Method of producing 3(r)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2,2,2]octane bromide

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

 

The present invention relates to a method for the preparation of 3(R)-(2-hydroxy-2,2-dition-2-RECETOX)-1-(3-phenoxypropan)-1-azoniabicyclo[2.2.2]octane.

This compound and its production method described in WO 01/04118 A2.

According to the invention the authors unexpectedly found that by proper selection of reaction conditions, the method described in WO 01/04118 A2, can be optimized to reduce the time of reaction and the number of used solvents and alkylating reagent with increasing output and low impurity content.

These tasks can be solved by carrying out the quaternization reaction between 1-azabicyclo[2.2.2]Oct-3(R)silt ether 2-hydroxy-2,2-dition-2-luxusni acid and 3-phenoxypropylamine in a solvent or mixture of solvents having a boiling point equal to from 50 to 210°C., and selected from the group including ketones and cyclic ethers. In a preferred embodiment of the present invention use the same solvent.

Below are some examples of ketones and cyclic ethers that can be used as solvents for the implementation of the present invention include acetone, methyl ethyl ketone, methyl isobutyl ketone, phenylmercaptan, Cyclopentanone, dioxane, tetrahydrofuran, utilityserver. Prepositionalphrase selected from the group including acetone, dioxane and tetrahydrofuran. Especially preferred solvent is tetrahydrofuran.

In particular, it is preferable to use the ratio of the number of equivalents of 3-phenoxypropylamine to the number of equivalents of 1-azabicyclo[2.2.2]Oct-3(R)of novogo ester 2-hydroxy-2,2-dition-2-luxusni acid in the range from 1.0 to 3.0, more preferably from 1.1 to 1.5, most preferably from 1.2 to 1.3.

In another preferred embodiment, 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid are suspended (or dissolved) in the amount of solvent or mixture of solvents comprising from 1.7 to 7 l of solvent (solvents) in terms of 1 mol of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid. More preferably, if the ester is suspended (or dissolved) in the amount of the solvent constituting from 1 to 7, preferably from 2 to 4 l in terms of 1 mol of ester.

It is established that under these conditions is sufficient to carry out the reaction in the mixture over a period of time not exceeding 24 hours, preferably not more than 12 hours, more preferably not more than 9 hours, and most preferably up to 6 hours

Especially good results are obtained when 1-azabicyclo[2.2.2]Oct-3(R)silt ether 2-guide the hydroxy-2,2-dition-2-luxusni acid is suspended in tetrahydrofuran, comprising from 2 to 4 l in terms of 1 mol of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid to the resulting suspension were added from 1.2 to 1.3 EQ. 3-phenoxypropylamine and the mixture is stirred for 9 h, preferably not more than 6 hours boiling under reflux in an inert atmosphere.

The following examples are illustrative of the methods of obtaining the compounds proposed in the present invention and do not limit the scope of the present invention.

Experimental section

COMPARATIVE EXAMPLE 1 (in accordance with WO 01/04118)

0.6 mmole 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid are suspended in 4 ml of CH3CN and 6 ml of CHCl3. To the resulting suspension was added to 0.48 ml 3-phenoxypropylamine and the mixture is stirred for 72 h at room temperature in an inert atmosphere. Then the solvent is evaporated and receive (90%) 3(R)-(2-hydroxy-2,2-dition-2-RECETOX)-1-(3-phenoxypropan)-1-azoniabicyclo[2.2.2]octane bromide. The product distinguish by filtration at room temperature and determines that the content of 3-phenoxypropylamine is 117 hours/million

EXAMPLES 2-8

The number of moles of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid listed in column C, suspended in number (column E) process is Italia, specified in column D. Then the resulting suspension is added the number of 3-phenoxypropylamine obtained by multiplying the figures in column C, on the number shown in column C, and the mixture is stirred for 6 h at boiling under reflux in an inert atmosphere. Then the solvent is evaporated and get 3(R)-(2-hydroxy-2,2-dition-2-RECETOX)-1-(3-epoxypropyl)-1-azoniabicyclo[2.2.2]octabrain. The product distinguish by filtration at room temperature and determine the yield and the content of 3-phenoxypropylamine listed in columns F and G, respectively.

The table below shows the data obtained in comparative example 1 and examples 2 to 8, in the present invention.

Table I
AndInDEFG
ExampleThe number of 1-Aza-bicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid (mmol)Relation (EQ.) number 3-phenoxypropan-bromide to the number of 1-azabicyclo[2.2.2] Oct-3(R)silt ester 2-hydroxy-2,2-who Etien-2-luxusni acid SolventSolvent content (l/mol)Output (%)Contents 3 phenoxy-propyl-bromide (h/m)
1*0,65,0CH3CN/CHCl316,790117
271,531,25THF**2,195,0148
371,531,10THF2,192,460
471,531,10Acetone2,1for 95.3152
571,531,25Acetone2,198,7173
671,53 1,25Acetone7,093,760
714,311,50Methyl ethyl ketone2,196,9304
814,311,50Methyl isobutyl ketone3,594,7410
942,921,25Dioxane2,1of 98.231
1071,531,25Methyl-THF2,196,7212
1142,921,25The acetophenone2,198,553
1242,921,25Cyclopent is non 2,194,4167
* Reaction in comparative example 1 is carried out by stirring for 72 h at room temperature
** Tetrahydrofuran

From the data presented in table I, it can be seen that the method proposed in the present invention can reduce the time of reaction and the number of used 3-phenoxypropylamine while increasing output and saving the content of genotoxic impurities 3-phenoxypropylamine at an acceptable level of less than 500 hours/million

1. Method for the preparation of 3(R)-(2-hydroxy-2,2-dition-2-RECETOX)-1-(3-phenoxypropan)-1-azoniabicyclo[2.2.2]octapamine by the reaction of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid and 3-phenoxypropylamine, in which the reaction is carried out in a solvent or mixtures of solvents having a boiling point equal to from 50 to 210°C., and selected from the group including ketones and cyclic ethers.

2. The method according to claim 1, in which the ratio of the number of equivalents of 3-phenoxypropylamine to the number of equivalents of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid is in the range from 1.0 to 3.0.

3. The method according to claim 2, in which the ratio of equivalents is in the range from 1.1 to 1.5.

4. The method according to claim 2, in which the ratio of equivalents is in the range from 1.2 to 1.3.

5. The method according to any preceding paragraph, in which 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid are suspended or dissolved in a volume of solvent or mixture of solvents comprising from 1.7 to 7 l of solvent (solvents) in terms of 1 mol of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid.

6. The method according to claim 5, in which the amount of solvent is from 2 to 4 l in terms of 1 mol of 1-azabicyclo[2.2.2]Oct-3(R)silt ester 2-hydroxy-2,2-dition-2-luxusni acid.

7. The method according to claim 1, wherein the solvent is selected from the group comprising acetone, dioxane and tetrahydrofuran.

8. The method according to claim 7, in which the solvent is tetrahydrofuran.

9. The method according to claim 1, in which the reaction mixture is carried out in a period of time not exceeding 24 hours

10. The method according to claim 9, in which the time period does not exceed 12 hours

11. The method according to claim 10, in which period of time does not exceed 9 hours

12. The method according to claim 11, in which period of time does not exceed 6 hours



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where B represents a hydrogen atom or a group selected from -R1, -OR1, hydroxy, - O(CO)R1, cyano and non-aromatic heterocycle which is a saturated or unsaturated C3-C10carbocyclic ring in which one or more carbon atoms, preferably 1 or 2 carbon atoms, are substituted with oxygen atoms as heteroatoms, where R1 is selected from a group containing hydrogen atoms, C1-C8alkyl, C2-C8alkenyl and C3-C8cycloalkyl, where the alkyl group is unsubstituted or substituted with one or more substitutes selected from halogen atoms and C1-C4alkyl, and where the alkenyl group is unsubstituted or substituted with one or more substitutes selected from C1-C4alkyl, n equals an integer from 0 to 4, A is selected from a group containing -CH2-, -CH=CR3-, -CR3=CH-, -CR3R4-, -O-, -CO-, -O-(CH2)2-O-, where R3 and R4 each independently represents a hydrogen atom or C1-C8alkyl, m equals an integer from 0 to 8, p equals 2, and the bicyclic azonium ring contains a substitute on position 3, including all possible configurations of asymmetrical centres, D is selected from a group containing: or where R5 is selected from a group containing phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, R6 is selected from a group containing 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, C3-C8cycloalkyl, C1-C8alkyl, C2-C8alkenyl and phenylethyl, R7 represents a hydrogen atom or a group selected from hydroxyl, hydroxymethyl and methyl, Q represents a single bond or a group selected from -CH2-, -CH2CH2-, -O-, -O-CH2-, equals an integer from 0 to 3, X represents a pharmaceutically acceptable anion of mono- or polybasic acid, under the condition that the B-(CH2)n-A-(CH2)m- group does not represent a straight C1-4alkyl and that the following compounds are excluded: 1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo[2.2.2]octane and 1-carboxymethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo [2.2.2]octane. The invention also relates to a method of producing formula (I) compounds, to a pharmaceutical composition, to use of compounds in any of paragraphs 1-14, as well as a combined product.

EFFECT: obtaining novel biologically active compounds with antagonistic activity towards muscarine receptors M3.

21 cl, 64 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

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

SUBSTANCE: invention relates to novel derivatives of quinuclidine of the general formula (I):

wherein © represents phenyl ring, (C4-C9)-heteroaromatic group comprising one or some heteroatoms, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 represent hydrogen halogen atom, phenyl and others; n represents a whole number from 0 to 4; A represents group -CH=CR6-, -CR6=CH-, -CR6R7 and others; R6 and R7 represent hydrogen atom, alkyl and others; m represents a whole number from 0 to 8; p represents a whole number from 1 to 2; and a substitute in azoniabicyclic ring can be at position 2, 3 or 4 including all possible configurations of asymmetric carbon atoms; B represents the group of the formula i) or ii) wherein R10 represents hydrogen atom, hydroxyl group or methyl; each R8 and R9 represents: wherein R11 represents hydrogen, halogen atom, alkyl; Q represents a single bond, -CH2- and others; X represents pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess antagonistic activity with respect to muscarinic M3-receptors and can be used in medicine for treatment of diseases wherein muscarinic M3-receptors are implicated.

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

36 cl, 164 ex

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

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: organic chemistry, pharmacology, pharmacy.

SUBSTANCE: invention relates to derivatives of quinuclidine of the general formula (I): wherein B means phenyl, pyrrolyl and other group; each among R1, R2 and R3 represents hydrogen, halogen atom, phenyl group and others; n means a whole number from 0 to 4; A represents the group chosen from -CH2-, -CH=CR9, -CR9R10 and others wherein R9 and R10 represent hydrogen atom or (C1-C8)-alkyl; m means a whole number from 0 to 8 under condition that if m = 0 then A doesn't mean -CH2-; p means a whole number from 1 to 2; R4 represents phenyl or 5-membered heteroaromatic cycle comprising oxygen or sulfur atom; R5 represents (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl and others; R6 represents hydrogen atom, hydroxy-group and others; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess the inhibitory activity with respect to M3-muscarinic receptors and can be used in medicine.

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

34 cl, 2 tbl, 104 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent eliciting immunomodulating, antitumor, bacteriostatic and anti-aggregation properties and representing 1-hexadecyl-R-(-)-3-oxy-1-azoniabicyclo[2.2.2]octane bromide and a method for its synthesis. Method involves quartenization of R-(-)-azabicyclo[2.2.2]octane-3-ol with hexadecyl bromide at heating in organic solvent medium. Agent shows low toxicity, high effectiveness, it doesn't cause allergic effect and doesn't possess cumulative effect.

EFFECT: valuable medicinal properties of agent.

3 cl, 9 dwg, 6 tbl, 2 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: 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, 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, 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, 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

Up!