Pyrrolopyramidines, with inhibiting properties to catepsin k and method of obtaining them (versions)

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

in which R denotes H,

R13 represents (lower)alkyl, C3-C10cycloalkyl or3-C10cycloalkyl(lower)alkyl, each of which is independently optionally substituted by halogen atom, hydroxyl, CN, NO2or optionally mono - or di(lower)alkyl substituted amino group;

R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(lower)alkyl-W-, C3-C10cycloalkyl,3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl-W- (where N is heterocyclyl represents a saturated or aromatic nitrogen-containing heterocyclic residue attached through its nitrogen atom, containing from 3 to 8 ring atoms, optionally additionally containing 1,2 or 3 heteroatoms selected from N, NR6, O, S, and S(O)2where R6 denotes H or optionally substituted lower alkyl, phenyl, where N is heterocyclyl optionally condensed with the formation of the bicyclic structure with a benzene or pyridine ring, and where N is heterocyclyl not necessarily associated in spirotrichous with a 3-8-membered cycloalkyl or heterocyclic ring, where the heterocyclic ring contains from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N, O, S), phthalimide, as oxazolidinone or 2,6-dioxopiperidin, where W denotes-O-, -C(O)-, -NH(R6)-, -NH(R6)-C(O)-, -NH(R6)-C(O)-O-, where R6 is PR is stavlennii above group) -S(O)-, -S(O)2- or-S-,

where R14 optionally substituted by a group R18, which is represented by 1-3 substituents selected from halo, hydroxyl, CN, NO2, oxo-, amide groups, carbonyl sulfonamidnuyu group and dioxymethylene, or optionally substituted (lower)alkoxy, (lower)alkyl, (lower)alkenyl, (lower)alkoxycarbonyl, optionally mono - or di(lower)alkyl substituted by amino, phenyl, phenyl(lower)alkyl, aryl(lower)alkenyl, N-heterocyclyl, N-heterocyclyl(lower)alkyl (where N is heterocyclyl is presented above group) or heterocyclyl(where heterocyclyl is a ring comprising from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, O, S, or R14, including phenyl, contains phenyl condensed with heteroaromatics ring, and

where R18 optionally substituted by a group R19, which is represented by 1-4 substituents selected from halo, hydroxyl, CN, NO2and the carbonyl group, or optionally substituted (lower)alkoxy, (lower)alkyl, (lower)alkoxy(lower)alkyl, C3-C10cycloalkyl, (lower)alkoxycarbonyl, halo(lower)alkyl, optionally mono-or di(lower)alkyl substituted by amino, phenyl, (lower)alkylsulphonyl, formyl, N-heterocyclyl or N-heterocyclyl(lower)alkyl (where N is heterocyclyl seat is no above group)

where R19 optionally substituted by 1-4 substituents selected from halo, hydroxyl, CN, NO2, oxo-, optionally mono - or di(lower)alkyl substituted amino, (lower)alkyl and (lower)alkoxy, or its pharmaceutically acceptable salt or ester.

2. The compound according to claim 1 or its pharmaceutically acceptable salt or ester selected from the following compounds:

derivatives of 6-vinyloxy-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamide, including

6-(6-Chloropyridin-3-intoximeter)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-2-carbonitril,

7-(2,2-Dimethylpropyl)-6-(pyridine-4-intoximeter)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile hydrochloride

6-(2-Diformylpiridine-4-intoximeter)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(6-methoxypyridazine-3-intoximeter)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Cyclohexyl-6- [4-(4-methylpiperazin-1-ylmethyl)phenoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-methylpiperazin-1-ylmethyl)phenoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(6-Chloropyrimidine-4-intoximeter)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[6-(4-methylpiperazin-1-yl)pyrimidine-4-intoximeter]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Di is ethylpropyl)-6-(6-morpholine-4-Yeremey-4-intoximeter)-7H-pyrolo[2,3-d]pyrimidine-2-carbonitrile,

derivatives of 6-phenylamino-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, including

6-[[(4-Chlorophenyl)methylamino]methyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[(4-Chloropyrimidine-2-ylamino)methyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

N-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]-4-perbenzoic,

derivatives of 6-phenylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, including

7-(2,2-Dimethylpropyl)-6-(pyridine-2-ylsulphonyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-Cyclopentanecarbonyl-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-Cyclohexanesulfonyl-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

derivatives of 6-azole-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, including

7-(2,2-Dimethylpropyl)-6-imidazol-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(3-nitro-[1,2,4]triazole-1-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidine-2-carbonitrile,

6-(3-Amino[1,2,4]triazole-1-ylmethyl)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

N-{1-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]-1H-[1,2,4]triazole-3-yl}-2-piperidine-1-ylacetamide,

7-(2,2-Dimethylpropyl)-6-tetrazol-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-tetrazol-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[5-(4-hydroxymethylene)tetrazol-2-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[5-(4-piperidine-1-ylmethylene)tetrazol-2-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

derivatives of 6-piperazinil-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, including

7-(2,2-Dimethylpropyl)-6-[4-(2-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(4-Acetylphenyl)piperazine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d)pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(5-ethylpyrimidine-2-yl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(2-methyl-4-nitrophenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(6-herperidin-3-yl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-piperazine-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(2-fluoro-4-were)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-fluoro-2-were)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

4-[2-Cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]piperazine-1-carboxamidine,

7-(2,2-Dimethylpropyl)-6-[4-(4-terbisil)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-Butylpiperazine-1-ylmethyl)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

N-(4-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]piperazine-1-yl}phenyl)methanesulfonamide,

7-(2,2-Dimethylpropyl)-6-[4-(4-trifloromethyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6- [4-(4-triptoreline)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2,4-Acid)piperazine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(3,4-Dimetilfenil)piperazine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2,6-Dimetilfenil)piperazine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-ethoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-Cyclopentylpropionyl-1-ylmethyl)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(2-ethoxyethyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(3-methoxyp who yl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(2-methoxyethyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(4-phenylpiperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-ethoxy-2-forfinal)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-{4-[2-fluoro-4-(2-hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2,4-Acid)piperidine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[4-(2-Dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(3-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[4-(2-dimethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[3-(2-dimethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[2-(2-dimethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[4-(2-diethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[3-(2-diethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-(2,2-dimethylpropyl the l)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[2-(2-diethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{2-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl} piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{2-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[4-(2-pyrrolidin-1 ylethoxy)phenyl]piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[3-(2-pyrrolidin-1 ylethoxy)phenyl]piperazine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[2-(2-pyrrolidin-1 ylethoxy)phenyl]piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[4-(2-hydroxyethoxy)phenyl]Pipera the Jn-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[3-(2-hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[2-(2-hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(2-piperidine-1-retil)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2-diethylaminoethyl)piperazine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(1-methylpiperidin-4-yl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-[4-(4-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-[4-(3-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(4-Ethoxyphenyl)piperazine-1-ylmethyl]-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2,4-acid)piperazine-1-ylmethyl]-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[3-(2-diethylaminoethoxy)phenyl]piperazine-1-ylmethyl}-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-(4-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-(4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl--(4-{2-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperazine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[4-(2-Hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(4-Methoxyphenyl)piperazine-1-ylmethyl]-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(3-Methoxyphenyl)piperazine-1-ylmethyl]-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2,4-acid)piperazine-1-ylmethyl]-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-[4-(4-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-[4-(3-methoxyphenyl)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-[4-(2,4-acid)piperazine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

derivatives of 6-piperidinylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, including

7-(2,2-Dimethylpropyl)-6-(4-oxopiperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(4-hydroxylaminopurine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-Aminopiperidin-1-ylmethyl)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(3-imidazol-1-ylpropionic)piperidine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

Phenylamide 1-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]piperidine-4-arbonboy acid,

7-(2,2-dimethylpropyl)-6-(1,1-dioxo-116-thiomorpholine-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile;

6-(4-[4-(2-dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(4-methoxyphenyl)piperidine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(2,4-acid)piperidine-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(3,4,5-trimethoxyphenyl)piperidine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-[4-(2-dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-[3-(2-dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[2-(2-dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[4-(2-diethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[3-(2-diethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-[2-(2-diethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{4-[2-(4-metile erasin-1-yl)ethoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{2-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-(4-{2-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[4-(2-pyrrolidin-1 ylethoxy)phenyl]piperidine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[3-(2-pyrrolidin-1 ylethoxy)phenyl]piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-{4-[2-(2-pyrrolidin-1 ylethoxy)phenyl]piperidine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-dimethylpropyl)-6-[4-(2-{3-[4-(2-hydroxyethyl)piperazine-1-yl]propoxy}phenyl)piperidine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(3-methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]eirenicon-2-carbonitril,

7-(2,2-Dimethylpropyl)-6-(1-methyl-2,4-dioxo-propyl-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(3-methyl-2,4-dioxo-1-propyl-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(3-methyl-2,4-dioxo-1-propyl-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(1-ethyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(2,4-dioxo-3-propyl-1-oxa-3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-(3-methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-[4-(4-methoxyphenyl)piperidine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-{4-[4-(2-dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-[4-(2-diethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-(4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-(4-{3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}piperidine-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Isobutyl-6-{4-[4-(2-pyrrolidin-1 ylethoxy)phenyl]piperidine-1-ylmethyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(3-Methylbutyl)-6-(3-methyl-2,4-dioxo-1,3,8-t is azaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[4-(4-Methoxyphenyl)piperidine-1-ylmethyl]-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-(3-methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-[4-(4-methoxyphenyl)piperidine-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

derivatives of 6-benzyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, including

6-Benzyl-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-naphthalene-2-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-Chlorobenzyl)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d|pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-[4-(4-methylpiperazin-1-yl)benzyl]-7H-pyrrolo[2,3-d|pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-(4-hydroxymethylbenzene)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-(4-Bromomethylphenyl)-7-cyclohexyl-7H-pyrrolo[2,3-d)pyrimidine-2-carbonitrile,

7-Cyclohexyl-6-(4-diethylaminomethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-ethylpiperazin-1-ylmethyl)benzyl]-7H-pyrrolo[2,3-d|pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(4-[1,2,4]triazole-1-iletileri)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(morpholine-4-CT is of IMT)benzyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

N-[4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}methanesulfonamide,

N-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}methanesulfonamide,

6-(4-Aminobenzyl)-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(4-pyrrol-1-ylbenzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

{4-[2-Cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}amide butane-1-sulfonic acid,

N-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}-N-methylmethanesulfonamide,

N-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}acetamide", she

N-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}of butyramide,

N-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]phenyl}succinamide acid,

N-{4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]|pyrimidine-6-ylmethyl]phenyl}succinamide acid,

phthalimide, hydantoine, oxazolidinone and 2,6-dioxopiperidin derivatives, including

7-(2,2-Dimethylpropyl)-6-(1,3-dioxo-1,3-dihydroindol-2-ylmethyl)-7H-pyrrolo[2,3-d)pyrimidine-2-carbonitrile,

N[-(2-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]|pyrimidine-6-ylmethyl]1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-C]pyridine-5-yl}methanesulfonamide,

7-(2,2-Dimethylpropyl)-6-(3-methyl-1,4-dioxo-3,4-dihydro-1H-phthalazine-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[3-(4-Chlorobenzyl)-2,5-dioxoimidazolidin-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-[(R)-3-(4-Chlorobenzyl)-4-isopropyl-2,5-dioxoimidazolidin-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d|pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(2,4,8,8-tetraoxo-1-oxa-8λ6-thia-3-azaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(2,4-dioxo-1-oxa-3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

2,2,2-Trichlorethylene ester of 3-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]-2,4-dioxo-1-oxa-3,8-diazaspiro[4,5]decane-8-carboxylic acid,

7-(2,2-Dimethylpropyl)-6-(2,4-dioxo-1-oxa-3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(8-ethyl-2,4-dioxo-1-oxa-3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(8-methanesulfonyl-2,4-dioxo-1-oxa-3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(1-methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d|pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(1-methyl-2,4-dioxo-8-propyl-1,3,8-diazaspiro[4,5]Dec-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile.

7-(2,2-Dimethylpropyl)-6-(2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(2,4-dioxo-8-propyl-1,3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(2,4-dioxo-8-pyrimidine-2-yl-1,3,8-diazaspiro[4,5]Dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

tert-Butyl ester 4-[2-cyano-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-6-ylmethyl]for 3,5-dioxopiperazinyl-1-carboxylic acid,

7-(2,2-Dimethylpropyl)-6-(2,6-dioxo-4-phenolsulfonephthalein-1-ylmethyl)-7H-pyrrolo[2,3-d|pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-(2,6-dioxopiperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

6-|4-(butane-1-sulfonyl)-2,6-dioxopiperidin-1-ylmethyl]-7-(2,2-dimethylpropyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

7-(2,2-Dimethylpropyl)-6-[4-(4-forfinal)-2,6-dioxopiperidin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile,

8-methyl bromide-9-(2,2-dimethylpropyl)-N-purine-2-carbonitrile,

9-(2,2-dimethylpropyl)-8-methyl-N-purine-2-carbonitrile,

8-Benzyl-9-(2,2-dimethylpropyl)-N - purine-2-carbonitrile,

9-(2,2-dimethylpropyl)-8-[4-(3-methoxyphenyl)piperazine-1-ylmethyl]-N-purine-2-carbonitrile,

9-(2,2-dimethylpropyl)-8-[4-(4-ethoxyphenyl)piperazine-1-ylmethyl]-N-purine-2-carbonitrile,

8-[4-(2,4-dimethoxy the Nile)piperazine-1-ylmethyl]-9-(2,2-dimethylpropyl)-N-purine-2-carbonitrile,

9-(2,2-dimethylpropyl)-8-{4-[4-(2-hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-N-purine-2-carbonitrile,

9-(2,2-dimethylpropyl)-8-[4-(4-methoxyphenyl)piperidine-1-ylmethyl]-N-purine-2-carbonitrile,

8-{4-[4-(2-dimethylaminoethoxy)phenyl]piperidine-1-ylmethyl}-9-(2,2-dimethylpropyl)-N-purine-2-carbonitrile,

9-(2,2-dimethylpropyl)-8-(3-methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-N-purine-2-carbonitrile,

9-Isobutyl-8-[4-(3-methoxyphenyl)piperazine-1-ylmethyl]-N-purine-2-carbonitrile,

8-{4-[4-(2-Hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-9-isobutyl-N-purine-2-carbonitrile,

8-[4-(2,4-acid)piperazine-1-ylmethyl]-9-isobutyl-N-purine-2-carbonitrile,

9-Isobutyl-8-(3-methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-N-purine-2-carbonitrile,

8-Methyl-9-phenyl-N-purine-2-carbonitrile,

8-[4-(4-Ethoxyphenyl)piperazine-1-ylmethyl]-9-phenyl-N-purine-2-carbonitrile,

8-{4-[4-(2-Hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-9-phenyl-N-purine-2-carbonitrile,

8-(3-Methyl-2,4-dioxo-1,3,8-diazaspiro[4,5]Dec-8-ylmethyl)-9-phenyl-N-purine-2-carbonitrile,

9-Cyclohexylmethyl-8-methyl-N-purine-2-carbonitrile,

9-Cyclohexylmethyl-8-{4-[4-(2-hydroxyethoxy)phenyl]piperazine-1-ylmethyl}-N-purine-2-carbonitrile,

9-Cyclohexylmethyl-8-[4-(4-ethoxyphenyl)piperazine-1-ylmethyl]-N-purine-2-carbonitrile,

9-Cyclohexyl the Il-8-[4-(2,4-acid)piperazine-1-ylmethyl]-N-purine-2-carbonitrile,

3. A method of obtaining a compound according to claim 1, where W denotes-O-, -S-, -NH(R6)-, with the exception of compounds where R14 and R6 is not hydrogen, and R14=R14' is optionally substituted phenyl, corresponding to the formula V':

where R13 has the above significance, and R14' has the values specified above for R14, and/or its pharmaceutically acceptable salt or a complex ester, including interaction haloesters the compounds of formula XI

where R13 has the above value, and the Halo signifies halogen, preferably a bromine atom, with a corresponding hydroxy-, amino - or mercaptoethanol containing residue R14', followed, if necessary, converting the resulting product into another compound of formula I or its pharmaceutically acceptable salt or ester.

4. A method of obtaining a compound according to claim 1, in which R14 has the values specified for R14 and denotes the corresponding optionally substituted phenyl or azole attached through its nitrogen atom, corresponding to the formula V '

where R13 has the meanings indicated in claim 1, and R14 has the values listed above,and/or its pharmaceutically acceptable salt or a complex ester, comprising the cyclization of the corresponding Hairdryer is l-l-npon-2-in or azole-1-prop-2-in formula XII with 5-galerimizin-2-carbonitrile compound of formula XIII

where Halo in a preferred embodiment denotes Br, a, R13 and R14 have the above values; followed, if necessary, converting the resulting product into another compound of formula I or its salt or ester.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

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

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to salts sulfoxides derived, namely the hydrochloride or the fumarate of 1-{ 2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholine-2-yl] ethyl} Spiro[benzo(C)thiophene-1(3H),4'-piperidine]-(2S)-oxide, which have a good absorption when taken orally and demonstrate excellent antagonistic activity as receptor NK1and receptor NK2

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

The invention relates to new derivatives of galantamine General formula I:

where R1-R5, G1-G3and W have the meanings indicated in the claims, and the invention relates to a method for producing these compounds, medicinal product and the method of its production

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione
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