoline-7-yl)ethyl]-2H-pyridazin-3-one,
5-(5-Bromopyridin-2-ylethoxy)-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinoline-7-yl)ethyl]-2H-pyridazin-3-one,
5-(5-Bromopyridin-2-ylethoxy)-2-[2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-oxoethyl]-2H-pyridazin-3-about the,
5-Benzyloxy-2-[2-(2,3-dihydro-1H-isoindole-5-yl)-2-oxoethyl]-2H-pyridazin-3-one and
5-Benzyloxy-2-[2-(2-methyl-2,3-dihydro-1H-isoindole-5-yl)-2-oxoethyl]-2H-pyridazin-3-one.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing mono-(di-, tetra-)methyl-1,2-bis-(1,3,5-dithiazinan-5-yl)ethanes of general formula (1-3): , (1) R1=CH3, R2, R3, R4=H (2) R1, R3=CH3, R2, R4=H (3) R1, R2, R3, R4=CH3, which involves reaction of hydrogen sulphide-saturated aqueous solution of (37%) formaldehyde and acetaldehyde with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: formaldehyde: acetaldehyde: hydrogen sulphide equal to 10:50:10:40 to obtain (1), 10:40:20:40 to obtain (2), 10:20:40:40 to obtain (3), at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,2-bis-(2,4,6-trialkyl-1,3,5-dithiazinan-5-yl)ethanes of general formula (1): . The method involves reaction of a hydrogen sulphide-saturated aldehyde of formula RCHO, where R=CH3, C2H5, n-C3H7, n-C4H9, n-C5H11, with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: aldehyde: hydrogen sulphide equal to 10:60:40 at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2(3H)-benzothiazolone. The method is realised by boiling bis-(2,2'-dimethoxycarboxamido)-phenyl disulphide with zinc dust for 7,5 hours in glacial acetic acid, followed by separating zinc salts, diluting the filtrate with ice water, filtering the crystalline product and washing said product with diluted HCl (1:1) and water and then drying on air and recrystallising from ethanol. The invention also relates to a method of producing 3-2-[2-oxo-1,3-benzothiazol-3(2H)-yl]ethyl-1,3-benzothiazol-2(3H)-one. The method is realised by boiling 2(3H)-benzothiazolone with 1,2-dibromoethane in acetone in the presence of K2CO3. Water is then added and the mixture is treated with diethyl ether, followed by washing the organic phase with 10% aqueous NaOH solution and water, drying with anhydrous potassium carbonate, removing the solvent and recrystallising from methanol. The invention relates to a method of producing 3-(2-chloroacetyl)-1,3-benzothiazol-2(3H)-one. The method is realised by boiling 2(3H)-benzothiazolone in anhydrous benzene with chloroacetyl chloride for 10 hours, then washing the cooled reaction mass with 2% aqueous NaOH solution, extracting with benzene, washing the merged extracts with water, drying with anhydrous calcium chloride and removing the solvent, followed by recrystallisation from chloroform.

EFFECT: improved method of producing 2(3H)-benzothiazolone derivatives.

3 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general structural formula:

or to pharmaceutically acceptable salts, where Z denotes -O- or -CH2- or -CH2-CH2-; X1 denotes a covalent bond or -O-; Y1 denotes a covalent bond or C1-C10 alkylene, provided that Y1 is a covalent bond only when X1 denotes a covalent bond; R1 denotes a) (C3-C7)cycloalkyl or b) phenyl or heteroaryl, which is a monovalent heteroatomatic monocyclic radical ring containing 1-2 heteroatoms, independently selected from nitrogen and sulphur, possibly substituted with 1-3 groups, independently selected from fluorine, chlorine, bromine, (C1-C6)alkyl or (C1-C6)-alkoxy; R2 denotes -OC(O)(NH2), -OC(O)(NHR9), -NHC(O)OR9, -C(O)R9, -C(O)(NH2), -C(O)(NHR9) or -NHC(O)H, where R9 denotes a linear or branched C1-C5 alkyl or a linear or branched (C1-C5)alkoxyalkyl; R3 denotes H, C1-C5 alkyl, -NHC(O)R10 or OH, where R10 denotes C1-C3 alkyl, provided that when R3 denotes -OH, X1 is not O and R2-Y1-X1 is not -OC(O)(NH2), -OC(O)(NHR9), -NHC(O)OR9 or -NHC(O)H; -Q denotes

, where N and N are bonded by bonds denoted by a wavy line; R4 denotes H; R5 and R6 independently denote: a) H, (C1-C10)alkyl, (C4-C10)cycloalkylalkyl, hydroxylated (C4-C10)cycloalkylalkyl, halo(C4-C10)cycloalkylalkyl, (C1-C2)alkyl(C4-C10)cycloakylalkyl, (C4-C10)bicycloalkyl(C1-C3)alkyl, (C1-C5)alkoxy(C1-C5)alkyl; or a saturated heterocyclyl(C1-C3)alkyl, where the saturated heterocyclic ring is selected from 5-, 6- or 7-member heterocyclic rings which contain 1 heteroatom independently selected from N and O; or b) phenyl(C1-C2)alkyl, phenoxymethyl, each of which is possibly with 1-3 groups independently selected from fluorine, chlorine, (C1-C3)alkyl, (C1-C3)alkoxy; provided that both R5 and R6 are not H; G denotes NH2 or NHR7; R7 denotes (C1-C6)alkyl; or R5 and R7 together denote -CH2, -(CH2)2 or -(CH2)3, possibly substituted with 1-2 groups independently selected from (C1-C8)-alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl or (C1-C8)alkoxy. The invention also relates to compounds selected from the group, pharmaceutical compositions, a method for antagonising one or more aspartate proteases, as well as methods of treating aspartate protease-mediated disorders.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

35 cl, 33 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof, where Q is CH or N; R2 is C1-C4 alkyl or C3-C4-cycloalkyl; Y is R5-O; where R5 is propynyl; X is selected from a group consisting of aryl, heteroaryl, C1-C5-alkyloxy, heterocycloalkyl, arylamino, heteroarylamino, heteroaryl-C1-C4-alkylamino, aryloxy, aryl-C1-C2-alkyloxy or C3-C6-cycloalkyl-C1-C4-alkyloxy, each of which is optionally substituted with 1-3 times; the optional substitute(s) for X is(are) independently selected from a group comprising halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyloxy-C1-C4-alkoxy, -SMe, SO2-C1-C2-alkyl, -NMe2, - C(O)O-C1-C5-alkyl, -SCF3, -SO2-NH2, -SO2-C2-alkyl-OH, -CONH2, -COMe, - CONH-C1-C4-alkyl, -CONMe2, -NHCOMe, -CH2COOEt, -OCH2COOEt, -CH2- cyclopropyl, and each R3 and R4 is H; where aryl denotes phenyl or naphthyl; heteroaryl denotes monocyclic or bicyclic hydrocarbon containing 5-10 ring atoms, one or more of which are heteroatoms selected from O, N or S; heterocyclyl denotes piperidinyl or benzodioxolyl; or a compound or pharmaceutically acceptable salt thereof, selected from a group comprising (4-dimethylaminophenyl)-[4-(4-cyclopropylphenyl)-6-propargyloxyquinazolin-2-yl]methanone, (3-sulphamoylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, [3-(2-hydroxyethanesulphonyl)phenyl]amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methylsulphanylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methanesulphonylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, and (5-ethanesulphonyl-2-hydroxyphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4- dihydroquinazoline -2-carboxylic acid. The invention also relates to a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel benzoquinazoline derivatives, which are useful in treating bone disorders, are obtained.

6 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-alkylamides of formula I

, where A is selected from such groups as -CH2-CH2-, -CH2-CH2-CH2- and -Y-CH2-CH2-, where Y is selected from O, S and NR11 and Y is bonded to a Het group; Het denotes a 5-member or 6-member monocyclic aromatic group which contains one or two identical or different heterocyclic ring elements selected from N, NR13 and S, and which can be substituted with one or more identical or different substitutes R5; X denotes a single bond; R1 and R2 together with a N-CO group which contains them, form a 4-10-member monocyclic or bicyclic saturated or unsaturated ring which, besides a nitrogen ring atom which is part of the N-CO group, can contain one or two additional heterocyclic ring elements selected from N, NR12, O and S, which can be identical or different, provided that two ring elements from O and S cannot be in neighbouring positions in the ring, where the ring, formed by R1 and R2 and the N-CO group containing them, can be substituted with one or more identical or different substitutes R8; R3 is selected from phenyl, naphthalinyl and heteroaryl, which all can be substituted with one or more identical or different substitutes selected from a halogen atom, (C1-C4)alkyl, (C1-C4)alkyloxy group, which can be substituted with one or more fluorine atoms, (C1-C4)alkylamino, di((C1-C4)alkyl)amino, ((C1-C4)alkyl)-CONH-, CONH2, CN, CF3, H2NSO2- and (C1-C4)alkyl-SO2-; R5 is selected from a halogen atom and (C1-C4)alkyl; R8 is selected from a halogen atom, (C1-C4)alkyl and an oxo-group; R11 denotes a hydrogen atom; R12 is selected from a hydrogen atom and (C1-C4)alkyl; R13 is selected from a hydrogen atom and (C1-C4)alkyl; heteraryl is a 5-member or 6-member monocyclic aromatic group which contains one, two or three identical or different heterocyclic ring elements selected from N, NR13, O and S; in any of its stereoisomeric forms or mixture of stereoisomeric forms in any ratio, or its physiologically acceptable salt; provided that the -N(R2)-CO-R1 group cannot be an unsubstituted 2-oxopyrrolidin-1-yl group or unsubstituted 2-oxoimidazolin-1-yl group if the -N(R2)-CO-R1 group simultaneously denotes a group of formula

,

in which the bond through which the group is bonded to group A, is denoted by a line starting from position 2 of the pyridine ring, and in which R90 is selected from imidazol-1-yl, isoxazol-5-yl, isothiazol-5-yl, 1,2,4-thiazol-1-yl, pyrazin-2-yl and pyrazol-3-yl, which can all be substituted with (C1-C4)alkyl and which can be substituted in the pyridine ring with at most four substitutes selected from (C1-C4)alkyl and a halogen atom; and provided that the -N(R2)-CO-R1 cannot be a 1,3-dioxoisoindol-2-yl group of formula

in which the bond through which the group is bonded to group A is denoted by a line beginning from the nitrogen atom. The invention also relates to a method of producing said compounds, a pharmaceutical composition for stimulating endothelia NO synthase, as well as to use thereof in preparing a medicinal agent.

EFFECT: novel compounds which can be used in conditions where high expression of the said enzyme, high content of NO or normalisation of low content of NO is desired are obtained and described.

18 cl, 87 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in which: X denotes S, N-R5 or O; R denotes H; alkyl; heteroaryl, which is a thienyl optionally substituted with alkyl; R1 denotes alkyl; aryl, optionally substituted with a halogen; heteroaryl which is a thienyl optionally substituted with an alkyl, a a halogen, a methoxy group; R2 denotes heteroaryl which is 2-, 3- or 4-pyridyl; R3 denotes H; aryl, optionally substituted with a halogen, a methoxy group; heteroaryl, which is a thienyl optionally substituted with a halogen; alkyl, optionally substituted with oxytetrahydropyranyl; R4 denotes H; R5 denotes H; alkyl; or salt thereof.

EFFECT: invention also relates to a method of producing said compounds, which can be used as antifungal agents for crops, as well as agents against other pests, such as insects or mites and weeds which can harm crops.

10 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

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