CA2417361C - New phenyl- and phenylalkyl-substituted ethanolamines and ethylenediamines - Google Patents

Abstract

The invention relates to compounds of the general formula (1), wherein A, R1 , R2, R3, R4, R5 and R6 are defined as in the description and the claims. The invention further relates to a method for producing said compounds and to their use as medicaments. The compounds of formula (1) are used as blockers of the voltage-dependent sodium channel and can be used for diseases that are associated with a functional disorder caused by hyperexcitability.

Description

Case 1/1143-Foreign filing text BOEHRINGER INGELHEIM PHARMA KG
73832fft.204 New Phenyl- and Phenylalkyl-substituted Ethanolamines and Ethylenediamines The present patent application relates to new compounds of general formula 1, Me 5 Ra X-A
_' Re R~ ~ N
Me R

wherein the groups A, X, Rl, RZ, R3, R' , R5 and R6 may have the meanings given in the specification and claims, processes for preparing them and their use as pharmaceutical compositions, particularly as pharmaceutical compositions for the prevention or treatment of diseases the cause of which is based on a functional disorder caused by overstimulation.

Bac_k_g-o ind _o t-.h .; nven _; ~n The aim of the present invention is to prepare new compounds which can be used as blockers of the voltage-dependent sodium channel. Compounds of this kind can be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischaemias, pain and neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.

1 = CA 02417361 2003-01-24 De ail d d-s- ipti_on of the invention The problem stated above is solved by the compounds of general formula 1 disclosed in the description which follows.

The present patent application relates to new compounds of general formula 1, ~ Ra Me X-A

R~ N
Me Rs wherein R1 denotes hydrogen, hydroxy, CF3, NO2, CN, halogen, Cl-CB-alkyl or Cl-CB-alkoxy;
RZ, R3 and R4 independently of one another denote hydrogen, C1-Ce-alkyl, hydroxy, NOa, CN, C,-CB-alkyloxy, CF3 or halogen;
R5 and R6 independently of one another denote hydrogen or a group selected from among C,-Ce-alkyl, Ca-CB-alkenyl, C3-C8-alkynyl, C3-Cg-cycloalkyl, C3-CB-cycloalkyl-Cl-C6-alkylene, C5-C8-cycloalkenyl, CS-CB-cycloalkenyl-Cl-C6-alkylene, C6-Cla-aryl and C6 -Clo-aryl-Cl-C6-alkylene, which may optionally be substituted by a group selected from among Cl-C6-alkyl, C2-C6-alkenyl, halogen, Cl-C6-alkyloxy, -NH2, -NH (Cl-C4-alkyl) , -N (C1-C4-alkyl) 2, hydroxy, =0, -COOH, -CO-OCl-C4-alkyl, -CONH21 -CONH (C1-C,-alkyl) , -CON (Cl-C4-alkyl) Z and CF3, or R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, 7- or 8-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulphur, oxygen and nitrogen and may optionally be mono-, di-or trisubstituted by a group selected from Cl-C4-alkyl, hydroxy, =0, -COOH, -CO-OCl-C4-alkyl, -CONH2, -CONH (CI-C,-alkyl) , -CON (CI-C,-alkyl) a, halogen and benzyl;
X denotes oxygen, -NH-, -N(CHO)-, -N(CO-C1-C6-alkyl), -N(Cl-C6-alkyl) or -N(C3-C6-cycloalkyl-C,-C4-alkylene), preferably oxygen or -NH-;
A denotes a group selected from Cl-C6-alkylene, CZ-C6-70 alkenylene and C3-C6-alkynylene, which may optionally be substituted by a group selected from halogen, =0 and hydroxy.

Preferred compounds of general formula 1 are those wherein R' denotes hydrogen, halogen, Cl-C6-alkyl, CF3 or methoxy;
RZ, R3 and R4 independently of one another denote hydrogen, Cl-C6-alkyl, Cl-C6-alkyloxy, CF3 or halogen;
R5 and R6 independently of one another denote hydrogen or a group selected from among Cl-C6-alkyl, CZ-C6-alkenyl, C3-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C,-C6-alkylene, C5-C6-cycloalkenyl, C5-C6-cycloalkenyl-Cl-C6-alkylene, phenyl and phenyl-Cl-C6-alkylene, which may optionally be substituted by a group selected from among Cl-C4-alkyl, CZ-C4-alkenyl, halogen, Cl-C4-alkyloxy, hydroxy, -CONHa, =0 and CF3 or R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6- or 7-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulphur, oxygen and nitrogen and may optionally be mono-, di-or trisubstituted by C1-C,-alkyl, -CONHZ or hydroxy;
X denotes oxygen, -NH-, -N (CHO) - , -N (CO-Cl-CS-alkyl ) - , -N(C,-C5-alkyl) - or -N(C3-C6-cycloalkyl-Cl-4-alkylene), preferably oxygen or -NH-;

A denotes Cl-CS-alkylene, C2-C4-alkenylene or C3-C4-alkynylene, preferably Cl-CS-alkylene .

Particularly preferred are compounds of general formula 1, wherein R' denotes hydrogen, CI-C,-alkyl or CF3;
R2, R3 and R4 independently of one another denote hydrogen, Cl-C4-alkyl, CF3 or halogen;
R5 and R6 independently of one another denote hydrogen, Cl-C6-alkyl, CF3-Cl-C6-alkylene, preferably selected from -CH2-CF3 and -CH2-CH2-CF3, Ca-C6-alkenyl, C3-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-Cl-C6-alkylene, preferably cyclopropylmethyl or cyclohexenemethyl, cyclohexenyl, cyclohexenyl-C1-C6-alkylene, propenyl-cyclohexenylene-C1-C6-alkylene, phenyl or phenyl-C1-C6-alkylene or R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6- or 7-membered heterocyclic group, which optionally contains another nitrogen atom and may optionally be mono-, di- or trisubstituted by C1-C4-alkyl, -CONH2 or hydroxy;
X denotes oxygen, -NH-, -N(CHO)-, -N(CO-methyl)-, -N(CO-ethyl) -, -N(Cl-CS-alkyl) - or -N(C3-C6-cycloalkyl-methylene)-, preferably oxygen or -NH;
A denotes -CH2-1 -CH2-CH2- or -CH2-CH2-CHa- .

Also particularly preferred are compounds of general formula 1, wherein R1 denotes hydrogen or methyl;
R2 and R3 independently of one another denote hydrogen, methyl, fluorine, chlorine or bromine;
R4 denotes hydrogen, fluorine, chlorine or bromine;
R5 and R6 independently of one another denote hydrogen, Cl-C6-alkyl, CF3-Cl-C6-alkylene, preferably -CHZ-CH2-CF3, C2-C6-alkenyl, preferably butenyl and pentenyl, C3-C6-cycloalkyl, preferably cyclohexyl, C3-C6-cycloalkyl-C1-C6-alkylene, preferably cyclopropylmethyl or cyclohexenemethyl, cyclohexenyl, cyclohexenyl-C1-C6-alkylene, preferably cyclohexenyl-CHZ-, or 5 R5 and R6 together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and azepan;
X denotes oxygen, -NH-, -N(CHO)-, -N(CO-methyl)-, -N(CO-ethyl)-, -N(methyl)-, -N(ethyl)-, -N(propyl)-, -N (butyl ) - , -N (pentyl ) - or -N ( cyclopropylmethyl ) - , preferably oxygen or -NH-;
A denotes -CH2-1 -CH2-CHa- or -CH2-CH2-CH2- .

Of particular importance according to the invention are compounds of general formula 1, wherein R' denotes hydrogen or methyl;
Ra and R3 independently of one another denote hydrogen, methyl, fluorine, chlorine or bromine;
R4 denotes hydrogen, fluorine, chlorine or bromine;
R5 and R6 independently of one another denote hydrogen, methyl, propyl, butyl, hexyl, cyclopropylmethyl or cyclohexenemethyl, or R5 and R6 together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and azepan;
X denotes oxygen, -NH-, -N(CHO)-, -N(CO-methyl)-, -N(CO-ethyl)-, -N(ethyl)-, -N(propyl)-, -N(butyl)-, -N(pentyl)- or -N(cyclopropylmethyl)-, preferably oxygen or -NH-;
A denotes -CH2-1 -CH2-CH2- or -CH2-CH2-CH2- .

Of outstanding importance according to the invention are compounds of general formula 1, wherein R1 denotes hydrogen or methyl;
R2 and R3 independently of one another denote hydrogen or fluorine;
R4 denotes hydrogen;

R5 and R6 independently of one another denote hydrogen, butyl, hexyl or cyclohexenemethyl, or R5 and R6 together with the nitrogen atom denote piperidine and 1,2,3,6-tetrahydropyridine;
X denotes oxygen or -NH-;
A denotes -CHZ-CH2- or -CH2-CH2-CHZ- .

Compounds of general formula 1 wherein R' denotes hydrogen, wherein R2 and R3 are in the ortho position and wherein X, A, R2, R3, R4, R5 and R6 may have the meanings given hereinbefore, correspond to general formula 11.

Me 3 X- R

N
Me R

These compounds are particularly important according to the invention.
Compounds of general formula 1 wherein R' denotes methyl and is in the para position, wherein R2 and R3 are in the ortho position and wherein X, A, R2, R3, R4, R5 and R6 may have the meanings given hereinbefore, correspond to general formula 111 Me 3 X-A R

Me ( N
Me R 1il These compounds are particularly important according to the invention. Of special importance are the compounds of general formulae 1, 11 and 11 1 wherein R4 denotes hydrogen.

The invention relates to the compounds of formula 1 in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts thereof with pharmacologically acceptable acids - such as for example acid addition salts with hydrohalic acids - e.g. hydrochloric or hydrobromic acid -or organic acids - such as e.g. oxalic, fumaric or diglycolic acid or methanesulphonic acid.
The present invention also relates to quaternary ammonium compounds such as may be formed from the compounds of formula 1 with alkyl halides of formula R'-X. Accordingly, the quaternary ammonium compounds of formula 1-Y are also important according to the invention Me Rs X~-A Rs +/ -N-Rs Y
Me R~

wherein the groups A, X, R1, R2, R3 and R4 may have the meanings given hereinbefore, RS and R6 may have the meanings given hereinbefore with the exception of hydrogen, R' denotes C1-4-alkyl, preferably methyl or ethyl and Y denotes a halide selected from among chlorine, bromine and iodine.

Compounds of general formula 1-Y wherein R1 denotes hydrogen, wherein R' and R3 are in the ortho position and wherein X, A, R2 , R3 , R' , R5, R6 and R' may have the meanings given hereinbefore, correspond to general formula 11-Y.

a a Me 3 Me R7 Y
1'-Y

These compounds are particularly important according to the invention.
Compounds of general formula 1-Y wherein R' denotes methyl and is in the para position, wherein RZ and R3 are in the ortho position and wherein X, A, R2, R3, R4, R5 and R6 may have the meanings given hereinbefore, correspond to general formula 1" -Y.

Me 3 _ X~RS R
Me ~ ~ 1+ 6 N-R
Me R7 Y 1' -Y

These compounds are also important according to the invention.
Of special importance are the compounds of general formulae 1-Y, 1'-Y and 11 1 -Y wherein R' denotes hydrogen.

Of particular interest according to the invention are the following compounds, inter alia:

- N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-n-butyl-amine;
- N- [ [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2-ethylbutyl)-N,N-dimethyl-ammonium iodide;

- 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-pyrrolidine;
- N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(4-penten-l-yl)-amine;
- N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-n-propyl-amine;
- N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 4, 6-trimethylphenyl)-ethyl]-N,N-dimethyl-amine;
- 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-piperidine;
- N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-n-butyl-N,N-dimethyl-ammonium iodide;
- N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-(1-cyclohexen-4-yl-methyl)-N,N-dimethyl-ammonium iodide.

Unless otherwise stated, the general definitions are used as follows:
The term alkyl groups (including those which are part of other groups) denotes branched and unbranched alkyl groups with 1 to 8 carbon atoms, preferably 1 - 6, most preferably 1-4 carbon atoms, which may optionally be substituted by one or more halogen atom(s), preferably fluorine. The following hydrocarbon groups are mentioned by way of example:
methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, i-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-l-methylpropyl and 1-ethyl-2-methylpropyl. Uilless otherwise stated, lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl are preferred. The definitions propyl, butyl, pentyl etc. always include the associated isomeric groups. In some cases the common abbreviations are used for the abovementioned alkyl groups, such as Me for methyl, Et for 5 ethyl, Prop for propyl, But for butyl etc.

The term alkylene groups denotes branched and unbranched alkylene bridges with 1 to 6, preferably 1 to 4 carbon atoms.
The following are mentioned, for example: methylene, ethylene, 10 propylene and butylene etc. Unless otherwise stated, the terms propylene, butylene etc. used above also include all the possible isomeric forms. Accordingly, the term propylene includes the isomeric bridges n-propylene, methylethylene and dimethylmethylene and the term butylene includes the isomeric bridges n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

Cycloalkyl generally denotes a saturated cyclic hydrocarbon group with 3 to 8 carbon atoms, which may optionally be substituted by a halogen atom or several halogen atoms, preferably fluorine, which may be identical to or different from one another. Cyclic hydrocarbons with 3 to 6 carbon atoms are preferred. Examples of these include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkenyl generally denotes a branched or unbranched hydrocarbon group with 2 to 8, preferably 2 to 6, most preferably 2 to 4 carbon atoms, which may have one or more double bonds and may optionally be substituted by one or more halogen atoms, preferably fluorine, while the halogens may be identical to or different from one another. The following alkenyl groups are mentioned by way of example:

vinyl, 2-propenyl (allyl), 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-l-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-l-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, etc.

Cycloalkenyl generally denotes a cyclic hydrocarbon group with 5 to 8 carbon atoms, which contains at least one double bond and may optionally be substituted by one halogen atom or several halogen atoms, preferably fluorine, which may be identical to or different from one another. Generally, cyclopentenyl or cyclohexenyl are preferred, and unless otherwise stated these groups may be substituted by C1-C4-alkyl or Ca-C4-alkenyl.

Alkynyl generally denotes a branched or unbranched hydrocarbon group with 3 to 8, preferably 3 to 6, most preferably 3 to 5 carbon atoms, which may contain one or more triple bonds and may optionally be substituted by one or more halogen atoms, preferably fluorine, while the halogens may be identical to or different from one another. The following alkynyl groups are mentioned by way of example:

ethynyl, 2-propynyl (propargyl), 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 3-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1,2-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-methyl-2-pentynyl, e t 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 3-methyl-3-pentynyl, 4-methyl-3-pentynyl, 1-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-2-butynyl, 1,2-dimethyl-3-butynyl, 1,3-dimethyl-2-butynyl, 1,3-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-l-butynyl, 2-ethyl-2-butynyl, 2-ethyl-3-butynyl, 1,1,2-trimethyl-2-propynyl, 1-ethyl-l-methyl-2-propynyl etc.
Alkyloxy, which may also optionally be referred to as alkoxy, generally denotes a straight-chain or branched hydrocarbon group with 1 to 6 carbon atoms linked via an oxygen atom - a lower alkoxy group with 1 to 4 carbon atom(s) is preferred. The methoxy group is particularly preferred.

The term aryl denotes an aromatic ring system with 6 to 10 carbon atoms. Unless otherwise stated, the preferred aryl group is phenyl.
By cycloalkyl-alkylene is meant, for the purposes of the invention, cycloalkyl groups linked via an alkylene bridge. By cycloalkenyl-alkylene is meant, for the purposes of the invention, cycloalkenyl groups linked via an alkylene bridge.
By aryl-alkylene is meant, for the purposes of the invention, aryl groups linked via an alkylene bridge.

The following are mentioned as examples of N-linked 5-, 6-, 7-or 8-membered, saturated or unsaturated heterocyclic groups which may be formed by the groups R5 and R6 together with the nitrogen atom: pyrrole, pyrroline, pyrrolidine, 1,2,3,6-tetrahydropyridine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, azepan, azepine, diazepine, etc., preferably pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and azepan.

The compounds claimed are blockers of the voltage-dependent sodium channel. These are compounds which displace batrachotoxin (BTX) with a high affinity (Ki < 1000 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances exhibit "use-dependency" in the blocking of the sodium channels, i.e. in order to bind the substances at the sodium channel, the sodium channels first have to be activated. Maximum blockage of the sodium channels is only achieved after repeated stimulation of the sodium channels. Consequently, the substances bind preferentially to sodium channels which are activated a number of times. As a result, the substances are in a position to become effective particularly in those parts of the body which are pathologically overstimulated. The compounds of general formula 1 according to the invention can thus be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischaemias, pain and neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.

The blocking action on the sodium channel may be demonstrated by the test system which tests the BTX binding to the sodium channel [S.W. Postma & W.A. Catterall, Mol. Pharmacol 2a, 219-227 (1984)] as well as by patch-clamp experiments which show that the compounds according to the invention block the electrically stimulated sodium channel in a "use-dependent"
manner [W.A. Catterall, Trends Pharmacol. Sci., $., 57-65 (1987)]. By a suitable choice of cell system (e.g. neuronal, cardiac, DRG cells) it is possible to test the effect of the substances on different subtypes of sodium channel.

The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blocking of the veratridine-induced release of glutamate [S. Villanueva, P.
Frenz, Y. Dragnic, F. Orrego, Brain Res. 4.51, 377-380 (1988)].
Veratridine is a toxin which opens the sodium channel permanently. This leads to an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx leads to an increased release of glutamate in the neuronal tissue. The compounds according to the invention antagonise this release of glutamate.

The anticonvulsant properties of the substances according to the invention were demonstrated by their protective effect against convulsions triggered by a maximum electric shock in mice [M. A. Rogawski & R.J. Porter, Pharmacol. Rev. 42., 223-286 (1990)].

Neuroprotective properties were demonstrated by a protective effect in a rat MCAO model [U. Pschorn & A. J. Carter, J.
Stroke, Cerebrovascular Diseases, 5., 93-99 (1996)] and a malonate-induced lesion model [M.F. Beal, Annals of Neurology, 3R, 357-366 (1995) and J.B. Schulz, R.T. Matthews, D.R. Henshaw and M.F. Beal, Neuroscience, 11, 1043-1048 (1996)].

Analgesic effects can be investigated in models of diabetic neuropathy and in a ligature model [C. Courteix, M. Bardin, C.
Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J. Lavarenne, Pain 53, 81-88 (1993); G. J. Bennett and Y.-K. Xie, Pain 33., 87-107 (1988)].
It has also been reported that sodium channel blockers can be used to treat cyclophrenia (manic depressive disorder) [J. R.
Calabrese, C. Bowden, M.J. Woyshville; in: Psychopharmacology:
The Fourth Generation of Progress (Eds.: D. E. Bloom and D. J.
Kupfer) 1099-1111. New York: Raven Press Ltd.].

The claimed compounds 1 can be prepared using methods known from the prior art. Some methods of synthesis will now be described by way of example.

Starting from the benzaldehyde derivatives of formula 2 it is possible to obtain the compounds of general formula 6 (corresponding to compounds of formula 1 wherein X denotes 0 5 and the groups R5 and R6 denote hydrogen), using the procedure illustrated in Diagram 1.

Me 0 Me OH Me OH
H NH2 ' / 1 CF3 R I -~ R I -~ R I 10 \ Me 0) Me (ii) \ Me R / ~

\

L "A 5 Me O' 6(=1 with X =0, R5 =H, R6 =H);

(iii) R~ I

Me Diagram 1=
10 Starting from the 2,6-dimethylbenzaldehyde derivatives 2 according to step (i) the 2-amino-ethanols 3 are obtained by first taking up 2 in trimethylsilylcyanide in the presence of a Lewis acid, preferably in the presence of zinc iodide. After the abovementioned reactants have been mixed together, 15 preferably at ambient temperature, the mixture is diluted with an anhydrous organic solvent, preferably with an ethereal organic solvent, most preferably with diethylether, tetrahydrofuran or dioxan. Then a reducing agent is added, preferably a metal hydride, most preferably a hydride selected from lithium aluminium hydride or sodium-bis-(2-methoxyethoxy)-aluminium hydride (Red-Al*). To complete the reaction the mixture is stirred at elevated temperature, most preferably at the reflux temperature of the solvent used, for 0.5 to 4, preferably 2 hours. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

At the aminoalcohol stage 3 the racemate may optionally be separated into the enantiomers. The subsequent separation of the mixture of the enantiomeric aminoalcohols of type 3 thus obtained may be carried out using the methods of enantiomer separation known from the prior art, e.g. by reacting with malic acid, tartaric acid, mandelic acid or camphorsulphonic acid, of which tartaric acid is particularly preferred.

The trifluoroacetates 4 (stage 3 (ii)) are prepared as follows from the compounds 3 optionally thus obtained in enantiomerically pure form. The alcohols 3 are dissolved in an organic solvent, preferably in an anhydrous organic solvent, most preferably in a solvent selected from among toluene, ether, dichloromethane, DMF and ethyl acetate and trifluoroacetic anhydride is added in the presence of an organic or inorganic base at ambient temperature or while cooling with ice and the resulting mixture is stirred for 1 to 8, preferably 2 to 6, most preferably about 4 hours. The inorganic base used may be an alkali metal- or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. The organic base is preferably an organic amine, most preferably diisopropylethylamine, triethylamine, a cyclic amine such as DBU, or pyridine. The abovementioned amines may optionally also be used as solvents. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

In order to prepare the compounds of formula 6 (corresponding to compounds of formula 1 wherein X denotes 0 and the groups R5 and R6 denote hydrogen) a compound 4 according to stage (iii) is dissolved in an organic solvent, preferably in an anhydrous organic solvent, most preferably in a solvent selected from among toluene, ether, dichloromethane, DMF and ethyl acetate and combined with a compound of formula 5, optionally dissolved in one of the abovementioned organic solvents, in the presence of an organic base, preferably selected from diisopropyl ethylamine, triethylamine, cyclic amines such as DBU, and pyridine, at ambient temperature or in the presence of an inorganic base, preferably in the presence of alkali or alkaline earth metal carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, or in the presence of the alkali metal and alkaline earth metal hydrides such as sodium hydride, calcium hydride or potassium hydride, or in the presence of the alkali metal alkoxides, preferably potassium tert.butoxide, sodium methoxide or sodium ethoxide, at ambient temperature or preferably at temperatures between -20 C and ambient temperature, most preferably at about 0 C. When sodium hydride is used as the base, it may be helpful to use chelating agents such as crown ethers, preferably 15-crown-5. To complete the reaction the mixture is stirred at ambient temperature or at elevated temperature, preferably at the boiling temperature of the solvent used, for 2 to 24, preferably 4 to 12, most preferably 6 to 7 hours. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

An alternative method of obtaining compounds of general formula 6 (corresponding to 1 wherein X denotes oxygen and R5 and R6 denote hydrogen), starting from the benzaldehyde derivatives of formula 2, is the procedure illustrated in Diagram 2.

R2 R' RZ R3 Me N02 HO~A 8 A
2 R' Me O"
(iv) Me (v) 7 R ~ 9 \ [:kAR4 F R 2 / R \

Me O'~ 6 (=1 with X =0, R5 =H, R6 =H);
NHZ
(vi) Ri Me Diagram 2 =
Starting from the 2,6-dimethylbenzaldehyde derivatives (2) according to stage (iv) the reaction to obtain the a,p-5 unsaturated nitro compounds 7 is carried out using nitromethane in glacial acetic acid at elevated temperature, preferably at above 60 C, most preferably above 100 C, preferably at about 120 C over a period of 2 to 8, preferably 3 to 6, most preferably about 4 hours. The reaction mixture is worked up in 10 the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

The ethers 9 may be obtained from the nitro compounds 7 by 15 reacting with the alcohols 8. This is done as follows. The alcohol 8 is dissolved in an organic solvent, preferably in an anhydrous organic solvent selected from among methylene chloride, tetrahydrofuran, diethylether and dioxan and combined with a base selected from the alkali metal alkoxides such as 20 sodium ethoxide, sodium methoxide or potassium tert.butoxide and the alkali metal- or alkaline earth metal hydrides, preferably sodium hydride. The mixture is stirred for 6 to 24, preferably about 10 to 14 hours at ambient temperature, optionally also at slightly elevated temperature and then a solution of the nitro compound 7, preferably in one of the abovementioned solvents, is added. Stirring is continued at a constant temperature until the reaction is complete. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

The final reduction of 9 leads to the compounds of formula 6 (corresponding to compounds of formula 1 wherein X denotes 0 and the groups R5 and R6 denote hydrogen). This reduction is preferably.carried out by catalytic hydrogenation, preferably on palladium catalysts or on Raney nickel in alcoholic solvents, preferably in methanol, at ambient temperature. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

The ammonium salts 1-Y are synthesised in the same way as the preparation of compounds 1 starting from the amines 6, using standard methods (Diagram 3).

R2 / R3 Rz R3 Me O'~A Me O"'A R5 R, / I NH2 N"Rs Me Me 6(=1 with X =0, R5 =H, R6 =H); R4 1 with X =0;
R2 Rs \

~s _ Me O R + Y
(viii) R~ / ; ;Rs \ I Me R 1Y with X=0;
Diagram 1!

The reaction according to stage (vii) may be carried out, on the one hand, in such a way that tertiary amines of formula 1 wherein neither R5 nor R6 denotes hydrogen, are obtained directly, or by a suitable choice of the reaction conditions 5 may lead to secondary amines of formula 1 wherein either R5 or R6 denotes hydrogen. The latter may then be alkylated, on the one hand, by repeating stage (vii) to obtain tertiary amines, or may be subjected directly to stage (viii), in order to give access to the ammonium salts 1-Y.

In order to carry out the process according to stage (vii) an amine of general formula 6 is dissolved in an organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and most preferably anhydrous, optionally absolute dimethylformamide or methylene chloride. The solution thus obtained is combined with an inorganic or organic base and a corresponding alkylating agent. The base used may be an alkali metal or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use the hydrogen carbonates of lithium, sodium and potassium. Moreover, the alkali metal-or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohols or water may also be used. It is also possible to use, as further bases, alkoxides of alkali metals and alkaline earth metals, preferably the ethoxides of sodium and potassium. It is also possible to use alkali metal- and alkaline earth metal hydrides, preferably of potassium or sodium, preferably in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran and toluene. The organic base is preferably an organic amine, most preferably diisopropylethylamine, triethylamine, a cyclic amine such as DBU, or pyridine. The alkylating agents used may be alkyl halides such as alkylchloride, alkylbromide, particularly alkyliodide as well as alkyl tosylates, mesylates, triflates = CA 02417361 2003-01-24 and dialkylsulphates. The alkyl groups of the alkylating agents correspond to the definitions of R5 and R6 specified hereinbefore. The reaction mixture is stirred for 0.5 to 4 days, preferably 1 to 2 days at ambient temperature and evaporated to dryness. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.
The method described above for stage (vii) may be used to prepare the ammonium salts 1-Y starting from the amines 1 (stage viii).

Alternatively to the procedure described above the compounds of formula 1 may also be prepared according to stage (vii) by reductive amination of the amines 6 with carbonyl compounds in the presence of a reducing agent. The reaction of the amines 6 with the carbonyl compounds to obtain the Schiff bases formed as intermediates is carried out in solvents such as toluene, dichloromethane, ethyl acetate, ether, tetrahydrofuran etc., preferably at ambient temperature. It may be carried out in the presence of an acid, preferably in the presence of acetic acid.
The subsequent reduction may be carried out with complex hydrides such as, for example, LiAlH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH (OAc) 3, etc. NaBH4 is preferably used for the reaction with primary amines, NaBH(OAc)3 for secondary amines.
When preparing the methyl compounds by reacting with formalin it is advisable to use formic acid as solvent. The reaction mixture is worked up in the usual way. The products are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

Alternatively to the procedure described above the compounds of formula 1 may also be prepared by the procedure shown in Diagram 4.

Me 0 Me 0 Me 0 / /
R~ \ I CI+ MeMgl (i R Me \ ~ (x) R Br ~ ~
Me Me Me R
Me 0 R5 Me OH 5 / I N~R6_~ 1 (xi) " R' (xii) R ~ (xiii) with X 0 Me Me D;agram 4 -Starting from suitably substituted benzoic acids the 5 desired acetophenone intermediates 12 may be obtained by methods known from the literature (Recl.Trav.Chim.Pays-Bas 61,1942,539,544) by Grignard reaction with the corresponding acid chlorides 10 (stage ix). These intermediates 12 are preferably brominated in ether to form 10 the compounds 13 (stage x) and conveniently converted without further purification into the aminoethanol intermediates 15 via the aminoketones 14 and immediate reduction thereof (stage xii), preferably with sodium boranate in isopropanol or with lithium alanate in diethylether or tetrahydrofuran. Optically active aminoethanol intermediates 15 may be obtained stereospecifically by asymmetric hydrogenation using methods known from the literature e.g. with rhodium catalysts using (S.S)- or (R.R)-BCPM (Chem. pharm. bull.
43, 738 (1995)).

Etherification to obtain the compounds 1 (wherein X denotes oxygen) with variation of the chain length of A is carried out for example using benzylhalides, preferably using potassium tert.butoxide as auxiliary base (A = C1), by Reppe reaction using optionally substituted phenylacetylenes and subsequent hydrogenation of the resulting Z/E olef ins (A = C2) and by Williamson etherification using phenylalkylhalides, preferably using crown ethers (e.g. A = C3). At this point reference should also be made to the general remarks on stage (iii) according to Diagram 1 which are also applicable here.

Starting from the compounds of formula 3 the compounds of general formula 1 wherein X denotes -NH- may also be obtained by the method shown in Diagram 5.

Me OH Me OH Rs Me L Rs N-~ R' / ~ N\RS-~ R~ N~Rs ~
Me (vii) \ Me (xiv) Me R2 p~R3 2 ~ R3 \
H2N'A 18 Me HN-" A Rs 1 with X=-NH-(xv) R1 Rs Me Diagram 5 -To perform the process according to stage (vii) an amine of general formula 3 is dissolved in an organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and most preferably anhydrous, optionally absolute dimethylformamide or methylene chloride. The solution thus obtained is combined with an inorganic or organic base and a corresponding alkylating agent. The base used may be an alkali metal or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use the hydrogen carbonates of lithium, sodium and potassium. Moreover, the alkali metal or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohols or water may also be used. It is also possible to use, as further bases, alkoxides of alkali metals and alkaline earth metals, preferably the ethoxides of sodium and potassium. It is also possible to use alkali metal and alkaline earth metal hydrides, preferably of potassium or sodium, preferably in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran and toluene. The organic base is preferably an organic amine, most preferably diisopropylethylamine, triethylamine, a cyclic amine such as DBU, or pyridine. The alkylating agents used may be alkyl halides such as alkylchloride, alkylbromide, particularly alkyliodide as well as alkyl tosylates, mesylates, triflates and dialkylsulphates. The alkyl groups of the alkylating agents correspond to the definitions of R5 and R6 specified hereinbefore. The reaction mixture is stirred for 0.5 to 4 days, preferably 1 to 2 days at ambient temperature and evaporated to dryness. The reaction mixture is worked up in the usual way. The products 16 are purified by crystallisation or by chromatographic methods depending on their crystallisation tendencies.

The compounds of formula 17 wherein L denotes a leaving group, selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate or para-toluenesulphonate may be prepared from the compounds of formula 16 by reaction according to stage (xiv). If R5 or R6 equals hydrogen, protecting groups according to the prior art should be used. If L denotes chlorine or bromine, the reaction may be performed using common halogenation reagents. If L denotes methanesulphonate, trifluoromethanesulphonate or para-toluenesulphonate the compounds 16 may be reacted with the corresponding sulphonic acid chlorides or anhydrides to obtain the compounds17 in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran and toluene in the presence of organic amines such as, preferably, diisopropylethylamine, triethylamine, cyclic amines such as DBU, or pyridine.

The compounds of formula 1 wherein X denotes -NH- may be obtained from the compounds 17 by reacting with the amines 18 under the reaction conditions described hereinbefore for stage (vii). The compounds of formula 1 wherein X denotes -N(C1-C6-5 alkyl) or -N(C3-C6-cycloalkyl-Cl-C4-alkylene) may also be obtained therefrom. This reaction is carried out under the reaction conditions described for stage (vii) by alkylation of the compounds of formula l wherein X =-NH- with alkylating reagents Cl-6-alkyl-L or C3-C6-cycloalkyl-Cl-C4-alkyl-L, where L
10 may have the meanings given hereinbefore.

Starting from the compounds of formula 1 wherein X = NH the compounds of general formula 1 wherein X denotes -N(CHO)- or -N(CO-C1-C6-alkyl)- may be obtained by the method illustrated in 15 Diagram 6.

R4 Fe Me HNA R6 Me 'N~A R6 N.R5 6~11 N 6Z"~

e e 1 with X = -NH- ~ (with R=H or CI-C6 AIkyI) [formylation or acylation]
20 iagram 6-The reactions according to Diagram 6 may be carried out analogously to formylation and acylation processes which are known per se.

25 The Examples which follow serve only to illustrate the invention without restricting its subject matter.

Example 1: 2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethylamine Me F ~ ~
O F
IITh Me Synthesis of the precursors 2, 5 and 8:
1 -1. 2, 6-dimethy1benzaldehyd ( -oponding .o tht- om= ound of f ormu1 a 21 336 ml (0.54 mol) of a 1.6 M solution of n-butyllithium in hexane are added dropwise within 1 h to a solution of 100 g (0.54 mol) of 2-bromo-1,3-dimethylbenzene in 690 ml of THF
cooled to - 65 C. The mixture is then stirred for 1 h at the same temperature. Then 100 ml of DMF are added dropwise at -65 C and the mixture is left to react for 30 min at this temperature. It is poured onto 500 ml of ice/135 ml of conc.
hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and evaporated down. Yield: 85.0 g of light-yellow oil.

1-2t -4-(2,6-diflLOro= henyl)-p _ros an-1 -o1 (corresponding -to t-he com= o ind of fo_rmLla 81 1.2.1: diethyl 2-(2,6-difluorobenzyl)-malonate:
19.3 g (121 mmol) of diethyl malonate are placed in 700 ml of THF and 14.9 g (132 mmol) of potassium tert. butoxide are added. The mixture is stirred for 1 h and 25 g (121 mmol) of 2,6-difluorobenzylbromide (3) are added. After 3 h stirring at ambient temperature the mixture is suction filtered through kieselguhr and concentrated by evaporation. Yield: 33.1 g of light-yellow oil.
monoethyl 2-(2,6-difluorobenzyl)-malonate:
33.1 g (116 mmol) of diethyl 2-(2,6-difluorobenzyl)-malonate (Example 1.2.1) are dissolved in 120 ml of ethanol and while cooling with ice 15 ml of a 40% sodium hydroxide solution are = CA 02417361 2003-01-24 added. The mixture is stirred for 4 h at ambient temperature, then the organic solvent is distilled off and the residue is washed with water. The aqueous solution is washed with dichloromethane and acidified with hydrochloric acid. It is extracted with dichloromethane, evaporated down, and a slowly crystallising brown oil is obtained. Yield 21.5 g, melting point: 60 C.

1.2.32 ethyl 3-(2,6-difluorophenyl)-propionate:
21.5 g (83.3 mmol) of monoethyl 2-(2,6-difluorobenzyl)-malonate (Example 1.2.2) are heated with stirring for 4 h, without a solvent (bath temperature 160 C). A light-brown liquid is obtained. Yield: 17.6 g.

1.2.4: 3-(2,6-difluorophenyl)-propan-l-ol (corresponding to the compound of formula 8):
8.80 g (41.0 mmol) of ethyl 3-(2,6-difluorophenyl)-propionate (Example 1.2.3) dissolved in 60 ml of THF are added dropwise while cooling with ice to a suspension of 1.71 g (41.1 mmol) of lithium aluminium hydride in 40 ml of THF. The mixture is stirred first for 1 h at ambient temperature, then for 2 h at 75 C. Diammonium tartrate solution and magnesium sulphate are added, the solution is separated off and the residue is washed with ethyl acetate. After drying and evaporation a clear liquid is obtained. Yield: 5.67 g.

1.2.5: 2-(3-bromo-propyl)-1,3-difluorobenzene (compound of formula 5) :
6.86 g (39.8 mmol) of 3-(2,6-difluorophenyl)-propan-l-ol (Example 1.2.4) are dissolved in 50 ml toluene and 19.1 g (92.0 mmol) of thionyl bromide are added. The mixture is refluxed for 3 h, the solvent is eliminated and excess thionyl bromide is eliminated. Then the residue is purified by flash-chromatography (cyclohexane).
Yield: 6.98 g.

Alternative method of synthesis according to Diagram 1:
i ,A = 2-Amino-1 - (2, 6-dimethyl= henyl) - _thanol ( _oc rr~pondi ngto the com= n,ind of form il a 3) -Method according to stage (i):
15.7 ml (117 mmol) of trimethylsilylcyanide and 10.0 g (110 mmol) of zinc diiodide are added to 14.4 g (107 mmol) of 2,6-dimethylbenzaldehyde (Example 1.1). The mixture is stirred for 30 min at ambient temperature and 150 ml of ether are added.
Then 8.10 g (213 mmol) of lithium aluminium hydride are added so that the mixture boils gently. After it has all been added the mixture is stirred for 2 h while refluxing. It is then carefully hydrolysed with diammonium tartrate solution while cooling with ice. The mixture is suction filtered through magnesium sulphate and washed with ether. It is evaporated down and the product is obtained in the form of yellow crystals.
Yield: 7.0 g, MS : m/z 166 [(M+H) +] .

l . 4 : N- [2-(2^6 -di methyl= henyl ) - 2 -hydroxyethyl ] -tri fl nroac ami de (corresnonding to the com= oi d of form ja 41,-Process according to stage (ii):
2,00 g (12.1 mmol) of 2-amino-l-(2,6-dimethylphenyl)-ethanol (Example 1.3) are dissolved in 100 ml dichloromethane, combined with 3.68 g (17.5 mmol) of trifluoroacetic anhydride and 1.60 g (15.8 mmol) of triethylamine and stirred for 4 h in the ice bath. The mixture is evaporated down, the residue is taken up in 100 ml of dichloromethane and washed with 30 ml of saturated sodium hydrogen carbonate solution. The organic phase is dried and evaporated down and the crude product is purified by flash-chromatography (dichloromethane/ethanol 90:10). Yield: 3.11 g, melting point: 96 C.

1_ 6~ 2- f 3-( 2, 6- di f 1 ioro= hen~sl )-p _ronoXyl - 2-( 2. , 6- di m_ h~sls hen~rl )-Pr yl ami ne (_oc rrPy= onding o th -.om= n>>nd of formLl a 6)-35 Process according to stage (iii):

261 mg (1.00 mmol) of N- [2- (2, 6-dimethylphenyl) -2-hydroxyethyl]-trifluoroacetamide (Example 1.4) are dissolved in 3 ml of THF and, while cooling with ice, 70.0 mg (1.46 mmol) of sodium hydride (50% suspension in mineral oil) are added. After min, 230 L (1.13 mmol) of 15-crown-5 is added and stirring is continued for a further 5 min. 236 mg (1.00 mmol) of 2-(3-bromo-propyl)-1,3-difluorobenzene are added (Example 1.2) and 5 stirring is continued for 2 h at ambient temperature. The mixture is then refluxed for 7 h. The mixture is purified by flash-chromatography (dichloromethane/ethanol 95:5). Yield: 120 mg, melting point: 166 C.

Alternative method of synthesis according to Diagram 2:
1 6 t, 3-dimethyl_2- (?-nitrovinyl)-b _nz .n _ (correenondi_nQ to the _omnound of formiil.a 7L-, Process according to stage (iv):
27.2 g of ammonium acetate and 48 ml (900 mmol) of nitromethane are added to 40.0 g (300 mmol) of 2,6-dimethylbenzaldehyde (Example 1.1) in 160 ml glacial acetic acid. The mixture is heated for 4 h to 120 C and poured onto 500 ml of ice. After thawing, it is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried and evaporated down. The crude product is purified by flash chromatography (cyclohexane/ethyl acetate 80:20). Yield: 15.0 g of slowly crystallising yellow oil.

1 7 = 2 - (1- ( 2 ~6 -di f 1 uoronhen~l= r ~~1 ~r, - . -ni ro- . _h~1~3i S31IDpthy1 - nere (So=reSnonding o.h __om= oind of form ula 9~
Process according to stage (v):
1.20 g (25.0 mmol) of sodium hydride (50% suspension in mineral oil) are added to 4.30 g (24.3 mmol) of 3-(2,6-difluorophenyl)-propan-l-ol (Example 1.2.4) dissolved in 20 ml of THF. The mixture is stirred for 14 h at ambient temperature and then 4.30 g (24.1 mmol) of 1,3-dimethyl-2-(2-nitrovinyl)-benzene (Example 1.6) dissolved in 40 ml of THF are added dropwise. It is stirred for 6 h at ambient temperature, acidified with glacial acetic acid, diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried and evaporated down. The crude product is purified by flash chromatography (cyclohexane/ethyl acetate 90:10). Yield: 3.20 g..

i Q= 2- [I - (2, 6-difltnrnphenyl) -propoxyl -2- (2, 6-dim - hyl= henyl )-Pt-hyl ami n- (_nrr _apnnding to the .nm= nund nf formula Process according to stage (vi):

5 1.50 g (4.29 mmol) of 2-(l-(2,6-difluorophenylpropyloxy)-2-nitro-ethyl)-1,3-dimethyl-benzene (Example 1.7) dissolved in 30 ml methanol are hydrogenated for 6 h at atmospheric pressure over 1.0 g of Raney nickel. The catalyst is separated off, the remainder is evaporated down and purified by flash 10 chromatography (dichloromethane/ethanol 95:5). Yield: 745 mg, yellow oil.

Example 2: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]N,N-bis-(2-ethylbutyl)-amine F D
Me F
CN t Et Me Et 15 Et Process according to stage (vii):
126 mg (0.39 mmol) of 2- [3- (2, 6-difluorophenyl) -propoxy] -2-(2,6-dimethylphenyl)-ethylamine (Example 1) are placed in 4 ml of dichloromethane and combined with 24 mg (0.39 mmol) of 20 glacial acetic acid and 39.5 mg (0.39 mmol) of 2-ethylbutyraldehyde. After 7 min, 117 mg (0.55 mmol) of sodium triacetoxyborohydride are added. The mixture us stirred for 2 h at ambient temperature, then combined with 10% sodium hydrogen carbonate solution and stirred for a further 30 min at ambient 25 temperature. The phases are separated, the organic phase is washed with saturated sodium chloride solution, dried, evaporated down and the crude product is separated by flash chromatography (dichloromethane/ethanol 95:5), with [2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-bis-(2-30 ethylbutyl)-amine being eluted first.
Yield: 72 mg, colourless oil, MS: m/z 488 [(M+H)'];

Example 3: N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimthylphenyl) -ethyl] -N- (2-ethylbutyl) -amine Me F
~
H F
N Et Me \--<
Et Prepared analogously to Example 2, the title compound being eluted second during the chromatographic separation;
Yield: 61 mg, colourless oil, MS: m/z 404 [(M+H)'].
Example 4: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2-ethylbutyl)-N-methyl-amine Me F

F
~We Et Me ~
Et Process according to stage (vii):
45 mg (0.11 mmol) of [2- [3- (2, 6-difluorophenyl) -propoxy] -2-(2,6-dimethylphenyl)-ethyl]-(1-ethylpropyl)-amine (Example 3) are dissolved in 2 ml of formic acid and combined with 1 ml of 37% formalin solution. The mixture is stirred for 4 h at a bath temperature of 120 C, cooled, diluted with water and extracted with dichloromethane. The residue obtained after drying and evaporation is purified by flash chromatography (dichloromethane/ethanol 95:5). Yield: 15 mg, MS: m/z 418 L (M+H) +] .

Example 5: N- [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,6-dimethylphenyl)-ethyl]-N-(2-ethylbutyl)-N,N-dimethyl-ammonium iodide F
Me F
O Me - N'MeEt Me + \-~
Et Process according to stage (viii):
30.0 mg (74 mol) [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-(2-ethylbutyl)-amine (Example 3) are dissolved in 3 ml of acetonitrile and combined with 20.5 mg (148 mol) of potassium carbonate, 6.0 mg (37 M) of potassium iodide and 22.0 mg (155 mol) of methyl iodide. The mixture is stirred for 3 h at ambient temperature, the solvent is eliminated and the residue is purified by flash chromatography (dichloromethane/ethanol 95:5). Yield: 33 mg, MS: m/z 432 L (M+H)']
Example 6: 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-pyrrolidine F ~ /
Me F

- NJ
Me Process according to stage (vii):
163 mg (0.51 mmol) of 2- [3- (2, 6-difluorophenyl) -propoxy] -2-(2,6-dimethylphenyl)-ethylamine (Example 1), 110 mg (0.51 mmol) of 1,4-dibromobutane, 200 mg of potassium carbonate and 50 mg of potassium iodide dissolved in 20 ml of acetonitrile are refluxed for 4 h. The mixture is then evaporated down and the residue is purified by flash chromatography (dichloromethane/ethanol 95:5), in order to obtain the product as a white crystalline solid. Yield: 58 mg, melting point: 173-175 C.

Example 7: 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-1-methyl-pyrrolidinium iodide F P
Me F
+/~
NJ
Me Me Process according to stage (viii):
25.0 mg (70 mol) of 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2-(2,6-dimethylphenyl)-ethyl]-pyrrolidine (Example 6), 10.0 mg (70 mol) of methyl iodide, 20.0 mg potassium carbonate and 6.0 mg potassium iodide are stirred in 2 ml of acetonitrile for 14 h at ambient temperature. The mixture is evaporated down and the residue is purified by flash chromatography (dichloromethane/ethanol 95:5). Yield: 20.0 mg, MS: m/z 389 [ (M+H)']

Example 8: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethyiphenyl)-ethyl]-N,N-dimethyl-amine Me F

F
NMe2 Me Process according to stage (vii):
200 mg (0.63 mmol) of 2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethylamine (Example 1) are dissolved in 12 ml of formic acid and combined with 6 ml of a 37% formalin solution. The mixture is stirred for 5 h at 120 C, poured onto ice and adjusted to pH 13-14 with conc. Sodium hydroxide solution. It is then extracted with ether, the organic phase is dried and evaporated down, as a result of which the product is obtained as a yellowish oil. Yield: 170 mg, MS: m/z 348 [ (M+H)']

= CA 02417361 2003-01-24 Example 9: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethyiphenyl)-ethyl]-N-cyclopropylmethyl-amine Me F

H F
N
Me ~a Prepared analogously to Example 3; oil; MS: m/z 374 [(M+H)'].
Example 10: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-cyclopropylmethyl-N-methyl-amine Me F

F
NMe Me --a Prepared analogously to Example 4., starting from Example 9;
melting point: 78 C;
MS: m/z 388 [ (M+H)'] .

Example 11: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N,N-bis-(1-cyclohexen-4-yl-methyl)-amine F PFF
Me ~

- ~/
N
Me Prepared analogously to Example 2; oil; MS: m/z 508 [(M+H)'].

= CA 02417361 2003-01-24 Example 12: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(1-cyclohexen-4-yl-methyl)-amine Me F
O
H F
Me N~ /~\
~-( i) Prepared analogously to Example 3; oil; MS: m/z 414 [(M+H)'].

Example 13: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-n-butyl-amine Me F

H F
Me Me Prepared analogously to Example 3; oil; MS: m/z 376 [(M+H)'].
Example 14: 1-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-piperidine F
Me F
Me Prepared analogously to Example 6; melting point(hydrochloride): >200 C; MS: m/z 388 [(M+H)`]
To prepare the hydrochloride of the title compound the free base is taken up in a little ether and ethereal hydrochloric acid is added dropwise until the precipitation is complete.
Then the solvent is removed, the residue is carefully washed with ether and dried.

Example 15: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethyiphenyl)-ethyl]-N-(1-cyclohexen-4-yl-methyl)-dimethyl-amm4onium iodide F P
Me F
Me F
N,Me Et Me +\--<
Et Prepared analogously to Example 5 starting from Example 12;
melting point: 105 C;
MS: m/z 432 [(M+H)'].

Example 16: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-n-butyl-N,N-dimethyl-ammonium iodide F
Me F Me F

N-Me Me +
\_~Me Prepared analogously to Example 5 starting from Example 13; MS:
m/z 404 [ (M+H) +]

Example 17: N- (2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,6-dimethylphenyl)-ethyl]-N-iso-propyl-amine Me F

H F
N
Me >-Me Me Prepared analogously to Example 3; oil; MS: m/z 362 [(M+H)'].

Example 18: 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-azepan F
Me F
N
CO
Me Prepared analogously to Example 6; oil; MS: m/z 402 [(M+H)`].
Example 19: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimthylphenyl)-ethyl]-N-neopentyl-amine F

CRN H F
Me Me "*-~Me Me Prepared analogously to Example 3; oil; MS: m/z 390 [(M+H)'].
Example 20: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N,N-diethyl-amine Me F

F
NE~
Me Prepared analogously to Example 2; oil; MS: m/z 376 [(M+H)'].
Example 21: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-cyclohexylmethyl-amine F

H F
CRN~_O
Me Prepared analogously to Example 3; melting point (hydrochloride) : 187 C; MS: m/z 416 [(M+H)+]

To prepare the hydrochloride of the title compound the free base is taken up in a little ether and ethereal hydrochloric acid is added dropwise until the precipitation is complete.
Then the solvent is removed, the residue is carefully washed with ether and dried.

Example 22: N- [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,6-dimethylphenyl)-ethyl]-N-iso-butyl-amine F

CRN H F
Me Me \--<
Me Prepared analogously to Example 3; oil; MS: m/z 376 [(M+H)+].
Example 23: N- [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,6-dimethylphenyl)-ethyl]-N-benzyl-amine Me L
H F
Me CPrepared analogously to Example 3; melting point (hydrochloride): 176 C; MS: m/z 410 [(M+H)'].
To prepare the hydrochloride of the title compound the free base is taken up in a little ether and ethereal hydrochloric acid is added dropwise until the precipitation is complete.
Then the solvent is removed, the residue is carefully washed with ether and dried.

= CA 02417361 2003-01-24 Example 24: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N,N-bis(benzyl)-amine F
Me F

- ~ ~
N
Me Prepared analogously to Example 2; melting point (hydrochloride): 108 C; MS: m/z 500 [(M+H)']
To prepare the hydrochloride of the title compound the free base is taken up in a little ether and ethereal hydrochloric acid is added dropwise until the precipitation.is complete.
Then the solvent is removed, the residue is carefully washed with ether and dried.

Example 25: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(4-isopropenyl-cyclohexen-1-yl-mthyl) -amine Me F

H F
- N
Me Prepared analogously to Example 3; melting point (hydrochloride): 155 C; MS: m/z 454 [(M+H)'].
To prepare the hydrochloride of the title compound the free base is taken up in a little ether and ethereal hydrochloric acid is added dropwise until the precipitation is complete.
Then the solvent is removed, the residue is carefully washed with ether and dried.

Example 26: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2-methylbutyl)-amine Me F

c CN H F
Me Me Me Prepared analogously to Example 3; oil; MS: m/z 390 [(M+H)`].

Example 27: N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N,N-bis-(2-methylbutyl)-amine F

Me F
O Me /---c N Me Me Me e Prepared analogously to Example 2; oil; MS: m/z 460 [(M+H)`].
$xample 28: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-neo-hexyl-amine Me F

N
Me Me Me e Prepared analogously to Example 3; oil; MS: m/z 404 [(M+H)'].

Example 29: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N,N-bis-(neo-hexyl)-amine F
Me F
O

Me Me Me e Me e Prepared analogously to Example 2; oil; MS: m/z 488 [(M+H)'].
Example 30: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2-trifluoromethyl-ethyl)-amine Me F

H F
N
Me ~

Prepared analogously to Example 3; oil; MS: m/z 416 [(M+H)'].
Example 31: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-cyclohexyl-amine Me F
O
H F
N
Me Prepared analogously to Example 3; oil; MS: m/z 402 [(M+H)'].

Example 32: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-iso-pentyl-amine Me F

- N
Me Me Me Prepared analogously to Example 3; oil; MS: m/z 390 [(M+H)'].
Example 33: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N,N,N-trimethyl-ammonium iodide F PFF
Me ~ Me F
N-Me Me +Me Prepared analogously to Example 5 starting from Example 1;
melting point: 190 C.

Example 34: [3- (2, 6-difluorophenyl) -propyl] - [1- (2, 6-dimethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-amine F p Me H F
N
- NJ
Me 34_l: 3-(2,6-diflioroph nyl)-=ropylamine (-orr_snonding to the nom= oLnd of fo_r_m__Ll a 18L
3.20 g (13.6 mmol) of 2-(3-bromopropyl)-1,3-difluorobenzene (corresponding to Example 1.2.5) are reacted with a solution of 5 g of ammonia in 30 ml of THF in the autoclave for 20 h at 80 C. The mixture is then evaporated down and the residue is purified by flash chromatography. Yield: 1.01 g, MS: m/z 172 [ (M+H)'] .

34 .2 : 1-(2, 6-dimethyl= henyl ) -2.-~yrrol i di n-I -yl -_-hanol (correaponding to the rompound of formul a 161_c_ Process according to stage (vii):
647 mg (3.00 mmol) of 1,4-dibromobutane, 1.0 g of potassium carbonate and 250 mg of potassium iodide are added to a solution of 500 mg (3.00 mmol) of 2-amino-l-(2,6-dimethylphenyl)-ethanol (Example 1.3) in 30 ml acetonitrile.
The mixture is refluxed for 3 h. Then the solvent is eliminated and the residue is taken up in dichioromethane. It is filtered, evaporated down and the crude product is purified by flash chromatography (dichloromethane/ethanol 90:10). Yield 360 mg, melting point: 126 C, MS: m/z 220 [(M+H)+]

34.3: 1_- (2, 6-dimethyl -nhenyl ) -2-pyrrol ic3in-1-y1 -Ppthyl methaneGLl = honate (-orr _Gpondi ng to the comno :n of orm il a 17)-.
Process according to stage (xiv) :
219 mg (1.00 mmol) of 1-(2,6-dimethylphenyl)-2-pyrrolidin-1-yl-ethanol (Example 34.2) are dissolved in 3 ml of dichloromethane and combined with 250 l (1.80 mmol) of triethylamine and 105 1 (1.30 mmol) of methanesulphonic acid chloride. The mixture is stirred for 14 h at ambient temperature, 2 ml of saturated sodium hydrogen carbonate solution are added, the mixture is extracted with dichloromethane, dried and evaporated down.
Yield: 192 mg of brown oil.

34 4: - l2 _ 6-di 1 :oro= hPnyl 1 -propyyl ] - ['I - (2, 6 -di m hy1 -lah _nyl ) -2-pyrrol i di n-1 -yl -et yl ]-ami nt- a Process according to stage (xv) :
140 mg (0.81 mmol) of 3-(2,6-difluorophenyl)-propylamine (Example 34.1) and 2 ml of diisopropylethylamine are added to a solution of 190 mg (0.63 mmol) of 1-(2,6-dimethyl-phenyl)-2-pyrrolidin-1-yl-ethyl methanesulphonate (Example 34.3) in 2 ml of acetonitrile. The mixture is stirred for 6 h at 80 C, evaporated down and the residue is purified by flash = CA 02417361 2003-01-24 chromatography. Yield: 13 mg of yellow oil, MS: m/z 373 [ (M+H)'] .

Example 35: [3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-ghenyl)-2-piperidin-l-yl-ethyl]-amine F
Me H F
N

NI , Me v Prepared analogously to Example 34; melting point (hydrochloride): 145 C, MS: m/z 387 [(M+H)+].
To prepare the hydrochloride of the title compound the free base is taken up in a little ether and ethereal hydrochloric acid is added dropwise until the precipitation is complete.
Then the solvent is removed, the residue is carefully washed with ether and dried.
Example 36: 1- [2- [2- (2-Fluorophenyl) -ethoxy] -2- (2, 6-dimethylphenyl)-ethyl]-piperidine (3-F

Me 16_ 1. . .6-d;m - -hy l-_n_-bromo-acetonh nP on - (correSi ondi ng -o t_he comr nund of formula 13) i Process according to stage (x):
23.3 g (0.15 mol) of 2,6-dimethylacetophenone, prepared according to Rec.Trav.Chim.Pays-Bas 51 539, 544 (1942), are dissolved in 250 ml of absolute ether, reacted with 7.5 ml (0.15 mol) of bromine within about 30 minutes and stirred for a further 2 hours at ambient temperature. The ethereal solution is washed 2 x with about 100 ml of water, NaHCO3 is added until a pH of 6 is reached and then dried. The ethereal solution is further reacted directly.

36 . 2: 0(,-N-13i = Pri rii no-2 _ 6-di m hyl -aceto= henone (corresponding 5 tn the _om= oimd of orm :1 a 14):
Process according to stage (xi):
The ethereal solution according to Example 36.1 is added dropwise to a solution of 30 ml (0.3 mol) of piperidine in 50 ml of absolute ether and the mixture is then stirred for a 10 further 3 hours at ambient temperature. The precipitate formed is suction filtered and the solvent is eliminated from the ether phase. The residue is immediately reduced.

36 . 3: 1- (2.6-di methyl= henyl )-2 -~i n i di no ._hanol ( correG= ondi ng 15 to the com= o,~nd of for___Ll a 15~
Process according to stage (xii):
The crude product according to Example 36.2 is taken up in 300 ml of isopropanol, mixed with 2.3 g (0.06 mol) of NaBH4, refluxed for 3 hours, the same amount of NaBH4 is added to 20 complete the reaction and the mixture is refluxed for a further 3 hours. Then the solvent is eliminated, the residue of about 30 g is divided between water and methylene chloride and the organic phase is dried and evaporated down. After flash chromatography on silica gel using methylene chloride/methanol 25 (95 : 5) to (90 : 10) as eluant, 15.1 g of the compound c) are obtained as a light-coloured oil.
Alternatively, the reduction may be carried out with LiAlH4 in THF, preferably at - 60 C; purification by chromatography can be omitted here.
3 6. 4: l-[2-[2-( 2- f 1 Lorophenyl )-~~~thox=l - 2-(2+ 6- di meth)zl phenyl )-ethyl) -pi = eridine:
Process according to stage (xiii):
2.3 g (0.01 mol) of the ethanolamine according to Example 36.3 and 0.6 g (0.01 mol) of finely powdered KOH are stirred for 15 minutes in DMSO, then stirred with 1.2 g (0.01 mol) of 2-fluorophenylacetylene for 4 hours at 70 C, mixed with water and worked up by extraction with methylene chloride. After the solvent has been eliminated, the residue is subjected to flash chromatography on silica gel with methylene chloride/methanol (95 : 5) as eluant. The main fraction of 2.5 g thus obtained is hydrogenated in 30 ml of methanol at ambient temperature with 0.5 g Pd/BaSO4 as catalyst under a pressure of 5 bar. The solvent is removed and the residue is subjected to flash chromatography on silica gel with ethyl acetate/cyclohexane (25 : 75). The clean fraction is mixed with the calculated amount of fumaric acid. There is no salt formation with fumaric acid:
after the elimination of the solvent the title compound is obtained as an amorphous compound.

Example 37: 1-[2-(2,6-dimethylbenzyloxy)-2-(2,6-dimethylphenyl)-ethyl]-piperidine Me Me O \ /Me Me Process according to stage (xiii):
1.5 g (0.006 mol) of the ethanolamine according to Example 36.3 are dissolved in 30 ml of absolute THF, mixed with 0.9 g (0.0077 mol) of potassium tert.butoxide and stirred for 30 minutes. After the addition of 1.5 g (0.0077 mol) of 2,6-dimethylbenzylbromide, the reaction mixture is stirred for a further 60 minutes at ambient temperature, then the solvent is eliminated and the residue is divided between water and methylene chloride. After being washed and dried, the organic phase is evaporated down and the oily residue of 2.2 g is purified by flash chromatography on silica gel and ethyl acetate/cyclohexane (25 : 75) as eluant. The oil obtained is converted into the hydrochloride (melting point 185 - 186 C).

Example 38: 1-[2-benzyloxy-2-(2,6-dimethylphenyl)-ethyl]-piperidine Me \ /
c Me CNO

Prepared analogously to Example 37; melting point(hydrochloride): 197-199 C;

Example 39: 1-[2-(4-bromobenzyloxy)-2-(2,6-dimethylphenyl)-ethyl]-piperidine Br Me O\ /

Me Prepared analogously to Example 37; melting point(hydrochloride): 152-154 C;

Example 40: 1-[2-(4-chlorobenzyloxy)-2-(2,6-dimethylphenyl)-ethyl] -piperidine CI
Me O\ /

Me Prepared analogously to Example 37; melting point (hydrochloride): 134-135 C;

Example 41: 1-[2-(2,6-dichlorobenzyloxy)-2-(2,6-dimethylphenyl)-ethyl]-piperidine CI ~ ~
Me O CI
- N~
Me Prepared analogously to Example 37; melting point (hydrochloride): 225-227 C;

Example 42: 1-[2-(2,6-difluorobenzyloxy)-2-(2,6-dimethylphenyl)-ethyl]-piperidine Me F ~ ~
F
~No Me 10 Prepared analogously to Example 37; melting point (hydrochloride): 183-185 C;

Example 43: 1-[2-(2-chloro-4-bromobenzyloxy)-2-(2,6-dimethylphenyl)-ethyl]-piperidine Br Me O\ CI
Me Prepared analogously to Example 37; melting point (hydrochloride): 222-224 C;

Example 44: 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-imidazole F
Me F
N
CN /--Me \::zj-Prepared analogously to Example 37 using sodium hydride as auxiliary base; melting point (hydrochloride): 184-185 C;
Example 45: N- [3- (2, 6-difluorophenyl) -propyl] - [1- (2, 6-dimethyl-phenyl)-2-piperidin-l-yl-ethyl]-N-cyclopropylmethyl-amine P F P
Me F
N

N, ) Me ~--/
150 mg (0.39 mmol) of [3- (2, 6-difluorophenyl) -propyl] -[1- (2, 6-dimethyl-phenyl)-2-piperidin-1-yl-ethyl]-amine (corresponds to Example 35) are placed in 3 ml of acetonitrile/DMF 1:1 and 107 mg of potassium carbonate and 20 mg of potassium iodide are added. Then 0.04 ml (0.39 mmol) of bromomethylcyclopropane are added and the mixture is stirred for 16 h at 75 C. It is then filtered through kieselguhr, the solution is evaporated down and the residue is purified by flash chromatography (cyclohexane/ethyl acetate 7:3).
MS: m/z 441 [ (M+H)']

Example 46: N-[3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-piperidin-l-yl-ethyl]-N-ethyl-amine F
Me Me ~ F
N

N, ) Me ~/
Prepared analogously to Example 45 starting from Example 35;
5 MS : m/z 416 [ (M+H) +] .

Example 47: N- [3- (2, 6-difluorophenyl) -propyl] -[1- (2, 6-dimethyl-phenyl)-2-piperidin-l-yl-ethyl]-N-isopentyl-amine Me Me F
Me F
N

Me No Prepared analogously to Example 45 starting from Example 35;
MS: m/z 457 [ (M+H)'] .

Example 48: N-[3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-piperidin-1-yl-ethyl]-N-isobutyl-amine Me F
Me Me F
N

, ) c Me N~.-/

Prepared analogously to Example 45 starting from Example 35;
MS: m/z 443 [ (M+H) `] .

Example 49: N- [3- (2, 6-difluorophenyl) -propyl] -[1- (2, 6-dimethYl-phenyl)-2-pyrrolidin-1-yl-ethyl]-N-isobutyl-amine Me F
Me Me F
N

Me NJ

Prepared analogously to Example 45 starting from Example 34;
MS: m/z 429 [ (M+H)'] .

Example 50: N-[3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-pyrrolidin-l-yl-ethyl]-N-isopentyl-amine Me -Me F
Me F
N

Me NJ

Prepared analogously to Example 45 starting from Example 34;
MS: m/z 443 [ (M+H)'] .

Example 51: N- [3- (2,6-difluorophenyl) -propyl] - [1- (2,6-dimethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-N-cyclopropylmethyl-amine F P
Me F
Me tNC]

Prepared analogously to Example 45 starting from Example 34;
MS: m/z 427 [ (M+H)']

Example 52: N- [3 - (2, 6-difluorophenyl) -propyl] - [1- (2, 6-dimethyl-phenyl)-2-piperidin-1-yl-ethyl]-N-acetyl-amine O F
Me Me~ F
-Me NO

150 mg (0.39 mmol) of [3- (2, 6-difluorophenyl) -propyl] -[1- (2, 6-dimethyl-phenyl)-2-piperidin-1-yl-ethyl]-amine (corresponds to Example 35) are placed in 3 ml of THF. Then 0.07 ml of DIPEA
and 0.02 ml (0.39 mmol) of acetic acid are added and finally 124.6 mg (0.39 mmol) of TBTU are added. Then the mixture is stirred for 6 h at RT, the solvent is eliminated, ethyl acetate and saturated NaHCO3 solution are added and the resulting mixture is stirred for 15 min. The phases are separated and the organic phase is washed twice more with NaHCO3 solution and twice with saturated NaCl solution. The organic phase is dried and evaporated down and the residue is purified by flash chromatography (cyclohexane/ethyl acetate 7:3).
MS: m/z 429 [ (M+H)'] .

Example 53: N-[3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-piperidin-1-yl-ethyl]-N-propionyl-amine M F ~ ~
O
Me F
N

No Me Prepared analogously to Example 52 starting from Example 35;
MS: m/z 443 [ (M+H)+] .

Example 54: N- [3- (2, 6-difluorophenyl) -propyl] -[1- (2, 6-dimethyl-phenyl)-2-piperidin-1-yl-ethyl]-N-formyl-amine F
H ~
Me~ F
Me NO

Prepared analogously to Example 52 starting from Example 35;
MS: m/z 415 [ (M+H)+] .

Example 55: N-[3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-N-formyl-amine F
H O
Me~ F
Me NJ

Prepared analogously to Example 52 starting from Example 34;
MS : m/z 401 [ (M+H)'] .

Example 56: N-[3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-N-acetyl-amine O F
Me Me~ F
Me NJ
Prepared analogously to Example 52 starting from Example 34;
MS: m/z 416 [(M+H)'].

Example 57: N- [3- (2, 6-difluorophenyl) -propyl] -[1- (2, 6-dimethyl-phenyl)-2-pyrrolidin-l-yl-ethyl]-N-propionyl-amine M F
O
Me F
N

NJ
Me Prepared analogously to Example 52 starting from Example 35;
MS: m/z 430 [ (M+H)') .

Example 58: [3-(2,6-difluorophenyl)-propyl]-[1-(2,6-dimethyl-phenyl)-2-cyclohexylamin-ethyl]-amine F ~ ~

Me H F
H
tN
Me 6 Prepared analogously to Example 34.4, but with reductive amination with cyclohexanone beforehand analogously to Example 2; MS: m/z 400 [ (M+H)'] .

Example 59: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-methyl-N-(1-cyclohexen-4-yl-methyl)-amine F P
Me F
Me N
Me ~--O

Prepared analogously to Example 5. The monomethyl compound was obtained; oil; MS: m/z 428 [(M+H)*]

Example 60 s 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2,4, 6-trimethylphenyl)-ethyl]-piperidine F P
Me F
/~
Me < Me N, ) - v Prepared analogously to Example 6; oil; MS: m/z 401 [(M+H)+].

Exaaaple 61s 1- [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,4,6-trimethylphenyl)-ethyl]-1-methyl-piperidinium iodide F ~ ~
Me F
O
Me ~ ~ +
- 'D I "
Me Me 10 Prepared analogously to Example 7; oil.

Example 62: [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2,4, 6-trimethyiphenyl)-ethyl]-dimethyl-amine F ~ ~

Me F
Me O
- NMe2 Me 15 Prepared analogously to Example 8; oil; MS: m/z 401 [(M+H)'].

= CA 02417361 2003-01-24 Example 63: [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,4,6-dimethylphenyl)-ethyl]-amine F P
Me F
Me ~
Me NH2 Prepared analogously to Example 1; oil; MS: m/z 334 [(M+H)'].
Example 64: [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,4,6-diaaethylphenyl) -ethyl] -trimethylamaaonium iodide F
Me F
Me + _ O
NMe3 I
Me Prepared analogously to Example 5; yellow crystals.
Bxample 65s N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethyiphenyl)-ethyl]-N-(3-phenylpropyl)-N,N-dimethyl-ammonium iodide F
Me F
~ O

Me Me Me -Prepared analogously to Example 5; oil; MS: m/z 466 [(M+H)'].

Example 66: N- [2- [3 - (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-methyl-N-cyclohexyl-amine F
Me F
O
Me .
- N
Me Prepared analogously to Example 4; oil; MS: m/z 416 [(M+H)'].
Example 67: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-n-propyl-amine Me F
-O F~ ~
N

Me ~--~
Me Prepared analogously to Example 3; oil; MS: m/z 362 [(M+H)'].
Example 68: N- [2- [3- (2,6-difluorophenyl) -propoxy] -2- (2,6-dimethyiphenyl)-ethyl]-N-(3-phenyl-ethyl)-amine F

Me F
~ ~ O

H - N

Me Prepared analogously to Example 3; oil; MS: m/z 424 [(M+H)'].

Example 69: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethyiphenyl)-ethyl]-N,N-bis(3-phenyl-propyl)-amine F
Me F

- N
Me Prepared analogously to Example 2; oil; MS: m/z 528 [(M+H)'].
gxample 70: N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-(2-methyl-but-l-yl)-N-ethyl-amine F

Me F
O
/-Me N Me Me Me Prepared analogously to Example 5; oil; MS: m/z 418 [(M+H)+].
Example 71: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(3,3-dimethyl-but-1-yl)-N-ethyl-amine F

Me F
O

Ce Me Me Prepared analogously to Example 5; oil; MS: m/z 432 [(M+H)`].

Example 72: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-benzyl-N-ethyl-amine F ~ ~
Me F
O
/--Me Me N Q

Prepared analogously to Example 5; oil; MS: m/z 437 [(M+H)'].
Example 73: N- (2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethyiphenyl)-ethyl]-N-isobutyl-N-ethyl-amine F ~ ~

Me F
O
r-Me - N, Me Me ~
Me Prepared analogously to Example 5; oil; MS: m/z 404 [(M+H)'].
Example 74: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2,2-dimethyl-prop-l-yl)-N-ethyl-amine F

Me F
E:LLÃMe Me Prepared analogously to Example 5; oil; MS: m/z 418 [(M+H)'].

Example 75: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2,2-dimethyl-prop-l-yl)-N,N-dimethyl-amawnium iodide F
Me F
C Me + !
- N'MeMe Me `-+ Me Me 5 Prepared analogously to Example 5; oil; MS: m/z 418 [(M+H)'].
8xaanple 76: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-cyclohexyl-N,N-dimethyl-ammaonium iodide F
Me F
0 Me N-.Me Me Prepared analogously to Example 5; oil; MS: m/z 430 [M'].
Example 77: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(2-trifluormethyl-ethyl)-N,N-dimethyl-15 ammonium iodide F

F
CR Me +N-Me Me `--`

Prepared analogously to Example 5; oil; MS: m/z 444 [(M+H)'].

= + CA 02417361 2003-01-24 Example 78: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(4-isopropenyl-cyclohexen-1-yl-methyl)-N,N-dimethyl-ammonium iodide F
Me F
~ Me N-e CH2 Me .,,.u ~
Me Prepared analogously to Example 5; oil; MS: m/z 482 [M'].
Example 79: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-ethyl-amine F
Me F

H
N
Me \--Me Prepared analogously to Example 3; oil; MS: m/z 348 [(M+H)'].
Example 80: N- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-N-(3-phenyl-propyl)-amine F
Me F

H
Me -Prepared analogously to Example 3; oil; MS: m/z 438 [(M+H)'].

Example 81: N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-(4-penten-1-yl)-amine F ~ ~
Me F
H N
Me Prepared analogously to Example 3; melting point: 116 C; MS:
m/z 338 [ (M+H)'] .

Example 82: 1- [2- [3- (2, 6-difluorophenyl) -propoxy] -2- (2, 6-dimethylphenyl)-ethyl]-1-methyl-piperidinium iodide F
Me F
o +/~
N, Me Me Prepared analogously to Example 7; melting point: 130 (decomp.); MS: m/z 402 [M+] .

The compounds according to the invention may be administered by oral, transdermal, intrathecal or parenteral route or by inhalation and occur as active ingredients in conventional preparations. The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
Suitable preparations include for example tablets, capsules, suppositories, solutions, elixirs, emulsions or dispersible powders. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

The following are examples of pharmaceutical preparations containing the active substance:

Tablets:
active substance of general formula 1 or 1-Y 20 mg magnesium stearate 1 mg lactose 190 mg Injectable solution active substance of general formula 1 or 1-Y 0.3 mg sodium chloride 0.8 g benzalkonium chloride 0.01 mg water for injections ad 100 ml A solution similar to that shown above is suitable for nasal administration in a spray, or in conjunction with a device which produces an aerosol with a particle size preferably between 2 and 6 pM, for administration via the lungs.
Solution for infusion A 5% by weight xylitol or saline solution which contains the active substance in a concentration of 2 mg/ml, for example, is adjusted to a pH of about 4 using a sodium acetate buffer.

Infusible solutions of this kind may contain an active substance according to general formula 1 in an amount, based on the total mass of the pharmaceutical preparation, in the range from 0.001 to 5 wt.%, preferably in the range from 0.001 to 3 wt.% and most preferably in the range from 0.01 to 1 wt.%.

Capsules for inhalation The active substance according to general formula I in micronised form is packed into hard gelatine capsules (particle size substantially between 2 and 6 M), optionally with the addition of micronised carrier substances, such as lactose. It can be inhaled using conventional equipment for powder inhalation. Between 0.2 and 20 mg of active substance and 0 to 40 mg of lactose, for example, are packed into each capsule.

Aerosol for Inhalation active substance of general formula 1 or 1-Y 1 part soya lecithin 0.2 parts propellant gas mixture ad 100 parts

Claims (48)

CLAIMS:

1. A compound of general formula 1, wherein:

R1 denotes hydrogen, hydroxy, CF3, NO2, CN, halogen, C1-C8-alkyl or C1-C8-alkoxy;

R2, R3 and R4 independently of one another denote hydrogen, C1-C8-alkyl, hydroxy, NO2, CN, C1-C8-alkyloxy, CF3 or halogen;

R5 and R6 independently of one another denote hydrogen or a group selected from among C1-C8-alkyl, C2-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkylene, C5-C8-cycloalkenyl, C5-C8-cycloalkenyl-C1-C6-alkylene, C6-C10-aryl and C6-C10-aryl-C1-C6-alkylene, which may optionally be substituted by a group selected from among C1-C6-alkyl, C2-C6-alkenyl, halogen, C1-C6-alkyloxy, -NH2, -NH (C1-C4-alkyl), -N(C1-C4-alkyl)2, hydroxy, =O, -COOH, -CO-OC1-C4-alkyl, -CONH2, -CONH(C1-C4-alkyl), -CON(C1-C4-alkyl)2 and CF3, or R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6-, 7- or 8-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulphur, oxygen and nitrogen and may optionally be mono-, di- or trisubstituted by a group selected from C1-C4-alkyl, hydroxy, =O, -COOH, -CO-OC1-C4-alkyl, -CONH2, -CONH(C1-C4-alkyl), -CON(C1-C4-alkyl)2, halogen and benzyl;

X denotes oxygen, -NH-, -N(CHO)-, -N(CO-C1-C6-alkyl), -N(C1-C6-alkyl) or -N(C3-C6-cycloalkyl-C1-C4-alkylene); and A denotes a group selected from C1-C6-alkylene, C2-C6-alkenylene and C3-C6-alkynylene;

or an optical isomer thereof, a mixture of individual enantiomers thereof, a racemate thereof, or an acid addition salt thereof.

2. A compound, isomer, mixture, racemate or salt according to claim 1, wherein:

R1 denotes hydrogen, halogen, C1-C6-alkyl, CF3 or methoxy;

R2, R3 and R4 independently of one another denote hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, CF3 or halogen;

R5 and R6 independently of one another denote hydrogen or a group selected from among C1-C6-alkyl, C2-C6-alkenyl, C3-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C6-alkylene, C5-C6-cycloalkenyl, C5-C6-cycloalkenyl-C1-C6-alkylene, phenyl and phenyl-C1-C6-alkylene, which may optionally be substituted by a group selected from among C1-C4-alkyl, C2-C4-alkenyl, halogen, C1-C4-alkyloxy, hydroxy, -CONH2, =O and CF3 or R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6- or 7-membered heterocyclic group which optionally contains one or two further heteroatoms selected from sulphur, oxygen and nitrogen and may optionally be mono-, di- or trisubstituted by C1-C4-alkyl, -CONH2 or hydroxy;

X denotes oxygen, -NH-, -N(CHO)-, -N(CO-C1-C5-alkyl)-, -N(C1-C5-alkyl)- or -N(C3-C6-cycloalkyl-C1-C4-alkylene); and A denotes C1-C5-alkylene, C2-C4-alkenylene or C3-C4-alkynylene.

3. A compound, isomer, mixture, racemate or salt according to claim 2, wherein A is C1-C5-alkylene.

4. A compound, isomer, mixture, racemate or salt according to claim 1, wherein:

R1 denotes hydrogen, C1-C4-alkyl or CF3;

R2, R3 and R4 independently of one another denote hydrogen, C1-C4-alkyl, CF3 or halogen;

R5 and R6 independently of one another denote hydrogen, C1-C6-alkyl, CF3-C1-C6-alkylene, C2-C6-alkenyl, C3-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C6-alkylene, cyclohexenyl, cyclohexenyl-C1-C6-alkylene, propenyl-cyclohexenylene-C1-C6-alkylene, phenyl or phenyl-C1-C6-alkylene or R5 and R6 together with the nitrogen atom denote a saturated or unsaturated 5-, 6- or 7-membered heterocyclic group, which optionally contains another nitrogen atom and may optionally be mono-, di- or trisubstituted by C1-C4-alkyl, -CONH2 or hydroxy;

X denotes oxygen, -NH-, -N(CHO)-, -N(CO-methyl)-, -N(CO-ethyl)-, -N(C1-C5-alkyl)- or -N(C3-C6-cycloalkyl-methylene)-; and A denotes -CH2-, -CH2-CH2- or -CH2-CH2-CH2-.

5. A compound, isomer, mixture, racemate or salt according to claim 4, wherein, in the definition of R5 and R6, the CF3-C1-C6-alkylene is -CH2-CF3 or -CH2-CH2-CF3.

6. A compound, isomer, mixture, racemate or salt according to claim 4 or 5, wherein, in the definition or R5 and R6, the C3-C6-cycloalkyl-C1-C6-alkylene is cyclopropylmethylene or cyclohexylmethylene.

7. A compound, isomer, mixture, racemate or salt according to claim 1, wherein:

R1 denotes hydrogen or methyl;

R2 and R3 independently of one another denote hydrogen, methyl, fluorine, chlorine or bromine;

R4 denotes hydrogen, fluorine, chlorine or bromine;
R5 and R6 independently of one another denote hydrogen, C1-C6-alkyl, CF3-C1-C6-alkylene, C2-C6-alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C6-alkylene, cyclohexenyl, cyclohexenyl-C1-C6-alkylene, or R5 and R6 together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and azepan;

X denotes oxygen, -NH-, -N(CHO)-, -N(CO-methyl)-, -N(CO-ethyl)-, -N(methyl)-, -N(ethyl)-, -N(propyl)-, -N(butyl)-, -N(pentyl)- or -N(cyclopropylmethyl)-; and A denotes-CH2-, -CH2-CH2- or -CH2-CH2-CH2-.

8. A compound, isomer, mixture, racemate or salt according to claim 7, wherein, in the definition of R5 and R6, the C3-C6-cycloalkyl-C1-C6-alkylene is cyclopropylmethylene or cyclohexylmethylene.

9. A compound, isomer, mixture, racemate or salt according to claim 7 or 8, wherein, in the definition of R5 and R6, the CF3-C1-C6-alkylene is -CH2-CH2-CF3.

10. A compound, isomer, mixture, racemate or salt according to any one of claims 7 to 9, wherein, in the definition of R5 and R6, the C2-C6-alkenyl is butenyl or pentenyl.

11. A compound, isomer, mixture, racemate or salt according to any one of claims 7 to 10, wherein, in the definition of R5 and R6, the C3-C6-cycloalkyl is cyclohexyl.

12. A compound, isomer, mixture, racemate or salt according to claim 1, wherein:

R1 denotes hydrogen or methyl;

R2 and R3 independently of one another denote hydrogen, methyl, fluorine, chlorine or bromine;

R4 denotes hydrogen, fluorine, chlorine or bromine;
R5 and R6 independently of one another denote hydrogen, methyl, propyl, butyl, hexyl, cyclopropylmethyl or cyclohexenemethyl, or R5 and R6 together with the nitrogen atom denote a heterocyclic group selected from among pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and azepan;

X denotes oxygen, -NH-, -N(CHO)-, -N(CO-methyl)-, -N(CO-ethyl)-, -N(ethyl)-, -N(propyl)-, -N(butyl)-, -N(pentyl)- or -N(cyclopropylmethyl)-; and A denotes -CH2-, -CH2-CH2- or -CH2-CH2-CH2-.

13. A compound, isomer, mixture, racemate or salt according to any one of claims 1 to 12, wherein X is oxygen or -NH-.

14. A compound, isomer, mixture, racemate or salt according to claim 1, wherein:

R1 denotes hydrogen or methyl;

R2 and R3 independently of one another denote hydrogen or fluorine;

R4 denotes hydrogen;

R5 and R6 independently of one another denote hydrogen, butyl, hexyl or cyclohexenemethyl, or R5 and R6 together with the nitrogen atom denote piperidine and 1,2,3,6-tetrahydropyridine;

X denotes oxygen or -NH-; and A denotes -CH2-CH2- or -CH2-CH2-CH2-.

15. A compound, isomer, mixture, racemate or salt according to any one of claims 1 to 14, wherein R1 denotes hydrogen and wherein R2 and R3 are in the ortho position.

16. A compound, isomer, mixture, racemate or salt according to any one of claims 1 to 14, wherein R1 denotes methyl and is in the para position and wherein R2 and R3 are in the ortho position.

17. A quaternary ammonium compound of formula 1-Y

wherein the groups A, X, R1, R2, R3 and R4 are as defined in any one of claims 1 to 14, R5 and R6 are as defined in any one of claims 1 to 14, but not hydrogen; R7 denotes C1-C4-alkyl and Y denotes a halide.

18. A compound according to claim 17, wherein R1 denotes hydrogen, and wherein R2 and R3 are in the ortho position.

19. A compound according to claim 17, wherein R1 denotes methyl and is in the para position and wherein R2 and R3 are in the ortho position.

20. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-n-butyl-amine.

21. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-(2-ethylbutyl)-N,N-dimethyl-ammonium iodide

22. 1-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-pyrrolidine.

23. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-(4-penten-1-yl)-amine.

24. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-n-propyl-amine.

25. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,4,6-trimethylphenyl)-ethyl]-N,N-dimethyl-amine.

26. 1-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-piperidine.

27. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-n-butyl-N,N-dimethyl-ammonium iodide.

28. N-[2-[3-(2,6-difluorophenyl)-propoxy]-2-(2,6-dimethylphenyl)-ethyl]-N-(1-cyclohexen-4-yl-methyl)-N,N-dimethyl-ammonium iodide.

29. A pharmaceutical composition, comprising a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28 and pharmaceutically acceptable carrier or diluent.

30. A pharmaceutical composition according to claim 29, formulated as a solution for infusion.

31. A pharmaceutical composition according to claim 30 for therapeutic treatment of a functional disorder caused by overstimulation.

32. A pharmaceutical composition according to claim 30 for therapeutic treatment of arrhythmias, spasms, cardiac ischemias, cerebral ischaemias, pain and neurodegenerative disorders of various origins.

33. A pharmaceutical composition according to claim 30 for therapeutic treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a heart rhythm disorder, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.

34. A use of a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28, in preparing a pharmaceutical composition for therapeutic treatment of a functional disorder caused by overstimulation.

35. A use of a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28, in preparing a pharmaceutical composition for therapeutic treatment of a condition selected from arrhythmias, spasms, cardiac ischemias, cerebral ischaemias, pain and neurodegenerative disorders of various origins.

36. A use of a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28 in preparing a pharmaceutical composition for therapeutic treatment of a condition selected from epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a heart rhythm disorder, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.

37. A use of a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16, or a compound according to any one of claims 17 to 28, for therapeutic treatment of a functional disorder caused by overstimulation.

38. A use of a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28, for therapeutic treatment of a condition selected from arrhythmias, spasms, cardiac ischemias, cerebral ischaemias, pain and neurodegenerative disorders of various origins.

39. A use of a compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28 for therapeutic treatment of a condition selected from epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a heart rhythm disorder, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.

40. A compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28, for therapeutic treatment of a functional disorder caused by overstimulation.

41. A compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28, for therapeutic treatment of a condition selected from arrhythmias, spasms, cardiac ischemias, cerebral ischaemias, pain and neurodegenerative disorders of various origins.

42. A compound, isomer, mixture, racemate or salt according to any one of claims 1 to 16 or a compound according to any one of claims 17 to 28 for therapeutic treatment of a condition selected from epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a heart rhythm disorder, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.

43. A process for preparing a compound of formula 1, wherein the groups A, R1, R2, R3, R4, R5 and R6 are as defined in any one of claims 1 to 14 and wherein X
denotes oxygen, wherein a compound of formula 6 wherein the groups A, R1, R2, R3 and R4 are as defined in any one of claims 1 to 14 is reacted in an organic solvent in the presence of an inorganic or organic base with a suitable alkylating agent in which the alkyl group is as defined for R5 and R6 in any one of claims 1 to 14, to obtain a compound of formula 1 or wherein an amine of formula 6 is converted into a compound of formula 1 by reductive amination with a suitable carbonyl compound in the presence of a reducing agent.

44. A process according to claim 43, wherein the compound of formula 6 wherein the groups A, R1, R2, R3 and R4 are as defined in any one of claims 1 to 14, is obtained by taking up a compound of formula 2 wherein R1 is as defined in any one of claims 1 to 14, in trimethylsilylcyanide in a first step in the presence of a Lewis acid, the resulting mixture is diluted using a suitable anhydrous organic solvent and then reduced by means of a suitable reducing agent to form a compound of formula 3 which is reacted with trifluoroacetic acid anhydride in a second step, optionally after separation of the enantiomers by taking up in a suitable organic solvent in the presence of a suitable organic or inorganic base, to form a compound of formula 4 and this is finally dissolved in a suitable organic solvent and reacted in the presence of a suitable organic base with a compound of formula 5 optionally dissolved in a suitable organic solvent wherein the groups R2, R3, R4 and A are as defined in any one of claims 1 to 14, and wherein L is a suitable leaving group, which is cleaved from the compound of formula 5 and the trifluoroacetyl group is cleaved from the compound of formula 4 to form a compound of formula 6.

45. A process according to claim 43, wherein the compound of formula 6 wherein the groups A, R1, R2, R3 and R4 are as defined in any one of claims 1 to 14, is obtained by reacting a compound of formula 2 wherein R1 is as defined in any one of claims 1 to 14, in a first step, using nitromethane in glacial acetic acid at elevated temperature, to obtain a compound of formula 7 which is reacted in a suitable organic solvent by means of an alcohol 8 wherein the groups R2, R3, R4 and A are as defined in any one of claims 1 to 14, in the presence of a suitable base, to obtain an ether of formula 9 from which the compound of formula 6 is obtained reductively.

46. A process according to claim 45 wherein the reduction by which the compound of formula 6 is obtained is a metal-catalysed reduction.

47. A process for preparing a compound of formula 1, wherein the groups A, R1, R2, R3, R4, R5 and R6 are as defined in any one of claims 1 to 14 and wherein X
denotes -NH-, wherein a compound of formula 3 wherein the group R1 is as defined in any one of claims 1 to 14 is reacted in a suitable organic solvent in the presence of a suitable inorganic or organic base using a suitable alkylating agent wherein the alkyl group is as defined for R5 and R6 in any one of claims 1 to 14, to obtain a compound of formula 16 which is reacted, if R5 or R6 denotes hydrogen, using suitable protecting groups, by means of suitable halogenating reagents, suitable sulphonic acid chlorides or suitable sulphonic acid anhydrides in the presence of suitable bases in suitable inert solvents to obtain a compound of formula 17 wherein L denotes a leaving group selected from among chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate and para-toluenesulphonate and the compound of formula 17 is reacted in a suitable organic solvent in the presence of a suitable inorganic or organic base using a compound of formula 18 wherein the groups R2, R3, R4 and A are as defined in any one of claims 1 to 14, to obtain a compound of formula 1.

48. A process for preparing a compound of formula 1, wherein the groups A, R1, R2, R3, R4, R5 and R6 are as defined in any one of claims 1 to 14 and wherein X
denotes a group selected from -N(CHO)-, -N(CO-C1-C6-alkyl)-, -N(C1-C6-alkyl)- and -N(C3-C6-cycloalkyl-C1-C4-alkylene), wherein a compound of formula 1 wherein X denotes -NH- is reacted in a suitable organic solvent in the presence of a suitable inorganic or organic base by means of a suitable alkylating, formylating or acylating agent.