EP1465868A1

EP1465868A1 - Phenoxy piperidines for treating diseases such as schizophrenia and depression

Info

Publication number: EP1465868A1
Application number: EP02793045A
Authority: EP
Inventors: Günter Hölzemann; Helmut Prücher; Kai Schiemann; Joachim Leibrock; Hartmut Greiner; Christa Burger; Laurie Von Melchner
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2002-01-17
Filing date: 2002-12-17
Publication date: 2004-10-13
Also published as: PL373946A1; AU2002358735B9; US20050131021A1; AU2002358735A1; ZA200406504B; DE10201550A1; HUP0500497A2; JP2005514457A; AU2002358735B2; CA2473409A1; WO2003059882A1; JP4727925B2; CA2473409C; US20090247584A1; CN1615297A

Abstract

The invention relates to compounds of formula (1), wherein R1, R2', R2'', R2''', R3 and n are defined as per claim 1. Said compounds are effectors of the nicotinic and/or muscarinic acetylcholine receptor and are suitable for the prophylaxis or treatment of schizophrenia, depression, panic attacks, dementia, Alzheimer's disease, Lewy body dementia, neurodegenerative diseases, Parkinson's disease, Huntington's chorea, Tourette's syndrome, learning limitations and memory loss, senile mnemasthenia, for relieving withdrawal symptoms in nicotine dependency, or for the prophylaxis or treatment of cerebral apoplexy or cerebral damage caused by toxic compounds.

Description

PHENOXY-PIPERIDINE FOR TREATING DISEASES LIKE SCHIZOPHRENIA AND DEPRESSION

The invention relates to phenoxy-piperidines of the formula where R ^{1 is} H or A,

R ² ', R ² ", R ² '" each independently of one another H, A, OH, OCH ₃ , OCF ₃ , Hai, CN, COOR ¹ , CONR ¹ or NO ₂ ,

R ^J A, Ar, A-Ar,

R ⁴ H, A, A unbranched or branched alkyl having 1-10 C atoms, in which one or two CH ₂ groups by O or S atoms and / or by -CH = CH groups and / or also 1- 7 H atoms can be replaced by F,

Ar unsubstituted or single, double or triple by shark, A, OR ⁴ , N (R ⁴ ) ₂ , N0 ₂ , CN, COOR ⁴ , CON (R ⁴ ) ₂ , NR ⁴ COA, NR ⁴ CON (R ⁴ ) ₂ , NR ⁴ SO ₂ A, COR ⁴ , S0 ₂ N (R ⁴ ) ₂ , S0 ₂ A substituted phenyl, naphthyl or biphenyl, A-Ar arylalkyl, where A and Ar have one of the meanings mentioned above, Hai F, CI , Br or I and n denotes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their pharmaceutically usable derivatives, solvates and stereoisomers have valuable pharmacological properties with good tolerability, since they have effects on the central nervous system. The compounds are in particular effectors of the nicotinic and / or muscarinic acetylcholine receptor, whereby they show agonistic or antagonistic effects.

Some members of the well-characterized class of acetylcholre receptors are held responsible for certain clinical pictures of the central nervous system. Known active ingredients that can interact with the class of acetylcholine receptors are, for example, pilocarpine, nicotine, lobeline and epibatidine.

Phenoxypiperidine derivatives with an antagonistic effect on the muscarinic acetylcholine receptor are, for example, from the

WO 98/06697 known; further muscarinic antagonists are disclosed in US 6,037,352. Substances that bind to the nicotinic acetylcholine receptor are e.g. described in WO 00/42044 and EP 0 955 301 A2.

The nicotinic acetylcholine receptors can be broken down into two principal

Subdivide major classes depending on the locations where they occur.

First, there are the neuromuscular receptors. These are further divided into (αiαißεδ) and (otiα-ißγδ) receptors. On the other hand, the neuronal nicotinic acetylcholine receptors that exist in the Ganglia can be found. In these, a distinction is made between the (β ₂ -β _δ ) receptors and the (α ₂ -αg) receptors, see also “Basic Neurochemistry”, Ed. Siegel et. Al., Raven Press, New York 1993.

The substances of the formula I are capable of all of these receptors

Receptor class to interact. The substances of formula I interact particularly well with the nicotinic α ₇ receptor.

An in vitro detection of the interaction with the nicotinic α ₇ -

For example, receptor can be analogous to J.M. Ward et al, FEBS 1990, 270, 45-48 or D.R.E. Macallan, FEB 1998, 226, 357-363. Further in vitro tests for nicotinic receptors can be found in F.E. D'Amour et al, Manual for Laboratory Work in Mammalian Physiology, 3rd Ed., The University of Chicago Press (1965), W. Sihver et al, Neuroscience 1998, 85, 1121-1133 or B. Latli et al, J. Med. Chem. 1999, 42, 2227-22234.

The subtypes m1, m2, m3 and m4 are known from the muscarinic acetylcholine receptors.

Interactions of substances with the muscarinic receptors m1 and m2 can be determined, for example, using the ³ H-QNB (quinuclidinyl benzilate) inhibition test. The test is carried out according to Yamamura and Snyder (Yamamura, Hl and Snyder SH, Proc Nat Acad Sei USA 1974; 71: 1725-9): rat brain is homogenized in 400 vol (w / v) 0.32 M sucrose and then at Centrifuged 1000 xg for 10 min at 2 ° C. 100 μl of the supernatant are incubated with 0.4 nM ³ H-QNB in a total volume of 500 μl (50 mM phosphate buffer, pH 7.4) at 25 ° C. for 1 h. Non-specific binding is determined with 1 μM QNB. The compounds of the formula I and their physiologically acceptable salts can be used for the prophylaxis or treatment of diseases of the central nervous system in which binding to the nicotinic and / or muscarinic acetylcholine receptor results in

Leads to improvement of the clinical picture.

These diseases include schizophrenia, depression, anxiety, dementia, in particular Alzheimer's disease and Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory impairments, age-related memory impairment, relief of withdrawal symptoms from nicotine addiction. Due to the neuroprotective effect, compounds of the formula I are used for strokes and damage to the brain by toxic compounds.

In the treatment of the diseases described, the compounds according to the invention can also be used in combination with other pharmacologically active compounds, such as e.g. with the substances disclosed in WO 98/06697. The compounds according to the invention are administered with the other substances mentioned either simultaneously or before or after.

Compounds of the formula I and their salts and solvates are also suitable as intermediates for the preparation of other active pharmaceutical ingredients.

The invention also relates to the stereoisomers (enantiomers and their racemates and diastereomers), hydrates and solvates of these compounds. Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are train because of their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are e.g. the salts of the compounds according to the invention as well as so-called

Prodrug compounds.

Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.

This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 115, 61-67 (1995).

The invention also relates to mixtures of the invention

Compounds of formula I, e.g. Mixtures of two diastereomers e.g. in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds. The invention relates to the compounds of the formula I and their physiologically acceptable acid addition salts. The invention also relates to the solvates, e.g. Hydrates or alcoholates, of these compounds.

The invention also relates to a method for producing

Compounds of formula I and their pharmaceutically usable derivatives, salts and solvates, characterized in that the following reaction steps are carried out:

a) A compound of formula V wherein R is a nucleophilic leaving group, such as F, CI, Br or I, which is usually used for nucleophilic substitutions on aromatics, with a compound of formula VI wherein R ² , R ² , R ² and n have a meaning given in claim 1, brought to reaction, whereby a compound of formula IV is obtained

b) The phenoxy-piperidine of the formula IV obtained is then reacted by hydrogenation and optionally alkylation to give a compound of the formula II wherein R ^{1 has} a meaning given in claim 1, which then c) further with a compound of formula III wherein R ³ has the meaning given in claim 1 and L is a nucleophilic leaving group known per se, preferably shark and particularly preferably CI, is converted into a compound of the formula I.

As a process variant, the sulfonation after step (c) can also take place before the alkylation after step (b).

A base of formula I obtained is converted into one of its salts by treatment with an acid.

The invention also relates to the hydroxypiperidines of the formula VI and the phenoxypiperidines of the formula IV as intermediates for the preparation of the compounds of the formula I.

The invention also relates to the compounds of the formula I as claimed in claim 1 and their pharmaceutically acceptable derivatives, salts or solvates as medicaments.

The invention also relates to the compounds of the formula I as claimed in claim 1 and their pharmaceutically acceptable derivatives, salts or solvates as effectors of the nicotinic acetylcholine receptor.

The invention also relates to the compounds of the formula I as claimed in claim 1 and their pharmaceutically acceptable derivatives, salts or solvates as effectors of the muscarinic acetylcholine receptor.

The invention further relates to the active pharmaceutical ingredients according to the invention as nicotinic acetylcholine receptor effectors and / or muscarinic acetylcholine receptor effectors for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory restrictions, age-related

Weak memory, relief of withdrawal symptoms from nicotine addiction, stroke or damage to the brain due to toxic compounds.

The invention furthermore relates to the use of compounds of the formula I for the production of medicaments, in particular medicaments which are used for the treatment of diseases which are based on a dysfunction of nicotinic and / or muscarinic acetylcholine receptors.

The invention also relates to the use of compounds of the formula I according to claim 1 and / or their physiologically acceptable

Salts or solvates for the manufacture of a medicament, in particular for

Production of a medicament for the prophylaxis or treatment of diseases in which the binding of one or more active substances contained in the said medicament to nicotinic and / or muscarinic acetylcholine receptors to improve the

Disease picture leads.

The invention furthermore relates to the use of compounds of the formula I according to claim 1 and / or of their physiologically acceptable salts and solvates for the manufacture of a medicament for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative Diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory impairments, age-related memory loss, relief from withdrawal symptoms with nicotine addiction, stroke or brain damage due to toxic compounds.

Finally, the invention relates to pharmaceutical preparations containing the compounds of the formula I and their pharmaceutically acceptable derivatives, salts or solvates, and to a process for the preparation of the pharmaceutical preparations.

The compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms.

For all radicals which can occur more than once, such as A, R ² or R ⁴ , the meanings are independent of one another.

A means alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,

5, 6, 7, 8, 9 or 10 carbon atoms.

A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl,

Isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1- , 2-,

3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1 -methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferably for example Trifluoromethyl.

A very particularly preferably denotes alkyl having 1-6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1 -

Trifluoroethyl.

A furthermore denotes cycloalkyl, preferably cyclopropyl, cyclobutyl,

Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 2,6,6-trimethylbicyclo [3.1.1] heptyl, but also mono- or bicyclic terpenes, preferably p-menthan, menthol, pinane, bornane or camphor, where any known stereoisomeric form is included or adamantyl. For campers, this means both L-campers and D-campers.

Ar means unsubstituted or singly or multiply by shark, A, OR ⁵ , N (R ⁵ ) 2, NO ₂ , CN, COOR ⁵ , CON (R ⁵ ) ₂ , NR ⁵ COR ⁵ , NR ⁵ CON (R ⁵ ) ₂ , NR ⁵ S0 ₂ A,

COR ⁵ , S0 ₂ NR ⁵ , SO ₂ NR ⁵ or S0 ₂ A substituted phenyl, naphthyl or biphenyl, where A has one of the meanings given above and R ⁵ and m have one of the meanings given below. Ar is preferably unsubstituted or substituted phenyl, naphthyl or biphenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p- isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-aminophenyl, o-, m- or p- Hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p- (TMfluoromethoxy) phenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m - or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (difluoromethoxy) -phenyl, o-, m- or p- (fluoromethoxy) phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3 -, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4- or 3,5-dibromophenyl, 2-chloro-3-methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl, 2-methyl-3 -chloro, 2-methyl-4-chloro, 2-methyl-5-chloro, 2-methyl-6-chloro, 3-chloro-4 -methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2- Bromine-6-methyl, 2-methyl-3-bromo, 2-methyl-4-bromo, 2-methyl-5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl -, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 2 , 3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-thchlorophenyl, 2,4,6-tri-tert-butylphenyl, further preferred 2-nitro-4- (trifluoromethyl) phenyl, 3,5-di (trifluoromethyl) phenyl, 2,5-dimethylphenyl, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5- or 4-fluoro- 3- (trifluoromethyl) phenyl, 4-chloro-2- or 4-chloro-3- (t fluoromethyl) -, 2-chloro-4- or 2-chloro-5- (trifluoromethyl) -phenyl, 4-bromo- 2- or 4-bromo-3- (trifluoromethyl) phenyl, p-iodophenyl, 2-nitro-4-methoxyphenyl, 2,5-dimethoxy-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2,4-dimethyl-3-nitrophenyl, 4-fluoro-3-chlorophenyl, 4- Fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6- methoxyphenyl, 2-methoxy-5-methylphenyl or 2,4,6-

Triisopropylphenyl, 2-, 3 or 4-methoxycarbonyl-phenyl, 2-, 3 or 4-ethoxycarbonyl-phenyl, 2-, 3 or 4-propoxycarbonyl-phenyl, 2-, 3 or 4-butoxycarbonyl-phenyl, 2-, 3rd or 4-pentoxycarbonylphenyl, 2-, 3 or 4-hexoxycarbonylphenyl, 2-, 3 or 4-methylaminocarbonylphenyl, 2-, 3 or 4-ethylaminocarbonylphenyl, 2-, 3 or 4-propylaminocarbonylphenyl , 2-, 3 or 4-butylaminocarbonyl-phenyl, 2-, 3 or 4-pentylaminocarbonyl-phenyl, 2-, 3 or 4-hexylaminocarbonyl-phenyl, 2,3-, 2,4- or 2,5-dimethylaminocarbonyl -phenyl or 2,3-, 2,4- or 2,5-diethylaminocarbonylphenyl. Ar is particularly preferred phenyl or o-methoxyphenyl.

A-Ar means arylalkyl, where A and Ar have one of the meanings given above. A-Ar is preferably benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, naphthylmethyl, naphthylethyl, naphthylpropyl or naphthylbutyl.

A-Ar is particularly preferred benzyl or phenylethyl.

Shark means fluorine, chlorine, bromine or iodine, particularly preferably fluorine, chlorine or bromine.

R ^{1 represents} hydrogen or A, where A has one of the meanings mentioned above. R ¹ is preferably hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. R ¹ is particularly preferably hydrogen.

R ² , R ² , R ² each independently represent H, A, OH, OCH ₃ , OCF ₃ , shark, CN, COOR ¹ , CONR ¹ or NO ₂ , where A, Hai and R ^{1 are} one of the have the aforementioned meanings. R ² , R ² , R ² are in particular hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, cyan, nitro, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, Hexoxycarbonyl, methylaminocarbonyl,

Ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, pentylaminocarbonyl or hexylaminocarbonyl. R ² , R ² , R ² are particularly preferably hydrogen.

R ^{3 represents} A, Ar, A-Ar, where A, Ar and A-Ar are one of the aforementioned

Have meanings. R ³ is in particular methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, trifluoromethyl, pentafluoroethyl or 2 , 2,2-trifluoroethyl, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o -, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-aminophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p- (thfluoromethoxy) phenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o- , m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p- chlorophenyl, o-, m- or p- (difluoromethoxy) phenyl, o-, m- or p- (Fluoromethoxy) phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2nd , 5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl , 2-chloro-3-methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl, 2-methyl-3-chloro, 2-methyl 4-chloro, 2-methyl-5-chloro, 2-methyl-6-chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4-chlorophenyl, 2 -Bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4- bromo, 2-methyl-5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl, 3-bromo-5-methyl or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 2,3,4-, 2,3, 5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, further preferably 2-nitro-4- (trifluoromethyl) phenyl , 3,5-di- (trifluoromethyl) phenyl, 2,5-dimethylphenyl, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5- or 4-fluoro-3- (trifluoromethyl) phenyl, 4- Chloro-2- or 4-chloro-3- (trifluoromethyl) -, 2-chloro-4- or 2-chloro-5- (trifluoromethyl) phenyl, 4-bromo-2- or 4-bromo-3- (trifluoromethyl) ) -phenyl, p-iodophenyl, 2-nitro-4-methoxyphenyl, 2,5-dimethoxy-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2,4-dimethyl-3-nitrophenyl, 4-fluoro-3- chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3- Chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl or 2,4,6-triisopropylphenyl, benzyl,, 2-, 3- or 4-nitro-phenylmethyl, 2,3-, 2,4-, 2,5 -, 2,6-, 3,4- or 3,5-di-nitro-phenylmethyl, 2,3,4-, 2,3 , 5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-tri-nitro-phenylmethyl, phenylpropyl, phenylbutyl,

Phenylpentyl, phenylhexyl, phenylheptyl, naphthylmethyl, naphthylethyl, naphthylpropyl or naphthylbutyl.

R ³ is particularly preferably 2,2,2-trifluoro-ethyl, n-propyl, i-propyl, n-butyl, phenyl, benzyl or 2-nitro-phenylmethyl.

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. n is preferably 0, 1, 2, 3, 4 or 5. Particularly preferred is n = 1.

In particular, the invention relates to those compounds of

Formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. The following principle applies to a given compound of the formula I: the more of the radicals contained therein have a preferred meaning, the more the compound as a whole is preferred. Some preferred groups of

Compounds can be expressed by the following partial formulas Ia to Ij, which correspond to the formula I and in which those are not specified designated radicals have the meaning given for the formula I, but in

in la R ^{1 is} hydrogen;

in Ib R ² ', R ² "and R ² " represent hydrogen;

in Ic R ³ n-propyl, i-propyl, n-butyl, 2,2,2-trifluoro-ethyl,

Is phenyl, benzyl or 2-nitrophenyl-methyl;

in id R ^{3 is} i-propyl;

in le R ^{3 is} benzyl;

in lf n denotes 1;

in Ig n is 0 or 1 and R ^{1 is} hydrogen, methyl or ethyl;

In him n 0 or 1,

R1 is hydrogen, methyl or ethyl and

R ² ', R ² ", R ² '" each independently represent hydrogen, shark, methyl or methoxy;

In li n 0 or 1,

R ^{1 is} hydrogen, methyl or ethyl,

R ² ', R ² ", R ² "' each independently of one another hydrogen, shark,

Is methyl or methoxy and R ^{3 is} n-propyl, i-propyl, n-butyl, 2,2,2-trifluoro-ethyl, phenyl, benzyl or 2-nitrophenyl-methyl;

In Ij n 0 or 1, R ^{1 is} hydrogen, methyl or ethyl,

R ² ', R ² ", R ² '" each independently of one another are hydrogen, shark,

Are methyl or methoxy and R ^{3 is} i-propyl or benzyl.

The invention relates in particular to the following compounds of the formula I:

a) N- [4- (1-benzyl-piperidin-4-yloxy) phenyl] -C-phenyl-methanesulfonamide, b) N- [4- (1-benzyl-piperidin-4-yloxy) phenyl] - C- [2-nitro-phenyl] methanesulfonamide, c) N- [4- (1-benzylpiperidin-4-yloxy) phenyl] benzenesulfonamide, d) propane-2-sulfonic acid [4- (1-benzyl -pipehdin-4-yloxy) -phenyl] -amide, e) butan-1 -sulfonic acid [4- (1-benzyl-piperidin-4-yloxy) -phenyl] -amide, f) propan-1-sulfonic acid [4- (1-benzylpiperidin-4-yloxy) phenyl] amide, g) 2,2,2-trifluoroethane-1-sulfonic acid [4- (1-benzylpiperidin-4-yloxy) phenyl] - amide and its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

The compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

The starting materials for the claimed process can also be formed in situ in such a way that they are not removed from the reaction mixture isolated, but immediately further converted to the compounds of formula I. On the other hand, it is possible to carry out the reaction in stages.

The phenoxy-piperidines of the formula I can preferably be obtained by nitrohalobenzenes of the formula V with piperidines

Formula VI is converted to phenoxy-piperidines of the formula IV which, after hydrogenation and optionally alkylation, are reacted with suitable sulfonyl compounds of the formula III, such as the corresponding sulfonic acid chlorides.

The nitrobenzene derivatives of the formula V are generally known and are commercially available; the unknown compounds of formula V can easily be prepared analogously to the known compounds. The same applies to the phenoxy-piperidines of the formula VI: These compounds are known or can preferably be prepared by reacting hydroxypiperidines with benzyl halides.

The reaction of compounds of the formula V with compounds of the formula VI is preferably carried out as follows: a hydroxypiperidine of the formula VI is dissolved in DMF and 1.5 equivalents of a strong base such as sodium hydride, sodium ethoxide or potassium tert-butoxide (preferably potassium tert-butoxide Butylate) added. The mixture is stirred for about one hour at room temperature and then a nitro compound of the formula V dissolved in DMF is added dropwise. The mixture is stirred at room temperature for another hour and then water is added. The crystals are filtered off, washed and optionally recrystallized.

The hydrogenation of the nitro compounds of the formula IV to the corresponding amine is usually carried out in accordance with standard organic chemistry regulations using a suitable hydrogenation catalyst, preferably Ra-Ni, in a polar, protic solvent such as, for example, methanol normal or elevated pressure and temperatures of 20 to 200 ° C, preferably at room temperature.

After the reaction, the solvent is removed and the residue is reacted further.

To prepare those variants of the compounds of the formula I in which the radical R ^{2 is} not hydrogen, an alkylation is then carried out, which can be carried out, for example, according to the Leuckart-Wallach reaction, a standard method for the alkylation of amines. Those obtained after hydrogenation and optionally alkylation

Finally, compounds of the formula II are reacted with the sulfone compounds of the formula III to give the phenoxy-piperidine-sulfonamides of the formula I.

The alkylation can just as well only take place after the sulfonation with deprotonation of the sulfonamide using suitable alkylenes, for example alkyl iodide.

The reactions described above are usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline, an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak Acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium.

Suitable inert solvents for the reactions described above are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or

xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane,

Carbon tetrachloride, chloroform or dichloromethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;

Glycol ethers such as ethylene glycol monomethyl or monoethyl ether

(Methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, N-methylpyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

Depending on the conditions used, the reaction temperature for the reactions described above is between approximately -10 ° and 150 °, normally between 0 ° and 130 °, preferably between 0 ° and 50 °, particularly preferably at room temperature.

The reaction time is between a few minutes and several days depending on the conditions used.

A base of the formula I obtained can be converted into the associated base with an acid

Acid addition salt are transferred. Acids which provide physiologically acceptable salts are suitable for this reaction. So inorganic acids can be used, e.g. Sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, acetic acid, Propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid,

Pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid; Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and

-disulfonic acids, lauryl sulfuric acid. If desired, the free bases of the formula I can be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate, provided that no further acidic groups are present in the molecule.

Compounds of formula I can also be obtained by

Compounds of formula I from one of their functional derivatives

Treat with a solvolysing or hydrogenolysing agent in

Freedom sets.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxy protecting group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group. Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removable, after the desired chemical reaction has been carried out elsewhere in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxyl protecting groups include benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p- Toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - z. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the aforementioned also come

Solvent in question. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.

Hydrogenolytically removable protective groups (e.g. CBZ, benzyl or the release of the amidino group from their oxadiazole derivative) can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are specified above, in particular z. B. alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, or reacted with CH ₃ -C (= NH) -OEt, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

Compounds of the formula I according to the invention can, owing to their

Molecular structure can be chiral and can accordingly occur in different enantiomeric forms. They can therefore be in racemic or optically active form. Since the pharmaceutical activity of the racemates or the stereo isomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or can already be used as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active release agent. As a separator agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Chromatographic separation of enantiomers with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous. Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3.

The invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament (pharmaceutical preparation), in particular in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, and solutions, preferably oily or aqueous solutions, for parenteral use Suspensions, emulsions or implants, for topical application of ointments, creams or powders. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives,

Contain stabilizing and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, coloring, flavoring and / or several other active ingredients, e.g. one or more vitamins.

The substances according to the invention are generally administered in analogy to known, commercially available preparations, preferably in doses between about 5 mg and 100 mg, in particular between 10 and 40 mg per dosage unit. The daily dosage is preferably between about 0.5 and 1 mg / kg

Body weight.

The specific dose for each individual patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion, combination of drugs and the severity of the respective disease to which the therapy applies. Oral use is preferred.

The invention thus also relates to medicaments comprising at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. The invention furthermore relates to medicaments comprising at least one compound of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.

The invention also relates to a set (kit) consisting of separate

Packs of

(a) an effective amount of a compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and

(b) an effective amount of another drug ingredient.

The set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can e.g. contain separate ampoules, in each of which an effective amount of a compound of formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient is dissolved or in lyophilized form.

The invention further relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease , Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's chorea, Tourette's syndrome, learning and memory impairments, age-related memory impairment, Relief of withdrawal symptoms from nicotine addiction, stroke or brain damage through toxic compounds, in combination with at least one other drug ingredient.

Even without further explanations, it is assumed that a person skilled in the art can use the above description to the greatest extent. The preferred embodiments are therefore only to be understood as a descriptive disclosure, and in no way as a limitation in any way.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: the solvent is removed if necessary, water is added if necessary, the pH is adjusted to between 2 and 10, if necessary, depending on the constitution of the end product, extracted with ethyl acetate or dichloromethane, separates, the organic phase is washed with NaCl solution, dried over sodium sulfate, filtered, concentrated and purified by chromatography using preparative HPLC:

Column: RP 18 (15 μm) Lichrosorb 250x50

Superplasticizer: A: 98H20; 2CH3CN; 0.1% TFA

B: 10H20; 90CH3CN; 0.1% TFA

UV detection: 250 nm

Flow: 10 ml / min

Mass spectrometry (MS): ESI (electrospray ionization) (M + H) ⁺

El (electron impact ionization) (M ⁺ )

Example 1: (Synthesis of the precursor) 1 g of 1-benzyl-4- (4-nitro-phenoxy) piperidine is dissolved in 30 ml of methanol and hydrogenated with 1 g of RaNi / H ₂ according to standard instructions. The mixture is filtered off and dried on a rotary evaporator: 4- (1-benzyl-piperidin-4-yloxy) phenylamine.

TLC in methanol, Rf = 0.73; EI-MS (M ⁺ ) 282.

Example 2:

200 mg of 4- (1-benzyl-piperidin-4-yloxy) phenylamine and 162 mg of phenylmethylsulfonyl chloride are dissolved in 10 ml of DMF and 0.25 ml of triethylamine are added. The mixture is stirred at room temperature for 14 h. The usual work-up is carried out: N- [4- (1-benzylpiperidin-4-yloxy) phenyl] -C phenyl methanesulfonamide. TLC in methanol, Rf = 0.40; HPLC-ESI-MS (M + H) ⁺ 437.

Example 3

Analogously to Example 2, 4- (1-benzylpiperidin-4-yloxy) phenylamine is also obtained from the reaction

a) Phenylsulfonyl chloride:

N- [4- (1-Benzyl-piperidin-4-yloxy) -phenyl] -benzenesulfonamide. TLC in methanol, Rf = 0.58; EI-MS (M) ⁺ 422.

b) (2-nitrophenyl) methanesulfonyl chloride: N- [4- (1-benzyl-pipehdin-4-yloxy) phenyl] -C- [2-nitrophenyl] methanesulfonamide. TLC in methanol, Rf = 0.32; HPLC-ESI-MS (M + H) ⁺ 482.

c) Propan-2-sulfonyl chloride: propan-2-sulfonic acid [4- (1-benzyl-pipehdin-4-yloxy) phenyl] amide. TLC in methanol, Rf = 0.63; HPLC-ESI-MS (M + H) ⁺ 425. d) Butane-1-sulfonyl chloride: butane-1-sulfonic acid [4- (1-benzyl-piperidin-4-yloxy) phenyl] amide.

e) Propan-1-sulfonyl chloride: propan-1-sulfonic acid [4- (1-benzyl-piperidin-4-yloxy) phenyl] amide.

TLC in methanol, Rf = 0.63; HPLC-ESI-MS (M + H) ⁺ 425.

f) 2,2,2-trifluoro-ethane-1-sulfonyl chloride: 2,2,2-trifluoro-ethane-1-sulfonic acid [4- (1-benzyl-piperidin-4-yloxy) phenyl] amide.

TLC in methanol, Rf = 0.66; HPLC-ESI-MS (M + H) ⁺ 429.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution of 1 g is prepared of a compound of formula I, 9:38 g of NaH ₂ P0 ₄ x 2 H ₂ 0, 28.48 g NaH ₂ PO ₄ x 12 H ₂ 0 and 0.1 g

Benzalkonium chloride in 940 ml of double distilled water. One poses to pH 6.8, make up to 1 I and sterilize by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: Coated tablets Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is filled into ampoules, lyophilized under aseptic conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of the general formula I where R ^{1 is} H or A,

R ² ', R ² ", R ² '" each independently of one another H, A, OH, OCH ₃ , OCF ₃ , Hai,

CN, COOR ¹ , CONR ¹ or N0 ₂ , R ³ A, Ar or A-Ar,

R ⁴ H or A,

A unbranched or branched alkyl with 1-10 C atoms, wherein one or two CH ₂ groups by O or S atoms and / or by -CH = CH groups and / or 1-7 H atoms by F Ar can be replaced, Ar unsubstituted or once, twice or three times by Hai, A, OR ⁴ , N (R ⁴ ) ₂ , N0 ₂ , CN, COOR ⁴ , CON (R ⁴ ) ₂ , NR ⁴ COA, NR ⁴ CON (R ⁴ ) ₂ ,

NR ⁴ S0 ₂ A, COR ⁴ , S0 ₂ N (R ⁴ ) ₂ , S0 ₂ A substituted phenyl, naphthyl or biphenyl, A-ar arylalkyl, where A and Ar have one of the abovementioned meanings, Hai F, CI, Br or I and n are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and their solvates, stereoisomers and pharmaceutically usable

Derivatives, including their mixtures in all proportions.

Compounds according to claim 1, wherein R ^{1 is} hydrogen, and their solvates, stereoisomers and pharmaceutically usable

Derivatives, including their mixtures in all proportions.

3. Compounds according to claim 1 or 2, wherein

R ² ', R ² ", R ² '" are hydrogen, and their solvates, stereoisomers and pharmaceutically usable derivatives, including their mixtures in all ratios.

4. Compounds according to one or more of claims 1-3, wherein R ^{3 is} n-propyl, i-propyl, n-butyl, 2,2,2-trifluoro-ethyl, phenyl, benzyl or 2-nitrophenyl-methyl, and their solvates, stereoisomers and pharmaceutically acceptable derivatives, including their mixtures in all proportions.

5. Compounds according to one or more of claims 1-4, wherein n is 1, and their solvates, stereoisomers and pharmaceutically usable derivatives, including their mixtures in all proportions.

6. Compounds according to claim 1 selected from the group N- [4- (1-benzyl-piperidin-4-yloxy) phenyl] -C-phenyl-methanesulfonamide, N- [4- (1-benzyl-pipehdin-4- yloxy) phenyl] -C- [2-nitro-phenyl] methanesulfonamide,

N- [4- (1-benzylpiperidin-4-yloxy) phenyl] benzenesulfonamide, propan-2-sulfonic acid [4- (1-benzylpiperidin-4-yloxy) phenyl] amide, butan-1 -sulfonic acid [4- (1-benzyl-piperidin-4-yloxy) phenyl] amide, propan-1-sulfonic acid [4- (1-benzyl-pipehdin-4-yloxy) phenyl] amide, 2.2 , 2-T fluoro-ethane-1 sulfonic acid [4- (1-benzylpiperidin-4-yloxy) phenyl] amide, as well as their solvates, stereoisomers and pharmaceutically usable derivatives, including their mixtures in all ratios.

Process for the preparation of compounds of the formula I according to claims 1-6 and their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that a) a compound of the formula V wherein R is a nucleophilic leaving group usually used for nucleophilic substitutions on aromatics, with a compound of formula VI wherein R ² , R ^{2 "} , R ^2" and n have the meaning given in Claim 1, to give a compound of the formula IV converts, b) the phenoxy-piperidine of formula IV thus obtained by hydrogenation and optionally alkylation to a compound of formula II R wherein R ^{1 has} a meaning given in claim 1, which is then c) further with a compound of formula III wherein R3 has a meaning given in claim 1 and L is a nucleophilic leaving group known per se, to one

Reacts compound of formula I and then optionally cleaves a protecting group and / or converts a base or acid of formula I into one of its salts.

Compounds of formula I and their pharmaceutically usable derivatives, solvates and stereoisomers according to one or more of claims 1 to 6 as effectors of the nicotinic acetylcholine receptor.

Compounds of formula I and their pharmaceutically usable derivatives, solvates and stereoisomers according to one or more of claims 1 to 6 as effectors of the muscarinic acetylcholine receptor.

Compounds of formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions according to one or more of claims 1 to 6 as medicaments. Medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions according to one or more of claims 1 to 6, and, if appropriate, carriers and / or auxiliaries.

Medicaments containing at least one compound of formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Ratios according to one or more of claims 1 to 6, and at least one further active pharmaceutical ingredient.

Use of compounds according to one or more of claims 1 to 6 and / or their pharmaceutically usable

Derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the prophylaxis or treatment of diseases in which the binding of one or more active substances contained in said medicament to nicotinic and / or muscarinic

Acetylcholine receptors improve the clinical picture.

Use of compounds according to one or more of claims 1 to 6 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their

Mixtures in all proportions, for the manufacture of a medicament for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome,

Learning and memory restrictions, age-related memory weakness, relief of withdrawal symptoms Nicotine addiction, stroke, or brain damage from toxic compounds.

15. Pharmaceutical preparation, characterized by a content of at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions according to one or more of claims 1 to 6. 16. Process for the preparation pharmaceutical preparations according to

Claim 15, characterized in that at least one compound of formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios according to one or 5 more of claims 1 to 6 together with at least one solid, liquid or brings semi-liquid carrier or excipient into a suitable dosage form.

17. Set (kit) consisting of separate packs of Q (a) an effective amount of a compound of the formula I according to one or more of claims 1 to 6 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and 5 (b) an effective amount of another

Drug ingredient.

18. Use of compounds of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, Q including their mixtures in all ratios according to one or more of claims 1 to 6, for the manufacture of a medicament for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory impairments, age-related memory impairment, relief of withdrawal symptoms Nicotine addiction, stroke, or brain damage from toxic compounds, in combination with at least one other drug ingredient.

19. Intermediate compounds of formula IV wherein R ² , R ² , R ² and n have the meaning given in claim 1 and their salts.

20. Intermediate compounds of formula VI wherein R ² , R ² , R ² and n have the meaning given in claim 1 and their salts.