Chinuclidin derivatives and pharmaceutic composition thereof

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

 

The text descriptions are given in facsimile form.

1. The compound of the formula I

in the form of a salt or zwitter-ion battery,
where R1and R3independently of one another denote phenyl, C3-C8cycloalkyl or thienyl group,
R2denotes halogen or hydroxy-group;
R4represents C1-C8alkyl, substituted-NR5-CO-R6or-CO-NR9R10;
R5denotes hydrogen;
R6represents C1-C8alkyl or C1-C8alkoxy, each of which is optionally substituted 5 - or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,
or
R6refers to a 5-10 membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur;
R9denotes hydrogen or C1-C8alkyl;
R10represents C1-C8alkyl, optionally substituted by cyano, C1-C8alkoxygroup or 5 - or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,
or
R10indicates 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur.

2. The compound according to claim 1, in which
R1and R3independently of one another denote phenyl or thienyl group,
R2denotes halogen or hydroxy-group;
R4represents C1-C8alkyl, substituted-NR5-CO-R6or-CO-NR9R10;
R5denotes hydrogen;
R6represents C1-C4alkyl or C1-C4alkoxy, each of which is optionally substituted 5 - or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,
or
R6refers to a 5-10 membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur;
R9denotes hydrogen or C1-C8alkyl;
R10represents C1-C4alkyl, optionally substituted by cyano, C1-C4alkoxygroup or 5 - or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulfur,
or
R10denotes a 5 - or 6-membered heterocyclic group containing at least one ring gets what roath, selected from nitrogen, oxygen and sulphur.

3. The compound according to claim 1, which is a compound of formula XIV

in which R1, R2, R3and R4take the values listed in the table below:



4. The compound according to claim 1, which is a compound of formula XIV

in which R1, R2, R3and R4take the values listed in the table below:

5. The compound according to claim 1, which represents bromide (R)-3-(2-hydroxy-2,2-diphenylacetate)-1-(isoxazol-3-ylcarbonyl)-1-azoniabicyclo[2.2.2]octane.

6. Pharmaceutical composition for treating inflammatory or obstructive diseases of the respiratory tract, comprising as active ingredient a compound according to any one of claims 1 to 5.

7. The use of compounds according to any one of claims 1 to 5 to obtain drugs for the treatment of condition mediated by the action of the muscarinic M3 receptor.

8. The use of compounds according to any one of claims 1 to 5 to obtain drugs for treatment in palielinamo or allergic conditions in particular inflammatory or obstructive diseases of the respiratory tract.

9. The method of obtaining the compounds of formula I according to claim 1, including
(i) the interaction of the compounds of formula II

or a protected form, in which R1, R2and R3have the meanings indicated in claim 1, with a compound of formula III
,
in which R4matter specified in claim 1 and X denotes a chlorine, bromine or iodine; and
(ii) isolation of the product in the form of a salt or zwitter-ion battery.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers and new polymers based on such monomers, intended for use in making two-photon photochromic recording media for three dimensional optical memory and photoswitches of optical signals. Description is given of monomers

Q=; ; ;

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H and X=CH2, O, S, NAlk; Y=O, S, NAlk; n=0-6; Q=; ; ; ; ;

Alk=CH3-C10H21, methods of obtaining them, photochromic polymers based on them, method of obtaining photochromic monomers and their application. The proposed materials exhibit thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

EFFECT: obtaining materials with thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

15 cl, 46 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: chemistry.

SUBSTANCE: ergot alkaloid is extracted from ergot with high yield and purity level using method including extraction of Claviceps purpurea, i.e. ergot, mix of solvents toluene/ethanol that leads to production of primary extract. The primary extract can be additionally treated within two stages of liquid-liquid extraction to provide alkaloid purification that gives purified toluene extract. Toluene extract can be additionally partially softened by stream, and crystalline product is produced by toluene crystallisation or mixture of toluene and aliphatic hydrocarbon.

EFFECT: development of method of ergot extraction with high yield and purity level.

23 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds of formula I which can be used in photopolymer composition hardening with catalyst, possible during rays, and as photoinitiators for coating preparation. In formulas (I) and (II) $ , in which R1 denotes phenyl, naphthyl, phenanthryl, anthryl, pyrenil 5,6,7,8-tetrahydro-2-naphthyl,5,6,7,8-tetrahydro-1-naphthyl, thienyl, tiantrenyl, anthraquinonyl, xantenyl, thioxantyl, phenoxantyinyl, carbazol, phenantridinyl, akridinyl, fluorenyl or phenoxazinyl, besides radicals is unsubstituted or once or several times substituted by C1-C18alkyl, C2-C18alkenyl, C1-C18haloalkyl, NO2, NR10R11, CN, OR12, SR12, halogen atom or radical of formula II or radical R1 denotes radical of formula III . R2 and R3 independently denote a hydrogen atom; R10, R11 R12 independently denote a hydrogen atom or C1-C18alkyl; R4 and R6 form C2-C12alkylen bridge, which is not substituted or substituted by or several C1-C4alkyl radicals; R15 denotes H or radical of formula II.

EFFECT: production of the nitrogen bases that can be used as a photopolymer composition, hardening with catalyst, and as photoinitiator for coating.

11 cl, 4 tbl, 21 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for synthesis of compounds of the formula (I): wherein one of substitutes A or B means hydrogen atom (H) and another one means aryl substituted optionally with one or two R2, heteroaryl substituted optionally with one or two R2, and so on; R represents H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl or -CHR3-OCO-(C1-C6)-alkyl or salt; R2 represents hydrogen atom, optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, and so on; R3 represents hydrogen atom, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Method for synthesis of these compounds involves the following steps: (a) condensation of substituted aldehyde of the formula: (A'-CHO) (17) wherein A' represents A, such as given above when B represents hydrogen atom; or B, such as given above when A represents hydrogen with derivative of 6-bromopenem of the formula (16): wherein R represents p-nitrobenzyl in the presence of Lewis acid and a weak base at low temperature that results to formation of intermediate aldol product of the formula (18): ; (b) interaction of intermediate compound of the formula (18) with chloroanhydride or acid anhydride of the formula: (R8)Cl or (R8)2O or with tetrahalogen methane of the formula: C(X1)4 and triphenylphosphine wherein R8 represents alkyl-SO2, aryl-SO2, alkyl-CO or aryl-CO; X1 represents Br, J or Cl atoms to form intermediate compound of the formula (19): wherein R9 represents X1 or -OR8, and conversion of intermediate compound of the formula (19) to the end compound of the formula (I). Also, invention relates to 4-nitrobenzyl-(5R,6S)-6-bromopenem-3-carboxylate of the formula (16) and to a method for its synthesis. Method involves the following steps: (A) (i) interaction of 6-aminopenicillanic acid with hydrobromic acid in organic solvent and water to form 6-bromopenicillanic acid of the formula (21): and its conversion to p-nitrobenzyl-6-bromopenicillanate of the formula (22): wherein R represents p-nitrobenzyl by interaction with 4-nitrobenzyl bromide in the presence of a base in organic solvent; (B) oxidation of compound of the formula (22) to form p-nitrobenzyl-6-bromopenicillanate-1-oxide of the formula (23) given in the invention description; (C) boiling compound of the formula (23) with 2-mercaptobenzothiazole in aromatic solvent to form 4-nirobenzyl-(2R)-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-3-enoate of the formula (24) given in the invention description; (D) dissolving compound of the formula (24) in organic solvent and interaction with an organic tertiary base to form 4-nitrobenzyl-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (25) given in the invention description; (E) conversion of compound of the formula (25) to 4-nitrobenzyl-2-[(3S,4R)-3-bromo-4-formylthio-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (26) given in the invention description as result of interaction of with organic acid in aromatic organic medium in the presence of a mixture acetic anhydride/organic tertiary base and trialkyl- or triarylphosphine in the range of temperature from about -10°C to about -30°C, and (F) passing ozonized oxygen through solution of compound of the formula (26) in organic solvent for 3-4 h at temperature from -70°C to -90°C and the following the intramolecular cyclization reaction using a phosphite reagent. Invention provides the increased yield and economy method for synthesis of derivatives of 6-alkylidenepenem.

EFFECT: improved method of synthesis.

41 cl, 2 tbl, 42 ex

FIELD: organic chemistry, medicine, pharmacy, biochemistry.

SUBSTANCE: invention relates to a method for treatment of states caused by activity of p38 kinase. Method involves administration to a patient needed in this treatment of at least one compound of the formula (I): or its pharmaceutically acceptable salt or solvate wherein R3 means hydrogen atom, methyl, perfluoromethyl, methoxy-group, halogen atom, cyano-group or NH2-group; X is chosen from -O-, -OC(=O)-, -S-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2-, -NR10-, -NR10C(=O)-, -NR10C(=O)NR11-, -NR10CO2-, -NR10SO2-, -NR10SO2NR11-, -SO2NR10-, -C(=O)NR10, halogen atom, nitro- and cyano-group, or X is absent; Z is chosen from oxygen (O), sulfur (S), nitrogen (N) atoms, and -CR20 being wherein Z means -CR20 optionally substituted bicyclic aryl or heteroaryl with R4 or R5; R1 means hydrogen atom, -CH3, -OH, -OCH3, -SH, -SCH3, -OC()=O)R21, -S(=O)R22, -SO2NR23R25, -CO2R21, -C(=O)NR24R25, -NH2, -NR24R25, -NR21SO2NR24R25, -NR21SO2R22, -NR24C(=O)R25, -NR24CO2R25, -NR21C(=O)NR24R25, halogen atom, nitro- or cyano-group; R2 is chosen from the following group: (a) hydrogen atom under condition that R2 doesn't mean hydrogen atom if X means -S(=O)-, -SO2-, -NR10CO2- or -NR10SO2-; (b) alkyl, alkenyl and alkynyl comprising up to four R26 groups or pentafluoroalkyl as substitutes; (c) aryl and heteroaryl comprising up to three groups R27 as substitutes, and (d) heterocyclo-group or heteroalkyl optionally comprising keto-group (=O), up to three groups R27 as substitutes, and/or comprising carbon-carbon bridge comprising 3-4 carbon atoms, or (e) R2 is absent if X means halogen atom, nitro- or cyano-group; R4 means substituted aryl, aryl comprising NOSE-alkyl, substituted heteroaryl or optionally substituted bicyclic 7-11-membered saturated or unsaturated carbocyclic or heterocyclic fragment as a substitute, and R5 means hydrogen atom, alkyl or substituted alkyl with exception of cases when Z means O or S and then R5 is absent, or R4 and R5 in common with Z form optionally substituted bicyclic 7-11-membered aryl or heteroaryl; R6 means hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group, substituted heterocyclo-group, -NR7R8, -OR7 or halogen atom; R10 and R11 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo-group and substituted heterocyclo-group; R7, R8, R21, R24 and R25 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group and substituted heterocyclo-group; R20 means hydrogen, lower alkyl or substituted alkyl, or R20 can absent if carbon atom to which is bound and in common with R4 and R5 represents part of bicyclic aryl or heteroaryl; R22 means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group or substituted heterocyclo-group; R26 is chosen from the following group: halogen atom, trifluoromethyl, halogenalkoxy-group, keto (=O)-, nitro-, cyano-group, -SR28, -OR28, -NR28R29, -NR28SO2, -NR28SO2R29, -SO2R28, -SO2NR28R29, -CO2R28, -C(=O)R28, -C(=O)NR28R29, -OC(=O)R28, -C(=O)NR28R29, -NR28C(=O)R29, -NR28CO2R29,=N-OH, =N-O-alkyl; aryl optionally comprising as a substitute from one to three R27 groups; cycloalkyl optionally comprising a substituted keto-group (=O), from one to three R27 groups, or carbon-carbon-containing bridge comprising of 3-4 carbon atoms; and heterocyclo-group comprising optionally as a substitute keto-group (=O), from one to three R27 groups or comprising carbon-carbon bridge comprising 3-4 carbon atoms, and wherein each R28 and R29 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl and (C3-C7)-heterocycle, or they can form in common (C3-C7)-heterocycle; and each R28 and R29, in turn, can comprise optionally up to two substitutes representing alkyl, alkenyl groups, halogen atoms, halogenalkyl groups, halogenalkoxy-, cyano-, nitro-, amino-, hydroxy-, alkoxy-, alkylthio-groups, phenyl, benzyl, phenyloxy- and benzyloxy-groups; and R27 is chosen from the following group: alkyl, R32 and (C1-C4)-alkyl comprising as substitutes from one to three R32groups and wherein each R32 group is chosen independently from the following group: halogen atom, halogenalkyl, halogenalkoxy-, nitro-, cyano-groups, -SR30, -OR30, -NR30R31, -NR30SO2, -NR30SO2R31, -SO2R30, -SO2NR30R31, -CO2R30, -C(=O)R30, -C(=O)NR30R31, --OC(=O)R30, -OC(=O)NR30R31, -NR30C(=O)R31, -NR30CO2R31 and from 3-7-membered carbocyclic or heterocyclic ring comprising optionally as a substitute alkyl, halogen atom, hydroxy-, alkoxy-group, halogenalkyl, halogenalkoxy-, nitro-, amino- or cyano-group, and wherein each R30 and R31 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl, and heterocycle, or they in common can form (C3-C7)-heterocycle. Also, invention describes pyrrolotriazine compounds, a pharmaceutical composition based on thereof and a method for treatment of inflammatory diseases using above proposed compounds and pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 14 tbl, 152 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns the method of obtaining of a Solifenacin composition or its salts for use in a solid preparation which includes at least one stage chosen of the group consisting of (i) stage of wet granulation with use of a dissolvent for Solifenacin or its salts, thereat quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent makes less than 0.1 mg, (ii) stage of dicrease of quantity or rate of addition of a dissolvent if the dissolvent moves Solifenacin or its salt in an amorphous condition, and quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent 10 mg or more and (iii) stage of activisation of process of crystallisation of a composition of the wet granulation received by means of a usual way. Also the pharmaceutical composition for use in the solid preparation, showing selective opposing action against muscarinic M3 receptors is revealed.

EFFECT: rising of stability of the compositions containing Solifenacin or its salt.

12 cl, 3 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1-azabicycloalkyl of general formula I, , in which X represents CH2 or simple bond; Y represents group of formula or and, where R has values given in description, which are agonists of alpha 7 nicotine acetylcholine receptor (nAChR).

EFFECT: possibility of using as pharmaceutical preparations.

18 cl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel quinuclidine derivatives and their using as pharmaceutical agents. Based on their pharmacological pattern proposed compounds can be useful in treatment of different diseases and disorders associated with cholinergic system of the central nervous system, peripheral nervous system, diseases and disorders associated with contraction of smooth muscle, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and abstinence syndrome caused by ceasing use of chemical substances.

EFFECT: valuable medicinal properties of compounds.

11 cl, 1 tbl, 46 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 1-(2S,3S)-2-benzhyryl-N-(5-tert.-butyl-2-methoxybenzyl)quinuclidin-3-amine (further named in the claim as "compound of the formula (I)" ) and its pharmaceutically acceptable salts. Invention relates to an improved method of synthesis of citrate monohydrate salt of compound of the formula (Ia):

EFFECT: improved method of synthesis.

10 cl, 2 sch,

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds selected from 3(R)-(2-hedroxy-2,2-dithiene-2yl acetoxy)-1-(3-phenoxypropyl)-1-azoaniabicyclo[2,2,2]octane,X-, and 1-phenerhyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoaniabicyclo[2,2,2]octane,X-, wherein X- represents pharmaceutically acceptable anion of mono- or polyvalen acid having inhibiting activity in relates to muscarinic M3 receptors. Also disclosed are pharmaceutical compositions containing such compounds and method for treatment of respiratory diseases.

EFFECT: new quinuclidine analogs useful in treatment of respiratory diseases.

20 cl, 1 tbl, 184 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carbamate of the formula (I): or to their pharmaceutically acceptable salts wherein R1 represents compounds of formulas: , , , ,

, , , or ; R3 means hydrogen, halogen atom or alkyl; R2 means benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophene-2-ylmethyl, thiophene-3-ylmethyl or alkyl; p = 1 or 2, and substitution in azabicyclic ring can be at position 2, 3 or 4. Compounds of the formula (I) and their salts possess inhibitory activity with respect to muscarinic M3 receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

25 cl, 1 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

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