Ligands of nicotine receptor α, their obtaining and application

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

 

This application claims earlier priority based on provisional application U.S. ser. room 60/637771, registered on December 22, 2004, full details of which are included in the description of the application as references.

The technical field to which the invention relates.

In General the present invention relates to ligands of nicotinic acetylcholine receptors (nAChR), to activation of the nAChR and treatment of pathological conditions associated with insufficient or impaired function of the nicotinic acetylcholine receptors, especially of the brain. In addition, the invention relates to new compounds, which act as ligands of α7 nAChR, to methods of producing such compounds, to compositions comprising such compounds, and to methods of their use.

Background of invention

There are two types of receptors of the neurotransmitter acetylcholine: muscarinic receptors and nicotinic receptors that function through selective action of muscarine and nicotine, respectively. Muscarinic receptors coupled with G-protein. Nicotinic receptors are members of a family of ligand-gated ion channels. Upon activation of this receptor increases the conductance of ions through nicotinic ion channels.

Protein nicotinic receptor α-7 forms in vitro homopentameric ka is al, highly permeable to many cations (such as CA++). Every nicotinic receptor α-7 consists of 4 transmembrane domain, called M1, M2, M3 and M4. It is considered that the domain of the M2 forms a wall of the channel. Analysis of the amino acid sequence shows a high conservatism nicotinic receptor α-7 in the process of evolution. Currently defined primary structure forming a channel domain M2 chicken and human. In more detail the structure and function of the receptor α-7 are described in the following publications: Revah and others, Nature, 353, 846-849 (1991), Galzi and other, Nature 359, 500-505 (1992), Fucile and others, PNAS 97(7), 3643-3648 (2000), Briggs and others, Eur. J. Pharmacol., 366 (2-3), 301-308 (1999), and Gopalakrishnan and others, Eur. J. Pharmacol., 290(3), 237-246 (1995).

Nicotinic receptor channel α-7 is expressed in different parts of the brain and is thought to be involved in many important biological processes in the Central nervous system (CNS), including learning and memory. Nicotinic receptors α-7 is localized on presynaptic and postsynaptic endings and is thought to participate in the modulation of synaptic transmission signal. Therefore, the development of new compounds that act as ligands nAChR α-7, is of interest in connection with the treatment of pathological conditions associated with insufficient or impaired function of the nicotinic acetyl is olenovich receptors.

Summary of the invention

The present invention relates to new compounds, which act as ligands nAChR α-7, to methods of producing such compounds, to compositions comprising such compounds, and to methods of their use.

Detailed description of preferred embodiments of the invention

The present invention includes compounds of formula I:

where X1-X4every means independently N or CR1and at least one of the

X1-X4means N

In means-C(O)-O - or-C(O)-NH-CH2-,

Y represents O, S or NH,

R1means N

With1-C4alkyl or C2-C4alkenyl, which is in each case unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, OR2, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4, Ar, Het, or combinations thereof (e.g., CH3With2H5, CF3With2H3or3H5),

With2-C4quinil, unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, OR2, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4Si(C1-C6alkyl)3, Ar, Het, or combinations thereof (for example, C2H, C3H3),

With1-C4alkoxy, unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, OR2, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4, Ar, Het, or combinations thereof (e.g., co3OS2H5, F3F2);

Ar, Het, halogen (such as F, Cl, Br, I), CN, NO2, NR3R4, SR4, SOR4, SO2R4, SO2NR3R4, NR3SO2R4, CONR3R4, CSNR3R4, COOR4, NR3COR4, NR3CSR4, NR3CONR3R4, NR3CSNR3R4, NR3COOR4, NR3CSOR4, OCONR3R4or OCSNR3R4;

R2means N

C1-C6alkyl, C3-C8cycloalkyl or4-C8cycloalkenyl, in each case unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, IT,1-C4alkoxy, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4, Ar, Het, or combinations thereof (e.g., CH3With2H , CF3cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl etc.),

R3and R4each independently mean H,

C1-C6alkyl or C3-C6alkenyl, which is in each case unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino (e.g., diethylamino)3-C8cycloalkyl, Ar, Het, or combinations thereof (e.g., CH3With2H5, CF3With2H3or3H5)3-C6quinil, unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1With6alkyl)amino (e.g., diethylamino)3-C8cycloalkyl, Si(C1-C6alkyl)3, Ar, Het, or combinations thereof (for example, C2H, C3H3),

With3-C8cycloalkyl, unsubstituted or substituted by one or more substituents selected from the group comprising F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1With6alkyl)amino (e.g., diethylamino)3-C8cycloalkyl, Ar, Het, or combinations thereof (for example, cyclepro the sludge, cyclobutyl, cyclopentyl),

With4-C10cycloalkenyl, unsubstituted or substituted in cycloalkyl group one or more substituents selected from the group comprising F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino (e.g., diethylamino)3-C8cycloalkyl, Ar, Het, or combinations thereof, and/or substituted in the alkyl group by one or more substituents selected from the group comprising F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino (e.g., diethylamino)3-C8cycloalkyl, Ar, Het, or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl etc.), Ar or Het,

Ar means6-C10aryl, unsubstituted or substituted by one or more substituents selected from the group comprising From1-C8alkyl, C2-C8alkenyl,2-C8quinil,3-C8cycloalkyl,4-C10cycloalkenyl,1-C8alkoxy, halogen (F, Cl, Br or I, preferably F or Cl), amino, cyano, hydroxyl, nitro, halogen(C1-C8)alkyl, halogen(C1-C8)alkoxy, hydroxy(C1-C8)alkyl, hydroxy(C2-C8)alkoxy, C3-C8alkenylacyl, mono(C1-C8alkyl)am is but di(C1-C8alkyl)amino, C3-C7cyclooctylamino,4-C8cycloalkylation, carboxy, alkoxycarbonyl, alkylaminocarbonyl, acylamino (e.g., acetamido), acyloxy (for example, acetoxy), C1-C8alkylthio,1-With8alkylsulfonyl,1-C8alkylsulfonyl, sulfo, sulfonylamino,6-C10aryl (e.g. phenyl, naphthyl, biphenyl), unsubstituted or substituted by one or more substituents selected from the group including halogen (F, Cl, Br or I, preferably F or Cl), C1-C8alkyl, halogen(C1-C8)alkyl, C1-C4alkoxy, amino, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, cyano, hydroxy, nitro, oxo or thio; heterocyclic group, a fully saturated, partially saturated or fully unsaturated, containing at cycle 5 to 10 atoms, of which at least one atom means N, O or S, unsubstituted or substituted by one or more substituents selected from the group including halogen (F, Cl, Br or I, preferably F or Cl), C1-C8alkyl, halogen(C1-C8)alkyl, C1-C4alkoxy, amino, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, cyano, hydroxy, nitro, oxo or thio, or combinations thereof, and Het means geterotsiklicheskikh the group (for example, furyl, thienyl, matiltan, bithienyl, benzylphenol, thiazolyl, methylthiazolyl, imidazolyl, methylimidazole, pyrrolidinyl, morpholinyl, thiomorpholine, dihydropyran, tetrahydropyranyl), a fully saturated, partially saturated or fully unsaturated, containing at cycle 5 to 10 atoms, of which at least one atom means N, O or S, unsubstituted or substituted by one or more substituents selected from the group comprising From1-C8alkyl, C2-C8alkenyl,2-C8quinil,3-C8cycloalkyl,4-C10cycloalkenyl,1-C8alkoxy, halogen (F, CL, Br or I, preferably F or CL), amino, cyano, hydroxyl, nitro, halogen(C1-C8)alkyl, halogen(C1-C8)alkoxy, hydroxy(C1-C8)alkyl, hydroxy(C2-C8)alkoxy, C3-C8alkenylacyl, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, C3-C7cyclooctylamino,4-C8cycloalkylation, carboxy, alkoxycarbonyl, alkylaminocarbonyl, acylamino (e.g., acetamido), acyloxy (for example, acetoxy), C1-C8alkylthio,1-C8alkylsulfonyl,1-C8alkylsulfonyl, sulfo, sulfonylamino, C6-C10aryl (e.g. phenyl, naphthyl, biphenyl), unsubstituted or C is displaced by one or more substituents, selected from the group including halogen (F, CL, Br or I, preferably F or CL), C1-C8alkyl, halogen(C1-C8)alkyl, C1-C4alkoxy, amino, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, cyano, hydroxy, nitro, oxo, or thio, heterocyclic group, a fully saturated, partially saturated or fully unsaturated, containing at cycle 5 to 10 atoms, of which at least one atom means N, O or S, unsubstituted or substituted by one or more substituents selected from the group including halogen (F, CL, Br or I, preferably F or CL), C1-C8alkyl, halogen(C1-C8)alkyl, C1-C4alkoxy, amino, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, cyano, hydroxy, nitro, oxo or thio, or combinations thereof,

and their pharmaceutically acceptable salt or solvate (e.g. hydrate), or a solvate of their pharmaceutically acceptable salts.

Another object of the invention are the compounds of formula I, selected from formulas IA and IB

Another object of the invention are compounds selected from formulas I, IA and IB, where

R1means N

CH3With2H5, CF3With2H3or3H5which in each case is unsubstituted or substituted by one or more groups F, Cl, Br, I, CN, OR2, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4, Ar, Het or combinations thereof,

C2H or C3H3that in each case unsubstituted or substituted one or more groups F, Cl, Br, I, CN, OR2, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4Si(C1-C6alkyl)3, Ar, Het or combinations thereof,

Och3OS2H5, F3or OCHF2that in each case unsubstituted or substituted one or more groups F, Cl, Br, I, CN, OR2, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4, Ar, Het or combinations thereof,

Ar, Het,

F, Cl, Br, I, CN, NO2, NR3R4, SR4, SOR4, SO2R4, SO2NR3R4, NR3SO2R4, CONR3R4, CSNR3R4, COOR4, NR3COR4, NR3CSR4, NR3CONR3R4, NR3CSNR3R4, NR3COOR4, NR3CSOR4, OCONR3R4or OCSNR3R4,

R2means N

CH3With2H5, CF3cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylmethyl or cyclopropylmethyl, which in each case independent is Eden or substituted by one or more groups F, Cl, Br, I, CN, IT,1-C4alkoxy, NR3R4, SH, SR3, SOR3With3-C8cycloalkyl, SO2R3, SO2NR3R4, Ar, Het or combinations thereof,

R3and R4each independently mean H,

CH3With2H5, CF3With2H3or3H5that in each case unsubstituted or substituted one or more groups F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, C3-C8cycloalkyl, Ar, Het or combinations thereof,

With2N or3H3that in each case unsubstituted or substituted one or more groups F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, C3-C8cycloalkyl, Si(C1-C6alkyl)3, Ar, Het or combinations thereof,

cyclopropyl, cyclobutyl or cyclopentyl, which is in each case unsubstituted or substituted one or more groups F, Cl, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, C3-C8cycloalkyl, Ar, Het or combinations thereof,

cyclopentylmethyl or cyclopropylmethyl, which is in each case unsubstituted or substituted in cycloalkyl group of one or more of the groups F, Cl, Br, I, CN, C1 -C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, C3-C8cycloalkyl, Ar, Het or combinations thereof, and/or substituted in the alkyl group by one or more groups F, C1, Br, I, CN, C1-C6alkoxy, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, C3-C8cycloalkyl, Ar, Het or combinations thereof,

Ar or Het,

Ar denotes phenyl, naphthyl or biphenyl, which is in each case unsubstituted or substituted by one or more halogen groups, With1-C8alkyl, hydroxy, C1-C8alkoxy, nitro, amino, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, hydroxy(C1-C8)alkyl, hydroxy(C1-C8)alkoxy, carboxy, cyano, C2-C9alkoxycarbonyl,1-C8alkylthio,1-C8alkylsulfonyl, C1-C8alkylsulfonyl, phenoxy, acetoxy or their combinations, and Het denotes furyl, thienyl, bithienyl, benzoylpyrazoles, thiazolyl, imidazolyl, methylimidazole, pyrrolidinyl, morpholinyl, thiomorpholine, dihydropyran or tetrahydropyranyl, which is in each case unsubstituted or substituted by one or more halogen groups, With1-C8alkyl, hydroxy, C1-C8alkoxy, nitro, amino, mono(C1-C8alkyl)amino, di(C1-C8alkyl)amino, is hydroxy(C 1-C8)alkyl, hydroxy(C1-C8)alkoxy, carboxy, cyano, C2-C9alkoxycarbonyl,1-C8alkylthio,1-C8alkylsulfonyl, C1-C8alkylsulfonyl, phenoxy, acetoxy, or combinations thereof, and their pharmaceutically acceptable salt or solvate (e.g. hydrate), or a solvate of their pharmaceutically acceptable salts.

In the description of the application alkyl means an aliphatic hydrocarbon radical with a straight or branched chain, preferably containing from 1 to 4 carbon atoms, unless otherwise indicated. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. In addition, the alkyl group may contain substituents.

In the description of the application of alkenyl means an alkyl radical with a straight or branched chain, preferably containing from 2 to 6, especially from 2 to 4 carbon atoms, unless otherwise specified, in which at least one group of CH2CH2replaced by the group CH=CH. Examples alkenyl groups include ethynyl, propenyl, butenyl, etc. in Addition, Alchemilla group may contain substituents.

In the description of the application quinil means an alkyl radical with a straight or branched chain, preferably containing from 2 to 6, especially from 2 to 4 carbon atoms, unless otherwise specified, in which at the ore one group CH 2CH2replaced by a group≡C. Examples etkinlik groups include ethinyl, PROPYNYL, butynyl, etc. in Addition, Alchemilla group may contain substituents.

Alkoxy means alkyl-O-group in which the alkyl group preferably contains 1-4 carbon atoms, unless otherwise indicated. Examples of alkoxygroup include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and second-butoxy.

Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical containing from 3 to 8 carbon atoms, unless otherwise indicated. Suitable cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other suitable cycloalkyl groups include spiropent, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl.

Cycloalkyl groups can contain substituents such as F, Cl, Br, C1-C4alkyl, C1-C4alkoxy, hydroxyl, amino, mono(C1-C4alkyl)amino and/or di(C1-C4alkyl)amino.

Cycloalkenyl means cycloalkenyl radicals, in which cycloalkyl and alkyl have the meanings specified above. Examples of such radicals include cyclopropylmethyl and cyclopentylmethyl.

Cycloalkane means cycloalkane radicals, in which cycloalkyl has the values listed above. Examples of such radicals include cycle is propyloxy, cyclopentyloxy.

AG as a group or substituent or part of a group or substituent, means an aromatic carbocyclic radical containing 6 to 10 carbon atoms, unless otherwise indicated. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-mentioned aryl group, substituted by one or more substituents selected from the group comprising halogen, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylsulfonyl, phenoxy, acyloxy (for example, acetoxy).

Het denotes a saturated, partially saturated or fully unsaturated heterocyclic group, containing one, two or three cycles and including cycle 5 to 10 atoms, of which at least one atom means N, O or S. Preferably the heterocyclic group contains in the cycle 1-3 heteroatoms selected from N, O and S. Suitable saturated and partially saturated heterocyclic groups include, without limitation, tetrahydrofuranyl, tetrahydrothieno, tetrahydropyranyl, dihydropyran, pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, isoxazolyl etc. Suitable heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imide who was Salil, pyridyl, pyrimidinyl, indolyl, chinoline, ethenolysis, naphthyridine etc. are Other examples of suitable heterocyclic groups are 2-chinoline, 1,3-benzodioxol, 2-thienyl, 2-benzofuranyl, 2-benzothiophene, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indolyl, 4-pyridyl, 3-chinoline, 4-chinoline, 1,4-benzodioxan-6-yl, 3-indolyl, 2-pyrrolyl, 3,4-1,2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxazepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazole-4-yl, 3-pyrazolyl, 3-carbazolyl, 2-thiazolyl, 2-oxazolyl and 2-imidazolyl.

Substituted heterocyclic group means a heterocyclic group, the above substituted in one or more positions, for example the groups halogen, aryl, alkyl, hydroxy, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino.

Radicals, substituted by one or more substituents, preferably contains 1-3 substituent, especially 1 or 2 of the above substituent. Halogen-substituted radicals, such as halogenated, preferably fluorinated and include fully halogenated radicals such as trifluoromethyl.

Another object of the invention X1preferably means CH.

Another object of the invention X2means SN or CR1. For example, X2means SN or CR1where R1means Het (for example, thiazolyl, substituted Ty who was Salil, such as alkylthiols (for example, methylthiazolyl), tetrahydropyranyl or dihydropyran)1-C4alkoxy (e.g.,- och3), or substituted C1-C4alkoxy (e.g., F3or F2).

Another object of the invention X3means SN or CR1. For example, X3means SN or CR1where R1means Het (for example, thiazolyl, substituted thiazolyl, such as alkylthiols (for example, methylthiazolyl), tetrahydropyranyl or dihydropyran)1-C4alkoxy (e.g.,- och3), or substituted C1-C4alkoxy (e.g., F3or OCHF2).

Another object of the invention X4means SN or CR1. For example, X4means SN or CR1where R1means substituted or unsubstituted C1-C4alkoxy (e.g., F3or OCHF2). More preferably X4means CH.

Another object of the invention X1-X4each denotes CH or CR1where R1differs from N. Another object of the invention X1and X4every means CH. Another object of the invention X2mean CR1where R1different from N, and X1X3and X4every means CH. Another object of the invention X3mean CR1where R1different from N, and X1X2 and X4every means CH. In addition, another object of the invention X4mean CR1where R1different from N, and X1X2and X3every means CH.

Another object of the invention preferred groups R1include N and Het (for example, thiazolyl, substituted thiazolyl, such as alkylthiols (for example, methylthiazolyl), tetrahydropyranyl or dihydropyran)1-C4alkoxy (e.g.,- och3), or substituted C1-C4alkoxy (e.g., F3or OCHF2).

Another object of the invention Y preferably denotes N or S, especially n

According to another object of the invention comprising compound and/or method, the compounds of formula I are selected from the group including

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether is 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(deformedarse)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(deformedarse)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(tetrahydro-2H-Puran-4-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(tetrahydro-2H-Puran-4-yl)-lH-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 5-methoxy-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(3,6-dihydro-2H-Puran-4-yl)-1H-indazol-3-carboxylic acid,

4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-and the new ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(tetrahydro-2H-Puran-4-yl)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(tetrahydro-2H-Puran-4-yl)-lH-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(triptoreline)-lH-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(triptoreline)-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1,2-benzisothiazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6-methoxy-1H-indazol-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1H-indazol-3-carboxylic acid,

formate N-1-(azabicyclo[2,2,2]Oct-3-ylmethyl)-5-triptoreline-1H-indazol-3-carboxamide,

N-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-5-triptoreline-1H-indazol-3-carboxamid,

formate N-1-(azabicyclo[2,2,2]Oct-3-ylmethyl)-6-methoxy-1H-indazol-3-carboxamide and

N-1-(azabicyclo[2,2,2]Oct-3-ylmethyl)-6-methoxy-1H-indazol-3-carboxamid,

moreover, the above-mentioned salts of the compounds may also be present in the form of another farmatsevticheskii acceptable salts, and above available basis the project may also be present in the form of a pharmaceutically acceptable salt,

moreover, the above-mentioned compounds (in free base form or in the form of a pharmaceutically acceptable salt) can also be present in the form of MES (such as a hydrate),

moreover, the above-mentioned compounds (in free base form or MES or in the form of pharmaceutically acceptable salts or its MES) may also be present in the form of polymorphic modifications, and if the connection is chiral, it may be present in the form of mixtures of enantiomers such as a racemate or a mixture of diastereomers, or it may be present in the form ydivitelnogo enantiomer or diastereoisomer.

According to another object of the invention comprising compound and/or method, the compounds of formula I are selected from the group including

formate 1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid,

1-azabicyclo[2,2,2]Oct-3-silt ester of 5-methoxy-1H-indazol-3-carboxylic acid,

formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6 ethoxy-1,2-benzisothiazole-3-carboxylic acid,

(3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6 ethoxy-1,2-benzisothiazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-yl-5-methoxy-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 5-methoxy-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ether 6-IU the hydroxy-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 7-methoxy-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 7-methoxy-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(deformedarse)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(deformedarse)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(triptoreline)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(triptoreline)-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 7-(triptoreline)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 7-(triptoreline)-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

form is t (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid and

(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,

moreover, the above-mentioned salts of the compounds may also be present in the form of another farmatsevticheskii acceptable salts, and the above free base may also be present in the form of a pharmaceutically acceptable salt,

moreover, the above-mentioned compounds (in free base form or in the form of a pharmaceutically acceptable salt) can also be present in the form of MES (such as a hydrate),

moreover, the above-mentioned compounds (in free base form or MES or in the form of pharmaceutically acceptable salts or its MES) may also be present in the form of polymorphic modifications, and if the connection is chiral, it may be present in the form of mixtures of enantiomers such as a racemate or a mixture of diastereomers, or it may be present in the form ydivitelnogo enantiomer or the individual is socially diastereoisomer.

A preferred object of the invention includes pharmaceutical compositions containing the compound of the present invention and a pharmaceutically acceptable carrier and optionally other active agent specified below, the method of stimulation or activation inhibition of nicotinic receptor α-7, and the specified activity assess, for example, a common method of analysis or the method of analysis described in the application, in vitro or in vivo (in animals, for example, in animal models, or in the body of a mammal or human), the method of treatment of a neurological syndrome, such as loss of memory, especially long-term memory, disturbance or loss of cognitive abilities, memory impairment and the like, a method of treating a pathologic condition which is modulated by the activity of nicotinic receptor α-7, a mammal, such as humans, for example, the condition specified in this context.

Compounds of the present invention receive known methods. Some of the known methods that can be used for obtaining the compounds described below. All starting materials are known compounds or can be obtained from known starting materials.

The synthesis of these compounds is described in the application US, ser. room 10/669645 registered on September 25, 2003, and ser. room 1/089533, registered March 25, 2005, the full contents of which are included in the description by reference.

Acids which can be used to obtain esters of bicyclic bases are commercial products. In addition, they can be obtained by known methods described in the literature or as described below. For example, 7-cryptomaterial-3-carboxylic acid is a commercial product. 5-Nitroindazole-3-carboxylic acid can be obtained by the nitration indazol-3-carboxylic acid (O. Kamm, Segur J.B., Org. Syn. Coll., 1, 372 (1941)). Bromination acid and 5-cryptomaterial-3-carboxylic acid can be obtained from the relevant satinov basic hydrolysis, by diazotization and recovery (H.R. Snyder and others, J. Am. Chem. Soc., 74, 2009 (1952)). 3-Substituted benzisothiazolinone acid can be obtained from the relevant thiophenols by reaction with oxalylamino and aluminium chloride followed by treatment with hydroxylamine, hydrogen peroxide and sodium hydroxide. Thiazolidine indazolinone acid can be obtained from bromination acid esterification, condensation in the presence of palladium with the corresponding cincticollis reagent (Reeder M.R. and others, Org. Proc. Res. Devel., 7, 696(2003)) and saponification. Similarly receive oxazolidine indazolinone acid. Digitope the EN - and territory.transnistria indazolinone acid obtained from Poslednij acid esterification, replacement of halogen to metal and condensation with tetrahydropyran-4-one, followed by dehydration, acid catalyzed, or recovery in an acid environment. Some substituted indazol-3-carboxylic acid is obtained from the normal derivatives of benzene. For example, 5-deformational-3-carboxylic acid is obtained from 3-bromo-4-NITROPHENOL by the reaction with ethyl ether diflorasone acid, reaction with diethyl ester of malonic acid, decarboxylases by saponification, esterification, the restoration of the nitro group and diazotization. In a similar manner from 2-bromo-5-diplomaticconferences get 6-deformational-3-carboxylic acid. The original 2-bromo-5-diplomaticconferences obtained from 4-NITROPHENOL according to the following sequence of reactions: simple ether, recovery nitro and simultaneous protection amide formation, nitration, hydrolysis of amide and reaction Sandmeyer with copper bromide (I). Bicyclic amine, which is used when obtaining the amide derivatives, obtained from binucleation by reaction with toiletrieschoice with subsequent recovery.

Esters of bicyclic bases obtained by condensation of acids with bicyclic alcohol using triphenylphosphine and diisopropylperoxydicarbonate acid (Ahn S., R. Correia, P. DeShong, J. Org. Chem., 67, 1751 (2002)). Another is ariante esters of bicyclic bases receive the reaction of the acids with bicyclic alcohol in the presence of para-toluensulfonate or oxalicacid in pyridine (Brewster J.H., Ciotti Jr. C.J., J. Am. Chem. Soc., 77, 6214 (1955)). Bicyclic amides bases obtained by condensation of the acid with the bicyclic amine in the presence of HBTU, HATU or HOBt and EDCI in DMF, or from an acid first obtained the corresponding acid chlorides, and then carry out the reaction of the bicyclic amine (Macor J.E., D. Gurley, Lanthorn So, Loch J., Mack, R. A., Mullen G., Tran A., Wright N., Macor J.E., Bioorg. Med. Chem. Lett., 9, point of 319-321 (2001)). The condensation is usually carried out at 0°C and at room temperature for 18-24 hours Obtained adducts isolated and purified by standard methods such as chromatography or recrystallization, well-known specialist in this field.

For the person skilled in the art it is evident that the compounds of formulas I, IA and IB can be in the form of various tautomers and geometric isomers. All the indicating compounds, including CIS-and TRANS-isomers, TRANS isomers, mixtures of diastereomers, racemates, nerezisca mixture of enantiomers, almost clean and pure enantiomers, included in the scope of the present invention. Almost pure enantiomers contain not more than 5 wt.% sootvetstvuyuschego opposite enantiomer, preferably not more than 2%, most preferably not more than 1%.

Optical isomers is obtained by separation of racemic mixtures by conventional means, for example, obtaining diastereoisomeric salts with an optically active acid which you or cause or due to the formation of covalent diastereomers. Examples of suitable acids are tartaric, diatsetilvinny, dibenzoyltartaric, ditawarkannya and camphorsulfonic acid. A mixture of diastereoisomers divided into individual diastereoisomer using the difference in physical and/or chemical properties, methods known to the person skilled in the art, such as chromatography or fractional crystallization. Then obtained from the diastereomeric salts of the free and optically active base or acid. Another method of separation of optical isomers involves the use of chiral chromatography (for example, columns for chiral IHVR), with or without obtaining derivatives to optimize the separation of enantiomers. Suitable columns for chiral GHUR are issued by the firm Diacel, for example column Chiracel OD and Chiracel OJ, usually selective. In addition, there is a separation with the use of enzymes with obtaining or without obtaining derivatives. Optically active compounds of formulas I, IA and IB can also be obtained from optically active starting materials chiral synthesis, excluding racemization.

In addition, for the person skilled in the art it is evident that the compounds can be used in forms, enriched with various isotopes, for example, enriched2H,3H,11C,13With and/or14

Replaced by deuterium compounds synthesized by various methods, such as described in the following publications: Dean Dennis C., Editor, Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr., Pharm. Des., 6 (10), cc.110 (2000) (CAN 133:68895'AN 2000:473538 CAPLUS), George W. Kabalka, Rajender Varma, S., The synthesis of radiolabeled compounds via organometallic intermediates, Tetrahedron, 45(21), 6601-6621 (1989) (CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS), and Evans Anthony E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 64(1-2), 9-32 (1981) (CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS).

In addition, the present invention relates to dosage forms of the compounds, such as free base and pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention, which can be obtained in the form of salts or prodrugs. Pharmaceutically acceptable salts include salts obtained by the reaction of the parent compound in the form of bases with inorganic or organic acids, for example salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic what islote, citric acid, formic acid, Hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, almond acid and carbonic acid. Pharmaceutically acceptable salts also include salts in which the original connection is acid and interact with the corresponding basis with education, for example, salts of sodium, potassium, calcium, magnesium, ammonium and choline. For professionals in this field also seems clear that the acid additive salts of the claimed compounds get the reaction of the compounds with the appropriate inorganic or organic acids by many known methods. In another embodiment, salts of alkaline and alkaline-earth metals are the reaction of the compounds according to the invention with the corresponding basis of various well-known methods.

Examples of the acid additive salts that can be obtained by reaction with inorganic or organic acids include acetates, adipate, alginates, citrates, aspartate, benzoate, bansilalpet, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, econsultancy, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate, methanesulfonate is, nicotinate, 2-naphthalenesulfonate, oxalates, palmoate (palmitate?), pectinate, persulfates, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartratami, thiocyanates, tozilaty, mesylates and undecanoate.

For example, pharmaceutically acceptable salt may be a hydrochloride, hydrobromide, formate, maleate or Las (for example, C1-C4Las, such as 4-methylbenzenesulfonate).

Preferably the salts are pharmaceutically acceptable salts for administration to a mammal. However pharmaceutically unacceptable salts of compounds suitable as intermediates, for example for the extraction of compounds in the form of salts and the subsequent conversion of a salt into the free base by interaction with the primary reagent. If necessary, the free base can then get pharmaceutically acceptable acid additive salt.

For professionals in this field also seems clear that some of the compounds of formulas I, IA and IB can sushestvovati in the form of various polymorphic modifications. Polymorphism means the ability of a compound to crystallize in different crystal or polymorphic forms. Polymorphic modification is a solid crystalline phase of a connection, harakterizuyut the at least two different types of packaging crystal or polymorphic forms of the compounds in the solid state. Polymorphic forms of any of the specific compounds are characterized by the same chemical formula or composition, but differ in the form of crystals, which can be viewed as two different connections.

For professionals in this field also it is evident that the compounds of formulas I, IA and IB can exist in various solvated forms. The solvate of the compounds according to the invention are formed also in the case if the solvent molecules included in the crystal lattice of the compound in the crystallization process.

Compounds according to the invention can be entered separately or as an active ingredient in the drug product. Thus, the present invention includes pharmaceutical compositions of compounds of formula I, IA or IB, containing, for example, one or more pharmaceutically acceptable carriers.

Methods of obtaining various dosage forms suitable for administration of the compounds according to the invention, are described in many standard reference books. Examples of effective lekarstvennyh forms and preparations contain, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (latest edition). Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, ed.) (latest edition). Marcel Dekker, Inc., and Remington''s Pharmaceutical Sciences (Arthur Osol, ed.), 1553-1593 (latest edition).

By stimulating the act is vnesti against receptor α-7 and preferably to their high selectivity of the compounds of the present invention can be introduced in any organism, in need of stimulation of receptors α-7. In accordance with the needs of the patient, the compounds can be administered orally, intranasal, parenteral (subcutaneous, intravenous, intramuscular, intrathecal method and injection), inhalation, rectal, vaginal and local way, as well as the inner method.

For oral administration the compounds according to the invention uses a variety of solid dosage forms, including tablets, gel capsules, capsules, microtablets, granules, pellets and powders. Compounds of the present invention can be entered separately or in a mixture with various pharmaceutically acceptable carriers, diluents such as sucrose, mannitol, lactose, starches) and excipients known in this area, including, without limitation, suspendresume agents, solubilization, buffer agents, binding agents, dezintegriruetsja agents, preservatives, dyes, fragrances, oil, etc. With the introduction of the compounds of the present invention is preferable also capsules, tablets and gels with a slow release.

For oral administration the compounds according to the invention are also used various liquid dosage forms, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such a medicament is i.i.d. forms may also contain suitable inert diluents, known in this field, such as water and suitable excipients known in this field, such as preservatives, wetting agents, sweeteners, flavoring agents, and agents for emulsification and/or suspension of the compounds according to the invention. Compounds of the present invention can be activated by injection, for example, intravenously in the form of an isotonic sterile solution. Alternative dosage forms.

Suppositories for rectal administration of the compounds of the present invention is produced by mixing the compound with suitable excipients, such as cocoa butter, musk and glycols. Compositions for vaginalnogo introduction receive in the form of pessaries, tampons, creams, gel, paste, foam, or aerosol, containing, along with the active ingredient known suitable media.

Pharmaceutical compositions for local introduction receive in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, aerosols and droplets, suitable for application to the skin, eyes, ears or nose. Local injection may also include percutaneous introduction using percutaneous patches.

Compounds according to the invention can also be obtained in the form of aerosol preparations for administration by inhalation. For example, for treating disorders of digitalinput compounds according to the invention can be activated by inhalation in the form of powder (for example, micronized) or in the form of a sprayable solutions or suspensions. Aerosol medications are placed in the compressed gas propellant is used.

Connections can be entered as the sole active agent or in combination with other pharmaceutical agents, such as agents used in the treatment of insufficiency of cognitive and/or memory loss, for example, other agonists of the receptor α-7, PDE4 inhibitors, calcium channel blockers, modulators of muscarinic receptors ml and m2 modulators, adenosine receptor modulators of ampakines NMDA-R modulators, mGluR, modulators of dopamine, serotonin modulators, modulators of cannabinoid and cholinesterase inhibitors (such as donepezil, rivastigmine and glentanner). In such combinations, each active ingredient can be entered in a regular interval dose or a lower dose.

Compounds according to the invention can be used in combination with "positive modulators, which increase the efficiency of agonists of nicotinic receptor. See, for example, a positive modulator claimed in WO 99/56745, WO 01/32619 and WO 01/32622. Such combination therapy can be used in the treatment of conditions/diseases associated with impaired signal transmission nicotinic receptor.

In addition, the compounds can be used in combination with the compounds, to the verge associated with peptides β and thanks to inhibit the binding of peptides to receptors subtype α-7 nAChR. See, for example, WO 99/62505.

Compounds of the present invention are ligands of nicotinic receptor α-7, preferably agonists, first of all partial agonists, nicotinic acetylcholine receptor α-7. Methods of analysis of the activity of nicotinic acetylcholine receptor known in the art. See, for example, A.R. Davies and others, Characterization of the binding of [3H]methyllycaconitine: a new radioligand for labelling alpha 7-type neuronal nicotinic acetylcholine receptors, Neuropharmacology, 38(5), 679-690 (1999). As nAChR agonists α-7 connection can be used for the prevention and treatment of many diseases and conditions associated with the Central nervous system. Nicotinic acetylcholine receptors are receptors ligand-gated ion channels composed of five protein subunits that form a Central ion-conducting pore. To date, we know of 11 subunits of the neuronal nAChR (α2-α9 and β2-β4). Known also 5 other subunits expressed in the peripheral nervous system (α1, β1, γ, δ, ε).

Subtypes of nAChR receptor may represent homopentameric or heteropentameric patterns. Subtype, which has attracted special attention is homopentameric receptor α-7 composed of five subunits α-7. Receptor nAChR α-7 has a high affinity for nicotine (agonist) and α-bungarotoxin (antagonist). Installed, Thu the agonists 7-nAChR can be used in the treatment of psychotic diseases, neurodegenerative diseases, lack of cognitive abilities, etc. Although nicotine is a known agonist, there is a need for other agonists of α7-nAChR, primarily selective agonists, which are less toxic and have lower side effects compared with nicotine.

Connection anabaseine, i.e. the 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine, a natural toxin isolated from some marine worms (nemertini worms and ants. See, for example. Kem and others, Toxicon, 9, 23 (1971). Anabaseine is an effective activator of nicotinic receptors in mammals. See, for example, Kem, Amer. Zoologist, 25, 99 (1985). Some analogues of anabaseine, such as anabasine and DMAB (3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2',3'-bipyridine) are also known agonists of nicotinic receptor. See, for example, US 5602257 and WO 92/15306. Another analogue of anabaseine, (E-3-[2,4-dimethoxybenzamide]anabaseine, also known as GTS-21 and DMXB (see, for example, US 5741802), is a selective partial agonist of α7-nAChR, which was investigated in detail. For example, abnormal inhibition sensitivity is a condition of the lack of sensitivity in schizophrenics and, as installed, GTS-21 increases the inhibition sensitivity by binding to α7-nAChR. See, for example, Stevens and others, Psychopharmacology,136, 320-327 (1998).

Other selective agonist of α7-nAChR is tropisetron, ie, 1α,5α-tropan-3α-silt ether indole-3-carboxylic acid. Cm. J.E. Masog and others, The 5-NT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist, Bioorg. Med. Chem. Lett., Point of 319-321 (2001).

The present invention also includes methods of treatment that are associated with activation of nicotinic receptors α-7. Thus, the present invention includes methods of selective activation/stimulation of nicotinic receptors α-7 in animals, for example mammals, especially humans, have such activation/stimulation has a therapeutic effect, for example, this activation facilitates condition, including neurological syndromes, such as loss of memory, especially long-term memory. Such methods include the introduction of an animal in need of such treatment, particularly a mammal, more preferably a human, an effective amount of a compound of formula I, IA or IB, individually or in dosage forms, specified in the proposal.

Thus, as the object of the invention features a method of treating a patient (e.g. a mammal such as a human)suffering from a pathological condition (e.g., insufficient memory), involving the introduction of a patient, compounds of formula I, IA or IB. Preferably pathological with the being, associated with low activity of nicotinic acetylcholine receptor.

Thus, as the object of the invention proposes a method of treatment or prevention of a disease or condition resulting from abnormalities in the signal transmission nicotinic acetylcholine receptor in a mammal, for example in humans, include the introduction of an effective amount of a compound of formula I, IA or IB.

Thus, in the description of the application as the object of the invention proposes a method of treatment or prevention of a disease or condition resulting from inadequate or impaired function of nicotinic acetylcholine receptors, especially of α7nACh receptors, mammalian, for example human, comprising introducing an effective amount of a compound of formula I, IA or IB.

Thus, as the object of the invention proposes a method of treatment or prevention of a disease or condition resulting from the suppression signal nicotinic acetylcholine receptor in a mammal, for example in humans, include the introduction of a number of compounds of formulas I, IA, or IB, is effective for activation of α7nACh receptors.

Another object of the invention is a method of treatment or prophylaxis of psychotic disorders, cognitive failure (e.g., is dostatochnosti memory), or neurodegenerative disease in a mammal, for example in humans, include the introduction of an effective amount of a compound of formula I, IA or IB.

Another object of the invention is a method of treatment or prevention of a disease or condition resulting from loss of cholinergic neurotransmission in a mammal, for example in humans, include the introduction of an effective amount of a compound of formula I, IA or IB.

Another object of the invention is a method of treatment or prevention of neurodegenerative disorders due to the activation of α7nACh receptors in a mammal, for example in humans, include the introduction of an effective amount of a compound of formula I, IA or IB.

Another object of the invention is a method for protecting neurons in a mammal, such as humans, from the neurotoxic effect induced activation of α7nACh receptors, including the introduction of an effective amount of a compound of formula I, IA or IB.

Another object of the invention is a method of treatment or prevention of neurodegenerative disorders by inhibiting the binding of peptides β with α7nACh receptors in a mammal, for example in humans, include the introduction of an effective amount of a compound of formula I, IA or IB.

Another object of the invention is a method for protecting neurons in a mammal, e.g. the measures in humans, from the neurotoxic effect induced by peptides β, including the introduction of an effective amount of a compound of formula I, IA or IB.

Another object of the invention is a method of reducing suppression of cholinergic function, induced by the peptides β in a mammal, for example in humans, include the introduction of an effective amount of a compound of formula I, IA or IB.

Agents that bind to nicotinic acetylcholine receptors, are recommended for use in the treatment and/or prevention of various diseases or conditions, especially psychosis, neurodegenerative diseases associated with dysfunction of the cholinergic system and memory disorders and/or lack of cognitive abilities, including, for example, schizophrenia, anxiety, mania, depression, manic depression (examples of psychotic disorders, Tourette's syndrome, Parkinson's disease, Huntington's disease (examples of neurodegenerative diseases), impairment of cognitive abilities (such as Alzheimer's disease, dementia associated with calves Levi, amyotrophic lateral sclerosis, lack of memory, memory loss, cognitive deficits, attention deficit, hyperactivity in attention deficit), and other applications such as the treatment is repichnia to nicotine, inducing the habit of Smoking, pain relief (i.e. as analgetika), neuroprotective effect, treatment fatigue that occurs during long flights, the treatment of inflammation and treatment of sepsis. See, for example, WO 97/30998, WO 99/03850, WO 00/42044, WO 01/36417, Holladay and others, J.Med. Chem., 40, 26, 4169-4194 (1997), Schmitt and others, Annual Reports Med. Chem., ch.5, 41-51 (2000), Stevens and others, Psychopharmatology, 136, 320-327 (1998), and Shytle and other, Molecular Psychiatry, 7, 525-535 (2002).

Thus, the invention features a method of treating a patient, especially a human, suffering from psychotic diseases, neurodegenerative diseases associated with dysfunction of the cholinergic system, and failure of memory and/or cognitive abilities, including, for example, schizophrenia, anxiety, mania, depression, manic depression (examples of psychotic disorders, Tourette's syndrome, Parkinson's disease, Huntington's disease (examples of neurodegenerative diseases), and/or impairment of cognitive abilities (such as Alzheimer's disease, dementia associated with calves Levi, amyotrophic lateral sclerosis, failure of memory, loss memory the cognitive deficit, attention deficit, hyperactivity in attention deficit), including introduction to the patient an effective amount of a compound of formula I, IA or IB.

Furthermore, the method for this is the overarching invention includes the treatment and/or profilaktika neurodegenerative disorders, including, without limitation, Alzheimer's disease Peak, diffuse disease associated with cells Levi, progressive Academy paralysis syndrome (Steele-Richardson), Multisystem degeneration (syndrome Shay-Drager), motor neuron disease, including side mitrovicali sclerosis (ALS), a degenerative ataxia, cortical basal degeneration, the complex of GUAM: ALS/Parkinson's disease/dementia, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, a degeneration of the striatum, disease, Machado-Joseph (spenomegaly ataxia type 3), olivopontocerebellar atrophy, disease, Gilles De La Tourette, bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy (Kennedy disease), primary lateral sclerosis, familial spastic a paraplegic disease werdnig-Hoffmann disease Kugelberg-Welander, disease, and Tay-Sachs disease Sandhoff, familial spastic disease, illness Wohlfahrt - Kugelberg-Welander, spastic prepares, progressive multifocal a leukodystrophy, prion disease (such as disease Creutzfeld-Jakob disease Gerstmann-Straussler-Sheinker, Kuru and fatal familial insomnia), and neurodegener the main violations, caused by cerebral ischemia or infarction including embolic occlusion and thrombotic occlusion, as well as intracranial hemorrhage of any type (including, but not limited to, epidural, subdural, subarachnoid and intracerebral), and intracranial and intravertebral damages (including, but not limited to, contusion, penetration damage, shear, compression and gap).

In addition, agonists α-7nAChR, such as compounds of the present invention, can be used to treat age-related dementia and other dementias and conditions associated with memory loss, including age-related memory loss, senility, vascular dementia, diffuse disease, associated with edema of the white matter disease Binswanger), dementia of endocrine or metabolic origin, dementia caused by head trauma and diffuse brain damage, dementia, caused by blows to the head (syndrome boxer) and dementia of the frontal lobe of the brain. See, for example, WO 99/62505. Thus, the invention features a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and conditions associated with memory loss, including the introduction to the patient an effective amount of a compound of formula I, IA or IB.

Thus, in another embodiment, we shall Aasee the invention includes a method of treating patients suffering from failure of memory, caused, for example, mild cognitive failure due to old age, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, diseases of the Peak, disease Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral aging, multi-infarct dementia and other neurological conditions, as well as patients suffering from HIV and cardiovascular diseases, comprising introducing an effective amount of a compound of formula I, IA or IB.

It is established that the amyloid precursor protein (APP) and formed from him peptides β, for example β1-40, β1-42and other fragments, involved in the pathology of Alzheimer's disease. Peptides β1-42not only participate in the development of neurotoxicity, but also inhibit the function of signal transmission cholinergic receptor. In addition, it was found that peptides β bind to receptors α-7 nAChR. Thus, agents that block the binding of peptides β with α-7 nAChR can be used for the treatment of neurodegenerative diseases. See, for example, WO 99/62505. In addition, stimulation of α-7 nAChR may protect neurons from the toxic actions associated with peptides β. See, for example, Kihara T., and others, Ann. Neurol., 42, 159 (1997).

Thus in another embodiment, the invention features a method of treatment and/or prophylaxis of patients with a diagnosis of Alzheimer's disease, includes introduction to the subject therapeutically effective amounts of compounds of formula I, IA or IB for the inhibition of the binding of amyloid β peptide (preferably β1-42with nAChR, preferably α-7 nAChR, most preferably α-7 nAChR person (and also a method of treating and/or preventing other clinical symptoms of Alzheimer's disease that include, without limitation, failure poznavatelnyh and verbal abilities, apraxia, depression, delusions and other neuropsychiatrically symptoms and signs, and abnormalities in movement and gait).

In the present invention are also treatments other amyloidoses, for example, hereditary cerebral angiopathy, pneumopathies hereditary amyloidosis, down's syndrome, macroglobulinemia, secondary familial Mediterranean fever syndrome Make wells, multiple myeloma, amyloidosis, associated with the pancreas and the heart, chronic hemodialysis of enteropatii and amyloidosis was detected in Finland and Iowa.

In addition, nicotinic receptors involved in the response of the body to alcohol. Therefore, agonists α-7 nAChR can be used for the treatment of syndrome of abstinence from alcohol and alcoholic intoxication. Thus, in another embodiment, the image is placed proposes a method of treatment of the patient from alcohol addiction or treatment of the patient from alcohol intoxication, includes introduction to the patient an effective amount of a compound of formula I, IA or IB.

Agonists of receptor subtype α-7 nAChR can also be used to protect neurons against damage associated with strokes and ischemia and glutamate-induced cytotoxicity. Thus, in another embodiment, the invention features a method of treating a patient, including the protection of neurons against damage associated with strokes and ischemia and glutamate-induced cytotoxicity, comprising the administration to a patient an effective amount of a compound of formula I, IA or IB.

As noted above, the subtype agonists α-7 nAChR can also be used to treat addiction to nicotine, inducing Smoking cessation, treating pain and treatment of fatigue that occurs during long flights, obesity, diabetes, inflammation and sepsis. Thus, in another embodiment, the invention features a method of treatment of a patient suffering from addiction to nicotine, pain, fatigue, occurs when long flights, obesity and/or diabetes, or a method of inducing Smoking cessation, including introduction to the patient an effective amount of a compound of formula I, IA or IB.

Inflammatory response is a response of the autonomic nervous system inflammatory signal. After the perception inflammatory tis the ula of the autonomic nervous system responds through the vagus nerve vysvobojdenie acetylcholine and activation of nicotinic receptor α7, localized in macrophages. In turn, these macrophages release cytokines. Dysfunction of these pathways is associated with inflammatory processes in humans, including rheumatoid arthritis, diabetes, and sepsis. Macrophages Express nicotinic receptor α7 receptor, and it is suggested that this receptor mediates cholinergic anti-inflammatory response. Therefore, compounds with affinity to α7nACh receptor of macrophages, can be used for the treatment of inflammatory diseases, including rheumatoid arthritis, diabetes, and sepsis. See, for example, Czura C.J., and others, J. Intern. Med., 257(2), 156-66 (2005).

Thus, in another embodiment of the invention along with an a method of treatment of a patient (e.g. a mammal such as a human)suffering from inflammatory diseases, such as, without limitation, rheumatoid arthritis, diabetes or sepsis, comprising the administration to a patient an effective amount of a compound of formula I, IA or IB.

In addition, due to the affinity to the receptor α-7nACh labeled derivatives of the compounds of formula I, IA or IB (e.g., With11or F18) can be used for imaging of receptors, for example, in the brain tissue. Thus, the use of such labeled agents for visualization of receptors in vivo can be the use, for example, positron emission tomography (PET).

State failure memory manifests itself in the inability to acquire new information and/or inability to reproduce the previously received information. Lack of memory is the primary sintoma dementia and may also predstavljaet a symptom associated with the disease such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, a disease of the Peak disease Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma, as well as age-related loss of cognitive abilities.

Thus, another option of the invention is a method of treating a patient suffering from, for example, from mild cognitive failure (MCI), vascular dementia (VD), age-related loss of cognitive abilities (AACD), amnesia associated with open heart surgery, cardiac arrest and/or General anesthesia, lack of memory associated with the action of anesthetic agents, lack of cognitive abilities, inducirowannoj a waiver of sleep, sydrome chronic fatigue, narcolepsy, dementia associated with AIDS, lack of cognitive abilities associated with epilepsy, down syndrome, dementia, associated with alcoholism, not what dostatochnosti cognitive abilities, associated with medication, Gemenii caused by blows to the head syndrome (boxer), and also treatment of dementia animals (e.g. dogs, cats, horses and the like), and this method includes the introduction to the patient an effective amount of a compound of formula I, IA or IB.

Doses of the compounds of the present invention depend on many factors, including primarily the syndrome to be treated, the severity of the symptoms, the route of administration, the frequency intervals of administration, type of connection, the effectiveness, toxicity profile, pharmacokinetic profile and the presence of any side effects.

Compounds according to the invention it is possible to enter a mammal, especially a human, in a typical doses taken for agonists of nicotinic receptor α7, such as known agonists nikotinova receptor α7 above. For example, the compounds can be introduced in the form of single or divided doses orally in amounts of, for example, of 0.0001-10 mg/kg/day, for example, 0.01 to 10 mg/kg/day. Standard dosage forms may contain, for example, 1-200 mg of active compound. Intravenous connection, you can enter as a single or divided doses.

When implementing the methods of the present invention assumes that references to specific buffer solutions,environment, reagents, types of cells, culturing conditions, etc. are not limited to, but include all such materials which are the specialist in this area considers useful and necessary in this context. For example, it is often possible to replace a single buffer system or culture medium on another system and get similar or even identical results. Specialists in this field have sufficient information about such systems and methods of their use, so that without additional experiments to carry out such substitution and in the optimal mode to reproduce the claimed methods and techniques.

The present invention is illustrated by the following examples without limiting its scope. Assume that within the essence and scope of the invention by the person skilled in the art will be offered other and other variants of the claimed methods.

In the examples all temperatures are not adjusted in degrees Celsius and unless otherwise indicated, all parts and percentages are wt. parts and in wt.%.

The content of each cited above and below applications, patents and publications included in the description of the application as references.

Examples

Unless otherwise stated, NMR spectra were taken on NMR-Bruker spectrometer at 300 MHz. Constants of spin-spin usaimage the effects are given in Hertz (Hz), and chemical shifts in ppm million relative to TMS (δ 0,00). Reactions under microwave irradiation were performed in the reactor firm Personal Chemistry Optimizer™ in vials for microwave reactor with a volume of 2.5 ml or 5 ml (firm Personal Chemistry Optimizer™). All reactions were carried out at 200°C for 600 s, unless otherwise noted. In this work, we used ion-exchange resin sulfonation SCX (firm Varian Technologies). Analytical GHUR was performed on column Xterra RP18of 3.5 μm, a 4.6×100 mm (eluent: gradient of water +0,1% formic acid/acetonitrile +0.1% of formic acid, from 20:80 to 80:20, 6 min). Preparative GHUR was performed on column Xterra RP18, 5 μm, 30×100 mm (eluent: gradient of water +0,1% formic acid/acetonitrile +0.1% of formic acid, from 95:5 to 20:80, 8 min).

Typical methods

I. Synthesis of acids

Method 1

Obtaining relevant indazol-3-carboxylic acids of the substituted satinov

Appropriate indazol-3-carboxylic acid was obtained from substituted satinov same way as described for indazol-3-carboxylic acid (H.R. Snyder and others, J. Chem. Soc., 74, 2009 (1952)). Derivative of isatin (22,1 mmole) was dissolved in 1 N. the solution of sodium hydroxide (24 ml) and heated at 50°C for 30 minutes, the red Solution was cooled to CT and kept for 1 h the Reaction mixture was cooled to 0°C and at 0°C was added a solution of sodium nitrite (22,0 mmole) in water (5.5 ml). Receive the config solution was added via pipette (immersed in water) in a solution of sulfuric acid (2.3 ml) in water (45 ml) at 0°C. and vigorous stirring. The solution was added for 15 min and then the reaction mixture was stirred for another 30 minutes Then the reaction mixture for 10 min was added to a chilled (0°C.) solution of chloride dihydrate tin (II) (52,7 mmole) in conc. hydrochloric acid (20 ml) and the suspension was kept for 60 minutes Dropped precipitated solid substance was separated by filtration, washed with water and dried, when it received the product in quantitative yield. The solid is recrystallized from acetic acid (20 ml/g), were obtained acid in the form of a solid of light yellow color. Acid are condensed with 1,4-diazabicyclo[3,2,2]nananom by the method of A.

In this procedure were obtained following acid:

5-bromo-1H-indazol-3-carboxylic acid,

5-methoxy-H-indazol-3-carboxylic acid,

6-methoxy-1H-indazol-3-carboxylic acid,

7-methoxy-1H-indazol-3-carboxylic acid,

5-(triptoreline)-1H-indazol-3-carboxylic acid and

6-(triptoreline)-1H-indazol-3-carboxylic acid.

Method 2

Getting 5-deformational-3-carboxylic acid from 3-bromo-4-NITROPHENOL

To a suspension of sodium hydroxide (29,0 mmole) in N,N-dimethylformamide (15 ml) was added 3-bromo-4-NITROPHENOL (10.0 mmole) and the suspension was kept at RT for 15 min, the Reaction mixture was cooled to 0°C was added ethyl ether Hortiflorexpo acid is (20,0 mmole), was heated at 70°C for 16 h and concentrated. To the residue was added ice water (200 ml) and was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulfate and concentrated, to receive deformational ether (yield 75%) as a yellow oil.

To a suspension of sodium hydride (328 mmol) in dimethyl sulfoxide (40 ml) at 0°C was added dropwise diethylmalonate (328 mmol), the reaction mixture was heated to 60°C. and maintained for 0.5 h and Then was added dropwise a solution of deformational ether (149 mmol) in dimethyl sulfoxide (80 ml) and the reaction mixture was heated at 100°C for 5 hours, the Cooled solution was poured into ice water and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layers were dried over magnesium sulfate and concentrated, to receive untreated fluids (exit 112%) as oil. Fluids (167 mmol), sodium hydroxide (500 mmol) and water (335 ml) were mixed and heated at 60°C for 1 h, the Reaction mixture was cooled to CT, the aqueous layer washed with dichloromethane (3×100 ml), was added conc. hydrochloric acid to pH 1 and the reaction mixture was heated at 60°C for 1 h, the Suspension was cooled to 5°C. the solid is separated by filtration and dried, to receive the specified acid (yield 61%).

In ethanol (300 ml) at 0°C was added dropwise acetyl is Lorig (203 mmole). After 0.5 h the mixture was added the acid (101 mmol) and the reaction mixture is boiled under reflux for 15 hours, the Reaction mixture was concentrated and the residue was distributed between dichloromethane (200 ml) and saturated sodium bicarbonate solution (100 ml). The aqueous layer was extracted with dichloromethane (2×200 ml), the combined organic layers were dried over magnesium sulfate and concentrated, to receive ether (yield 60%) as a brown oil.

Ether (60,4 mmole) was dissolved in ethanol (103 ml), diluted with water (71 ml) was added ammonium chloride (243 mmole) and powdered iron (301 mmol). The reaction mixture is boiled under reflux for 10 min, the suspension was filtered through celite and the filter cake washed three times with ethanol. The filtrate was concentrated, the residue is suspended in 2 N. hydrochloric acid and was intensively stirred for 0.5 hours the Aqueous layer was washed with ethyl acetate (3×50 ml) and was added 5 M aqueous sodium hydroxide solution to pH 9-10. The aqueous layer was extracted with chloroform (3×100 ml), the combined organic layers were dried over magnesium sulfate. The organic layer was added acetic anhydride (392 mmole), isoamylase (291 mmol) and potassium acetate (51,0 mmol) and the suspension is boiled under reflux for 16 hours, the Solution was evaporated and the residue was distributed between saturated sodium bicarbonate solution(50 ml) and dichloromethane (100 ml). The aqueous layer was extracted with dichloromethane (2×100 ml), the combined organic layers were dried over magnesium sulfate and concentrated, to receive the ether N-acetylimidazole (yield 79%) as a brown oil.

Ether (63,8 mmole), sodium hydroxide (193 mmole) and water (65 ml) were mixed and heated at 60°C for 24 hours After cooling to CT the aqueous layer washed with dichloromethane (3×50 ml) and was added conc. hydrochloric acid to pH 1. A solid substance was separated by filtration, washed with water, dichloromethane and dried, to receive acid (yield 27%).

In this procedure also received 5-(deformedarse)-1H-indazol-3-carboxylic acid.

Method 3

Getting alkyl - and aryl-substituted derivatives by condensation of brominated esters of carboxylic acids in the presence of zinc-containing reagent

In the vial for microwave reactor with a volume of 5 ml was placed chloride bis(triphenylphosphine)palladium (II) (0,030 mmole, 0.1 EQ.) and Posledny ether (0.30 mmole). The vial was evacuated and filled with argon. In a separate vessel in a solution of 0.5 M zinc chloride (1.2 mmole, 4 equiv.) in tetrahydrofuran at RT was added the Grignard reagent (1.2 mmole, 4 EQ.). The suspension was kept for 30 min and the contents through the tube was transferred into a vial, which was tightly closed and heated in a microwave reactor at 100°C for all austan lively adding acetic acid (0.5 ml) and the mixture was concentrated. The residue was dissolved in saturated sodium bicarbonate solution and was extracted with dichloromethane/methanol (9:1, 5×40 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by chromatography (eluent: gradient of hexane/ethyl acetate, from 1:1 to 0:1), to receive the broadcast. Ether was added 2 n sodium hydroxide solution and the suspension was heated at 60°C for 2 hours the Solution was cooled to CT and acidified to pH 2. A solid substance was separated by filtration, washed with water and dried, to receive acid in the form of a solid of light yellow color. Acid are condensed with 1,4-diazabicyclo[3,2,2]nananom by the method of A.

The Grignard reagent containing a thiazole, a commercial drug. In another embodiment, ability and the corresponding arylzinc was obtained according to the method described in the article Reeder M.R. and others, Org. Proc. Res. DeveL, 7, 696 (2003). Oxazolin and appropriate reagents received by the given method.

In this procedure were obtained following acid:

5-(1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

6-(1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

6-(1,3-oxazol-2-yl)-1H-indazol-3-carboxylic acid,

5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,

6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid and

6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid.

Method 4 Getting substituted benzisothiazole-3-carboxylic acids from the corresponding thiophenols

To a solution of 3-methoxythiophene (to 26.7 mmole) in ether (20 ml) was added dropwise oxalicacid (43 mmole). The mixture was boiled under reflux for 1.5 h, cooled to CT and concentrated in vacuum. The resulting yellow oil was dissolved in dichloromethane (50 ml), cooled to 0°C and the portions was added aluminium chloride (32.0 mmole). The mixture was boiled under reflux for 30 min, cooled to CT and with stirring, poured into ice-cold water. The organic layer was separated and sequentially washed with a saturated solution of sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by chromatography (eluent: ethyl acetate/hexane, 4:1), was obtained 6-methoxy-1-benzothiophen-2,3-dione (47%) as a solid orange color.

In the mixture of the dione (of 0.44 mmole) in 30% ammonium hydroxide solution (2.0 ml) was added 35% hydrogen peroxide solution (0.2 ml) and the reaction mixture was stirred for 12 hours Fell in the sludge solid pink color was separated by filtration, washed with water and dried in a high vacuum, to receive 6-methoxybenzothiazole-3-carbox the MFA (42%).

In the solution of amide (5,46 mmole) in methanol (100 ml) was added 10 n sodium hydroxide solution (12 ml). The mixture was boiled under reflux for 12 h, cooled to CT and was slowly added conc. hydrochloric acid to pH<2. The organic layer was twice extracted with dichloromethane and dried over sodium sulfate. The crude product was purified by chromatography (eluent: dichloromethane/methanol/formic acid, 300:50:1), was obtained 6-methoxy-1,2-benzisothiazol-3-carboxylic acid (89%) in a solid pink color.

In this procedure were obtained following acid:

6-methoxy-1,2-benzisothiazol-3-carboxylic acid and

6 ethoxy-1,2-benzisothiazol-3-carboxylic acid.

Method 5

Interaction imidazolinone with ketones and condensation with 3-aminoquinuclidine with the formation of heterocyclic derivatives

tert-Butyl ester 6-brominated-3-carboxylic acid obtained from the acid by reaction with a twofold excess of di-tert-BUTYLCARBAMATE followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% dispersion in mineral oil, 4.8 mmole) in tetrahydrofuran (40 ml) at 0°C was slowly added a solution of tert-butyl methyl ether 6-brominated-3-carboxylic acid (4.0 mmole) in tetrahydrofuran (4 ml) and the mixture was stirred at 0°C for 0.5 h Then the mixture was cooled to -78°C. was added 1.7 M p is the target tert-utility in pentane (5.1 mmole) and kept at -78°C for 0.5 hours Then was added dropwise a solution of tetrahydropyran-4-it (5 mmol) in tetrahydrofuran (1 ml), the mixture was stirred at -78°C for 1 h and warmed up to 0°C. the Reaction was stopped by adding a saturated solution of ammonium chloride and the mixture was distributed between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated, washed with brine (50 ml), dried over magnesium sulfate and concentrated. The residue was purified by chromatography (eluent: ethyl acetate/hexane, 70:30), it was obtained tert-butyl ester 6-(4-hydroxyethylamino-4-yl)-1H-indazol-3-carboxylic acid (68%) as a colourless solid.

tert-Butyl ester 6-(4-hydroxyethylamino-4-yl)-1H-indazol-3-carboxylic acid (0.86 mmol) was dissolved in triperoxonane acid (3 ml) and the mixture was stirred at RT for 16 h the Solvent was removed in vacuo and the residue triturated in ethyl acetate, was thus obtained 6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid (76%).

tert-Butyl ester 6-(4-hydroxyethylamino-4-yl)-1H-indazol-3-carboxylic acid (1.0 mmol) was dissolved in triperoxonane acid (5 ml), triethylsilane (2 ml) and dichloromethane (3 ml), the mixture was boiled under reflux for 16 hours the Solvent was removed in vacuo, the residue triturated in ethyl acetate, was thus obtained 6-(tetrahydropyran-4-yl)-1H-indazol-3-carboxylic acid (60%) in the de solid yellow brown.

In this procedure were obtained following acid:

5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,

6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,

5-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid and

6-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid.

Methodology 6

Getting 6-deformational-3-carboxylic acid from 4-NITROPHENOL

To a suspension of sodium hydroxide (485 mmol) in N,N-dimethylformamide (150 ml) was added 4-NITROPHENOL (162 mmole) and maintained at RT for 15 min, the Reaction mixture was cooled to 0°C was added ethyl ether Hortiflorexpo acid (329 mmol). The reaction mixture was heated at 70°C for 16 h and concentrated. The residue was dissolved in ice water (200 ml) and was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over magnesium sulfate and concentrated, to receive deformational ether (59%) as a yellow oil.

Nitrocefin (149 mmol) was dissolved in ethanol (37.5 ml), diluted with water (25 ml) was added ammonium chloride (84,7 mmole) and powdered iron (105 mmol). The reaction mixture is boiled under reflux for 30 min and the suspension was filtered through celite. The residue on the filter is washed three times with ethanol and the combined filtrates were concentrated. The residue was dissolved in water and we use the 5 M sodium hydroxide solution to pH 9-10. The aqueous layer was extracted with ethyl acetate (3×100 ml), the combined organic layers were dried over magnesium sulfate and concentrated, to receive a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmole) and the reaction mixture was stirred at RT for 16 h, the Reaction mixture was dissolved in water (50 ml) and neutralized by addition of solid sodium bicarbonate. A solid substance was separated by filtration, washed with water and dried, thus received ndimethylacetamide (yield 62%) as a solid light yellow color.

In the solution ndimethylacetamide (13.2 mmole) in chloroform (20 ml) was added acetic anhydride (19.6 mmole) and the reaction mixture is boiled under reflux. Then was added dropwise fuming nitric acid (16,0 mmole) and the reaction mixture is boiled under reflux for 30 minutes the Solution was cooled, added water (20 ml) and the aqueous layer was extracted with dichloromethane (3×10 ml). The combined organic layers were dried over magnesium sulfate and concentrated, to receive nitrone (yield 83%).

Amide (11.0 mmol), sodium hydroxide (43,8 mmole) and water (10 ml) were mixed and kept at 60°C for 1.5 h, the Reaction mixture was cooled to CT, a solid substance was separated by filtration, washed with water and dried, to receive aniline (yield 98%) as a solid light yellow color.

Aniline (15.7 mmole) was mixed with 40% Hydrobromic acid (14.3 g) and water (10 ml) and the reaction mixture was heated at 80-90°C. until complete dissolution of aniline. The reaction mixture was cooled to 0°C and for 15 min, the solution was added sodium nitrite (to 23.2 mmole) in water (5.3 ml). The solution was kept at 0-5°C for 40 min and filtered. The copper bromide (I) (18,8 mmole) was dissolved in 40% Hydrobromic acid (21 ml) and cooled to 0°C. To the resulting solution was slowly added salt the page and the mixture was stirred at 0-10°C for 30 minutes and Then the reaction mixture was heated at 60°C for 30 min and at 100°C for 10 min until the reaction was cooled to CT and was extracted with dichloromethane (3×40 ml). The combined organic layers washed with 1 M sodium hydroxide solution, water, 1 N. hydrochloric acid and water, dried over magnesium sulfate and concentrated, this has been microbraid (yield 76%) as a solid light yellow color.

To a suspension of sodium hydride (from 25.8 mmole) in dimethyl sulfoxide (5 ml) at 0°C was added dropwise diethylmalonate (25,7 mmole). The reaction mixture was heated to 60°C. and kept for 30 minutes and Then was added dropwise a solution of nitrosamide level (11.7 mmole) in dimethyl sulfoxide (7 ml) and the reaction mixture was heated at 100°C for 5 hours, the Cooled solution was poured into ice water and the aqueous layer was extragere the Ali dichloromethane (3×100 ml). The combined organic layers were dried over magnesium sulfate and concentrated, to receive untreated fluids in the form of oil. Fluids (11,7 mmole), sodium hydroxide (35 mmol) and water (20 ml) were mixed and heated at 60°C for 1 h, the Reaction mixture was cooled to CT and the aqueous layer washed with dichloromethane (3×100 ml). The water layer was carefully added conc. hydrochloric acid to pH 1 and the reaction mixture was heated at 60°C for 1 h, the Suspension was cooled to 0°C., the solid was separated by filtration and dried, to receive acid (yield 64%).

In ethanol (50 ml) at 0°C was added dropwise acetylchloride (15.3 mmole). After 30 min was added to the resulting acid (7,69 mmole) and the reaction mixture is boiled under reflux for 15 hours, the Reaction mixture was concentrated and the residue was distributed between dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was extracted with dichloromethane (2×20 ml), the combined organic layers were dried over magnesium sulfate and concentrated, to receive ether (yield 94%) as a brown oil.

The suspension obtained ether (of 3.64 mmol) in acetic acid (7.0 ml) at 0°C was added acetic anhydride (6.0 ml). Then portions over 15 min was added zinc dust (to 14.6 mmole) and the reaction mixture was stirred at 0°C for 30 min and then at RT is for 1.5 hours Then add the second portion of powdered zinc (6,15 mmole) and maintained for 3 hours, the Suspension was filtered through celite and the filtrate was concentrated. The residue was distributed between saturated sodium bicarbonate solution (10 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulfate and concentrated, this has been ndimethylacetamide (yield 92%) as a brown oil.

In the solution ndimethylacetamide (to 3.92 mmole) in chloroform (20 ml) was added acetic anhydride (13.7 mmole), isoamylase (13.7 mmole) and potassium acetate (2,04 mmole) and the suspension is boiled under reflux for 16 hours, the Solution was evaporated and the residue was distributed between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml). The aqueous layer was extracted with dichloromethane (2×20 ml), the combined organic layers were dried over magnesium sulfate and concentrated, to receive the crude ether N-acetylimidazole in the form of a brown oil.

Ether (3,36 mmole), sodium hydroxide (10 mmol), water (5 ml) were mixed and kept at 60°C for 24 hours After cooling to CT the aqueous layer washed with dichloromethane (3×30 ml), was added conc. hydrochloric acid to pH 1, the solid substance was separated by filtration, washed with water and dichloromethane, and dried, to receive acid (o is d 26%).

In this procedure also received 6-(deformedarse)-1H-indazol-3-carboxylic acid.

II. Synthesis of reason

Methodology 7

Obtaining 3-aminomethylpyrrolidine of binucleation

In the solution hioliday (40.0 mmol) in dimethyl ether of ethylene glycol (155 ml) solution was added toiletrieschoice (50.0 mmol) in ethanol (4 ml) and the mixture was cooled to -5°C. Then portions over 20 min was added solid tert-piperonyl potassium (130 mmol). After 30 min the reaction mixture was heated to CT and was kept for a further 3 hours, the Reaction mixture was filtered and diluted conc. hydrochloric acid in isopropanol. Then added diethyl ether and the solid was separated by filtration, it was obtained the desired product (yield 88%) as a solid yellow color.

To a solution of nitrile (35,0 mmol) in methanol (720 ml) at 0°C. was added conc. hydrochloric acid (12 ml) and 10% palladium on coal (9.6 g). The reaction mixture was stirred in hydrogen atmosphere for 4.5 hours, the Catalyst was removed by filtration through celite and the filtrate was concentrated, it was obtained a solid yellow color. The solid was dissolved in methanol and again besieged with ethyl ether (400 ml). A solid substance was separated by filtration and dried, it was obtained the desired product (yield 32%) as a solid yellow color.

1N-I Is R (CD 3OD): δ 3,30 (m, 1H), 3,14 (m, 4H), 2,90 (m, 2H), 2,85 (m, 1H), 2,2 (m, 1H), 2,0 (m, 1H), of 1.85 (m, 2H), 1,6 (m, 1H).

III. Condensation and modification of derivatives

Method And

Receipt of ester by the reaction of Mitsunobu

Example 1

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

To a solution of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid (0,50 mmole), (3R)-Hinkley-3-ol (0.57 mmole) and triphenylphosphine (0.57 mmole) in tetrahydrofuran (5 ml) at 0°C was added a solution of diisopropyl ester of azodicarboxylic acid (0.57 mmole) in tetrahydrofuran (1 ml). The mixture was heated up to CT for 2 h and kept for 16 hours Then the mixture was applied to a SCX column (5 g) and washed with methanol. The product was suirable methanol/dimethylethylamine (9:1) and the eluate was concentrated. The residue was purified preparative GHUR, to receive the desired product (yield 1%). LC/MS (EI): tR4,7 min, m/z 369 (M++1).

1H-NMR (CD3OD): δ 8,65 (s, 1H), 8,51 (s, 1H), 8,04 (d, J 6,0, 1H), 7,74 (d, J 6,0, 1H), 7,55 (s, 1H), the 5.45 (m, 1H), 3,81 (m, 1H), 3,45-3,20 (m, 5H), to 2.55 (s, 3H), by 2.55 (m, 1H), a 2.36 (m, 1H), 2.21 are of 1.93 (m, 3H).

Example 2

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 20%). LC/MS (EI): tR4,8 min, m/z 356 (M++1).

Note the R 3

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 17%). LC/MS (EI): tRthe 2.4 min, m/z 302 (M++1).

Example 4

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 20%). LC/MS (EI): tR3,3 min, m/z 302 (M++1).

Example 5

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(triptoreline)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 14%). LC/MS (EI): tR5,0 min, m/z 356 (M++1).

Example 6

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(deformedarse)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 10%). LC/MS (EI): tRthe 4.3 min, m/z 338 (M++1).

Example 7

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 10%). LC/MS (EI): tR4,7 min, m/z 369 (M++1).

Example 8

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 1%). LC/MS (EI): tR4,7 min, m/z 369 (M++l).

Example 9

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 10%). LC/MS (EI): tR2,8 min, m/z 356 (M++1).

Example 10

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 7%). LC/MS (EI): tRthe 4.3 min, m/z 354 (M++1).

Example 11

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by method A (yield 8%). LC/MS (EI): tR3,0 min, m/z 356 (M++1).

Method In

Receipt of ester using activated mozillateam (or oxalylamino)

Example 12

(3S)-1-Azabicyclo[2,2,2]Oct-3-silt ester of 6-(triptoreline)-1H-indazol-3-carboxylic acid

To a solution of 6-(triptoreline)-1H-indazol-3-carboxylic acid (0,81 mmole) in pyridine (5,00 ml) at 0°C was added para-toluensulfonate (0.16 mmole). Then was added (3S)-Hinkley-3-ol (0,81 mmole), the reaction mixture is load the Wali to CT, kept for 16 h, filtered and the filtrate was concentrated. The residue was re-dissolved in methanol, was applied to a SCX column (5 g), washed with methanol, the product was suirable methanol/dimethylethylamine (9:1) and the eluate was concentrated. The residue was purified preparative GHUR, to receive the desired product (yield 16%). Note: similar results were obtained when replacing a pair of toluensulfonate on oxalicacid. LC/MS (EI): tR4,9 min, m/z 356 (M++1).

1H-NMR (Dl3): δ charged 8.52 (s, 1H), of 7.96 (d, J 8,9, 1H), 7,49 (s, 1H), to 7.09 (d, J 8,9, 1H), 5,31 (m, 1H), 3.72 points to be 3.29 (m, 6H), of 2.56 (m, 1H), 2,32 (m, 1H), 2.06 to a 1.88 (m, 3H).

Example 13

(3S)-1-Azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 3%). LC/MS (EI): tR4,8 min, m/z 356 (M++1).

Example 14

(3S)-1-Azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 1%). LC/MS (EI): tR2,5 min, m/z 302 (M++1).

Example 15

(3S)-1-Azabicyclo[2,2,2]Oct-3-silt ester of 5-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 2%). LC/MS (EI): tR2,5 min, m/z 302 (M++1).

Example 16

(3S)-1-Azabicyclo[2,2,2]Oct-3-silt ester 5-(13-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 3%). LC/MS (EI): tR3,9 min, m/z 355 (M++1).

Example 17

4-Methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 4%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

Example 18

4-Methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 4%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

Example 19

4-Methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 2%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

Example 20

4-Methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 3%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

Example 21

(3S)-1-Azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1,2-benzisothiazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 24%). LC/MS (EI): tRthe 4.3 min, m/z 319(M++1).

Example 22

Formate 1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 8%). LC/MS (EI): tR2,9 min, m/z 302 (M++1).

Example 23

Formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6 ethoxy-1,2-benzisothiazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 38%). LC/MS (EI): tR4,7 min, m/z 333 (M++1).

Example 24

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 11%). LC/MS (EI): tR2,5 min, m/z 302 (M++1).

Example 25

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ether 6-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 2%). LC/MS (EI): tR3,3 min, m/z 302 (M++1).

Example 26

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 7-methoxy-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 9%). LC/MS (EI): tR2,9 min, m/z 302 (M++1).

Example 27

Formate (3R)-1-Aza icicle[2,2,2]Oct-3-silt ester 6-(deformedarse)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 3%). LC/MS (EI): tR4,7 min, m/z 338(M++1).

Example 28

(3R)-1-Azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 3%). LC/MS (EI): tR4,9 min, m/z 356 (M++1).

Example 29

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(triptoreline)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 12%). LC/MS (EI): tR4,9 min, m/z 356 (M++1).

Example 30

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 7-(triptoreline)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 3%). LC/MS (EI): tR4,8 min, m/z 356 (M++1).

Example 31

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 2%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

Example 32

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 2%). LC/MS (E): t R4,8 min, m/z 369 (M++1).

Example 33

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 1%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

Example 34

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 1%). LC/MS (EI): tR4,9 min, m/z 369(M++1).

Example 35

Formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid

The specified connection was obtained by the method In (yield 2%). LC/MS (EI): tR3,9 min, m/z 354 (M++1).

Methods With

Getting amide when activated HATU

Example 36

Formate N-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-5-triptoreline-1H-indazol-3-carboxamide

To a solution of 5-(triptoreline)-1H-indazol-3-carboxylic acid (0.40 mmole) in tetrahydrofuran (5.0 ml) and N,N-dimethylformamide (5.0 ml) was added the dihydrochloride of 1-(1-azabicyclo[2,2,2]Oct-3-yl)methanamine (0.40 mmole) and HATU (0.40 mmole). Then was added N,N-diisopropylethylamine (10.0 mmol) and the reaction mixture was stirred for 16 hours Then the reaction mixture was heated at 60°C is for 1 h, was filtered and concentrated. The residue was re-dissolved in methanol and applied to a SCX column (5 g). The column was washed with methanol, the product was suirable methanol/dimethylethylamine (9:1), the eluate was concentrated. The residue was purified preparative GHUR, to receive the desired product (yield 20%). LC/MS (EI): tR4,8 min, m/z 369 (M++1).

1H-NMR (CDCl3): δ of 8.47 (s, 1H), 8,10 (s, 1H), to 7.67 (d, J 9,1, 1H), was 7.36 (d, J 9,1, 1H), 3,63-to 3.52 (m, 3H), 3,48 is 3.23 (m, 4H), is 3.08-a 3.01 (m, 1H), 2,66 is 2.44 (m, 1H), 2,32-2,22 (m, 1H), 2,14-of 2.08 (m, 1H), 2.06 to of 1.85 (m, 3H).

Example 37

Formate N-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-6-methoxy-1H-indazol-3-carboxamide

The specified connection was obtained by the method With (yield 20%). LC/MS (EI): tR2,5 min, m/z 315 (M++1).

Example 38

Binding of [3H]MLA

Materials

Brain tissue of rats (company Pel-Freez Biologicals, cat no.56004-2)

A mixture of protease inhibitors (pill) (firm Roche, cat no.1697498)

Obtain the membrane fraction

Brain tissue of rats in 20 volumes (wt./about.) of 0.32 M sucrose solution, cooled in an ice bath, homogenized in the presence of protease inhibitors (one tablet per 50 ml) in the homogenizer Polytron for 10 sec (speed 11), and then centrifuged at 1000 g and 4°C for 10 min. the Supernatant was centrifuged again for 20 min at 20000 g and 4°C. the Precipitate resuspendable in buffer solution for binding (200mm Tris/HCl, 20 mm HEPES, pH 7.5, 144 mm NaCl, 1.5 mm KCl, 1 mm MgSO4, 2 mm CaCl2, 0.1% (wt./about.) BSA) and stored at -80°C.

For analysis by saturation of the mixture in 200 µl of buffer solution to link contained 200 µg membrannogo protein and 0.2-44 nm [3H]MLA. Nonspecific binding was determined using 1 μm MLA. Analysis of competitive binding was performed using 2 nm of [3H] MLA and the corresponding concentrations of the analyzed compounds. The reaction mixture was incubated at 22°C for 2 h, and then filtered on the filter, GF/B, pre-soaked in 0.3% PEI solution in the buffer solution for binding using Tomtec. The filter is washed three times with buffer solution for binding and measured the radioactivity on the Trilux counter.

The affinity of binding of preferred compounds according to the invention is from 1 nm to 10 μm, especially from 250 nm to 8 μm.

Examples can be repeated with equal result when replacing the reagents described in General terms or specifically, and/or conditions according to the invention, used in these examples.

Although the present invention is illustrated in the methods of obtaining and specific compounds, for professionals it is clear that within the essence and scope of the invention various changes and modifications of the present invention.

1. Connect the s of the formula I

where X1-X4each independently mean CR1,
In means-C(O)-O - or-C(O)-NH-CH2-,
Y represents S or NH,
R1means N
With1-C4alkoxy, unsubstituted or substituted one or more times F, or Het, and
Het means a heterocyclic group, a fully saturated, partially saturated or fully unsaturated, containing at cycle 5 to 10 atoms, of which at least one atom means N, O or S, unsubstituted or substituted one or more times With1-C8the alkyl, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where
R1means H, och3OS2H5, F3or F2and
Het denotes furyl, thienyl, bithienyl, benzoylpyrazoles, thiazolyl, imidazolyl, methylimidazole, pyrrolidinyl, morpholinyl, thiomorpholine, dihydropyran or tetrahydropyranyl, which is in each case unsubstituted or substituted by one or more1-C8alkilani

3. The compound according to claim 1 of formula IA

or its pharmaceutically acceptable salt.

4. The compound according to claim 1 of formula IB

or its pharmaceutically acceptable salt.

5. The connection of claim 1, wherein X1means CH.

6. The connection of claim 1, wherein X2mean CR1where R1Osnach is no Het, C1-C4alkoxy or substituted C1-C4alkoxy.

7. The connection of claim 1, wherein X2mean CR1where R1means thiazolyl, alkylaryl, tetrahydropyranyl, dihydropyran, -och3, -F3or OCHF2.

8. The connection of claim 1, wherein X3mean CR1where R1means Het,1-C4alkoxy or substituted C1-C4alkoxy.

9. The connection of claim 1, wherein X3mean CR1where R1means thiazolyl, alkylaryl, tetrahydropyranyl, dihydropyran, -och3, -F3or F2.

10. The connection of claim 1, wherein X4mean CR1where R1means substituted or unsubstituted With1-C4alkoxy.

11. The connection of claim 1, wherein X4mean CR1where R1means F3or OCHF2.

12. The connection of claim 1, wherein X1and X4every means CH.

13. The connection of claim 1, wherein X2mean CR1where R1different from N, and X1X3and X4every means CH.

14. The connection indicated in paragraph 13, where R1means thiazolyl, alkylaryl, tetrahydropyranyl, dihydropyran, -och3, -F3or OCHF2.

15. The connection of claim 1, wherein X4mean CR1where R1different from N, and X1X2and X3 every means CH.

16. The connection indicated in paragraph 15, where R1means thiazolyl, alkylaryl, tetrahydropyranyl, dihydropyran, -och3, -F3or F2.

17. The compound according to claim 1, where X4mean CR1where R1different from N, and X1X2and X3every means CH.

18. The connection 17, where X4means SN or CR1where R1means F3or OCHF2.

19. The compound according to claim 1. where In means-C(O)-O-, a Y means S.

20. The compound according to claim 1 where In the means-C(O)-NH-CH2-, a Y means S.

21. The compound according to claim 1 where In the means-C(O)-O-, and Y represents NH.

22. Connection item 21, where the means-C(O)-NH-CH2-, a Y represents NH.

23. The compound according to claim 1, where the specified connection selected from the group including
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(deformedarse)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-and the new ester of 5-methoxy-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(triptoreline)-1H-indazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1,2-benzisothiazol-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1H-indazol-3-carboxylic acid,
N-(1-azabicyclo[2,2,2]Oct-3-ylmethyl)-5-triptoreline-1H-indazol-3-carboxamid,
N-1-(azabicyclo[2,2,2]Oct-3-ylmethyl)-6-methoxy-1H-indazol-3-carboxamide, and their pharmaceutically acceptable salts.

24. Connection item 23, where the specified connection is present in the form of formate or 4-methylbenzenesulfonate.

25. The compound according to claim 1, where the specified connection selected from the group including
4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid, formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indiso the-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(deformedarse)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-N-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,
4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-ilove ester 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
4-methylbenzenesulfonate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(tetrahydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(triptoreline)-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6-methoxy-1H-indazol-3-carboxylic acid,
formate N-1-(azabicyclo[2,2,2]Oct-3-ylmethyl)-5-triptoreline-1H-indazol-3-carboxamide is formate, N-1-(azabicyclo[2,2,2]Oct-3-ylmethyl)-6-methoxy-1H-indazol-3-carboxamide.

26. The compound according to claim 1, where the specified connection selected from the group including
1-azabicyclo[2,2,2]Oct-3-silt ester of 5-methoxy-1H-indusl-3-carboxylic acid,
(3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6 ethoxy-1,2-benzisothiazol-3-carboxylic acid,
(3R)-1-azabicyclo [2,2,2]Oct-3-silt ester of 5-methoxy-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-methoxy-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 7-methoxy-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(deformedarse)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(triptoreline)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(triptoreline)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo [2,2,2]Oct-3-silt ester 7-(triptoreline)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo [2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 6-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
(3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acids and their pharmaceutical is acceptable salt.

27. Connection p, where the specified connection is present in the form of formate or 4-methylbenzenesulfonate.

28. The compound according to claim 1, where the specified connection selected from the group including
formate 1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ether 6 ethoxy-1,2-benzisothiazol-3-carboxylic acid,
formate (3S)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-methoxy-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ether 6-methoxy-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester of 7-methoxy-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(deformedarse)-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(triptoreline)-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 7-(triptoreline)-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(5-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(4-methyl-1,3-thiazol-2-yl)-1H-indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 6-(5-methyl-1,3-thiazol-2-yl)-1H-shall indazol-3-carboxylic acid,
formate (3R)-1-azabicyclo[2,2,2]Oct-3-silt ester 5-(3,6-dihydro-2H-Piran-4-yl)-1H-indazol-3-carboxylic acid.

29. Pharmaceutical composition for the selective activation/stimulation of nicotinic α7 receptors, comprising the compound according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier.

30. The use of compounds according to any one of claims 1 to 28 for selective activation/stimulation of nicotinic α7 receptors in the patient's body, in which such activation/stimulation has a therapeutic effect.

31. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient suffering from psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system and/or state failure memory and/or cognitive failure.

32. Use p, where the specified patient suffering from schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia associated with calves Levi, amyotrophic lateral sclerosis, failure of memory, loss of memory, cognitive deficit, attention deficit and/or increased activity in the form of attention deficit.

33. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient suffering from dem is ncie and/or other status, associated with memory loss.

34. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient suffering from memory impairment due to mild deficiency of cognitive abilities during aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, diseases of the Peak, disease Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral aging, multi-infarct dementia, HIV, and/or cardiovascular diseases.

35. The use of compounds according to any one of claims 1 to 28 for the treatment and/or prophylaxis of dementia in a patient diagnosed with Alzheimer's disease.

36. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient with the syndrome of abstinence from alcohol or treatment of the patient from alcohol intoxication.

37. The use of compounds according to any one of claims 1 to 28 for the treatment of the patient to protect neurons against damage associated with strokes and ischemia and glutamatinduzierter cytotoxicity.

38. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient suffering from addiction to nicotine, inducing Smoking cessation, pain, disturbances of circadian biorhythm, obesity and/or diabetes.

39. The use of compounds according to any one of claims 1 to 28 for inducing Smoking cessation in a patient.

40. The use of compounds according to any of the at one of claims 1 to 28 for the treatment of the patient, suffering from mild cognitive failure (MCI), vascular dementia (VD), age-related loss of cognitive abilities (AACD), amnesia associated with open heart surgery, cardiac arrest, General anesthesia, lack of memory for the actions of anesthetic agents, cognitive failure, induced by sleep deprivation, chronic fatigue syndrome, narcolepsy, dementia associated with AIDS, lack of cognitive abilities associated with epilepsy, down syndrome, dementia associated with alcoholism, lack of cognitive abilities associated with medication, dementia caused by strokes head syndrome (boxer), or dementia animals.

41. The use of compounds according to any one of claims 1 to 28 for the treatment of memory loss.

42. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient suffering from insufficient memory.

43. The application of § 42, where the lack of memory caused by decreased activity of nicotinic acetylcholine receptor.

44. The use of compounds according to any one of claims 1 to 28 for the treatment or prevention of a disease or condition caused by disruption of signal transmission nicotinic acetylcholine receptor in a patient.

45. Primeministerial according to any one of claims 1 to 28 for the treatment or prevention of a disease or condition associated with insufficient or impaired function of nicotinic acetylcholine receptors in a patient.

46. The use of compounds according to any one of claims 1 to 28 for the treatment or prevention of a disease or condition caused by a suppressed signal transmission nicotinic acetylcholine receptor in a patient.

47. The use of compounds according to any one of claims 1 to 28 for the treatment or prevention of a disease or condition caused by the loss of cholinergic synapses in the patient.

48. The use of compounds according to any one of claims 1 to 28 for protecting neurons in a patient from the neurotoxic effect induced activation of α7nACh receptors.

49. The use of compounds according to any one of claims 1 to 28 for the treatment or prevention of neurodegenerative disorders by inhibiting the binding of peptides β with α7nACh receptors in a patient.

50. The use of compounds according to any one of claims 1 to 28 for the treatment of a patient suffering from inflammatory diseases.

51. Use item 50, where the specified inflammatory disease of the means of rheumatoid arthritis, diabetes or sepsis.

52. The use according to any one of p-51, where the specified patient is human.



 

Same patents:

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: 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

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: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel azole compounds, which contain carbamoyl group, of general formula IX: where A stands for azole group of general structural formula or G stands for ring, selected from group, consisting of piperonyl, indanyl, naphtyl, possibly substituted phenyl, benzodioxole and phenoxymethyl, (values of radicals are given in the invention formula), their pharmaceutically acceptable salts and pharmaceutical compositions, containing them, which can be applied for treatment of various central nervous system disorders, especially such as anxiety, depression, convulsions, epilepsy, migraine, bipolar disorder, medication abuse, smoking, ADHD, obesity, sleep disorder, neurogenic pain, stroke, cognitive impairment, neurodegeneration and muscle spasm.

EFFECT: obtaining novel azole compounds and their pharmaceutically acceptable salts and pharmaceutical compositions, containing them, which can be applied for treatment of various central nervous system disorders.

71 cl, 3 tbl, 199 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula 1: where R is selected from group, consisting of C1-C3alkyls, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which possess activity of dopamine neurotransmission modulator.

16 cl, 2 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of medication, which possesses anti-inflammatory and regenerating action. Medication contains the following ingredients: conifer needle extract, purified oleoresin of cedar or pine, or spruce, or fir, or larch or their mixture in equal proportions, vegetable oil.

EFFECT: medication has increased effectiveness and efficiency and also extends arsenal of medications, which have anti-inflammatory and regenerating action.

7 cl, 9 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to psychiatry and gynecology, and can be used in treatment of endometriosis in women with anxiety-and-depressive disorders. For this purpose one month after performing laparoscopy at the background of drug hormonal treatment during 6 months phenotropil in dose 100 mg/day is additionally administered for 90 days.

EFFECT: administration of phenotropil in said dose and introduction regimen makes it possible to reduce anxiety-and-depressive symptoms, and has positive impact on functional state of immune and vegetative nervous system.

4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of psychoneurology, in particular to medications for treatment of disseminated sclerosis, representing 1,3-dialkylbenzimidazolium halogenides of general formula

EFFECT: medications ensure high treatment efficiency.

1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and pharmaceutics and deals with application of 3-methyl-6-(1-methylethenyl)cyclohex-3-ene-1,2-diol, its isomers and derivatives as medication for treatment of Parkinson's disease.

EFFECT: medication possesses high activity, low toxicity and can be obtained from available natural compound of a-pinene.

7 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 7-[2-[4-(6-fluoro-3-methyl-1,2-benzioxazol-5-yl)-1-piperazinyl]ethyl]-2-(propynyl)-7H-pyrazolo-[4, 3-e]-[1, 2, 4]-triazolo-[1, 5-c]pyrimidine-5-amine or pharmaceutically acceptable salt thereof, having A2a receptor selective antagonist properties, a pharmaceutical composition based on said compound and use thereof in preparing a medicinal agent for treating central nervous system diseases.

EFFECT: enhanced efficiency of composition and treatment method.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 7-[2-[4-(6-fluoro-3-methyl-1,2-benzioxazol-5-yl)-1-piperazinyl]ethyl]-2-(propynyl)-7H-pyrazolo-[4, 3-e]-[1, 2, 4]-triazolo-[1, 5-c]pyrimidine-5-amine or pharmaceutically acceptable salt thereof, having A2a receptor selective antagonist properties, a pharmaceutical composition based on said compound and use thereof in preparing a medicinal agent for treating central nervous system diseases.

EFFECT: enhanced efficiency of composition and treatment method.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of compounds, characterised by formulae (I) and (IB), or pharmaceutically acceptable salts thereof, isomers or hydrates to prepare a medicinal agent for treating or preventing diseases or conditions mediated by the sigma-receptor, selected from psychosis, neuropathic pain or inflammatory pain and movement disorder, such as dystonia or tardive dyskinesia, motor defects, including allodynia/or hyperalgesia. Radicals and symbols in compounds of formulae (I) and (IB) are described in claims 1 and 2. The invention also relates to novel compounds of formulae (I') and (IB'), in which radicals and symbols are described in claims 4 and 5, having pharmacological activity on the sigma-receptor, methods of producing such compounds, a pharmaceutical composition containing said compounds and use of said compounds in preparing a medicinal agent for treating and/or preventing diseases or conditions whose development involves the sigma-receptor. (I), (IB) (I') and (IB').

EFFECT: high effectiveness of the inhibitors.

22 cl, 1 tbl, 3 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which are methyl-3-azabicyclo[3.3.0]octane-7-carboxylate, N-methyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, N-propyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, or pharmaceutically acceptable salts thereof. The invention also relates to compounds selected from a group, a pharmaceutical composition, methods of treating or preventing central nervous system disorders, as well as use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds having activity on neural nicotinic acetylcholine receptor.

11 cl, 14 ex, 7 tbl, 2 dwg

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