UA78812C2 - Quinuclidine derivatives and their use - Google Patents

Abstract

This invention relates to novel quinuclidine derivatives and their use as pharmaceuticals. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Description

Description of the invention

This invention relates to new quinuclidine derivatives and their use as pharmaceutical preparations. 2 Due to their pharmacological profile, the compounds of the invention may be useful in the treatment of various diseases or disorders involving the cholinergic system, central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders involving smooth muscle contracture, endocrine diseases or disorders, diseases or disorders relating to neurodegeneration, diseases or disorders relating to inflammation, pain and withdrawal symptoms resulting from cessation of chemical abuse.

The endogenous cholinergic neurotransmitter, acetylcholine, exerts its biological effects through two types of cholinergic receptors, muscarinic acetylcholine receptors (mACRs) and nicotinic acetylcholine receptors (nACRs).

It is well known that muscarinic acetylcholine receptors are important for memory and cognition, and 19 much research aimed at improving the treatment of memory disorders has focused on the synthesis of muscarinic acetylcholine receptor modulators.

Indeed, several CNS disorders can be attributed to cholinergic insufficiency, dopaminergic insufficiency, adrenergic insufficiency, or serotonergic insufficiency.

Brown et al. |Vhom/p ek ai: Oiipisiidile Ipriryoge oii 2,3-Okhidozdoaiyuepe Susiaze-I apoviego! BZupiave:

Oriiptiganyop iot I iriy Rgoyev; U. May. Spent 1999 42 1306-1311)| describes the synthesis of tri-substituted quinuclidine derivatives useful as cholesterol biosynthesis inhibitors. There are no reports of effects on nicotinic and/or monoamine receptors.

The presented invention relates to the preparation of new quinuclidine derivatives - modulators of nicotinic and/or monoamine receptors, which are useful for the treatment of diseases or disorders related to cholinergic c 29 receptors, and, in particular, the nicotinic acetylcholine receptor, monoamine receptors, in particular, (3 serotonin receptor (5 -NTK), dopamine receptor (DAR) and noradrenaline receptor (NAR), and transporters of biogenic amine to serotonin (5-HT), dopamine (DA) and norepinephrine (NA).

Due to their pharmacological profile, the compounds of the invention may be useful in the treatment of various diseases or disorders involving the cholinergic system, central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders involving smooth muscle contracture, endocrine - diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by cessation of substance abuse. Gee)

The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic modalities, and in particular for receptor ip mimo (neuroimaging), and may be used in labeled or unlabeled form. c- According to the first aspect, the invention relates to quinuclidine derivatives represented by Formula I of their enantiomer, or a mixture of their enantiomers, or their pharmaceutically acceptable additive salt, or their "onium salt, where shsh c - represents, as an option, a double bond; and n is equal to 1, 2 or 3; "" X is selected from the groups: -О-, -О-СНо-, -О-СНо-СНо-, -5-, -80-, -5О05) -СНо-, -З-СНо-СНо-, «СНо -, -F(-СН»)-, -МНУ-,

M(alkyl)-, -b(-50)-, -C(-5)-,

A represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted with one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, o-hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkyl, cycloalkyl, halogen ,

C3, CM, MH", MH", carboxy, carbamoyl, amide, sulfamoyl, and phenyl, or another monocyclic or (o) polycyclic, carbocyclic or heterocyclic group, where an additional monocyclic or polycyclic, shu 90 carbocyclic or heterocyclic group may, as variant, to be substituted by one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkyloxy,

I» cycloalkoxy, cycloalkoxyalkyl, cycloalkoxyalkoxy, halogen, CE3, CM, MO», MH», carboxy, carbamoyl, amide, sulfamoyl, and phenyl; provided, however, that X represents O or 5; o then A is not phenyl or phenyl substituted with any group other than phenyl (ie, a diphenyl group). Namely) In a second aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a quinuclidine derivative of the invention. 60 In a third aspect, the invention relates to the use of a quinuclidine derivative of the invention, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition/medicine for the treatment, prevention or amelioration of a disease or disorder or condition in a mammal, including a human, disease, disorder or condition that is susceptible to effects of the nicotinic acetylcholine receptor modulator.

In a further aspect, the invention relates to a method of treating or ameliorating a disease or disorder in an animal, including a human, whose disease or disorder is sensitive to the action of a nicotinic acetylcholine receptor modulator, the method comprising the step of administering to such an animal, including a human, if necessary, therapeutically an effective amount of the quinuclidine derivative of the invention.

Other objects of the invention will be apparent to those skilled in the art from the following detailed description and examples.

Quinuclidin derivatives

In a first aspect, the present invention relates to the novel quinuclidine derivatives presented

Formula I

And: and their enantiomer, or a mixture of their enantiomers, or their pharmaceutically acceptable additive salt, or their onium salt, where represents, as an option, a double bond; n equals 1, 2 or 3;

X is selected from the groups: -О-, -ОО-СНо-, -ОО-СНо-СНо-, -5-, -50-, -505, -СНо-, -5-СНо-СН»о-, -СНо -, -FSH(-CH»)-, -MH-, "M(alkyl), -b(-50)-, -С(-5)-,

A represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted with one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, t-hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkyl, cycloalkyl, halogen,

SEz, CM, MO», MH», carboxy, carbamoyl, amide, sulfamoyl, and phenyl, or another monocyclic or polycyclic, carbocyclic or heterocyclic group, where additional . a monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted by one or more substituents selected from the group: alkyl, or more substituents selected from the group: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkylalkyl , cycloalcoxyalkoxy, halogen, CEz, CM, MO», MH», carboxy, carbamoyl, amide, sulfamoyl, and phenyl; provided, however, that X represents O or 5; then A is not phenyl or phenyl substituted by any group other than phenyl (that is, if X represents O or 5 and A represents a phenyl group, then this phenyl group must be only diphenyl (group 3).

In a preferred embodiment, the quinuclidine derivative of the invention is a compound of formula I, where it represents a single (covalent) bond.

In another preferred embodiment, the quinuclidine derivative of the invention is a compound of formula I, where n is 1, 2 or cm 3. "-

In the third preferred embodiment, the quinuclidine derivative of the invention is a compound of the formula I, where X is selected from the groups: -0-, -0-Cno-, -O-СНо-СНе-, -5-, and -СНо-. In a more preferred embodiment, X is selected from the groups: -O-, -0O-CH»o-, and 09 -O-cSnNo-CH»o-. (se)

In the fourth preferred embodiment, the quinuclidine derivative of the invention is a compound of formula I, where A represents a monocyclic or polycyclic carbocyclic group selected from the groups: phenyl; indanyl, in particular, 4-indanyl and - 5-indanyl; indenyl, in particular, 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular, 1-naphthyl and 2-naphthyl; 5,6,7,8-tetrahydronaphthyl, in particular, 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl;.azulenyl, in particular, 1-azulenyl, 2 -azulenil and Z-azulenil; and fluorenyl, in particular, 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, and 4-fluorenyl; and anthracenyl, in particular, 1-anthracenyl and 2-anthracenyl; where the carbocyclic group, as an option, is substituted with one or two substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxyalkyl, hydroxyalkyl, alkyloxy, cycloalkyl, cycloalkyl, cycloalkyl, halogen, ", MH", carboxy, carbamoyl, amide, sulfamoyl and phenyl.

In the fifth preferred embodiment, the quinuclidine derivative of the invention is a compound of formula I, where A represents an aromatic monocyclic or polycyclic carbocyclic group selected from the groups: phenyl; indenyl, in particular, - 75 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular, 1-naphthyl and 2-naphthyl; azulenyl, in particular, 1-azulenyl, 2-azulenyl and 3-azulenyl; and anthracenyl, in particular, 1-anthracenyl and 2-anthracenyl; where the aromatic carbocyclic (ee) group is optionally substituted one or two times by substituents selected from the groups: alkyl, cycloalkyl, bo cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, halogen, CE3, CM, MO ", MH", carboxy, carbamoyl, amide, sulfamoyl and phenyl. - 70 In the most preferred embodiment, the quinuclidine derivative of the invention of formula | represents "with (-)-3-22-Phenylphenyloxy)-1-azadicycloi|2.2.2|octane; (-)-3-(3-Phenylphenyloxy)-1-azadicycloi|2.2.2|octane; (-)- 3-(4-Phenylphenyloxy)-1-azadicycloi|2.2.2|octane; 5B ()-3-(4-Phenylphenylmethoxy)-1-azadicyclo|2.2.2|octane; (--3-(Naphthalene-2- yloxy)-1-azadicyclo|2.2.2|octane;

F, (--3-(5,6,7,8-Tetrahydro-2-naphthyloxy)-1-azadicyclo|2.2.2|octane; or co (--3-(5-indanyloxy)-1-azadicyclo| 2.2.2|octane; or its enantiomer, or its pharmaceutically acceptable addition salt, or its onium salt. 60 In the sixth preferred embodiment, the quinuclidine derivative of the invention is a compound of formula I, where A represents a monocyclic or polycyclic heterocyclic group selected from the groups: pyridyl, in particular, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl, thienyl, in particular thien-2-yl and thien-Z-yl, furanyl, in particular furan-2-yl and furan-Z- yl; pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl, in particular 1,3,4- Thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl and 65 1,2,4-thiadiazol-5-yl; quinolinyl, particularly quinoline-2 -yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and quinolin-6b-yl; quinoxalinyl, in particular quinoxalin-2-yl and quinoxalin-3-yl; benzimidazolyl, in particular

benzimidazol-2-yl; benzoxazolyl, in particular, benzoxazol-2-yl; benzthiazolyl, in particular, benzthiazol-2-yl; where is monocyclic. or a polycyclic heterocyclic group, optionally substituted with one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkoxyalkoxy, halogen, CEz, CM, MO», MH», carboxy, carbamoyl, amide, sulfamoyl, and phenyl, or another monocyclic or polycyclic, carbocyclic, or heterocyclic group, wherein the additional monocyclic or polycyclic, carbocyclic, or heterocyclic group is optionally substituted with one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyaloxy, cycloalkyl, cycloalkoxyalkyl, cycloalkoxyalkoxy, /o Halogen, CE", CM, MO", MH", carboxy, carbamoyl, amide, sulfamoyl, and phenyl.

In the seventh preferred embodiment, the quinuclidine derivative of the invention is a compound of formula I, where A represents a monocyclic group selected from the groups: pyridyl, in particular, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; thienyl, in particular, thien-2-yl and thien-Z-yl; furanyl, in particular, furan-2-yl and furan-Z-yl; pyridazinyl, in particular, pyridazin-3-yl and pyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl, in particular, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-b- silt; wherein the monocyclic heterocyclic group is optionally substituted with one or more cyclic group is optionally substituted with one or more substituents selected from the groups: alkyl, cycloalkyl, alkoxy, cycloalkyl, halogen, CE3, CM, MO", MH", phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, and 3-pyridinyl, phenyl, wherein the 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, and 3-pyridinyl groups may optionally , be substituted by one or two substituents selected from the groups: alkyl, cycloalkyl, alkoxy, halogen, CEz, CM, MO", MH", and phenyl.

In the most preferred embodiment, the quinuclidine derivative of the invention of formula | represents ()-3-(3,4,5-Trichlorothien-2-yloxy)-1-azadicyclo|2.2.2|octane; (-)-3-(5-Bromothiazol-2-yloxy)-1-azadicycloyl|2.2.2|octane; ()-3-(5-Phenylthiazol-2-yloxy)-1-azadicyclo|2.2.2|octane; Ha ()-3-I5-(2,4-Difluorophenyl)-thiazol-2-yloxy)|-1-azadicycloi|2.2.2|octane; o (-)-3-I5-13-Thienyl)-thiazol-2-yloxy)|-1-azadicyclo|2.2.2|octane; (-)-3-I5-2-Thienyl)-thiazol-2-yloxy|-1-azadicycloi|2.2.2|octane; (-)-3-15-(3-Furanyl)-thiazol-2-yloxy|-1-azadicycloyl|2.2.2|octane; ()-3-15-(3-Pyridyl)-thiazol-2-yloxy|-1-azadicycloyl|2.2.2|octane; c ()-3-(6-Chlorpyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane; "- (-)-3-(6-Bromopyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane; (--3-(6-Phenylpyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane; co (z)-3-I6-(3-Thienyl)-pyridazin-3-yloxy)|-1- azadicyclo|2.2.2|octane; (ee) ()-3-16-(2-Thienyl)-pyridazin-3-yloxy)|-1-azadicyclo|2.2.2|octane; chn ()-3-16-(2-Furanyl)-pyridazin-3-yloxy)|-1-azadicyclo|2.2.2|octane; ()-3-I6--3-Furanyl)-pyridazin-3-yloxy)|-1-azadicyclo|2.2.2|octane; (-)-3-I6-(3-Pyridyl)-pyridazin-3-yloxy|-1-azadicyclo|2.2.2|octane; ()-3-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azadicycloyl|2.2.2|octane; (-3-(5-Phenyl-1,2,4-thiadiazol-3-yloxy)-1-azadicyclo|2.2.2|octane; or - c (-)-3-I5-(2-Thienyl)-1 ,3,4-thiadiazol-2-yloxy|-1-azadicyclo/|2.2.2|octane; "" or its enantiomer, or its pharmaceutically acceptable addition salt, or its onium salt. " In the eighth preferred embodiment, the quinuclidine derivative of the invention is a compound of the formula I, where A represents a polycyclic heterocyclic group selected from the groups: indolyl, in particular, indol-2-yl and indol-3-yl; isoindolyl, in particular isoindol-2-yl; quinolinyl, in particular quinolin-2-yl , quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and - quinolin-6b-yl; quinoxalinyl, in particular, quinoxalin-2-yl and quinoxalin-3-yl; benzimidazolyl, in particular, benzimidazol-2 -yl; benzoxazolyl, in particular, benzoxazol-2-yl; benzthiazolyl, in particular, benzthiazol-2-yl; benzisothiazolyl, in particular benzisothiazol-3-yl; benztriazolyl, in particular 1,2,3-benztriazol-1 -yl; bo 1,2-Vpyridazinyl, in particular, imidazo|1,2-B|pyridazin-b-yl: dibenzofuranyl, in particular, dibenzofuran-2-yl; where -shЩ 70 Mmonocyclic or polycyclic the heterocyclic group is optionally substituted by one or more substituents selected from the groups: alkyl, cycloalkyl, alkoxy, cycloalkyloxy, halogen, CE3, CM, MO", MH", and phenyl, phenyl o) group which can optionally be substituted by one or more substituents selected from the groups: alkyl, cycloalkyl, alkoxy, halogen, CEz, CM, MO", MH", and phenyl.

In the most preferred embodiment, the quinuclidine derivative of the invention of formula | represents (--3-K1,3-Dione)-2-isoindolylmethoxy|-1-azadicycloi|2.2.2|octane;

HF) (--3-1,3-Dione)-2-isoindolylethoxy)|-1-azadicyclo|2.2.2|octane; ()-3-22-Quinolinyloxy)-1-azadicyclo|2.2.2|octane; by (--3-(2-Quinolinyloxy)-1-azadicyclo|2.2.2|octane methyl iodide; ()-3-(6-Quinolinyloxy)-1-azadicyclo|2.2.2|octane; bo ()-3 -(2-Quinoxaliniloxy)-1-azadicyclo|2.2.2|octane; (--3-2-Quinoxaliniloxy)-1-azadicyclo|2.2.2|)octane methyl iodide; (-)-3-(3-Chloro-2-quinoxaliniloxy)-1-azadicyclo|2.2.2|octane; ()-3-(3-Methoxy-2-quinoxaliniloxy)-1-azadicycloi|2.2.2|octane; 65 (-)-3-(Benzoxazol-2-yloxy)-1-azadicyclo|2.2.2|octane; ()-3-(Benzothiazol-2-yloxy)-1-azadicyclo|2.2.2|octane;

(--3-(6-Chloro-benzothiazol-2-yloxy)-1-azadicyclo|2.2.2|octane; ()-3-(1,2-Benzoisothiazol-3-yloxy)-1-azadicyclo|2.2. 2|octane; (-)-3-(1,2-Benzoisothiazol-3-yloxy)-1-azadicyclo|2.2.2|octane; (--3-(1-Methylbenzoimidazoli-2-yloxy)-1-azadicyclo |2.2.2|octane; or (--3-(Benzotriazol-1-yloxy)-1-azadicycloi|2.2.2|octane; or its enantiomer, or its pharmaceutically acceptable additive salt, or its onium salt. and other preferred an embodiment of the quinuclidine derivative of the invention is a compound of the formula II n is equal to 1, 2 or 3,

X is selected from the groups: -О-, -ОО-СНо-, -ОО-СНо-СНо-, -5-, -50-, -505, -СНо-, -5-СНо-СНо-, -СНо-, -FSH(-CH»)-, -MH-, -IR(alkyl)-, -(-0)-, -FSH(-5)-, sh-.

U represents O, 5, 50", or MK, where KK represents hydrogen or alkyl.

In a more preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of formula II, where "represents a single (covalent) bond.

In another preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of formula III, where n is 1, 2 or 3.

In a third preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of formula II, where X is selected from the group: -O-, -O-СНо-, -О-СНа-Снг, -5-, and -СНо-.

In a fourth preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of formula II, wherein

U represents O, 5, 50", or MK, where K' represents hydrogen or alkyl.

In the most preferred embodiment, the quinuclidine derivative of the invention of formula II is (--3-(Dibenzofuran-2-yloxy)-1-azadicyclo|2.2.2|octane; ch or its enantiomer, or its pharmaceutically acceptable additive salt, or its onium salt.

In yet another preferred embodiment, the quinuclidine derivative of the invention is a compound of the formula HER (8) as

X is selected from the groups: -О-, -ОО-СНо-, -ОО-СНо-СН»о, -5-, -50-, -505, -СН»-, -5-СНо-СНо-, -СНо -, -FSH-СНо)-, -МН-, -М(alkyl)-, -(-0)-, -Ф(-5)-, сч ш-.

B represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, as an option, "- substituted by one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkyl, cycloalkyl, halogen , co

CEz, CM, MO", MH", carboxy, carbamoyl, amide, sulfamoyl, and phenyl, or other monocyclic or He) polycyclic, carbocyclic or heterocyclic group, where the additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted by one or more substituents - selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxy, hydroxy, alkyl, alkyl, cycloalkoxy, cycloalkoxyalkyl, cycloalkoxyalkoxy, halogen, SEZ, CM, MO», MH», carboxy, carbamoyl, amide, sulfamoyl and phenyl; "

In a more preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of the formula IP, where represents a single (covalent) bond. no) c In another preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of the formula III, where n z" equals 1, 2 or 3.

In the third preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of the formula I, where X is selected from the groups: -O-, -O-СНо-, -О-СНо-СН», -5-, and -СН-.

In a fourth preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of formula I, where

Che B represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted with one or more substituents selected from the groups: oalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, cycloalkoxyalkoxy, halogen, CO . by one or more substituents selected from the groups: alkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkoxyalkoxy, halogen, CEz, CM, MO», MH», carboxy, carbamoyl, amide, sulfamoyl, and phenyl; 29 In a fifth preferred embodiment of this aspect, the quinuclidine derivative of the invention is a compound of formula II, wherein B (FI represents a phenyl group, wherein the phenyl is optionally substituted with one or two substituents selected from the groups: alkyl, cycloalkyl, alkoxy, cycloalkyl, halogen , SEz, SM, MO", MH", and phenyl. In the most preferred embodiment, the quinuclidine derivative of the invention of formula II! represents 1-azadicyclo|2.2.2|octane;60 or an enantiomer thereof, or a pharmaceutically acceptable addition salt thereof, or an onium salt thereof.

Any combination of two or more embodiments described herein is contemplated within the scope of the present invention.

Definition of substitutes

In the context of the present invention, halogen is fluorine, chlorine, bromine or iodine. Accordingly, the trihalogenmethyl group is represented, for example, by trifluoromethyl, trichloromethyl, and, similarly, trihalogen-substituted methyl groups. for In the context of the present invention, an alkyl group means a monovalent saturated, linear or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (C.4.4c-alkyl), more preferably from one to b carbon atoms (Ci-c-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl In a preferred embodiment, alkyl is

Sidealkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of the present invention, alkyl is C. 3-alkyl, which may, in particular, be methyl, ethyl, propyl or isopropyl.

In the context of the present invention, a cycloalkyl group means a cyclic alkyl group preferably containing from three to seven carbon atoms (C3-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

In the context of the present invention, a cycloalkylalkyl group means a cycloalkyl group as defined above, where the cycloalkyl group is substituted on an alkyl group also defined above. Examples of preferred cycloalkylalkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.

In the context of the present invention, an alkoxy group means an "alkyl-CO" group, where alkyl is defined above. Examples of preferred alkyloxy groups of the invention include methoxyl and ethoxyl.

In the context of the present invention, a hydroxyalkyl group means an hydroxy group as defined above, where the hydroxy group is substituted by one or more hydroxy groups. Preferred hydroxyalkyl groups of the invention include 2-hydroxyethoxyl, 3-hydroxypropoxyl, 4-hydroxybutoxyl, 5-hydroxypentoxyl and β-hydroxyl.

In the context of the present invention, a cycloalkyl group means a "cycloalkyl-O-" group, where cycloalkyl is defined above.

In the context of the present invention, the alkoxyalkyl group means "alkyl-O-alkyl group, where alkyl is defined above.

Examples of preferred alkoxyalkyl moieties of the invention include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

In the context of the present invention, an alkoxyalkoxy group means an "alkyl-O-alkyl-O-" group, where alkyl is defined above.

Examples of preferred alkoxyalkyl groups of the invention include methoxymethoxy, methoxyethoxyl, ethoxymethoxyl, and ethoxyethoxyl.

In the context of the present invention, the cycloalkyl group means "cycloalkyl-O-alkyl" group, where cycloalkyl and i) alkyl are defined above.

In the context of the present invention, a cycloalkoxyalkoxy group means a "cycloalkyl-O-alkyl-O-" group, where cycloalkyl and alkyl are defined above. c zo In the context of the present invention, a mono- or polycyclic carbocyclic group is a mono- or polycyclic carbocyclic group containing carbon only as a ring atom. The ring structure may, in particular, be -- aromatic (ie, an aryl group), or saturated, or partially saturated. co

Preferred mono- or polycyclic carbocyclic groups of the invention include phenyl; indanyl, in particular, 4-indanyl and b5-indanyl; indenyl, in particular, 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular, 1-naphthyl and so 2-naphthyl; 5,6,7,8-tetrahydronaphthyl, in particular, 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl; y-azulenyl, in particular, 1-azulenyl, 2-azulenyl and 3-azulenyl; fluorenyl, in particular, 1-fluorenyl, 2-fluorenyl,

C-fluorenyl and 4-fluorenyl; and anthracenyl, particularly 1-anthracenyl and 2-anthracenyl.

A mono- or polycyclic carbocyclic group may, in particular, be an aromatic group (aryl). Preferred aryl groups of the invention include phenyl; indenyl, in particular, 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular, "-naphthyl and 2-naphthyl; azulenyl, in particular, 1-azulenyl, 2-azulenyl and 3-azulenyl; and anthracenyl, in particular, with 1-anthracenyl and 2-anthracenyl.

In the context of the present invention, a mono- or polycyclic heterocyclic group represents a mono- or polycyclic;" a compound that contains one or more heteroatoms in its ring structure. The term poly-heterocyclic group covers a benzo-fused, five- and b-membered heterocyclic ring containing one or more

Heteroatoms. Preferred heteroatoms include nitrogen (M), oxygen (0), and sulfur (5). One or more -I ring structures may, in particular, be aromatic (ie, heteroaryl).

Preferred monocyclic heterocyclic groups of the invention include pyridyl, in particular, pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; thienyl, in particular, thien-2-yl and thien-Z-yl; furanyl, in particular, furan-2-yl and furan-Z-yl;

Go! pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl and thiazol-b-yl; and thiadiazolyl, in particular, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-b-yl, 1,2,4-thiadiazol-3-yl and - 1,2,4-thiadiazol- 5-il.

He Preferred polycyclic heterocyclic groups of the invention include indolyl, in particular, indol-2-yl and indol-3-yl; isoindolyl, in particular, isoindol-2-yl; quinolinyl, in particular, quinolin-2-yl, quinolin-Z-yl, quinolin-4-yl, quinolin-b-yl, and quinolin-b-yl; quinoxalinyl, in particular, quinoxalin-2-yl and quinoxalin-33-yl; benzimidazolyl, in particular, benzimidazol-2-yl; benzoxazolyl, in particular, benzoxazol-2-yl; benzthiazolyl, in particular, benzthiazol-2-yl; benzisothiazolyl, in particular, benzisothiazol-3-yl; benztriazolyl, in particular, 1,2,3-benztriazol-1-yl; (F) imidazo|1,2-B|pyridazinyl, in particular, imidazo|1,2-B|Ipyridazin-6-yl; and dibenzofuranyl, in particular, ka di-benzofuran-2-yl. Pharmaceutically acceptable salts.

The quinuclidine derivative of the invention can be offered in any form suitable for the intended use. Suitable forms include pharmaceutically (ie, physiologically) acceptable salts, and pre- or pro-drug forms of the quinuclidine derivative of the invention.

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic addition salts of inorganic and organic acids, such as hydrochloride derived from hydrochloric acid, hydrobromide derived from bromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, 65 phosphate, derived from phosphoric acid, sulfate, derived from sulfuric acid, formate, derived from formic acid, acetate, derived from acetic acid, aconate, derived from aconitic acid, ascorbate,

ascorbic acid derivative, benzosulfonate, benzenesulfonic acid derivative, benzoate, benzoic acid derivative, p-phenylacrylate, cinnamic acid derivative, citrate, citric acid derivative, embonate, embonic acid derivative, enanthate, enanthate derivative, fumarate, fumaric acid derivative, glutamate, glutamic acid derivative, glycolate, glycolic acid derivative, lactate, lactic acid derivative, maleate, maleic acid derivative, malonate, malonic acid derivative, mandelate, mandelic acid derivative, methanesulfonate , derived from methanesulfonic acid, naphthalene-2-sulfonate, derived from naphthalene-2-sulfonic acid, phthalate, derived from phthalic acid, salicylate, derived from salicylic acid, sorbate, derived from sorbic acid, /o stearate, derived from stearic acid , succinate, derived from succinic acid, tartrate, derived from tartaric acid, toluene-p-sulfonate, derived from p-toluenesulfo acids, and the like. Such salts can be prepared by methods well known in the art.

Other acids, such as oxalic acid, which are not considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in the preparation of the chemical compounds of the invention and their 7/5 pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of the chemical compound of the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, and ammonium salts, etc., of the chemical compounds of the invention containing an anionic group. Salts of such cations can be prepared by methods well known in the art.

In the context of the present invention, "onium salts" of M-containing compounds are also considered as pharmaceutically acceptable salts (aza-onium salts). Preferably, aza-onium salts contain alkyl-onium salts, especially methyl- and ethyl-onium salts; cycloalkyl-onium salts, especially cyclo-propyl-onium salts; and cycloalkylalkyl onium salts, especially cyclopropylmethyl onium salts.

Stereoisomers

The quinuclidine derivatives of the present invention can exist in (Ж) and (-) forms, as well as in racemic forms (5). Racemates of these isomers and the individual isomers themselves are within the scope of the present invention.

Racemic forms can be separated into optical antipodes by known methods and techniques. One i) method of separation of diastereoisomeric salts is the use of optically active acids, and the separation of optically active amine compounds by treatment with a base. Another way of separating racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can be accordingly separated into their optical antipodes, for example, by fractional crystallization of 4- or 1-("tartrates, mandelates, or camphorsulfonates). -

The quinuclidine derivatives of the present invention can also be separated by the formation of diastereoisomeric amides by the reaction of the chemical compound of the present invention with an optically active activated carboxylic acid, such as derivatives (g) or (-) phenylalanine, (y-) or 1-) phenylglycine, (y) or (-) camphanic acid or so

35 by the formation of diastereoisomeric carbamates by the reaction of chemical compounds of the present invention with optically active chloroformate or the like.

Additional methods for resolving optical isomers are known in the art. Such methods include those described in YuShadtsevz

U, SoPes A, 5 UMiep 5 in "Epapiotegv, Kasetaiez, and KezoYishiopeg", dopp UMIeu and bopv, Mem Hogk (1981).

Optically active compounds can also be obtained from optically active starting materials. "

Methods of obtaining 8 s Quinuclidine derivatives of the invention can be obtained by appropriate methods of chemical synthesis, for example, those described in the working examples. Raw materials for the methods described in the submitted application; known or their "" can be easily obtained by appropriate methods from commercially available reagents.

Also, one compound of the invention can be converted into another compound of the invention using appropriate methods. -and The final products of the reactions described herein can be isolated by suitable methods, for example, extraction, crystallization, distillation, chromatography, etc. because Biological activity

Ho) The presented invention relates to new quinuclidine derivatives, which, as found, are cholinergic ligands on nicotinic acetylcholine receptors (nACH), and modulators of monoamine receptors, in particular, biogenic amine transporters, such as the serotonin receptor (5-NTK), dopamine with receptor (DAR) and noradrenoline receptor (NAR), and transporters of biogenic amine to serotonin (5-HT), dopamine (DA) and norepinephrine (NA). Also, preferred quinuclidine derivatives of the invention show selective os7 activity as shown in the working examples. Compounds of the presented invention, in particular,

They can be agonists, partial agonists, antagonists and allosteric modulators of the receptor.

Due to their pharmacological profile, the compounds of the invention may be useful in the treatment of various iF) diseases or disorders involving CNS diseases, PNO diseases, diseases or disorders involving smooth muscle contracture, endocrine diseases or disorders, diseases or disorders involving neurodegeneration, diseases or disorders involving inflammation, pain, and withdrawal symptoms resulting from cessation of substance abuse.

In a preferred embodiment, quinuclidine derivatives of the invention are used to treat diseases, disorders, or conditions affecting the central nervous system. Such illnesses or disorders include anxiety, cognitive impairment, learning disabilities, memory deficits and dysfunctions, illness

Alzheimer's, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Gentinton's disease, amyotrophic lateral sclerosis, Gilles de la Tourette syndrome, psychoses, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorders ( NPR), panic disorders, eating disorders,

such as anorexia nervosa, increased hunger and obesity, narcolepsy, nociception, AIDS dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, Hanser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania, and violations of the body's daily rhythm.

In a preferred embodiment, the diseases, disorders, or conditions related to the central nervous system for which quinuclidine derivatives of the invention are used are cognitive disorders, psychosis, schizophrenia, and/or depression. 70 In another preferred embodiment, quinuclidine derivatives of the invention may be useful in the treatment of diseases, disorders, or conditions involving smooth muscle contracture, including convulsive disorders, angina pectoris, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive, dyskinesia, " hyperkinesia, premature ejaculation and erectile dysfunction.

In yet another preferred embodiment, quinuclidine derivatives of the invention may be useful for 7/5 treatment of endocrine disorders such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In addition, in another preferred embodiment, the quinuclidine derivatives of the invention may be useful in the treatment of neurodegenerative disorders, including short-term oxygen starvation and induced neurodegeneration.

In yet another preferred embodiment, the quinuclidine derivatives of the invention may be useful in the treatment of inflammatory diseases, disorders, or conditions, including inflammatory skin disorders such as acne and erythema, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and diarrhea.

In addition, in another preferred embodiment, the quinuclidine derivatives of the invention may be useful in the treatment of mild, moderate, or even severe pain, acute, chronic, or recurrent, as well as migraine pain, postoperative pain, and phantom limb pain. In particular, the pain may be neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, post-therapeutic neuralgia, or peripheral nerve injury. and)

Finally, quinuclidine derivatives of the invention may be useful in the treatment of withdrawal symptoms due to cessation of abuse of addictive substances. Such an addictive substance includes products that contain nicotine, such as tobacco, opioids such as heroin, cocaine, and morphine, benzodiazepines and benzodiazepine-like drugs, and alcohol. Abstinence from an addictive substance is a common traumatic experience characterized by anxiety and hopelessness, anger, anxiety, difficulty concentrating, dysphoria, decreased heart rate, and decreased appetite and weight gain.

In this context, "treatment" includes the treatment, prevention, prevention, and relief of withdrawal and withdrawal symptoms, as well as treatment that results in the voluntary reduction of abuse of addictive substances. Cha

In another aspect, the quinuclidine derivatives of the invention are used as diagnostic agents, for example, for the identification and localization of nicotinic receptors in various tissues.

Pharmaceutical compositions

In another aspect, the invention relates to new pharmaceutical compositions containing a therapeutically effective amount of quinuclidine derivatives of the invention. Although the chemical compound of the invention for use in therapy can be applied in the form of unprocessed. chemical compounds, it is better to introduce the active ingredient, as an option, in the form of a physiologically acceptable salt in the pharmaceutical composition together with one or more adjuvants, fillers, carriers, buffers, diluents, and/or other conventional pharmaceutical aids.

In a preferred embodiment, the invention relates to a pharmaceutical composition containing a quinuclidine derivative -I together with one or more pharmaceutically acceptable carriers and, optionally, with other therapeutic and/or prophylactic ingredients known and used in the industry. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and harmless to the recipient. o The pharmaceutical composition of the invention can be applied in any convenient way that corresponds to the desired therapy. Preferred routes of administration include oral administration, particularly in tablet, capsule, dragee, powder, or liquid form, and parenteral administration, particularly dermal, subcutaneous,

Ge intramuscular or intravenous injection. The pharmaceutical composition of the invention can be prepared by specialists in the field using standard methods and appropriate methods appropriate for the production of the desired composition. When necessary, you can use compositions adapted to prolonged release of the active ingredient,

Further details of formulation and application methods can be found in the latest edition of Ketipdiops

F) Rpagtaseciisa! Zsiepsez (Maask Rybiizpipd So., Eazyup, RA). The actual dosage depends on the nature and severity of the disease being treated, and is at the discretion of the physician, and can be changed by titrating the dosage to the specific circumstances of the present invention to obtain the desired therapeutic effect. However, it is now contemplated that pharmaceutical compositions containing from about 0.1 to 500mg of the active ingredient in an individual dose, preferably from about 1 to 100mg, most preferably from about 1 to 10mg, are suitable for therapeutic treatment.

The active ingredient can be applied in one or more doses per day. In some cases, the corresponding result can be obtained at a dosage below 0.1 μg/kg intravenously (iv) and 65 μg/kg orally (po). Currently, the upper limit of dosage is considered to be approximately 1Omg/kg i.v. and 10 ug/kg PO. Preferred levels are about 0.1 ug/kg to 1 ug/kg/day IV, and about 1 ug/kg to 10 ug/kg/day PO.

Methods of therapy

Due to their pharmacological profile, the compounds of the invention may be useful in the treatment of a variety of diseases or disorders involving the CNS, diseases (PNO), diseases or disorders involving

Contractures of smooth muscles, endocrine. diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms due to cessation of chemical abuse.

In another aspect, the invention relates to a method of treating or alleviating a disease or disorder of an animal organism, including a human, the disease or disorder of which is sensitive to the action of a monoamine receptor modulator, the 7/0 method involves the step of administering to such an animal organism, including a human, if necessary, therapeutically an effective amount of the quinuclidine derivative of the invention.

In the context of the present invention, the term "treatment" includes treatment, prevention, prevention, and alleviation, and the term "disease" includes ailments, diseases, disorders, and conditions related to these diseases.

A suitable dosage is currently considered to be in the range of about 0.1 to 500 mg of active 7/5 daily, more preferably about 10 to 70 mg of active daily, administered once or twice daily, depending of course on the precision of the regimen application, form of application, indication for which the application is directed, subject of intervention, body weight of the subject of intervention, and away from the preference and experience of the responsible physician or veterinarian.

Examples 20 The invention is further illustrated by the following examples, which are not intended to limit the scope of the claimed invention.

General remarks: All reactions that contain air-sensitive reagents or intermediates are carried out under nitrogen and in non-aqueous solvents. In the techniques involved, magnesium sulfate is used as a drying agent, and the solvents are evaporated under reduced pressure.

Method A p 25 (-3-3-(Naphthalin-2-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound AT) o

Add: diethyl azodicarboxylate (5.4 ml, 34.5 mmol) at room temperature for 30 minutes. The reaction mixture is stirred for 20 hours at 50 oC. Add aqueous sodium hydroxide (100 ml, 1 M). The mixture is extracted with dichloromethane (3 x 100 Oml). Chromatography on silica gel with dichloromethane, methanol and conc. with ammonia (89:10:11) gives the named compound. The corresponding salt is obtained - by adding a mixture of diethyl ether and methanol (9:1) saturated with fumaric acid. Output 3.7 g (4390). T.pl. pp. 140.9-141.626. ()-3-(4-Phenylphenyloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound Ag) with 35 Obtained by method A from 4-phenylphenol. T.pl. 173.5-185.1 26. - ()-3-(3-Phenylphenyloxy)-1-azadicycloi|2.2.2|octane, free base (Compound AZ)

Obtained by method A from 3-phenylphenol. The product is isolated in the form of oil. ()-3-(2-Phenylphenyloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound A4) «

Obtained by method A from 2-phenylphenol. T.pl. 125,496. C ()-3-(6-Quinolinoxy)-1-azadicyclo|2.2.2|octane, fumaric acid salt (Compound AB) c Obtained by method A from b-hydroxyquinoline. T.pl. 146.0-147.096. :z» (-)-3-(5-Indanyloxy)-1-azadicyclo|2.2.2)octane, salt of fumaric acid (Compound Ab)

Obtained by method A from 5-indanol. T.pl. 149.3-150.520. ()-3-(5,6,7,8-Tetrahydro-2-naphthyloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound A?7) and -I Obtained by method A from 5,6 ,7 8-tetrahydro-2-naphthol.

T.pl. 109.7-111.396. co Method B (ee) ()-2-(1-Azadicycloi|2.2.2|oct-3-yloxy)-quinoline, salt of fumaric acid (Compound B1) shu 20 Mixture of (-)-3-quinuclidinol (2.0g , 15.7 mmol), 2-chloroquinoline (2.6 g, 15.7/mmol) and DMF (30 ml) were stirred at room temperature. Add sodium hydride (0.94 g, 23.6 mmol, 6095 in oil) in small portions. The reaction mixture is stirred for 1.5 hours at 502C. add aqueous sodium hydroxide (5 ml, 1 M), then extract with diethyl ether (3 x 500 ml). The combined ether phases are washed with aqueous sodium hydroxide (2 x 5 Oml, 1M).

The corresponding salt is obtained by adding diethyl ether and a mixture of methanol (9:11) saturated with fumaric acid. Output 4.62g (79905). T.pl. 160.0-160.520.

GF! (3-3-(6-Chlorobenzothiazol-2-yloxy)-1-azadicyclo|2.2.2|octane, fumaric acid salt (Compound B2)

Obtained by method B from 2,6-dichlorobenzothiazole. T.pl. 203-205960. o (-)-3-(Benzothiazol-2-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound BZ)

Obtained by method B from 2-chlorobenzothiazole. T.pl. 173.7-174.296. 60 (-2-(1-Azadicycloi|2.2.2)oct-3-yloxy)-3-chloroquinoxaline, salt of fumaric acid (Compound B4)

Obtained by method B from 2,3-dichloroquinoxaline. T.pl. 120.8-122.126, (--3-(1-Methylbenzoimidazol-2-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound B5)

It is obtained by method B from 2-chloro-1-methylbenzoimidazole. 184.9-185.996. 65 (-)-3-(Benzoxazol-2-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound Bb)

It is obtained by method B from 2-chlorobenzoxazole. 187.2-188.8260.

(-2-(1-Azadicycloi|2.2.2)oct-3-yloxy)-quinoxaline, salt of fumaric acid (Compound B7)

Obtained by method B from 2-chloroquinoxaline. T.pl. 127.7-128.596. (-)-3-(6-Phenylpyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane, fumaric acid salt (Compound B8)

Obtained by method B from 3-chloro-b6-phenylpyridazine. T.pl. 168.5-172.096. (--355-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azadicyclo|2.2.2|octane, fumaric acid salt (Compound B9)

Obtained by method B from 2-chloro-5-phenyl-1,3,4-thiadiazole. T.pl. 168.5-172.0960, (-3-3-(5-Bromothiazol-2-yloxy)-1-azadicyclo|2.2.2|octane, fumaric acid salt (Compound B10)

Obtained by method B from 2,5-dibromothiazole, using 02С as the reaction temperature. T.pl. 157.8-162.1260. ()-3-(1,2-Benzoisothiazol-3Z-yloxy)-1-azadicycloi|2.2.2|octane, salt of fumaric acid (Compound B11)

Obtained by method B from 3-chloro-1,2-benzoisothiazole. T.pl. 172.3-173.690. ()-3-(5-Phenyl-1,2,4-thiadiazol-3-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound B12)

Obtained by method B from 3-chloro-5-phenyl-1,2,4-thiadiazole. T.pl. 155.0-159.3960, ()-3-(6-Bromopyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound B13)

Obtained by method B from 3,6-dibromopyridazine. T.pl. 152,826. (-)-3-(6-Chloropyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound B14)

Obtained by method B from 3,6-dichloropyridazine. T.pl. 164-164,590, ()-3-(3,4,5-Trichloro-2-yloxy)-1-azadicyclo|2.2.2|octane, fumaric acid salt (Compound B15)

Obtained by method B under conditions: potassium tert-butoxide, crown ether (18:6), from tetrach-lorthiophene. T.pl. 188-189,426. (-)-3-(3-Methoxy-2-quinoxalinyloxy)-1-azadicycloi|2.2.2|octane, salt of fumaric acid (Compound B16)

A mixture of /(-)-2-(1-Azadicyclo|2.2.2|oct-3-yloxy)-3-chloroquinoxaline Compound B4; 1.38g, 4.7bmmol), cesium carbonate (1.55g, 4.76mmol) and methanol (15ml) were stirred for 3 hours at 452С. Add aqueous sodium CM hydroxide (5Oml, 1M), then extract with diethyl ether (3 x 5Oml). The corresponding salt is obtained by adding d) a mixture of diethyl ether and methanol (9:11), saturated with fumaric acid. Output 0.51g, 2795, T.pl. 168.5-170.026. (z-)-3-I5-(3-Thienyl)-1,3,4-thiadiazol-2-yloxy|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound B17)

Obtained by method B from 2-chloro-5-(3-thienyl)-1,3,4-thiadiazole. T. pl., 186-18820. cm (-3-3-К1,3-Dione)-2-isoindolylmethoxy|-1-azadicyclo/|2.2.2|octane, salt of fumaric acid (Compound B18) -

Obtained by method B from M-(2-bromomethyl)-phthalimide. T. pl. 212-21396, so (--3-1,3-Dione)-2-isoindolylethoxyl-1-azadicyclo|2.2.2|octane-free base (Compound B19)

Obtained by method B from IR-(2-bromomethyl)-phthalimide. Isolated as free base, oil. co (-)-3-(Benzotriazol-1-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound B20) h-

It is obtained by method B from 1-(chloromethyl)-1H-benzotriazole. 163.3-164.5960.

Method C (13-2-(1-Azadicyclo|2.2.2|oct-3-yloxy)-quinoxaline methylium, iodide " (Compound C1)

To a mixture of /(z)-3-(quinoxalin-2-yloxy)-1-azadicyclo|2.2.2|octane (1.27g, 5.Omol) dichloromethane (1Oml) sh-s is added at -702C: methyl iodide (0.31g, 5.0mmol) dissolved in dichloromethane (1.5ml) was added after 10 minutes. h The reaction mixture is stirred at -709C for 40 minutes. The reaction mixture is stirred at room temperature and . . . . temperature for 3 hours. The precipitate is isolated by filtration. T.pl. 229-23090. (1)-2-(1-Azadicyclo|2.2.2|oct-3-yloxy)-quinoline methyl iodide (Compound C2)

Obtained by method C from (--)-2-(1-Azadicyclo|2.2.2|oct-3-yloxy)-quinoline. T.pl. 156.6-175.2960. it. ()-3-(1,2-Benzoisothiazol-3-yloxy)-1-azadicyclo|2.2.2|octane methyl iodide (Compound C3)

Go) Obtained by method C from (--)-3-(1,2-benzoisothiazol-3-yloxy)-1-azadicyclo|2.2.2)octane. T.pl. 180.1-186.420.

Method O so (--3-(5-Phenylthiazol-2-yloxy)-1-azadicycloi|2.2.2|octane, fumaric acid salt - 70 (Compound 01)

Kz Mixture of (-)-3-(5-Bromothiazol-2-yloxy)-1-azadicyclo|2.2.2|octane (1.25g, 4.32mmol), phenylboronic acid (0.791g, b.48mmol), Ra( RRNIz); (0.150 g, 0.1 mmol), aqueous potassium carbonate (b.5 ml, 2 M), 1,3-propanediol (0.97 ml, 13.0 mmol) and 1,2-dimethoxyethane (30 ml) are mixed under reflux for 15 hours

Aqueous sodium hydroxide (50 ml, 1 M) was added, the mixture was extracted with ethyl acetate (3 x 5 Oml). Chromatography on silica gel with dichloromethane, methanol and conc. with ammonia (89:10:11) gives the named compound Yield 3.7 g (43905).

GF) The corresponding salt is obtained by adding a mixture of diethyl ether and methanol (9:1) saturated with fumar

HF acid. T.pl. 170.9-172.296. ()-3-15-(2,4-Difluoro-phenyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound O2) in Obtained by method ОХ. T.pl. 84.3-86.320. (-)-3-I5-(3-Thienyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound OZ)

They are obtained by the method of Yu. T.pl. 68.5-74.390. ()-3-I5-(2-Thienyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound 04)

Obtained by the method of O. T.pl. 152.6-154.996. 65 (-)-3-I5-(3-Furanylthiazol-2-yloxy|-1-azadicyclo|2.2.2octane, salt of fumaric acid (Compound Y5)

Obtained by the method of O. T.pl. 127.6-136.226.

()-3-I5-(3-Pyridyl)-thiazol-2-yloxy|-1-azadicyclo/2.2.2|octane, salt of fumaric acid (Compound Ob)

Obtained by the 0O method. T.pl. 82.7-86.026. (-)-3-I6-(3-Thienyl)-pyridazin-3-yloxy)|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound 07)

Obtained by method B from (4)-3--6-bromopyridazin-3-yloxy)-1-azadicycloi|2.2.2|octane. T.pl. 197,996, ()-3-I6-(2-Thienyl)-pyridazin-3-yloxy)|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound O8)

Obtained by method B from (-3)-3-(6-bromopyridazin-3-yloxy)-1-azadicyclo|2.2.2)octane. M.pl.. 180.3-191.190, ()-3-I6-(2-Furanyl)-pyridazin-3-yloxy|-1-azadicyclo!|2.2.2|octane, salt of fumaric acid (Compound 09) 70 Obtained by method B from (4)-3-(6-bromopyridazin-3-yloxy)-1-azadicycloi|2.2.2|octane. T.pl. 175.8-178.296. ()-3-I6-(3-Furanyl)-pyridazin-3-yloxy|-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound 010)

Obtained by method B from (4)-3-(6-bromopyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane. T.pl. 224.8-225.496. ()-3-I6-(3-Pyridyl)-pyridazin-3-yloxy|-1-azadicyclo|2.2.2)octane, salt of fumaric acid (Compound Y11)

Obtained by method B from (-)-3-(6-bromopyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane. T.pl. 137.2-143.296.

Method E (-3-3-(4-Phenylphenylmethoxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound EB)

A mixture of (-)-3-quinoclidinol (2.0g, 15.7mmol), 4-phenylbenzyl chloride (3.2g, 15.7mmol), sodium hydride, 6095 in oil (1.26g, 31.4mmol), and DMF ( ZOml) are kept at 502C for 4.5 hours. Add aqueous sodium hydroxide (10 Oml, 1 M). The mixture was extracted with diethyl ether (3 x 5 Oml). Chromatography on silica gel with dichloromethane, methanol and conc. with ammonia (89:10:1) gives the title compound. Output 2.0g (2996).

The corresponding salt is obtained by adding a mixture of diethyl ether and methanol (9:1) saturated with fumaric He

with acid T.pl. 159.8-160.490, Fr

The compound can also be called (--)-3-(diphenyl-4-ylmethoxy)-quinuclidine.

Method E ()-3-(2-Phenylimidazo|1,2-in|Ipyridazine-b-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid (Compound E1) c

To the mixture of b-chloro-2-phenylimidazo|1,2-8|Ipyridazine (obtained accordingly in). Ne(egosusi. SNet. 39, 737, 2002) "-- (3.6 g, 15.7 mmol), (-)-3-quinuclidinol 2.0 g, 15.7 mmol) in DMF (ZOml): after 20 minutes, add sodium hydride (1.26 g, »« 31.4 mmol) at room temperature, then stir at 502C for 4 hours. Add aqueous sodium hydroxide (100 ml, 1 M). The mixture was extracted with diethyl ether (3 x 100 ml). Chromatography on silica gel with dichloromethane, methanol and conc. with ammonia (89:10:1) gives the title compound. Output 2.9g (57960).

The corresponding salt is obtained by adding a mixture of diethyl ether and methanol (9:1), saturated with fumaric acid. T.pl. 211-216260,

Method G (--3--"Dibenzofuran-2-yloxy)-1-azadicyclo|2.2.2|octane, salt of fumaric acid" (Compound O1) -o 70 To the mixture of (-3-3-quinoclidinol (3.0g . ). The mixture was stirred at 509 for 7 days. Aqueous sodium hydroxide (10Oml, 1M) was added. The mixture was extracted with dichloromethane (3 x 100ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound . Yield 2.Og (2996). - The corresponding salt of fumaric acid is obtained by adding a mixture of diethyl ether and methanol (9:1), saturated with fumaric acid. M.p. 131.3-133.820. Because the compound can also be called (--) -3-(Dibenzofuran-2-yloxy)-quinuclidine.

Ho) Biological activity of shu 20 Inhibition of binding of ZN-y-bungarotoxin and migo in the rat brain.

In this example, the ability of the compounds of the invention to bind the os-subtype of nicotinic receptors is determined. that) co-Bungarotoxin is a peptide isolated from the venom of a snake of the genus Eiaridae of the species Vypdagis tiyipsiii5. It has a high affinity for neuronal and neuromuscular nicotinic receptors and acts as a potential antagonist.

ZH-os-Bungarotoxin marks nicotinic acetylcholine receptors formed by the os;-subunit isoform found in the brain and the osgiziform in the neuromuscular junction. o Obtaining fabric

Obtaining is carried out at 0-42C. The cerebral cortex of male Wuiziag rats (150-250 g) is homogenized for 10 seconds in 15 ml of 20 mmol Hepes buffer, which contains 118 mmol of Masi, 4.8 mmol of KSI, 1.2 mmol of Mo5O, and 2.5 mmol of Sasi" (pH 7.5 ), using the Oiga-Tigtakh homogenizer. The tissue suspension is centrifuged at 27,000 x 60 g for 10 minutes. The supernatant is discarded and the pellet is washed twice by centrifugation at 27,000 x d for 10 minutes in 20 ml of fresh buffer, and the final pellet is then resuspended in fresh buffer containing 0.0195 bovine serum albumin (35 ml per g of starting tissue) and used for analysis of yawning

Analysis bo Aliquots of 500 μl of the homogenate are added to 25 μl of the test solution and 25 μl of ZN-a-bungarotoxin (2 NM,

final concentration), mix and incubate for 2 hours at 37 C. Non-specific binding is determined using (-)-nicotine (1 mmol, final concentration). After incubation, 5 ml of ice-cooled Hepes buffer containing 0.0595 polyethyleneimine is added to the samples and poured onto a glass fiber filter

MMpytap COP/C (soaked with 0.195 polyethyleneimine for at least b hours) under suction, and immediately washed with 2 x 5 ml of ice-cold buffer.

The amount of radioactivity on the filters is determined by a suitable scintillation counter in the liquid. Specific binding equals total binding minus nonspecific binding.

The experimental value is given as IR 50 (the concentration of the test substance that inhibits the specific 70 binding of ZN-y-bungarotoxin by 5096).

The results of these experiments are presented below in Table 1.

Table 1

Inhibition of ZN-os-bungarotoxin binding 5 ov sh 2» o re | education with zo

Claims (35)

The formula of the invention "- 1. A quinuclidine derivative of the formula c 2 () with its enantiomer, a mixture of its enantiomers, its pharmaceutically acceptable additive salt, or its onium salt, where, - tttst----- represents a possible double bond; n-1, 2 or 3; X is a linker from the group: -O-, -0-СНо-, -0-СНо-СНе-, -5-, -50-, -505-, -СНо-, -5-СНо-СНо-, -СНо , -FSHCH»)-,-MH-, "-M(alkyl)-, -(-0)-, -F(-5)-, Ty, shi c A- "z monocyclic or polycyclic carbocyclic group, as- i.e.: k indanyl; indenyl; naphthyl; -i 5,6,7,8-tetrahydronaphthyl; o azulenyl and anthracenyl; or (o) a monocyclic heterocyclic group such as: pyridazinyl and thiazolyl; or a polycyclic heterocyclic group such as -to: indolyl; I» isoindolyl; quinolinyl; quinoxalinyl; benzoxazolyl; o benzthiazolyl; benzisothiazolyl; imo) benztriazolyl and imidazo|1,2-VIpyridazinyl; these mono or polycyclic, carbocyclic or heterocyclic groups are optionally substituted by one or more 60 from the substituents: alkyl, cycloalkyl, cycloalkylalkyl, alkoxyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxyl, cycloalkoxyl, cycloalkoxyalkyl, cycloalkoxyalkoxyl, halogen, CEz, CM, MO», MH», carboxyl, carbamoyl, amido, sulfamoyl and phenyl, or other monocyclic or polycyclic , carbocyclic or heterocyclic group y, this additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted with one or more of the following substituents: alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, hydroxy, SM, MO», MN», carboxyl, carbamoyl, amido, sulfamoyl and phenyl. 2. A quinuclidine derivative according to claim 1, where ---------- represents a single (covalent) bond. 3. A quinuclidine derivative according to any of claims 1-2, where n-1, 2 or 3. 4. A quinuclidine derivative according to item C, where item 2. 5. A quinuclidine derivative according to any of claims 1-4, where X is a linker from the group: -О-, -0-СНо-, -ОО-СНо-СНе-, -5- and -СН»о-. 6. A quinuclidine derivative according to claim 5, where X is -O-, -O-СНо- or -ОО-СНо-СН»о-. 7. A quinuclidine derivative according to claim 5, where X is -O-. 8. A quinuclidine derivative according to any of claims 1-7, where A is a monocyclic or polycyclic carbocyclic group, such as: 70 indanyl; indenyl; naphthyl; 5,6,7,8-tetrahydronaphthyl; azulenil and anthracenil; this carbocyclic group is optionally substituted with one or two of the following substituents: alkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxyalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkoxyalkyl, cycloalkoxyalkyl, halogen, CEz, CM, MO», MH», carboxyl, carbamoyl, amido, sulfamoyl, and phenyl. 9. A quinuclidine derivative according to claim 8, where A is a monocyclic or polycyclic carbocyclic group, such as: 4-indanyl and 5-indanyl; 1-indenyl, 2-indenyl and 3-indenyl; 1-naphthyl and 2-naphthyl; 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7-8-tetrahydro-2-naphthyl; 1-azulenyl, 2-azulenyl and 3-azulenyl; and 1-anthracenyl and 2-anthracenyl; this carbocyclic group is optionally substituted with one or two of the following substituents: alkyl, cycloalkyl, s.c. , amido, sulfamoyl and phenyl. (8) 10. A quinuclidine derivative according to claim 9, which is (0 3)-3-(naphth-2-yloxy)-1-azadicyclo|2.2.2|octane; ()-3-(5,6,7,8-tetrahydro-2-naphthyloxy)-1-aza-dicyclo|2.2.2)octane or (-)-3-(5-indanyloxy)-1-azadicyclo|2.2 .2|octane; si or an enantiomer thereof, a pharmaceutically acceptable addition salt thereof, or an onium salt thereof. 11. A quinuclidine derivative according to any of claims 1-7, where A is a monocyclic or polycyclic heterocyclic group, such as: (ee) pyridazinyl; thiazolyl; co quinolinil; h- quinoxalinil; benzoxazolyl; benzthiazolyl; "this monocyclic or polycyclic heterocyclic group is optionally substituted by one or more of the 470 substituents: alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkyloxy, -c cycloalkyl, cycloalkylalkyl, cycloalkyloxy, halogen, CEz, SM, MO", MH", carboxyl, carbamoyl, and amido, sulfamoyl and phenyl, or another monocyclic or polycyclic, carbocyclic or heterocyclic" group, this additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted by one or more of the substituents: alkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkyl, cycloalkyl, halogen, SEz, SM, MO», -| MH", carboxyl, carbamoyl, amido, sulfamoyl and phenyl. co 12. A quinuclidine derivative according to claim 11, where A is a monocyclic or polycyclic heterocyclic group, such as: pyridazin-3Z-yl and pyridazin-4-yl; (ee) thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; 20 quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and quinolin-b-yl; quinoxalin-2-yl and quinoxalin-3-yl; k) benzoxazol-2-yl and benzthiazol-2-yl; this monocyclic or polycyclic heterocyclic group is optionally substituted with one or more of the following substituents: alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkoxyalkyl, cycloalkoxyalkyl, halogen, C3, CM, MO, MH, carboxyl , carbamoyl, amido, sulfamoyl and phenyl, or another monocyclic or polycyclic, carbocyclic or heterocyclic IF) group, this additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted with one or more of the substituents: alkyl, cycloalkyl, cycloalkylalkyl, alkoxyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, cycloalkoxyl, cycloalkoxyalkyl, cycloalkoxyalkoxyl, halogen, CEz, CM, MO», bo MH», carboxyl, carbamoyl, amido, sulfamoyl, and phenyl. 13. A quinuclidine derivative according to claim 11, where A is pyridazin-3-yl or pyridazin-4-yl; which is optionally substituted by one or more of the following substituents: alkyl, cycloalkyl, cycloalkylalkyl, alkyl, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkoxyalkyl, cycloalkoxyalkyl, halogen, CEz, CM, MO», MH», carboxyl, carbamoyl, amido, sulfamoyl and phenyl, or another monocyclic or polycyclic, carbocyclic or heterocyclic group, this additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted with one or more of the substituents: alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, hydroxyalkyl, alkoxyalkyl, alkyloxy, cycloalkyl, cycloalkoxyalkyl, cycloalkyloxy, halogen, CEz, CM, MO», MH», carboxyl, carbamoyl, amido, sulfamoyl, and phenyl. 14. A quinuclidine derivative according to claim 13, where A is pyridazin-3-yl or pyridazin-4-yl; optionally substituted with a polycyclic heterocyclic group. 15. A quinuclidine derivative according to claim 14, where A is pyridazin-3-yl or pyridazin-4-yl; 70 optionally substituted with indolyl; isoindolyl; quinolinil; quinoxalinil; benzoxazolyl; benzthiazolyl; benzisothiazolyl; benztriazolyl or imidazo|1,2-v|pyridazinyl. 16. A quinuclidine derivative according to claim 15, where A is pyridazin-3-yl or pyridazin-4-yl; optionally substituted with indolyl. 17. A quinuclidine derivative according to claim 16, where A is pyridazin-3-yl substituted by indolyl. 18. A quinuclidine derivative according to any of claims 1-7, where A is a monocyclic heterocyclic group, such as: pyridazinyl and thiazolyl; this monocyclic heterocyclic group is optionally substituted with one or more of the substituents alkyl, c-cycloalkyl, alkoxy, cycloalkyl, halogen, CE3, CM, MO», MH», phenyl, 2-thienyl, 3-thienyl, 2-furanyl, C -furanyl and 3-pyridinyl, these phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl and 3-pyridinyl can, like i) variant, be substituted by one or two of the substituents: alkyl, cycloalkyl, alkyl, halogen, SEz, SM, MO», MN» and phenyl. 19. A quinuclidine derivative according to any of claims 1-7, where A is a monocyclic heterocyclic group, such as: c zo pyridazin-3-yl and pyridazin-4-yl; and thiazol-2-yl thiazol-4-yl and thiazol-5-yl; - this monocyclic heterocyclic group, as an option, is substituted by one or more of the following substituents: alkyl, co-cycloalkyl, alkyl, cycloalkyl, halogen, CEz, CM, MO», MH», phenyl, 2-thienyl, 3-thienyl, 2-furanyl . , halogen, SEz, SM, MO», MH», and phenyl. 20. A quinuclidine derivative according to any of claims 1-7, where A is a monocyclic heterocyclic group, such as: pyridazin-3-yl and pyridazin-4-yl; and thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; this monocyclic heterocyclic group is optionally substituted with one or more of halogen, phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl and 3-pyridinyl, these phenyl, 2-thienyl, 3-thienyl , 2-furanyl, 3-furanyl and 3-pyridinyl may optionally be substituted with one or two halogens. 21. A quinuclidine derivative according to claim 18, which is: ; » (--3-(5-bromothiazol-2-yloxy)-1-azadicyclo|2.2.2)octane; (-)-3-(5-phenylthiazol-2-yloxy)-1-azadicyclo|2.2.2|octane; ()-3-15-(2,4-difluorophenyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane; -| (-)-3-15-(3-thienyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane; co (-)-3-15-(2-thienyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane; (-)-3-15-(3-furanyl)-thiazol-2-yloxy|-1-azadicyclo|2.2.2|octane; bo (-)-3-15-(3-pyridyl)-thiazol-2-yloxy|-1-azadicyclo|2,2.2|octane; -k 70 ()-3-(6b-chloropyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane; (3-3-(6-bromopyridazin-3-yloxy)-1-azadicyclo|2.2.2|octane; iz (-)-3-(6-phenylpyridazin-3-yloxy)-1-azadicyclo|2.2.2| octane; ()-3-16-(3-thienyl)-pyridazin-3-yloxy|-1-azadicycloyl|2.2.2|octane; 5 ()-3-16-(2-thienyl)-pyridazin-3- yloxy|-1-azadicyclo/|2.2.2|octane; ()-3-16-(2-furanyl)-pyridazin-3-yloxy|-1-azadicyclo/|2.2.2|octane; (F) (-- 3-I6-(3-furanyl)-pyridazin-3-yloxy|-1-azadicyclo|2.2.2|octane or co ()-3-I6-(3-pyridyl)-pyridazin-3-yloxy|-1- azadicycloi|2.2.2|octane; or an enantiomer thereof, a pharmaceutically acceptable addition salt thereof, or an onium salt thereof. 22. A quinuclidine derivative according to any of claims 1-7, where A is a polycyclic heterocyclic group, such as: indolyl ; isoindolyl; quinolinyl; quinoxalinyl; 65 benzoxazolyl; benzthiazolyl; benzisothiazolyl; benztriazolyl and imidazo|1,2-VIpyridazinyl; this monocyclic or polycyclic heterocyclic group is optionally substituted with one or more of the following substituents: alkyl, cycloalkyl, alkyl, cycloalkyl, halogen, CE3, CM, MO", MNO and phenyl, this phenyl may optionally be substituted with one or more from substituents: alkyl, cycloalkyl, alkyl, halogen; SEz, SM, MO», MN» and phenyl. 23. A quinuclidine derivative according to claim 22, where A is a polycyclic heterocyclic group, such as: indol-2-yl and indol-3-yl; 70 isoindol-2-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and quinolin-b-yl; quinoxalin-2-yl and quinoxalin-3-yl; benzoxazol-2-yl; benzthiazol-2-yl; benzisothiazol-3-yl; 1,2,3-benztriazol-1-yl and imidazo|1,2-b|pyridazin-6-yl; this monocyclic or polycyclic heterocyclic group is optionally substituted with one or more of the following substituents: alkyl, cycloalkyl, alkyl, cycloalkyl, halogen, CE3, CM, MO", MNO and phenyl, this phenyl may optionally be substituted with one or more from the substituents: alkyl, cycloalkyl, alkoxyl, halogen, CE3, CM, MO», MH» and phenyl. 24. A quinuclidine derivative according to claim 23, where A is a polycyclic heterocyclic group, such as: isoindol-2-yl; quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and quinolin-b-yl; quinoxalin-2-yl and quinoxalin-3-yl; ch benzoxazol-2-yl; benzthiazol-2-yl; (8) benzisothiazol-3-yl; 1,2,3-benztriazol-1-yl and imidazo|1,2-b|pyridazin-6-yl; this monocyclic or polycyclic heterocyclic group is optionally substituted with one or more of the following substituents: alkyl, alkyl, and halogen. 25. A quinuclidine derivative according to claim 24, which is: - (--3-К1,3-dione)-2-isoindolylmethoxy|-1-azadicyclo|2.2.2|octane; co (--3-(1,3-dione)-2-isoindolylethoxy|-1-azadicyclo|2.2.2|octane; ()-3-(2-quinolinyloxy)-1-azadicyclo|2 2.2|octane; co (--3-(2-quinolinyloxy)-1-azadicyclo|2.2.2)octane methyl iodide; h- ()-3-(6-quinolinyloxy)-1-azadicyclo|2.2.2|octane; ()-3 -(2-quinoxalinyloxy)-1-azadicyclo|2.2.2|octane; (--3-(2-quinoxalinyloxy)-1-azadicyclo|2.2.2|octane methyl iodide; " ()-3-(3-chloro -2-quinoxalinyloxy)-1-azadicyclo|2.2.2|octane; 50 ()-3-(3-methoxy-2-quinoxalinyloxy)-1-azadicyclo|2.2.2|octane; With c (-3-3- (benzoxazol-2-yloxy)-1-azadicyclo|2.2.2|octane; ; with" (-3-3-(benzthiazol-2-yloxy)-1-azadicyclo|2,2.2|octane; (--3- (b-chloro-benzthiazol-2-yloxy)-1-azadicyclo|2.2.2|octane; (--3-(1,2-benzisothiazol-3-yloxy)-1-azadicyclo|2.2.2|octane; - And (--3-(1,2-benzisothiazol-3-yloxy)-1-azadicyclo|2.2.2|octane; (--3-(benztriazol-1-yloxy)-1-azadicyclo|2.2.2|) octane or co (-)-3-(2-phenylimidazo|1,2-b|pyridazine-b-yloxy)-1-azadicyclo|2.2.2|octane; (ee) or its enantiomer, its pharmaceutically acceptable addition salt, or his onieva si l. Shu 20 26. A pharmaceutical composition containing a therapeutically effective amount of a quinuclidine derivative according to any one of claims 1-25 or a pharmaceutically acceptable addition salt thereof. What) 27. Use of a quinuclidine derivative according to any of claims 1-25 or its pharmaceutically acceptable additive salt for the production of a pharmaceutical composition/medicine for the treatment, prevention or mitigation of a disease, disorder or condition of a mammal, including a human, and the disease, disorder or condition are sensitive to modulation of cholinergic receptors and/or monoamine receptors. 28. The use of claim 27, wherein the disease, disorder or condition involves the central nervous system. at 29. Use according to claim 28, wherein the disease, disorder or condition is anxiety, cognitive disorders, learning disabilities, memory deficits and dysfunctions, Alzheimer's disease, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, 60 Gilles de la Tourette syndrome, psychosis, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorders (OC), panic disorders, eating disorders, such as anorexia nervosa, bulimia, and obesity , narcolepsy, nociception, AIDS dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia, Hanser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome 65, mutism, trichotillomania and disruption of the body's daily rhythm. 30. The use of claim 27, wherein the disease, disorder or condition is associated with smooth muscle contraction, covering convulsive disorders, angina pectoris, preterm labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile dysfunction. 31. The use of claim 27, wherein the disease, disorder or condition relates to the endocrine system, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias. 32. The use of claim 27, wherein the disease, disorder or condition is a neurodegenerative disorder, including transient anoxia and induced neurodegeneration. 33. The use of claim 27, wherein the disease, disorder or condition is an inflammatory disorder, including inflammatory skin disorders such as acne and rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis and 70 diarrhea. 34. Use according to claim 27, where the disease, disorder or condition is mild, moderate or even severe pain of an acute, chronic or recurrent nature, pain caused by migraine, postoperative pain, phantom limb pain, neuropathic pain, chronic headache, central pain, pain in diabetic neuropathy, post-therapeutic neuralgia, or peripheral nerve damage. 35. The use of claim 27, wherein the disease, disorder or condition is associated with withdrawal symptoms caused by cessation of habit-forming substances, including nicotine products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepine-like drugs, and alcohol. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 5 04/25/2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 6) s «- (ee) (ee) and - - and? -i (ee) (ee) - 70 Ko) ime) bo b5