WO1997040038A1

WO1997040038A1 - Piperidines and pyrrolidines

Info

Publication number: WO1997040038A1
Application number: PCT/EP1997/001853
Authority: WO
Inventors: Joachim März; Henning Böttcher; Ralf Devant; Hartmut Greiner; Gerd Bartoszyk; Jürgen Harting; Christoph Seyfried; Ronny Andersson Bengt; Lars Olov Hansson; Clas Ake Sonesson; Nils Peter STJERNLÖF
Original assignee: Merck Patent Gmbh
Priority date: 1996-04-18
Filing date: 1997-04-14
Publication date: 1997-10-30
Also published as: NO984861L; EP0898569A1; AU2696797A; HUP9901389A2; BR9708677A; AR006690A1; SK141998A3; ZA973301B; JP2000508670A; CA2252385A1; HUP9901389A3; CZ330598A3; PL329351A1; DE19615232A1; NO984861D0; KR20000005505A

Abstract

The invention relates to novel piperidine and pyrrolidine derivatives of formula (I) in which R?1, R2, R3¿, k, l, m and n have the meanings indicated in Claim 1, and their salts, novel intermediates and processes for the preparation of the compounds according to the invention. The compounds of formula (I) act as 5-HT¿1A? receptor antagonists and exhibit 5-HT reuptake-inhibiting actions and can be used for the production of medicaments.

Description

Piperidines and pyrrolidines

The invention relates to compounds of the formula I

in which

R¹ is phenyl which is unsubstituted or mono-, di- or trisubstituted by A, A-O- , OH, Hal, CN, N0₂,

NH₂, Ph, -0-S0₂A and/or -0-S0₂CF₃, 2- or 3-indolyl which is unsubstituted or mono- or disubstituted by A, A-0-, OH, Hal and/or CN,

1, 4-benzodioxan-5- or -6-yl or

1- or 2-naphthyl, R² is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-O, OH, Hal and/or CN, R³ is H, A, A-O-, Ph, NHR⁴ or NR⁵R⁶, R⁴ is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-O- , OH, Hal and/or CN or cycloalkyl having 3 to 10 C atoms, R and R⁶ together are an alkylene chain having 4 , 5 or

6 C atoms, A is straight-chain or branched alkyl having

1-10 C atoms, which can be substituted by 1 to

5 F and/or Cl atoms or is cycloalkyl having

3-10 C atoms, Hal is F, Cl, Br or I, k and 1 each independently of one another are 0 or 1, m is 0, 1 or 2 and n is 1 or 2, with the proviso that k is not equal to 1 and k=0 when m=2, and their salts. Compounds of similar structure are known from various earlier publications and patent applications. For example, WO 95/02592 describes compounds of the structure

in which R can be a mono-, bicyclic or heterocyclic radical, A can be a branched or unbranched alkylene chain and the heterocyclic ring can have a double bond. In this application, however, only compounds are disclosed in which A is an ethylene group substituted by a methyl group and R is a thiophene, 1,4-benzodioxane, 4-indolyl or methoxyphenyl ring. Corresponding compounds exhibit 5-HT_1A receptor binding.

Piperazine derivatives having 5-HT_1A-antago- nistic action are described, for example, in WO 95/33743.

The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have particularly useful pharmacological properties combined with good tolerability, as, in particular, they have actions on the central nervous system, especially 5-HT_1A- antagonistic and in particular 5-HT-reuptake-inhibiting actions.

For compounds which have both 5-HT_1A-antago- nistic and 5-HT-reuptake-inhibiting actions, a particu- larly good antidepressant, anxiolytic action, as well as a positive effect on obsessive-compulsive behaviour (OCD) , eating disorders such as bulimia, tardive dyskinesias, learning disorders, age-dependent memory disorders and psychoses is to be expected. No 5-HT-reuptake-inhibiting action is described for the compounds of WO 95/02592. The activity of the compounds according to the invention as 5-HT_1A-antagonists and their 5-HT-reuptake- inhibiting action were confirmed experimentally for some representative compounds of the formula I . The pharmacological test data are compiled in Table I.

Compounds of the formula I and their physiologi¬ cally acceptable acid addition salts have particularly useful pharmacological properties combined with good tolerability, as, in particular, they have actions on the central nervous system, especially 5-HT^- antagonistic and 5-HT-reuptake-inhibiting actions. They inhibit the binding of tritiated serotonin receptor ligands to hippocampal receptors (Cossery et al. , European J. Pharmacol. 140 (1987) , 143-155) and inhibit synaptosomal serotonin reuptake (Sherman et al. , Life

Sci. 21 (1978), 1863-1870) . Additionally, alterations in the 5-HT accumulation in various cerebral regions occur

(Seyfried et al. , European J. Pharmacol. 160 (1989) ,

31-41) . The 5-HT_1A-antagonistic action is demonstrated in vitro, for example, by inhibition of the abolition of the electrically induced contraction of the guinea-pig ileum caused by 8-OH-DPAT (Fozard and Kilbinger, Br. J. Pharmacol. 86 (1985) 601P) . Ex vivo, the inhibition of the 5-HT accumulation decreased by 8-OH-DPAT (Seyfried et al . , European J. Pharmacol. 16Q (1989), 31-41) and the antagonization of the effects induced by 8-OH-DPAT in the ultrasound vocalization test (DeVry, Psychopharmacol. 121 (1995), 1-26) are used to demon¬ strate the 5-HT_1A-antagonistic action. Synaptosomal uptake inhibition (Wong et al. , Neuropsychopharmacol .

£ (1993), 23-33) and p-chloroamphetamine antagonism

(Fuller et al . , J. Pharmacol. Exp. Ther. 212 (1980) ,

115-119) are used for the ex vivo demonstration of serotonin reuptake inhibition. The compounds of the formula I are therefore suitable both in veterinary and in human medicine for the treatment of functional dis¬ orders of the central nervous system and of inflammations. They can be used for the prophylaxis and for the control of sequelae of cerebral infarcts (apoplexia cerebri) such as stroke and cerebral ischaemias, and also for the treatment of extrapyramidal motor side effects of neuroleptics and also of Parkinson's disease. In particular, however, they are suitable as pharmaceutical active compounds for anxioly- tics, antidepressants, antipsychotics and/or for posi¬ tively influencing obsessive-compulsive behaviour, sleep disorders, tardive dyskinesias, learning disorders, age- dependent memory disorders, eating disorders such as bulimia, and/or sexual functional disorders.

The compounds of the formula I and their physio¬ logically acceptable acid addition salts can therefore be used as pharmaceutical active compounds for anxio- lytics, antidepressants, antipsychotics, neuroleptics and/or antihypertensives, and for positively affecting obsessive-compulsive behaviour, eating disorders such as bulimia, tardive dyskinesias, learning disorders and age-dependent memory disorders.

The invention thus relates to the compounds of the formula I and their physiologically acceptable acid addition salts.

The invention relates in particular to compounds of the formula I selected from the group consisting of

a) N- {2- [4- (2-methoxyphenyl)piperidin-1-yl] ethyl}- N- (2-pyridyl)cyclohexanecarboxamide;

b) N-{2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] - ethyl}-N- (2-pyridyl) cyclohexanecarboxamide;

c) N-{2- [3- (2-naphthyl)pyrrolidin-l-yl]ethyl}-N-

(2-pyridyl) cyclohexanecarboxamide;

d) N- {2- [3- (2-methoxyphenyl)pyrrolidin-1- yl]ethyl} -N- (2-pyridyl) cyclohexanecarboxamide;

e) N- (2- (3- (l,4-benzodioxan-6-yl)pyrrolidin-l-yl) - ethyl) -N- (2-pyridyl)cyclohexanecarboxamide; f) N- (2- (3- (6-fluoroindol-3-yl)pyrrolidin-l-yl) - ethyl) -N- (2-pyridyl) cyclohexanecarboxamide;

g) N- (2- (3- (7-methoxy-2-naphthyl)pyrrolidin-l-yi; ethyl) -N- (2-pyridyl) cyclohexanecarboxamide;

h) R- (+) -N-{2- [3- (2-naphthyl)pyrrolidin-l-yl] - ethyl}-N- (2-pyridyl)cyclohexanecarboxamide;

i) S- (-) -N-{2- [3- (2-naphthyl)pyrrolidin-l-yl] - ethyl}-N- (2-pyridyl)cyclohexanecarboxamide;

j) N- (2- (4- (6-fluoroindol-3-yl)piperidin-l-yl) - ethyl) -N' - (3-fluorophenyl) -N- (2-pyridyl)urea;

k) N-cyclohexyl-N' - (2- (4- (6-fluoroindol-3-yl) - piperidin-1-yl) ethyl) -N' - (2-pyridyl)urea;

1) N-cyclohexyl-N' - (2- (3- (6-fluoroindol-3-yl) - piperidin-1-yl) ethyl) -N' - (2-pyridyl)urea;

m) N- (2- (4- (6-fluoroindol-3-yl)piperidin-l-yl) - ethyl-N- (2-pyridyl) -N' - (4-trifluoromethyl- phenyl)urea;

and their salts.

The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine. They can further be employed as intermediates for the preparation of further pharmaceutical active compounds.

The invention accordingly relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to Claim 1, characterized in that

a) a compound of the formula II

in which R¹, R², m and n have the meanings given in Claim 1, is reacted with a compound of the formula III

R -CO-L (III)

in which L is Cl, Br, I or a free or reactive functionally modified OH group and

R has the meanings given in Claim 1,

or

b) a compound of the formula IV

in which R¹ and n have the meanings given in Claim 1, is reacted with a compound of the formula V

in which L is Cl, Br, I or a free or reactive functionally modified OH group and R², R³, m, k and 1 have the meanings given in Claim 1,

or

c) in a reductive amination a compound of the formula VI

in which R², R³, m, k and 1 have the meanings given in Claim 1, is reacted with a compound of the formula IV,

or

d) a compound of the formula VII

FT

/

H-N. -R^J

(VII)

in which R and R have the meanings given in Claim 1, is reacted with a compound of the formula VIII

in which L is Cl, Br, I or a free or reactive functionally modified OH group and R , m and n have the meanings given in Claim 1,

or

e) an amide of the formula VII in which R and R³ have the abovementioned meanings, is reacted with a compound of the formula IX

in which R , n and m have the meanings given in Claim 1 and Q is Cl, Br, I or a free or reactive functionally modified OH group,

or

f) a compound of the formula X

in which R¹, R³, m and n have the meanings indicated in Claim 1, is reacted with a suitable phenyl or pyridyl derivative to give a compound of the formula I, which is optionally converted into another compound of the formula I,

or

for the preparation of a compound of the formula I iinn wwhhiicchh RR³ is NHR and R⁴ has the meanings given in Claim 1,

a compound of the formula II in which R¹, R², m and n have the meanings given in Claim 1 is reacted with a compound of the formula XI

R³-N=C=0 (XI) in which R³ has the meanings given in Claim 1,

and/or in that a basic compound of the formula I is converted into one of its salts by treating with an acid.

Above and below, the radicals R¹, R², R³, L, Q, k, 1, m and n have the meanings indicated in the formulae I, II, III, IV, V, VI, VII, VIII, IX, X and XI, if not expressly stated otherwise. The invention likewise relates to medicaments of the formula I and their physiologically acceptable salts having 5-HT_1A-antagonistic and 5-HT-reuptake- inhibiting action. The invention relates to the compounds of the formula I according to Claim 1, and to their enantiomers and diastereomers and to their salts.

For all radicals which occur several times, such as, for example, A, it holds true that their meanings are independent of one another.

Alkyl has 1 to 10, preferably 1, 2, 3, 4, 5 or 6 C atoms. Alkyl is therefore in particular, for example, methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3 , 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-l- methylpropyl, l-ethyl-2-methylpropyl , 1,1,2- or 1, 2, 2-trimethylpropyl, further also fluoromethyl, difluoromethyl, trifluoromethyl, 1, 1, 1-trichloroethyl or pentafluoroethyl.

A-O- is in particular, for example, methoxy, ethoxy, propoxy or butyloxy. Cycloalkyl is in particular, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-adamantyl. Ph is phenyl .

R¹ is phenyl which is unsubstituted, mono-, di- or trisubstituted, but in particular mono- or disubstituted, by A, A-O- , OH, Hal, CN, N0₂, NH₂, Ph, - 0-S0₂A or -0-S0₂-CF₃; 1- or 2-naphthyl or 2- or 3- indolyl, which can likewise be unsubstituted, mono-, di- or trisubstituted, in particular mono- or disubstituted, by A, A-O- , OH, Hal or CN, and further is also 1,4-benzodioxan-5- or -6-yl.

R¹ is therefore preferably, for example, 1- or 2-naphthyl, 2- or 3-indolyl, 5- or 6-methylindol-2-yl, 5- or 6-methylindol-3-yl, 5- or 6-methoxyindol-2-yl, 5- or 6-methoxyindol-3-yl, 5- or 6-hydroxyindol-2-yl, 5- or 6-hydroxyindol-3-yl, 5- or 6-f luoroindol-2-yl, 5- or 6-fluoroindol-3-yl, 5- or 6-cyanoindol-2-yl , 5- or 6-cyanoindol-3-yl, phenyl, o-, m- or p-tolyl, o- , m- or p-trif luoromethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p- hydroxyphenyl, o-, m- or p-f luorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl, 2-, 3- or 4-biphenylyl, o- , m- or p-methylsulfonyl- oxyphenyl, o-, m- or p-trif luoromethylsulfonyloxyphenyl (o-, m- or p-trif latoxyphenyl) , 1, 4-benzodioxan-5- or -6-yl, 2-fluoro-3-methoxyphenyl, 2-f luoro- 4 -methoxy - phenyl, 2-f luoro-5-methoxyphenyl , 2 -bromo- 3 -methoxy - phenyl, 2-bromo-4-methoxyphenyl, 2 -bromo- 5 -methoxy - phenyl, 2,3-, 2,4-, 2,5-, 2,6- or 3 , 4-dimethoxyphenyl , 2,3-, 2,4-, 2,5-, 2,6- or 3 , 4-dif luorophenyl , 2,3-, 2,4-, 2,5-, 2,6- or 3, 4-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6- or 3, 4 -methylphenyl, further 3,4,5- trichloro- or 3 , 4 , 5-trimethoxyphenyl .

R² is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-0-, OH, Hal or CN and is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-trif luoromethylphenyl , o-, m- or p-methoxyphenyl, o-, m- or p- hydroxyphenyl , o-, m- or p- fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl, o-, m- or p-ethylphenyl, 2-, 3- or 4-pyridyl, 3-, 4-, 5- or 6-fluoropyridin-2-yl, 2- or 3-fluoropyridin-4-yl, 3-, 4-, 5- or 6-trif luoromethylpyridin-2-yl .

R³ is preferably, for example, H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert- butyl, methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, further also pentyl, hexyl, trifluoromethyl, pentaf luoroethyl , cyclopentyl, cyclo¬ hexyl, 1-adamantyl, anilino, o-, m- or p-tolylamino, o- , m- or p-trif luoromethylanilino, o- , m- or p-methoxyanilino, o-, m- or p-hydroxyanilino, o-, m- or p-fluoroanilino, o-, m- or p-chloroanilino, o-, m- or p-cyanoanilino, o-, m- or p-ethylanilino, 2-, 3- or 4-pyridylamino, 3-, 4-, 5- or 6-f luoropyridin-2- ylamino, 2- or 3-fluoropyridin-4-ylamino, cyclopentylamino, cyclohexylamino or 1-adamantylamino. R³ is furthermore preferably pyrrolidin-1-yl, 1-piperidinyl or 1-azepanyl. R⁴ is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-0-, OH, Hal or CN, and also cycloalkyl having 3-10 C atoms and is pre¬ ferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl, o-, m- or p-ethylphenyl, 2-, 3- or 4-pyridyl, 3-, 4-, 5- or 6-fluoropyridin-2-yl, 2- or 3-fluoropyridin-4-yl, cyclopentyl, cyclohexyl or 1-adamantyl. For the whole invention, it holds true that all radicals which occur several times can be identical or different, i.e. are independent of one another.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ia to lh, which correspond to the formula I and in which the radicals not described in greater detail have the meaning indicated in the formula I, but in which

in Ia k is 0, 1 is 1, m is 2 and n is 1 or 2;

in lb R³is H, k is 1, 1 is 0 and m is 1; - -

in Ic R is H, k is 0 , 1 is 0 and m is 2 ;

in Id R³ is cycloalkyl having 3-10 C atoms,

A is straight-chain or branched alkyl having 1-6 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms, k is 0,

1 is 1, m is 2 and n is 1 or 2;

in Ie R is A-0-,

A is straight-chain or branched alkyl having 1-6 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms, k is 0, 1 is 1, m is 2 and n is 1 or 2;

in If R³ is NHR⁴ or NR⁵R⁶, and

A is straight-chain or branched alkyl having 1-6 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms;

in lg R¹ is phenyl, which is mono- or disubstitued by methoxy, F, Cl, Br, OH, CN, Ph, -0-S0₂CH₃ or -0-S0₂CF₃, or 2- or 3-indolyl which is monosubstituted by F and/or CN, 1, 4-benzodioxan-5- or -6-yl or 1- or 2-naphthyl,

R² is phenyl or 2-pyridyl, which is mono- substituted by F, R³ is cycloalkyl having 5 or 6 C atoms, A-O- , NHR⁴ or NR⁵R^ε, R⁴ is phenyl or pyridyl, which is monosubstituted by A, A-0-, Hal or CN or cycloalkyl having 5 or 6 C atoms, k is 0, 1 is 1, m is 2 and n is 1 or 2;

in Ih R^xis phenyl which is mono- or disubstituted by methoxy, F, Cl, Br, OH, CN, Ph, -0-S0₂CH₃ or

-0-S0₂CF₃,

2- or 3-indolyl which is monosubstituted by F and/or CN,

1,4-benzodioxan-5- or -6-yl or 1- or 2-naphthyl,

R² is phenyl which is monosubstituted by F or A, R³ is cycloalkyl having 5 or 6 C atoms, A-O-,

NHR⁴ or NR⁵R⁶, R⁴ is phenyl or pyridyl, which is mono- substituted by A, A-0-, Hal or CN or cycloalkyl having 5 or 6 C atoms, R⁵ and R together are an alkylene chain having

4, 5 or 6 C atoms, k is 0, 1 is 1, m is 2 and n is 1 or 2.

The invention also relates in particular to compounds of the formula I according to Claim 1, in which R³=H, k=l, 1=0 and m=l . In particular, these are compounds selected from the group consisting of: 2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] -N- (2-pyridyl) - acetamide

2- [3- (6-fluoroindol-3-yl)pyrrolidin-l-yl] -N- (2-pyridyl) - acetamide

2- [3- (5-fluoroindol-3-yl)pyrrolidin-l-yl] -N- (2-pyridyl) - acetamide

2- [3- (5-cyanoindol-3-yl)pyrrolidin-l-yl] -N- (2-pyridyl) - acetamide - -

2- [3- (6-cyanoindol-3-yl)pyrrolidin-l-yl] -N- (2-pyridyl) - acetamide

2- [3- (l-naphthyl)pyrrolidin-l-yl-N- (2-pyridyl)acetamide 2- [3- (2-naphthyl)pyrrolidin-l-yl-N- (2-pyridyl)acetamide 2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] -N- (2-pyridyl) - acetamide

2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] -N- (2-pyridyl) - acetamide

2- [4- (6-cyanoindol-3-yl)piperidin-l-ylj -N- (2-pyridyl) - acetamide

2- [3- (1-naphthyl)piperidin-l-yl-N- (2-pyridyl)acetamide and 2- [3- (2-naphthyl)piperidin-l-yl-N- (2-pyridyl)acetamide.

The compounds are also suitable for use as intermediates for the preparation of the compounds of formula I according to the invention.

The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry] , Georg-Thieme-Verlag, Stuttgart) , namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail .

L in the compounds of the formula III, V and VIII or Q in the compounds of the formula IX is Cl, Br, I or a free or reactive esterified OH group.

If L or Q is a reactive esterified OH group, this is preferably trichloromethoxy, alkoxy, such as, for example, methoxy, ethoxy, propoxy or butoxy, and further phenoxy, alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl- or p-tolyl- sulfonyloxy, and further also 2-naphthalene- sulfonyloxy) .

The starting substances, if desired, can also be formed in situ such that they are not isolated from — — the reaction mixture, but immediately reacted further to give the compounds of the formula I .

On the other hand, it is possible to carry out the reaction stepwise. The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.

The starting substances of the formulae II and III are known in some cases. If they are not known, they can be prepared by methods known per se.

Examples for the N-acylation of suitable derivatives of the compounds of the formula III are acid halides, preferably chlorides, azides, anhydrides, imidazolides (which can be obtained, for example, from carbodiimidazoles) , activated esters or O-acylureas, which are obtained from suitable carboximides, such as dialkylcarbodiimides, in particular cyclohexyl- carbodiimide. It may be necessary before carrying out this reaction to exclude further amino groups contained in the compound of the formula II from the acylation reaction by introduction of suitable protective groups.

The reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, preferably of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amide component of the formula II or of the alkylating derivative of the formula III may also be favourable. The reaction time, depending on the conditions used, is between a few minutes and 14 days, and the reaction temperature is between approximately 0° and 150°, normally between 20° and 130°.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetra- chloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol) , ethylene glycol dimethyl ether (diglyme) ; ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide

(DMF) ; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO) ; carbon disulfide carboxylic acids such as formic acid or acetic acid nitro compounds such as nitromethane or nitrobenzene esters such as ethyl acetate or mixtures of the solvents mentioned.

The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at another position in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl (e.g. dinitrophenyl (DNP) , aralkoxymethyl (e.g. benzoxymethyl (BOM)) or aralkyl groups (e.g. benzyl, 4-nitrobenzyl, triphenylmethyl) . As the amino protective groups are removed after the desired reaction (or reaction sequence) , their nature and size is otherwise uncritical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" in this connection is to be interpreted in the widest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups . Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenacetyl; aroyl such as benzoyl or tolyl; aryloxyalkanoyl such as phenoxy- acetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl, iso- propoxycarbonyl, tert-butoxycarbonyl (BOC) , 2-iodo- ethoxycarbonyl; aralkyloxycarbonyl such as benzyloxy- carbonyl (CBZ) , 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC) .

Preferred amino protective groups are BOC, DNP and BOM, and further CBZ, benzyl and acetyl. A crucial factor in the choice of the protective group employed is the possibility of being able to remove this selectively again after the actual reaction.

Amines of the formula II can be prepared by methods known per se, such as described, for example, in EP 512755 A2, by reductive alkylation of compounds of the formula IV.

Compounds of the formula I can furthermore preferably be obtained by reaction of compounds of the formula IV with compounds of the formula V.

The starting substances of the formulae IV and V are known in some cases. If they are not known, they can be prepared by methods known per se. The reaction is carried out in solvents and at temperatures as described above.

Compounds of the formula I can furthermore preferably be obtained by reductive amination of compounds of the formula IV with compounds of the formula VI .

The starting substances of the formula IV and VI are known in some cases. If they are not known, they can be prepared by methods known per se.

The reducing amination can be carried out in the presence of reducing agents such as, for example, NaBH₃CN and NaBH(0Ac)₃. In the case where 1 = 0 and R is H, it is recommended before the reductive amination to replace R³ by an amino protective group, preferably by a tert-butoxycarbonyl group, so that the amino group is protected from attack by a reducing agent. The protective group can be removed again in a simple manner known to the person skilled in the art after reductive amination has taken place. If, for example, this protective group is a tert-butoxycarbonyl group, it can be removed by treatment with tri¬ fluoroacetic acid or in dilute hydrochloric acid. Compounds of the formula I can futhermore preferably be obtained by reaction of compounds of the formula VII with compounds of the formula VIII.

The starting substances of the formulae VII and

VIII are known in some cases. If they are not known, they can be prepared by methods known per se. The reaction is carried out in solvents and at temperatures as described above.

In a further process for the preparation of the compounds according to the invention, amides of the

2 3 formula VII in which R and R have the meanings given above are reacted with an alkylating agent of the formula IX in which R , n and m have the meanings mentioned and the leaving group Q is preferably a halogen, such as, for example, bromine, or an ester, such as, for example, a tosylate or a trifluoro- methylsulfonate.

The starting substances of the formulae VII and IX are known in some cases. If they are not known, they can be prepared by methods known per se . The reaction is carried out in solvents and at temperatures as described above.

A further method of preparing the compounds according to the invention consists in reacting a compound of the formula X in which R¹, R³, m and n have the given meanings, with a suitable phenyl or pyridyl derivative. Those suitable are, for example, appro¬ priate fluoro-substituted compounds which can be employed for the reaction in the presence of a strong, non-nucleophilic base, such as, for example, Li diiso- propylamide. For the preparation of a compound of the formula I in which R² is 2-pyridyl, a compound of the formula X is preferably reacted with 2-fluoropyridine N-oxide and then reduced to the desired 2-pyridyl com¬ pound of the formula I in the presence of a suitable reducing agent, such as, for example, phosphorus trichloride.

A further method of preparing compounds of the formula I in which R³ is NHR⁴ consists in the reaction of compounds of the formula II with compounds of the formula XI. The starting substances of the formula XI are known in some cases. If they are not known, they can be prepared by methods known per se.

It is further possible to convert a radical R¹, R² and/or R⁴ in a compound of the formula I into another radical R , R and/or R , e.g. by reducing nitro groups (for example by hydrogenation on Raney Nickel or Pd/carbon in an inert solvent such as methanol or ethanol) to amino groups, hydrolysing cyano groups to COOH groups or cleaving an ether by, for example, converting an aromatic methoxy group into the corresponding hydroxyl derivative.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, possible acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, further organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane- sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane- sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I . On the other hand, compounds of the formula I can be converted using bases (e.g. sodium or potassium hydroxide or carbonate) into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts. Compounds of the formula I according to the invention can be chiral on account of their molecular structure and can accordingly occur in two enantiomeric or two or more diastereomeric forms. On account of one or more chiral centres, they can therefore be present in racemic or in optically active form.

As the pharmaceutical activity of the racemates or of the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the diastereomers or enantiomers. In these cases, the final product or else even the intermediates can be resolved into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed in the synthesis as such.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Suitable resolving agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl- tartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonyl- proline) or the various optically active camphor- sulfonic acids. Also advantageous is a chromatograpic resolution of enantiomers with the aid of an optically active resolving agent (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers attached to silica gel) . Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such as, for example, hexane/isopropanol/acetonitrile, e.g. in the ratio 82:15:3.

In the case of racemic acids, optically active bases, such as, for example, the R and S form of

1-phenylethylamine, 1-naphthylethylamine, dihydro- abietylamine, cinchonine or cinchonidine can analogously be used.

Under particular conditions, however, it is also even possible during the synthesis to employ appropriate enantiomerically pure intermediates which have been prepared by one of the abovementioned processes. In this case, the chirality is maintained in the course of further synthesis. As in the case of racemic esters (e.g. 4- (2-naphthyl) -2-oxopyrrolidine-3- carboxylic acid esters) , these intermediates can also be advantageously cleaved into the enantiomers in aqueous solution by the enantioselective enzymatic hydrolysis. The enantiomeric esters can be hydrolysed to give the enantiomeric acids. The enantiomeric or diastereomeric acids can be decarboxylated to give the corresponding enantiomeric intermediates (e.g. the corresponding pyrrolidones) . Suitable enzymes for the ester cleavage are lipases (such as, for example, lipase of Pseudomonas cepacia) and esterases. A particularly favourable case is if the chiral centre is in the α-position to the escer group. In this case, the undesired enantiomer can be racemized via enolization and thus subjected to a fresh racemate resolution. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.

The test results of the 5-HT_1A receptor binding and the 5-HT reuptake-inhibiting actions of some representative compounds of the formula I are compiled in Table I which follows. The inhibition constants IC₅₀ are indicated (concentrations in nmol/litre) for the inhibition of the binding of tritiated ligands to hippocampal serotonin-IA receptors (method analogous to Cossery et al. ) , and for the inhibition of synaptosomal serotonin reuptake (method analogous to Sherman et al.) .

Table I

IC_S0 values (concentrations in nmol/litre) of representative compounds of the formula I, which were obtained analogously to the methods of Cosssery et al . or Sherman et al. , and the measured melting points (m.p. ) .

(1) = 2-naphthyl (2) = 6-fluoroindol-3-yl

(3) = 5-fluoroindol-3-yl (4) = 7-methoxynaphth-2-yl

(A) = 2-pyridyl (B) = 4-fluorophenyl

(C) = 2,4-difluorophenyl

(a) = cyclohexyl (b) = NH-cyclohexyl (c) = 1-adamantyl ¹¹ 3-R^x-pyrrolidin-l-yl compound ²¹4-R¹-piperidin-l-yl compound ³⁾ (S) -(-) -enantiomer ⁴⁾3-R¹-piperidin-l-yl compound ⁵¹ (R) -(+) -enantiomer ^6>R_f 0.39 (CH₂C1₂/methanol 9:1) The pharmacological data confirm the 5-HT_1A receptor binding and the inhibiting action of the compounds of the formula I according to the invention on serotonin reuptake.

The invention further relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical way. In this context, they can be brought into a suitable dose form together with at least one solid, liquid and/or semiliquid excipient or auxiliary and if appropriate in combination with one or more of the further active compounds.

The invention further relates to pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.

These preparations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petro¬ leum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used in particular for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parentaral admini¬ stration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.

The compounds of formula I according to the invention are generally administered in analogy to other known commercially available preparations for the indications claimed (e.g. imipramine, fluoxetin, clomi- pramine) , preferably in doses of between 0.1 mg and 500 mg, in particular between 5 and 300 mg per dose unit. The daily dose is preferably between approxi- mately 0.01 and 250 mg/kg, in particular between 0.02 and 100 mg/kg of body weight.

In this case, the substances according to the invention are generally preferably administered in doses of between approximately 1 and 500 mg, in par- ticular between 5 and 100 mg per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient, however, depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceu¬ tical combination and severity of the particular dis¬ order to which the therapy relates. Oral administration is preferred.

Above and below, all temperatures are indicated in °C. In the examples which follow, "customary working up" means: if necessary, water is added, the mixture is adjusted if necessary, depending on the constitution of the final product, to pH values of between 2 and 10, and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel, it also being possible for a separation of the isomers described below to be carried out, and/or by crystallization. R_f values on silica gel; eluent: ethyl acetate/methanol 9:1. Mass spectrometry: El (electron impact ionization) : M⁺

FAB (fast atom bombardment) : (M+H) ⁺ The given specific rotations of the optically active compounds were in each case measured on solutions of the free bases.

Example...1

a)

20.4 g (0.12 mol) of 4- (6-fluoroindol-3- yl)piperidine, 26.16 g (0.12 mol) of N-2- (1- chloroacetamido)pyridine [obtainable by reaction of 2-aminopyridine with chloroacetyl chloride] and 8.3 g of potassium carbonate are stirred at 100°C for 2 hours in 250 ml of DMF, then the DMF is distilled off and the mixture is worked up in the customary manner.

Yield: 20.4 g of 2- [4- (6-fluoroindol-3-yl]piperidin-1- yl] -N- (2-pyridyl) acetamide (48% of theory) .

The following are obtained analogously: 2- [3-6-fluoroindol-3-yl)pyrrolidin-l-yl] - N- (2-pyridyl)acetamide;

2- [3- (5-fluoroindol-3-yl)pyrrolidin-l-yl] - N- (2-pyridyl) acetamide;

2- [3- (5-cyanoindol-3-yl)pyrrolidin-l-yl] - N- (2-pyridyl) acetamide;

2- [3- (6-cyanoindol-3-yl)pyrrolidin-1-yl] - N- (2-pyridyl)acetamide; 2- [3- (1-naphthyl)pyrrolidin-1-yl] -N- (2-pyridyl) - acetamide;

2- [3- (2-naphthyl)pyrrolidin-1-yl] -N- (2-pyridyl) - acetamide; - -

2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] - N- (2-pyridyl)acetamide;

2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] - N- (2-pyridyl) acetamide; 2- [4- (6-cyanoindol-3-yl)piperidin-l-yl] -

N- (2-pyridyl)acetamide;

2- [4- (1-naphthyl)piperidin-l-yl] - N- (2-pyridyl) acetamide.

2- [4- (2-naphthyl)piperidin-l-yl] - N- (2-pyridyl) acetamide;

(R) - (+)-2- [3- (2-methoxyphenyl)pyrrolidin-l-yl] -N- (2-pyridyl)acetamide, α_D ²⁰ (+) 12.6° (c l.O, methanol);

(S) - (-) -2-[3- (2-methoxyphenyl)pyrrolidin-l-yl] -N- (2-pyridyl) acetamide, α_D ²⁰ (-) 12.2° (c 1.0, methanol) ; 2- [3- (4-methoxyphenyl)pyrrolidin-1-yl] -N- (2- pyridyl) acetamide, R_f 0.67 (CH₂Cl₂/methanol 19:1) .

The following are obtained analogously by reaction of 2-chloro-N- (4-fluorophenyl) acetamide with 4- (6-fluoroindol-3-yl)piperidine 2- [4- (6-fluordindol-3-yl)piperidin-l-yl] -N-

(4-fluorophenyl) acetamide; with 3- (6-fluoroindol-3-yl)pyrrolidine

2- [3- (6-fluoroindol-3-yl)pyrrolidin-l-yl] -N- (4-fluorophenyl) acetamide; with 3- (5-fluoroindol-3-yl)pyrrolidine

2- [3- (5-fluoroindol-3-yl)pyrrolidin-l-yl] -N- (4-fluorophenyl) acetamide; with 3- (5-cyanoindol-3-yl)pyrrolidine

2- [3- (5-cyanoindol-3-yl)pyrrolidin-l-yl] -N- (4-fluorophenyl)acetamide; with 3- (6-cyanoindol-3-yl)pyrrolidine

2- [3- (6-cyanoindol-3-yl)pyrrolidin-l-yl] -N- (4-fluorophenyl) acetamide; with 3- (1-naphthyl)pyrrolidine 2- [3- (l-naphthyl)pyrrolidin-l-yl] -N- (4-fluoro- phenyl)acetamide; with 3- (2-naphthyl)pyrrolidine

2- [3- (2-naphthyl)pyrrolidin-1-yl] -N- (4-fluoro- phenyl)acetamide, R_f 0.21 (n-hexane/ethyl acetate 2:1); with 4- (5-fluoroindol-3-yl)piperidine

2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] -N- (4-fluorophenyl)acetamide; with 4- (5-cyanoindol-3-yl)piperidine 2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] -N-

4-fluorophenyl)acetamide; with 4- (6-cyanoindol-3-yl)piperidine

2- [4- (6-cyanoindol-3-yl)piperidin-l-yl] -N- (4-fluorophenyl)acetamide; with 4- (l-naphthyl)piperidine

2- [4- (l-naphthyl)piperidin-l-yl] -N- (4-fluorophenyl)acetamide, F.112-116° ; with 4- (2-naphthyl)piperidine

2- [4- (2-naphthyl)piperidin-l-yl] -N- (4-fluorophenyl) acetamide.

b)

20 g of 2- [4- (6-fluoroindol-3-yl)piperidin-l- yl] -N- (2-pyridyl)acetamide are dissolved in 400 ml of absolute tetrahydrofuran. 20 ml of sodium bis (methoxyethoxy) aluminium hydride (Vitride (ft) are then added dropwise at room temperature. After stirring for two hours, 10 ml of Vitride are added dropwise again. The mixture is additionally stirred for a further two hours. Water is added, a precipitate being formed which is filtered off with suction. The mother liquor is concentrated. The residue is dissolved in HCl and the mixture is worked up in the customary manner.

Yield: 17 g of 2-{2- [4- (6-fluoroindol-3-yl)piperidin- l-yl] ethylamino}pyridine

The following are obtained analogously from (R) - (+) -2- [3- (2-methoxyphenyl)pyrrolidin-l-yl] - N- (2-pyridyl) acetamide

(R) - (+) -2-{2- [3- (2-methoxyphenyl)pyrrolidin- l-yl]ethylamino}pyridine, otj,²⁰ (+)11.8° (c 1.0, methanol) ; from (S) - (-) -2- [3- (2-methoxyphenyl)pyrrolidin-l-yl] - N- (2-pyridyl) acetamide

(S) - (-) -2-{2- [3- (2-methoxyphenyl)pyrrolidin- 1-yl] ethylamino}pyridine, c^²⁰ (+)13.0° (c 1.0, methanol) ; from 2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] -N- (4-fluorophenyl) acetamide

2- {2- [4- (6-fluoroindol-3-yl)piperidin- 1-yl] ethylamino}-4-fluorobenzene; from 2- [3- (6-fluoroindol-3-yl)pyrrolidin-1-yl] -N- (4-fluorophenyl) acetamide

2- {2- [3- (6-fluoroindol-3-yl)pyrrolidin- 1-yl] ethylamino} -4-fluorobenzene; from 2- [3- (5-fluoroindol-3-yl)pyrrolidin-1-yl] -N- (4-fluorophenyl) acetamide

2- {2- [3- (5-fluoroindol-3-yl)pyrrolidin- 1-yl] ethylamino}-4-fluorobenzene; from 2- [3- (5-cyanoindol-3-yl)pyrrolidin-l-yl] -N- (4-fluorophenyl) acetamide 2- {2- [3- (5-cyanoindol-3-yl)pyrrolidin- 1-yl] ethylamino}-4-fluorobenzene; from 2- [3- (6-cyanoindol-3-yl)pyrrolidn-l-yl] -N- (4-fluorophenyl) acetamide

2- {2- [3- (6-cyanoindol-3-yl)pyrrolidin- 1-yl] ethylamino} -4-fluorobenzene; from 2- [3- (l-naphthyl)pyrrolidin-1-yl] -N- (4-fluorophenyl) acetamide

2-{2- [3- (l-naphthyl)pyrrolidin-1-yl]ethylamino} - 4-fluorobenzene; from 2- [3- (2-naphthyl)pyrrolidin-l-yl] -N-

(4-fluorophenyl)acetamide, R_f 0.21 (n-hexane/ethyl acetate 2:1)

2- {2- [3- (2-naphthyl)pyrrolidin-1-yl] ethylamino} - 4-fluorobenzene R_f 0.39 (CH₂Cl₂/methanol 45:1) ; from 2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] -N- (4-fluorophenyl) acetamide

2- {2- [4- (5-fluoroindol-3-yl)piperidin- l-yl] ethylamino} -4-fluorobenzene; from 2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] -N- (4-fluorophenyl) acetamide

2-{2- [4- (5-cyanoindol-3-yl)piperidin- l-yl] ethylamino} -4-fluorobenzene; from 2- [4- (6-cyanoindol-3-yl)piperidin-l-yl] -N- (4-fluorophenyl) acetamide

2- {2- [4- (6-cyanoindol-3-yl)piperidin- l-yl] ethylamino} -4-fluorobenzene; from 2- [4- (l-naphthyl)piperidin-l-yl] -N- (4-fluorophenyl) acetamide

2-{2- [4- (l-naphthyl)piperidin-l-yl] ethylamino}- 4-fluorobenzene, R_f 0.44 (CH₂Cl₂/methanol 30:1) ; from 2- [4- (2-naphthyl)piperidin-l-yl] -N- (4-fluoro- phenyl) acetamide 2- {2- [4- (2-naphthyl)piperidin-l-yl] ethylamino} - 4-fluorobenzene.

The following is obtained analogously

from 2- [3- (3-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-1-yl] -N- (2-pyridyl) acetamide

2-{2- [3- (3-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-1-yl] ethylamino}pyridine, R_f 0.51 (CH₂Cl₂/methanol 9:1) .

c)

1.02 g (0.003 mol) of 2-(2- [4- (6-fluoroindol- 3-yl)piperidin-l-yl] ethylamino}pyridine and 0.3 g (0.003 mol of triethylamine are initially introduced into 20 ml of dichloromethane. 0.44 g (0.003 mol) of cyclohexanecarbonyl chloride ("A"), dissolved in 5 ml of dichloromethane, is added dropwise with stirring. The reaction mixture is stirred at room temperature for two hours and worked up in the customary manner.

Yield: 0.5 g of N-{2- [4- ⁽6-fluoroindol-3-yl)piperidin- 1-yl] ethyl}-N- (2-pyridyl)cyclohexanecarboxamide, hydro¬ chloride, m.p. 201°. The following is obtained analogously: N-{2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl} -N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 182-185° . The following are obtained analogously by reac¬ tion of "A" with 2- {2- [4- (5-fluoroindol-3-yl)piperidin- 1-yl] ethylamino}pyridine

N- {2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] ethyl} - N- (2-pyridyl)cyclohexanecarboxamide; with 2-{2- [3- (6-fluoroindol-3-yl)piperidin- l-yl] ethylamino}pyridine

N- {2- [3- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl}- N- (2-pyridyl) cyclohexanecarboxamide; with 2-{2- [3- (indol-2-yl)piperidin-l-yl] - ethylamino}pyridine

N- {2- [3- (indol-2-yl)piperidin-l-yl] ethyl}-N- (2-pyridyl) cyclohexanecarboxamide; m.p. 192-195°; with 2- {2- [3- (2-methoxyphenyl)piperidin-l-yl] - ethylamino}pyridine

N- {2- [3- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 153-157°; with 2-{2- [3- (6-fluoroindol-3-yl)pyrrolidin-l- yl] ethylamino}pyridine

N- {2- [3- (6-fluoroindol-3-yl)pyrrolidin-l-yl] - ethyl} -N- (2-pyridyl) cyclohexanecarboxamide; with 2- {2- [3- (5-fluoroindol-3-yl)pyrrolidin-l-yl] - ethylamino}pyridine N- (2- [3- (5-fluoroindol-3-yl)pyrrolidin-

1-yl] ethyl} -N- (2-pyridyl) cyclohexanecarboxamide; with 2- {2- [3- (6-cyanoindol-3-yl)pyrrolidin- 1-yl] ethylamino}pyridine

N-{2- [3- (6-cyanoindol-3-yl)pyrrolidin-l-yl] ethyl}- N- (2-pyridyl) cyclohexanecarboxamide; with 2-{2- [3- (5-cyanoindol-3-yl)pyrrolidin- 1-yl] ethylamino}pyridine

N- {2- [3- (5-cyanoindol-3-yl)pyrrolidin-l-yl] ethyl}- N- (2-pyridyl) cyclohexanecarboxamide; with 2-{2- [4- (5-cyanoindol-3-yl) -1-piperi¬ dinyl] ethylamino}pyridine

N- {2- [4- (5-cyanoindol-3-yl) -1-piperidinyl] ethyl}- N- (2-pyridyl)cyclohexanecarboxamide, fumarate, m.p. 198-200°; with 2- {2- [4- (2-methoxyphenyl)piperidin- l-yl]ethylamino}pyridine

N-{2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl-N- (2-pyridyl)cyclohexanecarboxamide, oxalate, m.p. 203-205°; with 2-{2- [3- (2-naphthyl)piperidin-l-yl] - ethylamino}pyridine

N-{2- [3- (2-naphthyl)piperidin-l-yl]ethyl}-N- (2-pyridyl) cyclohexanecarboxamide, m.p. 150-155°; with 2- {2- [3- (2-methoxyphenyl)pyrrolidin- 1-yl] ethylamino}pyridine

N-{2- [3- (2-methoxyphenyl)pyrrolidin-l-yl] ethyl}-N- (2-pyridyl)cyclohexanecarboxamide, oxalate, m.p. 158-162°; with 2- {2- [3- (l-naphthyl)pyrrolidin- 1-yl] ethylamino}pyridine

N-{2- [3- (l-naphthyl)pyrrolidin-1-yl] ethyl}-N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 160-164°; with 2- {2- [3- (2-naphthyl)pyrrolidin- l-yl] ethylamino}pyridine

N- {2- [3- (2-naphthyl)pyrrolidin-1-yl] ethyl}-N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 183-185°; with 2-{2- [3- (1-methoxy-2-naphthyl)pyrrolidin- 1-yl] ethylamino}pyridine

N-{2- [3- (1-methoxy-2-naphthyl)pyrrolidin- 1-yl] ethyl} -N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p.183-186° ; with 2-{2- [3- (l^-benzodioxan-δ-yDpyrrolidin- l-yl] ethylamino}pyridine

N- {2- [3- (l,4-benzodioxan-6-yl)pyrrolidin-l-yl ethyl}-N- (2-pyridyl)cyclohexanecarboxamide, oxalate, m.p. 156-160°; with 2- {2- [3- (7-methoxy-2-naphthyl)pyrrolidin- 1-yl] ethylamino}pyridine

N-{2- [3- (7-methoxy-2-naphthyl)pyrrolidin- 1-yl] ethyl} -N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 122-125°; with R- (+) -2-{2- [3- (2-naphthyl)pyrrolidin- 1-yl]ethylamino}pyridine

R- (+) -N-{2- [3- (2-naphthyl)pyrrolidin-l-yl] ethyl} - N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p.174-176°, α_D ²⁰ (+) 19° (c 0.99, CHCl₃) ; with S- (-) -2-{2- [3- (2-naphthyl)pyrrolidin- 1-yl] ethylamino}pyridine

S- (-) -N-{2- [3- (2-naphthyl)pyrrolidin-1-yl] ethyl}- N- (2-pyridyl)cyclohexanecarboxamide, m.p.173-176°, α_D ²° (-) 19.7° (c 1.05, CHC1₃) ; with 2- {2- [4- (4-methoxyphenyl)piperidin- l-yl] ethylamino}pyridine

N- {2- [4- (4-methoxyphenyl)piperidin-l-yl] ethyl} -N- (2-pyridyl) cyclohexanecarboxamide; with 2- {2- [3- (4-methoxyphenyl)pyrrolidin- l-yl]ethylamino}pyridine, R_f 0.13 (CH₂Cl₂/MeOH = 19:1)

N- {2- [3- (4-methoxyphenyl)pyrrolidin-1-yl] ethyl} -N- (2-pyridyl) cyclohexanecarboxamide, m.p. 151-154°; by ether cleavage is obtained from this N- {2- [3- (4-hydroxyphenyl)pyrrolidin-1-yl] -ethyl} - N- (2-pyridyl) cyclohexanecarboxamide, m.p.186-188° ; with 2- {2- [3- (3-methoxyphenyl)pyrrolidin- l-yl]ethylamino}pyridine, R_f 0.28 (CH₂Cl₂/methanol 19:1) N- {2- [3- (3-methoxyphenyl)pyrrolidin-1-yl] etheyl} - N- (2-pyridyl)cyclohexanecarboxamide, m.p.159-161° ; with 2-{2- [4- (4-methoxy-3-bromophenyl)piperidin- l-yl]ethylamino}pyridine

N-{2- [4- (4-methoxy-3-bromophenyl)piperidin- l-yl] ethyl}-N- (2-pyridyl)cyclohexanecarboxamide; with 2-{2- [3- (4-methoxy-3-bromophenyl)pyrrolidin- l-yl]ethylamino}pyridine, R_f 0.32 (CH₂Cl₂/MeOH = 19:1) N- {2- [3- (4-methoxy-3-bromophenyl)pyrrolidin- 1-yl]ethyl}-N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 95-102°; with (R) - (₊) -2(2- [3- (2-methoxyphenyl)pyrrolidin- 1-yl] ethylamino}pyridine

(R) - (+) -N-(2- [3- (2-methoxyphenyl)pyrrolidin-l- yl]ethyl} -N- (2-pyridyl) cyclohexanecarboxamide, m.p. 158-161°, α_D ²⁰ (+) 6.3° (c 1.0, methanol) ; with (S) - (-) -2-{2- [3- (2-methoxyphenyl)pyrrolidin- 1-yl] ethylamino}pyridine

(S) - (-) -N-{2- [3- (2-methoxyphenyl)pyrrolidin- 1-yl] ethyl}-N- (2-pyridyl)cyclohexanecarboxamide, oxalate, m.p. 157-160°, a^²⁰ (-) 5.8° (c 1.0, methanol) ; with 2- {2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl¬ amino}-4-fluorobenzene

N- {2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl}- N- (4-fluorophenyl)cyclohexanecarboxamide; with 2-{2- [3- (6-fluoroindol-3-yl)pyrrolidin-1-yl]ethyl¬ amino}-4-fluorobenzene

N-{2- [3- (6-fluoroindol-3-yl)pyrrolidin- 1-yl] ethyl} -N- (4-fluorophenyl) cyclohexane- carboxamide; with 2- {2- [3- (5-fluoroindol-3-yl)pyrrolidin- 1-yl] ethylamino}-4-fluorobenzene

N- {2- [3- (5-fluoroindol-3-yl)pyrrolidin- 1-yl] ethyl} -N- (4-fluorophenyl) cyclohexane- carboxamide; with 2- {2- [3- (5-cyanoindol-3-yl)pyrrolidin- 1-yl] ethylamino} -4-fluorobenzene

N- {2- [3- (5-cyanoindol-3-yl)pyrrolidin-1-yl]ethyl} - N- (4-fluorophenyl) cyclohexanecarboxamide; with 2-{2- [3- (6-cyanoindol-3-yl)pyrrolidin- 1-yl] ethylamino} -4-fluorobenzene

N- {2- [3- (6-cyanoindol-3-yl)pyrrolidin-l-yl] ethyl} - N- (4-fluorophenyl) cyclohexanecarboxamide; with 2- {2- [3- (l-naphthyl)pyrrolidin-l-yl] ethylamino}-4- fluorobenzene

N- (2- {3- (l-naphthyl)pyrrolidin-1-yl] ethyl}-N- (4-fluorophenyl) cyclohexanecarboxamide; with 2-{2- [3- (2-naphthyl)pyrrolidin-l-yl]ethylamino}- 4-fluorobenzene R_f 0.39 (CH₂Cl₂/methanol 45:1) - -

N- {2- [3- (2-naphthyl)pyrrolidin-1-yl] ethyl}-N- (4-fluorophenyl) cyclohexanecarboxamide, 192-194° ; with 2- {2- [4- (5-fluoroindol-3-yl)piperidin- 1-yl] ethylamino}-4-fluorobenzene N-{2- [4- (5-fluoroindol-3-yl)piperidin-l-yl]ethyl}- N- (4-fluorophenyl) cyclohexanecarboxamide; with 2-{2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] - ethylamino}-4-fluorobenzene

N- (2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] ethyl}- N- (4-fluorophenyl) cyclohexanecarboxamide, fumarate, m.p. 214-216°; with 2- {2- [4- (6-cyanoindol-3-yl)piperidin- l-yl] ethylamino}-4-fluorobenzene

N- (2- [4- (6-cyanoindol-3-yl)piperidin-l-yl]ethyl}- N- (4-fluorophenyl) cyclohexanecarboxamide; with 2- {2- [4- (l-naphthyl)piperidin-l-yl]ethylamino}- 4-fluorobenzene, R_f 0.44 (CH₂Cl₂/methanol 30:1)

N- {2- [4- (l-naphthyl)piperidin-1-yl] ethyl}-N- (4-fluorophenyl) cyclohexanecarboxamide, oxalate, m.p. 223-225°; with 2- (2- [4- (2-naphthyl)piperidin-l-yl] ethylamino} - 4-fluorobenzene

N-{2- [4- (2-naphthyl)piperidin-l-yl] ethyl}-N- (4-fluorophenyl) cyclohexanecarboxamide; with 2- {2- [4- (2-methoxyphenyl)piperidin- l-yl] ethylamino}-4-fluorobenzene

N- {2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N- (4-fluorophenyl) cyclohexanecarboxamide, fumarate, m.p. 172-176°; with 2- {2- [4 ,4-diphenylpiperidin-l-yl] ethylamino}- 4-fluorobenzene

N- [ 2 - [4,4-diphenylpiperidin-l-yl] ethyl} -N- (4-fluorophenylcyclohexanecarboxamide, R_f 0.55 (methanol) ; with 2- {2- [3- (3-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-1-yl] ethylamino}pyridine

N-{2- [3- (3-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-1-yl] ethyl}-N- (2-pyridyl) cyclohexane¬ carboxamide, oxalate, m.p. 134-136°; with 2-{2- [3- (4-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-1-y1] ethylamino}pyridine

N-{2- [3- (4-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-1-yl] ethyl}-N- (2-pyridyl) cyclohexane- carboxamide, oxalate, m.p. 180-184°; with 2- (2- [3- (biphenyl-3-yl)pyrrolidin-l-yl]ethyl¬ amino}pyridine

N- {2- [3- (biphenyl-3-yl)pyrrolidin-1-yl]ethyl} -N- (2-pyridyl) cyclohexanecarboxamide, oxalate, m.p. 103-106°.

The following are obtained analogously by reaction of adamantylcarbonyl chloride with 2- {2- [3- (2-naphthyl)pyrrolidin-l-yl] ethylamino} - 4-flurobenzene N- {2- [3- (2-naphthyl)pyrrolidin-1-yl] ethyl} -N-

(4-fluorophenyl) adamantylcarboxamide, oxalate, m.p. 107-110°; with 2- {2- [4- (l-naphthyl)piperidin-l-yl]ethylamino}- 4-fluorobenzene N-{2- [4- (l-naphthyl)piperidin-l-yl] ethyl}-N-

(4-fluorophenyl) adamantylcarboxamide, oxalate, m.p. 123-126°; with 2- {2- [3- (2-methoxyphenyl)piperidin-l-yl] ethyl¬ amino}pyridine N-{2- [3- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N- (2-pyridyl) adamantylcarboxamide, oxalate, m.p. 175-177° .

The following is obtained analogously by reaction of benzoyl chloride with 2-{2- [3- (2-naphthyl)pipridin-1-yl]ethylamino} - pyridine

N-{2- [3- (2-naphthyl)piperidin-l-yl] ethyl}-N- (2-pyridyl)phenylcarboxamide, m.p. 174-176°.

The following is obtained analogously by reaction of 3-cyclopentylpropionyl chloride with 2- {2- [3- (4-methoxyphenyl)pyrrolidin-1-yl] ethyl¬ amino}pyridine, - -

N- {2- [3- (4-methoxyphenyl)pyrrolidin-l-yl] ethyl}-N- (2-pyridyl) -3-cyclopentylpropionamide, oxalate, m.p. 123-126°.

The following is obtained analogously by reaction of 3- [1- (2-phenylaminoethyl)piperidin- 4-yl] indole-5-carbonitrile [obtainable by reaction of 2-chloro-N-phenylacetamide with 4- (5-cyanoindol- 3-yl)piperidine to give 2- [4- (5-cyanoindol- 3-yl)piperidin-l-yl] -N-phenylacetamide and subsequent reduction] with "A"

N- {2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] ethyl} - N-phenylcyclohexanecarboxamide, fumarate, m.p. 198-200° .

The following are obtained analogously by reaction of "A" with N- [2- (4- (5-fluoroindol-3-yl)piperidin-l-yl) ethyl] - aniline

N- {2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] ethyl} - N-phenylcyclohexanecarboxamide; with N- [2- (4- (6-fluoroindol-3-yl)piperidin-l-yl) - ethyl] aniline

N- (2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl}- N-phenylcyclohexanecarboxamide; with N- [2- (4-benzo [1,3] dioxol-5-ylpiperidin-l-yl) - ethyl] aniline

N- {2- [4-benzo [1, 3] dioxol-5-yl)piperidin-l-yl] - ethyl} -N-phenylcyclohexanecarboxamide, R_f 0.75 (methanol) ; with N- [2- (4- (3-bromo-6-methoxyphenyl)piperidin- 1-yl) ethyl] aniline

N-{2- [4- (3-bromo-6-methoxyphenyl)piperidin- l-yl]ethyl}-N-phenylcyclohexanecarboxamide, fumarate, m.p. 177-179°; with N- [2- (4- (3-fluoro-6-methoxyphenyl)piperidin- 1-yl) ethyl] aniline

N-{2- [4- (3-fluoro-6-methoxyphenyl)piperidin- l-yl] ethyl}-N-phenylcyclohexanecarboxamide, R_f 0.76 (methanol) , R_£ 0.61 (ethyl acetate) ; with N- [2- (4- (3-fluoro-2-methoxyphenyl)piperidin- l-yl) ethyl] aniline

N- {2- [4- (3-fluoro-2-methoxyphenyl)piperidin- l-yl] ethyl} -N-phenylcyclohexanecarboxamide, R_f 0.76 (methanol) , R_f 0.47 (ethyl acetate) ; with 3- [1- (2-phenylaminoethyl)pyrrolidin-3-yl] indole- 5-carbonitrile

N-{2- [3- (5-cyanoindol-3-yl)pyrrolidin-1-yl] ethyl} - N-phenylcyclohexanecarboxamide; with N- [2- (3- (5-fluoroindol-3-yl)pyrrolidin- 1-yl)ethyl] aniline

N-{2- [3- (5-fluoroindol-3-yl)pyrrolidin- 1-yl]ethyl}-N-phenylcyclohexanecarboxamide; with N- [2- (3- (6-fluoroindol-3-yl)pyrrolidin- 1-yl)ethyl] aniline

N- {2- [3- (6-fluoroindol-3-yl)pyrrolidin- l-yl] ethyl} -N-phenylcyclohexanecarboxamide; with N- [2- (3-benzo [1, 3] dioxol-5-ylpyrrolidin- 1-yl) ethyl] aniline N- {2- [4- (benzo [l;3] dioxol-5-yl)piperidin- l-yl] ethyl}-N-phenylcyclohexanecarboxamide, R_f 0.75 (methanol) ; with N- [2- (4- (2-methoxyphenyl)piperidin-l-yl)ethyl] - 3-ethylaniline N- {2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl} -N-

(3-ethylphenyl) cyclohexanecarboxamide, R_f 0.78 (methanol) ,- with N- [2- (4- (2-methoxyphenyl)piperidin-l-yl)ethyl] -4- ethylaniline N-{2-[4- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N-

(4-ethylphenyl) cyclohexanecarboxamide, R_f 0.78 (methanol) ; with N- [2- (4- (2-methoxyphenyl)piperidin-l-yl) ethyl] -2- ethylaniline N- {2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N-

(2-ethylphenyl)cyclohexanecarboxamide, R_f 0.74 (methanol) . - -

Example 2

1.02 g (0.003 mol) of {2- [4- (6-f luoroindol -

3-yl) piperidin-l-yl] ethylamino} -2-pyridine and 0.3 g

(0.003 mol) of triethylamine are taken up in 20 ml of dichloromethane. 0.63 g (0.003 mol) of 2,2,2- trichloroethyl chloroformate, dissolved in 5 ml of dichloromethane, is added dropwise with stirring. The mixture is then stirred at room temperature for two hours. It is worked up in the customary manner and purified on a silica gel column (eluent: ethyl ether/methanol 9:1)

Yield: 0.7 g of 2 , 2 , 2 -trichloroethyl-N- {2- [4- (6- f luoroindol -3-yl) piperidin-l-yl] ethyl} -N- (2-pyridyl) - carbamate, m.p. 140.8° (dihydrochloride) .

The following were prepared in an analogous manner :

2, 2, 2 -trichloroethyl-N- {2- [3- (6- fluoroindol- 3-yl) - pyrrolidin- 1 -yl] ethyl } -N- ( 2 -pyridyl ) carbamate ; 2,2,2- trichloroethyl -N- { 2 - [4 - ( 6 - fluoroindol - 3 -yl ) - piper idin- 1 -yl ] ethyl } -N- ( 2 -pyridyl ) carbamate ;

2, 2, 2 -trichloroethyl N-{2- [3- (6-f luoroindol -3-yl) - pyrrolidin-1-yl] ethyl} -N- (2-pyridyl) carbamate;

2 -methy lpropyl N- { 2 - [4 - ( 6 - fluoroindol - 3 -yl ) piperidin- 1 - yl ] ethyl }-N- (2 -pyridyl) carbamate; decomposition >80° (dihydro¬ chloride)

2 -methylpropyl N-{2- [3- (6-fluoroindol-3-yl)pyrrolidin- 1 - yl ] ethyl } -N- ( 2 -pyridyl ) carbamate ;

2 -methylpropyl N- { 2 - [4 - ( 6 - fluoroindol - 3 -yl ) piperidin- 1 - yl ] ethyl } -N- ( 2 -pyridyl ) carbamate ;

2 -methylpropyl N-{2- [3- (6 -f luoroindol-3 -yl) pyrrolidin - 1 -yl ] ethyl } -N- ( 2 -pyridyl ) carbamate .

Example 3 1.02 g of {2- [4- (6-f luoroindol- 3-yl) piperidin- l-yl] ethylamino} -2-pyridine and 0.44 g of 3- fluorophenyl isocyanate are stirred at room temperature for 2 hours in 20 ml of THF. The solvent is removed and the residue thus obtained is purified by chromatography on a silica gel column (eluent: ethyl acetate/CH₃OH 9:1) . Yield: 0.9 g of N-{2- [4- (6-fluoroindol-3-yl)piperidin-l- yl]ethyl}-N'- (3-fluorophenyl) -N- (2-pyridyl)urea, m.p. 199° (dihydrochloride) .

The following are prepared analogously: N-cyclohexyl-N' -{2- [3- (6-fluoroindol-3-yl)pyrrolidin- 1-yl] ethyl} -N' - (2-pyridyl) urea;

N-cyclohexyl-N' -{2- [3- (6-fluoroindol-3-yl)piperidin- 1-yl] ethyl}-N' - (2-pyridyl)urea, m.p. 159° (hemihydrate) ;

N-{2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl}-N- (2-pyridyl) -N' - (4-trifluoromethylphenyl)urea, m.p. 187°

N- {2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl}-N- (2,4-difluorophenyl) - N' -cyclohexylurea, m.p. 188°.

A solution of equivalent amounts of 4- (2-methoxyphenyl)piperidine, trifluoroacet anhydride and triethylamine is stirred at room temperature for one hour in dichloromethane. After customary working up 4- (2-methoxyphenyl) -1- (trifluoroacetyl)piperidine is obtained. Subsequent reaction with trifluoroacet anhydride and ammonium nitrate in dichloromethane affords, after customary working up, a 1:1 mixture of the compounds 4- (2-methoxy-3-nitrophenyl) -1- (trifluoro-acetyl)piperidine and 4- (2-methoxy-5-nitrophenyl) -

1- (trifluoroacetyl)piperidine. The mixture is separated with silica chromatography using hexane/EtOAc (4:1 - 1:1) as eluent.

The reduction of the nitro group is carried out by reaction with ammonium formate and Pd/C in ethanol. After separating off the catalyst and customary working up, a mixture of 4- (2-methoxy-3-aminophenyl) - 1- (trifluoroacetyl)piperidine, formate and 4- (2-methoxy- 5-aminophenyl) -1- (trifluoro- cetyl)piperidine, formate is obtained.

The substitution of the amino group by fluorine is carried out by reaction with NaN0₂ in aqueous hydrochloric acid and addition of 65% hexafluoro-phosphoric acid (HPFJ at temperatures between 0 and -10°. After customary workup, the solid is heated, stirred for one hour, methanolic potassium hydroxide solution is added, the mixture is stirred for a further hour and worked up in the customary manner and 4- (3- fluoro-2-methoxyphenyl) piperidine and 4- (3-fluoro-6- methoxyphenyl)piperidine is obtained. The two compounds are dissolved in methanol with N- (2-oxoethyl) -N- phenylcyclohexanecarboxamide, NaCNBH₃ and acetic acid and the mixture is additionally stirred for 3 hours. After customary working up the following are obtained

N-{2- [4- (3-fluoro-2-methoxyphenyl)piperidin- l-yl] ethyl}-N-phenylcyclohexanecarboxamide, R_f 0.76 (methanol), R_f 0.47 (ethyl acetate) and

N- {2- [4- (3-fluoro-6-methoxyphenyl)piperidin-l- yl] ethyl} -N-phenylcyclohexanecarboxamide, R_f 0.76 (methanol), R_f 0.61 (ethyl acetate) .

The following are obtained analogously by reaction of N- (2-oxoethyl) -N-phenylcyclohexanecarbox-amide with 3- (5-cyanoindol-3-yl)pyrrolidine

N-{2- [3- (5-cyanoindol-3-yl)pyrrolidin-1-yl] ethyl}-N- phenyl cyclohexanecarboxamide; with 3- (5-fluoroindol-3-yl)pyrrolidine N~{2-[3- (5-cyanoindol-3-yl)pyrrolidin- l-yl] ethyl}-N-phenylcyclohexanecarboxamide.

Example 5

A solution of 2- [2- (4- (6-fluoroindol- 3-yl)piperidin- 1-yl) ethylamino]pyridine in dichloro-methane is treated with the equivalent amounts of triethylamine and trichloromethyl piperidine- 1-carboxylate ("B" ) [obtainable by reaction of trichloromethoxycarbonyl chloride with piperidine] and the mixture is stirred for 1 hour. After customary working up, N- {2- [4- (6-fluoroindol-3-yl)piperidin- 1-yl] ethyl} -N- (2- pyridyl)piperidine-1-carboxamide is obtained.

The following are obtained analogously by reaction of

"B" with (R) - (+) -2- {2- [3- (2-methoxyphenyl)pyrrolidin-1-yl] - ethylamino}pyridine

(R) - (+) -N-{2- [3- (2-methoxyphenyl)pyrrolidin-l- yl] ethyl}-N- (2-pyridyl)piperidine-l-carboxamide, fumarate, m.p.

70-78°; α_D ²⁰ (+)2.8° (c 1.0, methanol) ; with (S) - (-) -2- {2- [3- (2-methoxyphenyl)pyrrolidin-l-yl] - ethylamino}pyridine

(S) - (-) -N-{2- [3- (2-methoxyphenyl)pyrrolidin-1-yl] - ethyl} -N- (2-pyridyl)piperidine-l-carboxamide, fumarate, m.p. 70-78°; α_D ²⁰ (-)2.3° (c 1.0, methanol); with 2- [2- (4- (5-fluoroindol-3-yl)piperidin-l-yl)ethyl- amino]pyridine

N- {2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] -ethyl} -N- (2-pyridyl)piperidine-1-carboxamide, R_f 0.19 (CH₂Cl₂/methanol 9:1) ; with 2-{2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl¬ amino}pyridine

N- (2- [4- (2-methoxyphenyl)piperidin-1-yl]ethyl}-N- (2- pyridyl)piperidine-1-carboxamide, fumarate, m.p. 136-139°; with 2- {2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] ethyl-amino}-4- fluorobenzene

N-{2- [4- (6-fluoroindol-3-yl)piperidin-l-yl] -ethyl}-N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- (2- [3- (6-fluoroindol-3-yl)pyrrolidin-l-yl] ethyl-amino}- 4-fluorobenzene

N- {2- [3- (6-fluoroindol-3-yl)pyrrolidin-1-yl] -ethyl}- N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- {2- [3- (5-fluoroindol-3-yl)pyrrolidin-1-yl]ethyl-amino} - 4-fluorobenzene N-{2- [3- (5-fluoroindol-3-yl)pyrrolidin-l-yl] -ethyl} -

N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- {2- [3- (5-cyanoindol-3-yl)pyrrolidin-l-yl] ethyl-amino}-4- fluorobenzene

N- {2- [3- (5-cyanoindol-3-yl)pyrrolidin-1-yl] -ethyl}-N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- {2- [3- (6-cyanoindol-3-yl)pyrrolidin-1-yl] ethyl-amino} -4- fluorobenzene

N-{2- [3- (6-cyanoindol-3-yl)pyrrolidin-l-yl] -ethyl} -N- (4-fluorophenyl)piperidine-1-carboxamide; with 2-{2- [3- (l-naphthyl) )pyrrolidin-1-yl] -ethylamino}-4- fluorobenzene

N-{2- [3- (l-naphthyl)pyrrolidin-1-yl]ethyl} -N- (4- fluorophenyl)piperidine-1-carboxamide; - - with 2- {2- [3- (2-naphthyl)pyrrolidin-1-yl] ethylamino}-4- fluorobenzene

N-{2- [3- (2-naphthyl)pyrrolidin-l-yl] ethyl} -N- (4- fluorophenyl)piperidine-1-carboxamide, fumarate, m.p. 85-90°; with 2- {2- [4- (5-fluoroindol-3-yl)piperidin-l-yl] ethyl-amino} -4- fluorobenzene

N- {2- [4- (5-fluoroindol-3-yl)piperidin-l-yl]ethyl}-N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- {2- [4- (5-cyanoindol-3-yl)piperidin-l-yl] ethyl-amino}-4- fluorobenzene

N- {2- [4- (5-cyanoindol-3-yl)piperidin- l-yl] ethyl}-N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- {2- [4- (6-cyanoindol-3-yl)piperidin-1-yl] ethyl-amino}-4- fluorobenzene N-{2- [4- (6-cyanoindol-3-yl)piperidin- l-yl]ethyl}-N- (4-fluorophenyl)piperidine-1-carboxamide; with 2- {2- [4- (l-naphthyl)piperidin-l-yl] ethylamino} -4- fluorobenzene

N- {2- [4- (l-naphthyl)piperidin-l-yl] ethyl}-N- (4-fluorophenyl)piperidine-1-carboxamide, fumarate, m.p. 172- 175°; with 2- {2- [4- (2-naphthyl)piperidin-l-yl] ethyl-amino} -4- fluorobenzene

N-{2- [4- (2-naphthyl)piperidin-l-yl] ethyl}-N- (4- fluorophenyl)piperidine-1-carboxamide; with 2-{2- [3- (3-trifluoromethylsulfonyloxyphenyl) -pyrrolidin-1- yl] ethylamino}pyridine

N- {2- [3- (3-trifluoromethylsulfonyloxyphenyl) - pyrrolidin-l-yl]ethyl} -N- (4-fluorophenyl)piperidine-1- carboxamide.

The following are obtained analogously by reaction of trichloromethy1 pyrrolidine-1-carboxylate with 2-{2- [3- (2-methoxyphenyl)pyrrolidin-1-yl] ethyl¬ amino}pyridine N- {2- [3- (2-methoxyphenyl)pyrrolidin-1-yl] -ethyl}-N-

(2-pyridyl)pyrrolidine-1-carboxamide, El 394 with 2- (2- [4- (2-methoxyphenyl)piperidin-l-yl] ethylamino} - pyridine N- {2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N- (2- pyridyl)pyrrolidine-1-carboxamide, R_f 0.55 (methanol) .

The following are obtained analogously by reaction of 2- {2- [4- (2-methoxyphenyl)piperidin-1-yl] -ethylamino}pyridine with trichloromethyl azepane-1-carboxylate

N- {2- [4- (2-methoxyphenyl)piperidin-1-yl] ethyl} -N- (2- pyridyl) azepane-1-carboxamide, R_f 0.46 (methanol) ; with trichloromethyl 2-ethylpiperidine-l-carboxylate

N- {2- [4- (2-methoxyphenyl)piperidin-1-yl]ethyl}-N- (2- pyridyl) -2-ethylpiperidine-l-carboxamide, R_f 0.52 (methanol) ; with trichloromethyl 3-ethylpiperidine-1-carboxylate

N- {2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl} -N- (2- pyridyl) -3-ethylpiperidine-l-carboxamide, R_f 0.55 (methanol) ; with trichloromethyl 4-ethylpiperidine-1-carboxylate N- {2- [4- (2-methoxyphenyl)piperidin-l-yl] ethyl}-N- (2- pyridyl) -4-ethylpiperidine-l-carboxamide, R_f 0.6 (methanol) ;

Example 6

By ether hydrolysis, the following is obtained from 2- {2- [3- (3-methoxyphenyl)pyrrolidin-1-yl] ethyl-amino}pyridine, R_f 0.28 (CH₂Cl₂/methanol 19:1)

2- {2- [3- (3-hydroxyphenyl)pyrrolidin-l-yl] ethyl¬ amino}pyridine, R_f 0.26 (CH₂Cl₂/methanol 9:1) .

Example 7

Separations ς_ diastereomers and enantiomers by means of analytical and preparative HPLC

By methods such as indicated in the description, the following separations were performed:

a) 4- (2-Methoxyphenyl)pyrrolidinone

Separation:

Column: chiral column

Eluent : tetrahydrofuran

Amount of substance per loading: 55 mg Amount separated: 55 mg Yield: in each case 20 mg per enantiomer

20

(1st enantiomer: [a] = +44° in methanol)

b) 3- (3-Methoxyphenyl) succinimide

Separation:

Column: chiral column

Eluent : heptane/ethanol (60:40)

Amount of substance per loading: 300 mg

Amount separated: 5.3 g

Yield: 1.8 g of the 1st enantiomer

/ r I ²⁰

( fa] D= -92.1° in methanol; m.p. 85.8°C) 0.8 g of the 2nd enantiomer

(([a]²⁰ _D= +93° in methanol; m.p. 85.9°C)

c) 4- (2-Naphthyl) pyrrolidinone

Separation:

Column: chiral column

Eluent : tetrahydrofuran

Amount of substance per loading: 200 mg

Amount separated: 4 g

Yield: 1.52 g of the 1st enantiomer

([a]²⁰ _D= -47.2° in methanol)

1.46 g of the 2nd enantiomer

(([a] °_D= +40° in methanol; m.p. 130.2°C)

(1.4-Renzodioxan-6-vl) -4-pyrrolidinone

Separation: Column: cellulose triacetate or Chiracel OJ^® and Chiracel OD^® Eluent: methanol or hexane/2-propanol

(90:10)

The examples which follow relate to the preparation of starting materials:

Example 8

a) 6.01 g of 5-fluoroindole and 8.67 g of maleimide are dissolved in glacial acetic acid and heated under reflux conditions for 120 hours. The two starting materials are hardly detectable by thin-layer chromatography after this reaction time. The reaction mixture is concentrated to give a residue. The residue is stirred with 200 ml of a solvent mixture consisting of diethyl ether and dichloromethane in the ratio 9:1 for a period of 2.5 hours. Yellow crystals precipitate, which are filtered off with suction and dried. The mother liquor is concentrated to give a residue and stirred with 50 ml of a solvent mixture as above. In this way, fresh yellow crystals precipitate, which are filtered off with suction and dried.

Yield: 7.84 g of 3- (succinimid-3-yl) -5-fluoroindole (yellow crystals) ;

R_f 0.25 (eluent: ethyl acetate/petroleum ether 1:1) .

b) 7.84 g of 3- (succinimid-3-yl) -5-fluoroindole are dissolved in 250 ml of THF. 48.8 g of sodium bis (methoxyethoxy) aluminium hydride (Vitride ) are then slowly added dropwise. With evolution of gas, the brown solution turns black and warms almost to the boiling point. The solution is heated under reflux conditions for a period of 12 to 16 hours. After cooling, the reaction solution is treated with water. The resulting precipitate is filtered off with suction and the mother liquor is concentrated. The residue is dissolved in ethyl acetate and hydrochloric acid (2 N) . The ethyl acetate phase separated off is washed twice more with hydrochloric acid. The aqueous phase is adjusted to an alkaline pH using 32% NaOH. The aqueous phase is then extracted several times with dichloromethane. The organic phase is dried over MgS0₄, filtered and concentrated to give a residue. Residue A: 1.2 g (dark brown, viscous mass) . The aqueous, alkaline phase is extracted once with n-butanol . The butanol phase is likewise concentrated to give a residue. Residue B: 2.6 g (processed further without working up) .

Yield: 3.8 g of 3- (pyrrolidin-3-yl) -5-fluoroindole (black, viscous oil, contaminated) .

c) 3.8 g of 3- (pyrrolidin-3-yl) -5-fluoroindole (A+B) are treated with 250 ml of tert-butanol and 250 ml of a 1 molar aqueous NaHC0₃ solution. 8.73 g of di-tert-butyl dicarbonate, diluted with some tert-butanol, are then slowly added dropwise. A brown suspension results, which is stirred at room temperature for approximately 12 to 16 hours. The suspension is extracted by shaking with water and diethyl ether. The organic phase is dried with MgS0₄, filtered and concentrated on a Rotavapor. 2.6 g of brown oil are obtained as a residue. This crude product is purified by chromatography on a column (silica gel 60; eluent: ethyl acetate/petroleum ether 4:1) .

Yield: 1.5 g of 3- (N-tert-butoxycarbonylpyrrolidin-3-yl) -5- fluoroindole (brown residue) , R_£ 0.55 (eluent: petroleum ether/ethyl acetate 2:1) .

d)

400 mg of 3- (N-tert-butoxycarbonylpyrrolidin-3-yl) -5- fluoroindole are dissolved in 50 ml of ethanol and treated with 5 ml of hydrochloric acid. The solution is allowed to stand at room temperature for 1 hour. The solution is concentrated to give a residue and the residue is treated with 1 N NaHC0₃ solution and EA, the mixture is extracted by shaking and the phases are separated. The organic phase is dried with MgS0₄, filtered and concentrated using a vacuum rotary evaporator. The residue is dissolved in EA and treated with 117.95 mg of oxalic acid, which is dissolved in some acetone. Crystals precipitate, which are filtered off with suction and dried.

Yield: 300 mg of 3- (pyrrolidin-3-yl) -5-fluoroindole oxalate (grey-blue crystals) , m.p. 175° (decomposition) , e)

A solution of aniline, 2-bromo-1, 1-diethoxy-ethane and NaHC0₃ in DMF is heated at 100° for 20 hours. After customary working up, N- (2, 2-diethoxyethyl) aniline is obtained. By subsequent reaction with cyclohexanecarbonyl chloride and triethylamine in dichloromethane, N- (2, 2-diethoxyethyl) -N- phenylcyclo-hexanecarboxamide is obtained.

The cleavage of the acetal is carried out using 10% aqueous oxalic acid and 15% sulfuric acid. After customary working up, N- (2-oxoethyl) -N-phenylcyclohexane-carboxamide is obtained.

The compounds

N- (2-oxoethyl) -N- (2-ethylphenyl) cyclohexane- carboxamide,

N- (2-oxoethyl) -N- (3-ethylphenyl) cyclohexane¬ carboxamide,

N- (2-oxoethyl) -N- (4-ethylphenyl) cyclohexane¬ carboxamide and N- (2-oxoethyl) -N- (4-fluorophenyl) cyclohexane¬ carboxamide.

are obtained analogously.

The following examples relate to pharmaceutical preparations:

Example A: Injection vials

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 1 of double-distilled water using 2 N hydrochloric acid, sterile-filtered, filled into injection vials and lyophilized under sterile conditions, and the vials are aseptically sealed. Each injection vial contains 5 mg of active compound.

Example B: Suppositories

A mixture of 20 g of an active compound of the formula I is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.

Example C: Solution

A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH₂P0₄.2H₂0, 28.48 g of Na₂HP0₄.12H₂0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The pH is adjusted to 6.8, and the solution is made up to

1 1 and sterilized by irradiation.

Example D: Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets A mixture of 1 kg of active compound of the formula I,

4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets in such a way that each tablet contains 10 mg of active compound.

Example F: Coated tablets

Analogously to Example E, tablets are pressed which are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colourant. Example G: Capsules

2 kg of active compound of the formula I are filled in a customary manner into hard gelatin capsules such that each capsule contains 20 mg of the active compound.

Example H: Ampoules

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

Claims

Patent Claims

1. Compounds of the formula I

in which

R¹ is phenyl which is unsubstituted or mono-, di- or trisubstituted by A, A-O- , OH, Hal, CN, N0₂, NH₂, A and/or -0-S0₂CF₃,

2- or 3-indolyl which is unsubstituted or mono- or disubstituted by A, A-O- , OH, Hal and/or CN,

1,4-benzodioxan-5- or -6-yl or

1- or 2-naphthyl, R is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-O, OH, Hal and/or CN, R³ is H, A, A-0-, Ph, NHR⁴ or NR⁵R⁶, R is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by A, A-O- , OH, Hal and/or CN or cycloalkyl having 3 to 10 C atoms,

R and R together are an alkylene chain having 4, 5 or 6 C atoms, A is straight-chain or branched alkyl having 1-10 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms or is cycloalkyl having 3-10 C atoms,

Hal is F, Cl, Br or I, k and 1 each independently of one another are 0 or 1, m is 0, 1 or 2 and n is 1 or 2, with the proviso that k is not equal to 1 and k=0 when m=2, and their salts.

2. Stereoisomers of the compounds of the formula I according to Claim 1.

3. Compounds according to Claim 1 or 2 a) N- {2- [4- (2-methoxyphenyl) piperidin-l-yl] ethyl} - N- (2-pyridyl) cyclohexane-carboxamide;

b) N- {2- [4- (5-fluoroindol-3-yl)piperidin-1-yl] - ethyl} -N- (2-pyridyl) cyclohexane-carboxamide;

c) N-{2- [3- (2-naphthyl)pyrrolidin-1-yl] ethyl }-N- (2- pyridyl) cyclohexane-carboxamide;

d) N- {2- [3- (2-methoxyphenyl)pyrrolidin-1-yl] ethyl}

N- (2-pyridyl) cyclohexane-carboxamide;

e) N- (2- (3- (1, 4-benzodioxan-6-yl) pyrrolidin-1-yl) - ethyl) -N- (2-pyridyl) cyclohexane-carboxamide;

f) N- (2- (3- (6-fluoroindol-3-yl)pyrrolidin-l-yl) - ethyl) -N- (2-pyridyl) cyclohexane-carboxamide;

g) N- (2- (3- (7-methoxy-2-naphthyl)pyrrolidin-l-yl) - ethyl) -N- (2-pyridyl) cyclohexane-carboxamide;

h) R- (+) -N-{2- [3- (2-naphthyl)pyrrolidin-1-yl] - ethyl}-N- (2-pyridyl) cyclohexane-carboxamide;

i) S- (-) -N- {2- [3- (2-naphthyl)pyrrolidin-1-yl] - ethyl} -N- (2-pyridyl) cyclohexane-carboxamide;

j ) N- (2- (4- (6-fluoroindol-3-yl)piperidin-1-yl) - ethyl) -N' - (3-fluorophenyl) -N- (2-pyridyl)urea;

k) N-cyclohexyl-N' - (2- (4- (6-fluoroindol-3-yl) - piperidin-l-yl) ethyl) -N' - (2-pyridyl) urea;

1) N-cyclohexyl-N' - (2- (3- (6-fluoroindol-3-yl) - piperidin-l-yl) ethyl) -N' - (2-pyridyl) urea;

m) N- (2- (4- (6-fluoroindol-3-yl) piperidin-l-yl) - ethyl-N- (2-pyridyl) -N' - (4-trifluoromethyl¬ phenyl) urea; and their salts.

4. Process for the preparation of compounds of the formula I according to Claim 1, characterized in that

a) a compound of the formula II

in which R , R , m and n have the meanings given in Claim 1, is reacted with a compound of the formula III

R³-CO-L (III)

in which L is Cl, Br, I or a free or reactive functionally modified OH group and R has the meanings given in Claim 1,

or

b) a compound of the formula IV

in which R and n have the meanings given in Claim 1, is reacted with a compound of the formula V

in which L is Cl , Br, I or a free or reactive functionally modified OH group and

R², R³, m, k and 1 have the meanings given in Claim 1, or

c) in a reductive amination a compound of the formula VI

in which R , R , m, k and 1 have the meanings given in Claim 1, is reacted with a compound of the formula IV,

or

a compound of the formula VII

R'

H-N. >-R°

(VII)

or

in which R , n and m have the meanings given in Claim 1 and

Q is Cl, Br, I or a free or reactive functionally modified OH group,

or

f) a compound of the formula X

in which R¹, R , m and n have the meanings indicated in Claim 1, is reacted with a suitable phenyl or pyridyl derivative to give a compound of the formula I, which is optionally converted into another compound of the formula I,

or

g) for the preparation of a compound of the formula I in which R³ is NHR⁴ and R⁴ has the meanings given in Claim 1,

a compound of the formula II in which R , R , m and n have the meanings given in Claim 1 is reacted with a compound of the formula XI

R³-N=C=0 (XI) in which R³ has the meanings given in Claim 1,

5. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and/or one of its physiologically tolerable salts, one of its enantiomers or diastereomers of the compounds of the formula I according to Claim 1 is brought into a suitable dose form together with at least one solid, liquid or semiliquid excipient or auxiliary and if appropriate in combination with one or more further active compounds.

6. Pharmaceutical preparation, characterized in that it contains at least one compound according to one of Claims 1 and 2 and/or one of its physiologically acceptable salts.

7. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts for the control of eating disorders, learning disorders, age-dependent memory disorders, tardive dyskinesias and for positively affecting obsessive-compulsive behaviour.

8. Pharmaceuticals of the formula I according to Claim 1 and their physiologically acceptable salts as 5-HT_1A antagonists having 5-HT reuptake-inhibiting, antidepressant or anxiolytic action.

9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the production of a medicament.

10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts in the control of eating disorders, learning disorders, age-dependent memory disorders, tardive dyskinesias and for positively affecting obsessive-compulsive behaviour.