SK120196A3 - 1,4-disubstituted piperidine derivatives, process for producing them and medicaments containing these substances - Google Patents

Abstract

Compounds having the formula (I) are disclosed, as well as their preparation and use in medicaments.

Description

The present invention relates to novel piperidine derivatives, to a process for their preparation and to medicaments acting on glutamate receptors containing them.

BACKGROUND OF THE INVENTION

Piperidine derivatives are known to have pharmacological effects and are useful in the treatment of psychotropic and cerebral vascular disorders. Surprisingly, it has been found that certain piperidine derivatives functionally affect glutamate receptor-dependent glutamate receptors or ion channels.

SUMMARY OF THE INVENTION

The present invention provides novel 1,4-disubstituted piperidine derivatives of formula (I)

R ¹ —Z — X — N B (I) in which

R ¹ represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridine group, a substituted or unsubstituted naphthalene group, a substituted or unsubstituted quinoline unsubstituted isoquinoline unsubstituted indole unsubstituted benzothiophene unsubstituted or substituted group, , substituted or unsubstituted tetrahydroquinoline group, substituted or unsubstituted tetrahydroisoquinoline group, substituted or

unsubstituted tetralin group substituted or unsubstituted a dihydronaphthalene group, substituted or unsubstituted indane group substituted or unsubstituted tetralone- group substituted or unsubstituted chromen-2-one group and substituted or

unsubstituted naphthoquinone means an oxygen atom, a sulfur atom, an SO group or an SO2 group,

X is - (CH 2) n CR ² R ³ - (CH 2) p - or - (CH 2) _m -CHR ₂ (CH ₂ ) g -CHR 3 - (CH ₂ ) p - and

B is = CH-R ⁴ wherein m, p and n are 0, 1, 2 or 3,

R ² and R ³ are the same or different and represent a hydrogen atom, a hydroxyl group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or a C 1 -C 6 alkanoyloxy group, and

R ⁴ represents a straight or branched alkyl group having 1 to 6 carbon atoms, a group of formula -C

or optionally C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, -CF 3, or -O-CF 3 substituted phenyl, benzyl, benzoyl, α-hydroxybenzyl, pyridinyl or naphthyl, wherein: the substituents may be the same or different, one to three times, wherein

Y represents an oxygen atom, a sulfur atom or an -NH- group, and physiologically acceptable salts thereof.

The substituent Fd may be one to three times as well or differently substituted by a C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, carboxyl, C1-C4 alkoxycarbonyl alkoxy, formyl, C 1 -C 4 alkylcarbonyl, phenyl, phenoxy, benzyl or formula-N

ΕΚ ⁶ -SO 2 N \ to ₆ wherein R 5 and R 6 are identical or different and denote hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, alkanoyl having 1 to 6 carbon atoms or together with the nitrogen atom a five or six membered a saturated or unsaturated heterocycle which may be substituted one or more times with an alkyl group having 1 to 4 carbon atoms or a phenyl group and may contain an additional oxygen, nitrogen or sulfur atom.

For example, saturated heterocycles include piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 2,6-dimethylmorpholine and phenylpiperazine, and as unsaturated heterocycles imidazole, pyrazole, pyrrole or triazole.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

Alkyl is in each case a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.

The C 1 -C 6 alkanoyl radical is derived from straight or branched aliphatic carboxylic acids, such as formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid.

When the residue Fd is substituted, the substituent may be at any position. Residues include pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1-naphthyl,

2-naphthyl, isoquinolin-5-yl, isoquinolinyl-4-yl, isoquinolin-6-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, 1,2,3 , 4-tetrahydro-5-naphthyl, 1,2,3,4-tetrahydro-6-naphthyl, 7,8-dihydro-6-naphthyl, 7,8-dihydro-1-naphthyl, chromen-2 -on-7-yl, chromen-2-one-4-yl, 1-oxo-1,2,3,4-tetrahydro-5-naphthyl,

1-oxo-1,2,3,4-tetrahydro-6-naphthyl, 2-oxo-1,2,3,4-tetrahydro-5-naphthyl, 2-oxo-1,2,3,4-tetrahydro- 6-naphthyl, indan-45-yl, indan-5-yl, indan-1-one-4-yl and naphthoquinone.

A preferred value for Z is an oxygen atom and a preferred value for X is an alkylene group having 1 to 4 carbon atoms, which can be straight or branched and can be substituted at any position. Particularly preferred are combinations with hydrogenated or non-hydrogenated naphthyl derivatives.

Physiologically acceptable salts are derived from inorganic and organic acids. Suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as aliphatic or aromatic monocarboxylic or dicarboxylic acids such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid , tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example alkanesulfonic acids of 1 to 4 carbon atoms such as methanesulfonic acid or optionally halogenated or alkyl groups of 1 and 4 carbon atoms substituted benzenesulfonic acids, for example p- toluenesulfonic acid.

When an acid function is present, suitable salts are physiologically acceptable salts with organic and inorganic bases, such as well-soluble salts of alkali metals and alkaline earth metals such as N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, sovacase and 1-amino-2,3,4-butanetriol.

The compounds of formula I include all possible optical isomers and mixtures thereof.

The preparation of the compounds of the formula I and their physiologically acceptable salts takes place in a manner known per se by:

a) reacting a compound of formula II R ¹ -ZH (II) in which R 1 and Z are as defined above with a compound of formula III

A-X-N

(m) wherein X and B are as defined above, and A is a leaving group or a group consisting of:

b) reacting a compound of formula IV AXZR ¹ (IV), in which X, Z and R ^{1 are} as defined above and A is a leaving group, with an amine of formula V

H — N B (V),

In which B is as defined above, or is

c) reacting an epoxide of formula VI

Λ

R-Z- (CH 2) _m -CH = CH ₂ (VI) in which R \ Z AM as defined above, with an amine of the formula V

(V) wherein B is as defined above, or is

d) reacting a compound of formula VII

HO-X-N

(VH) in which X and B are as defined above, according to Mitschunobu with a compound of the formula - OH in which R ^{1 is} as defined above, and then the carbonyl group is reduced or the hydroxyl group is esterified or etherified or formed physiologically acceptable salts and / or isomers separated.

The nucleophilic substitutions of the leaving group A according to process variants a) and b) are carried out by conventional methods under basic conditions in an organic solvent which is inert under the reaction conditions.

Suitable leaving groups A are, for example, halogens such as chlorine, bromine or iodine, or organic sulfonic acid residues such as alkanesulfonic acid residues such as mesylate or tosylate or aromatic sulfonic acid residues such as toluenesulfonic acid or bromobenzenesulfonic acid.

Suitable inert organic solvents are polar solvents such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, alcohols such as ethanol or methanol, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons or aromatic hydrocarbons, or mixtures of said solvents.

Suitable bases are inorganic and organic bases. Examples of inorganic bases include alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates or alcoholates; organic bases include tertiary organic amines such as tripropylamine, triethylamine, N-alkylmorpholine, N-alkylpiperidine, Hunig's bases, 1,4-diazabicyclo [2,2,2] octane and 1,5-diazabicyclo [5,4,0] undec-5-ene.

Reaction temperatures may vary between room temperature and the boiling point of the solvent.

The reaction according to process c) is generally carried out in protic solvents such as alcohols at elevated temperatures up to the boiling point.

The Mitsunobi reaction (method d) is carried out in the presence of triphenylphosphine and ethyl azodicarboxylic acid ester in inert solvents at elevated temperature, or also in the presence of an organic acid at room temperature (Synthesis, 1981, 1).

The reduction of the carbonyl group can be carried out using conventional reducing agents, such as sodium borohydride, to the corresponding hydroxy compounds or using triethylsilane and trifluoroacetic acid at room temperature to methylene compounds.

When esterification is desired, it is carried out in a known manner by reaction with an activated acid derivative such as an acid anhydride, an acid halide or an acid imidazolide.

The optional etherification of the hydroxyl group is carried out by conventional methods in the presence of bases, for example by reaction with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride.

The compounds of formula I can also be isolated and purified from the reaction mixture in a known manner. The acid addition salts may be converted into the free base by conventional methods and these may be converted into physiologically acceptable acid addition salts by known methods, for example, by mixing the solution with a concentrated solution of the desired acid.

When the compounds of formula I have one or more chiral atoms, the optically active compounds can be obtained starting from optically active starting compounds or from known racemates by known methods. Separation of enantiomers may be carried out, for example, by chromatography over optically active carriers, or by reaction with optically active acids followed by fractional crystallization.

The compounds of formula I and their physiologically acceptable salts are useful as medicaments by virtue of their functional action on glutamate receptors or glutamate receptor ion channels.

The pharmacological activity of the compounds of formula I was determined by the tests described below.

Male NMRI mice weighing 18-22 g are maintained at controlled ratios (6.00-18.00 hrs light / dark rhythm, free food and water intake) and randomized to grouping. Groups consist of 5 to 16 animals. Observation of the animals is performed between 8.00 and 13.00.

AMPA is injected into the left ventricular of freely moving mice. The applicator consists of a cannula with a stainless steel device that limits the injection depth to 3.2 mm. The applicator is connected to a syringe pump. The injection needle is inserted perpendicular to the surface of the skull according to the Montemurra and Dukelow coordinates. The animals are observed until clonic or tonic seizures occur for up to 180 seconds. Clonic movements that last longer than 5 seconds are counted as convulsions. The onset of clonic seizures is used as the endpoint for determining the seizure threshold. The dose needed to increase or decrease the seizure threshold by 50% (THRD50) is determined in 4-5 experiments. THRD50 values and confidence limits are determined by regression analysis.

The results of these experiments show that the compounds of formula I and their acid addition salts affect functional disorders of the AMPA receptors. They are therefore suitable for the manufacture of medicaments for the symptomatic and prophylactic treatment of diseases caused by a change in the function of the AMPA-receptor complex.

Treatment with the compounds of the present invention reduces or suppresses cell damage and functional disorders due to diseases and suppresses the resulting symptoms.

Diseases that may be caused by excitatory amino acid dysfunction, possibly altered by glutamate-dependent neurotransmission include, for example, neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementias, mu Iti infarct dementias, aids-dementia, encephalopathic dementia lateral sclerosis, olivopontocerebral degeneration, epilepsy; cell damage by hypoglycemia, hypoxia, ischemia and energy exchange disorders; neuronal damages caused by brain damage, such as stroke, brain trauma and asphyxia, as well as psychoses, schizophrenia, fear states, pain states, migraines and emesis. Functional disorders such as memory disturbances (amnesia), learning process disorders, manifestations of vigilance, denial manifestations after chronic intake of addictive substances such as sedative drugs, hallucinogens, alcohol, cocaine and opiates are also based on glutamate-dependent neurotransmission.

Indications may be shown by conventional pharmacological tests.

The present invention also relates to pharmaceutical compositions comprising said compounds, to the manufacture thereof, and to the use of the compounds of the present invention for the manufacture of medicaments which can be used for the treatment and prophylaxis of the aforementioned diseases. The pharmaceutical compositions are prepared by known methods by converting the active ingredient with suitable carriers, excipients and / or additives into a pharmaceutical preparation suitable for enteral or parenteral administration.

Administration can be carried out orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, emulsions or elixirs, or rectally in the form of suppositories or in the form of possibly also subcutaneously injectable solutions.

Suitable excipients for the desired dosage forms are inert organic and inorganic carrier materials known to those skilled in the art, such as water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyethylene glycols and the like. In addition, preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure or buffers may also be included.

The pharmaceutical preparations may be in solid form, for example as tablets, dragees, lace, capsules and the like, or in liquid form, for example as solutions, suspensions or emulsions.

Excipients such as gallic acid salts or animal or plant phospholipids, but also mixtures thereof, such as liposomes or components thereof, can be used as carrier systems.

Particularly suitable for oral administration are tablets, dragees or capsules containing talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch. The use may also take place in liquid form, for example as a juice to which a sweetener may optionally be added.

For parenteral administration, particularly suitable are injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil.

The dosage of the active ingredient may vary depending on the type of application, the age and weight of the patient, the type and severity of the disease to be treated and the like. The daily dose may be administered as a single dose or may be divided into two or more daily doses. The compounds are present in an amount of 0.05 to 100 mg of active substance in a physiologically acceptable carrier per dosage unit. Usually a dose of 0.1 to 500 mg per day, preferably 0.1 to 50 mg per day, is used.

Unless the production of the starting compounds is described, they are known or can be produced analogously to known compounds or by the methods described herein.

The following Examples illustrate the preparation of the compounds of Formula I of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 {1- [3- (3-Dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone

265 mg of 3-dimethylaminophenyl are placed in 20 ml of acetone, 265 mg of potassium carbonate and 824 mg of (4-fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone are added and the reaction mixture is heated for 3 hours. under an argon atmosphere under reflux. After concentration of the organic phase, it is chromatographed on silica gel with methylene chloride / acetone (1: 1). 375 mg of {1- [3- (3-dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone are obtained.

Mp: 48-50 ° C.

(4-Fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone is obtained according to literature methods by alkylating 4- (4-fluorobenzoyl) -piperidine with 3-bromo-1-propanol and potassium carbonate in dimethylformamide; and followed by reaction with methanesulfonic acid and triethylamine in methylene chloride. The following are produced in an analogous manner:

{1- [3- (2-Dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (4-Dimethylaminophenoxy) -propyl] -4-piperidyl} - (4- Fluorophenyl) ketone {1- [3- (3-morpholinophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, mp 110-111 ° C {1- [3- (1-Naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, m.p. 61-64 ° C {1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, m.p. 114-115 ° C {1- [3- (2-Nitro-1-naphthyloxy) -propyl] {1- [3- (3-dibutylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (1-nitro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, mp 137-138 ° C {1- [3- (2,4-Dinitro-1-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- [3- (3-anilinophenoxy) -propyl -4-piperidyl} - (4-fluorophenyl) ketone, m.p. 75-78 ° C {1- [3- (1-Bromo-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, m.p. 97-100 ° C {1- [3- (4-Chloro-1-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (3-acetylaminophenoxy) -propyl] - 4-piperidyl} - (4-fluorophenyl) ketone, m.p. 108-111 ° C (4-Fluorophenyl) - {1- [3- (5-isoquinolyloxy) -propyl] -4-piperidyl} -ketone, m.p. 31-33 ° C (4-fluorophenyl) - {1- [3- (3-pyridyl-oxy) -propyl] -4-piperidyl} -ketone, m.p. 52-55 ° C (4-fluorophenyl) - {1- (3- (3- (N-methylanilino) -phenoxy) -propyl] -4-piperidyl} -ketone, mp 75-77 ° C

4- {3- [4- (4-Fluoro-benzoyl) -1-piperidyl] -propoxy} -indan-1-one, m.p. 126-127 ° C

5- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] propoxy} -3,4-dihydro-naphthalen-1 (2H) -one (oily substance) {1- (3- (7,8) -dihydro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, mp 72 74 ° C {1- [3- (7,8-dihydro-2-naphthyloxy) -propyl] - 4-piperidyl} - (3,4-difluorophenyl) -ketone {1- (3- (7,8-dihydro-2-naphthyloxy) -propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) -ketone ( 4-Fluorophenyl) - {1- (3- (2- (1H-imidazol-1-yl) -phenoxy) -propyl] -4-piperidyl} -ketone (oily substance) (4-fluorophenyl) - {1 - [3- (4-hydroxy-3,5-di-tert-butyl-phenoxy) -propyl] -4-piperidyl} ketone

7- {3- [4- (4-fluorobenzoyl) -1-piperidyl] propoxy} -2H-chromen-2-one, m.p. 128-139 ° C

7- {3- [4- (4-fluoro-benzoyl) -1-piperidyl] -propoxy} -4-methyl-2H-chromen-2-one, m.p. 139-140 ° C

4- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] propoxy} -2H-chromen-2-one, m.p. 132-133 ° C {1- [3- (6-Bromo-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, m.p. 126 DEG-127 DEG C. {1- [3- (2-Naphtyloxy) -propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone, m.p. 107-108 ° C

Example 2

- {1- [3- (3-Dimethylaminophenoxy) -propyl] -4-piperidyl} -1- (4-fluorophenyl) -methanol

384 mg of {1- [3- (3-dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone were added portionwise at room temperature to a solution of 15 ml of ethanol and 80 mg of sodium borohydride. After stirring for four hours, the reaction solution is neutralized, mixed with water and then extracted with ethyl acetate. After drying, the organic phase is concentrated and the residue is chromatographed on silica gel with acetone / methylene chloride (1: 1).

1). 154 mg of 1- {1- [3- (3-dimethylaminophenoxy) -propyl] -4-piperidyl} 1- (4-fluorophenyl) methanol are obtained.

Mp: 63-64 ° C

The following are produced in an analogous manner:

- {1- [3- (1-Naphthyloxy) -propyl] -4-piperidyl} -1- (4-fluorophenyl) -methanol

1- {1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol, m.p. M.p. 136-137 ° C

Example 3 (3-Dimethylaminophenyl) - {3- [4- (4-fluorobenzyl) -1-piperidyl] -propyl} -ether g of triethylsilane was added dropwise to a solution of 384 mg of {1- [3- (3-dimethylaminophenoxy) -propyl] 4-Piperidyl} - (4-fluorophenyl) ketone in 25 ml of trifluoroacetic acid is added and the reaction mixture is stirred for 3 days. It is then concentrated to dryness, the residue is taken up in diethyl ether and extracted three times with 1N hydrochloric acid. The combined extracts were basified, extracted with diethyl ether and concentrated. 197 mg of (3-dimethylaminophenyl) - {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether are obtained in the form of an oily liquid.

The following are produced in an analogous manner:

1- {3- [4- (4-fluorobenzyl) -1-piperidyl] -pthyl} -ethanol

2-naphthyl- {3- [4- (4-fluorobenzyl) -1-piperidyl] -propyl} -ether,

mp 79-80 ° C.

Example 4 {1- [1- (3-Dimethylaminophenoxy) butyl] -4-piperidyl} - (4-fluorophenyl) ketone

630 mg of (4-chlorobutyl) - (3-dimethylaminophenyl) ether were stirred in 25 ml of dimethylformamide under argon for 8 hours at a bath temperature of 100 ° C with 950 mg of 4- (4-fluorobenzoyl) -piperidine and 0.5 ml triethylamine. After distilling off the solvent, the residue was taken up in methylene chloride and washed once with water and saturated sodium chloride solution. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with acetone / methylene chloride (1: 1) to give 420 mg of {1- [1- (3-dimethylaminophenoxy) butyl] -4-piperidyl} (4-fluorophenyl) ketone.

The (4-chlorobutyl) - (3-dimethylaminophenyl) ether necessary as a starting material is obtained by etherification of 3-dimethylaminophenol with 1-bromo-4-chlorobutane and potassium carbonate in dimethylformamide.

Example 5 {1- [1- (3-Dimethylaminophenoxy) -ethyl] -4-piperidyl} - (4-fluorophenyl) ketone

From 590 mg of (4-chloroethyl) - (3-dimethylaminophenyl) ether and 950 mg of 4- (4-fluorobenzoyl) -piperidine, analogously to the method of Example 4, 590 mg of {1- [1- (3-dimethylaminophenoxy) -ethyl] were obtained. 4-Piperidyl} - (4-fluorophenyl) ketone as an oil.

Example 6 {1- [3- (3-Dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone

380 mg of (3-dimethylaminophenyl) - (2,3-epoxypropyl) ether were dissolved in 50 ml of methanol and treated with 430 mg of 4- (4-fluorobenzoyl) piperidine. After heating for 3 hours, the solvent is distilled off, the residue is taken up in 50 ml of 1 N hydrochloric acid and extracted several times with chloroform. The aqueous phase was basified with 2N sodium hydroxide and then extracted with ethyl acetate. The combined ethyl acetate phases are washed, dried, filtered and concentrated. The residue is chromatographed on silica gel with acetone / methylene chloride (1: 1) to give

446 mg of {1- [1- (3-dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone.

The (3-dimethylaminophenyl) - (2,3-epoxypropyl) -ether required as starting material is obtained by reacting 3-dimethylaminophenol with epichlorohydrin and sodium hydride in dimethylformamide.

The following are produced in an analogous manner:

[3- (4 - ((4-fluorobenzyl) -piperidino) -2-hydroxypropoxy] -dimethylaminoaniline, mp 85-87 ° C {1- [3- (3-morpholinophenoxy) -2-hydroxypropyl] -4- piperidyl} - (4-fluorophenyl) -ketone [2- (4 - ((4-fluorobenzyl) -piperidino) -2-hydroxypropoxy] -naphthalene, mp 89-90 ° C

1- [4 - ((4-benzyl) piperidino) -2-hydroxy-propoxy] naphthalene, mp. 104 - 105 ° C {1- [3- (1-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- [3- (2-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone (4-fluorophenyl) - {1- [3- (1-oxo-1,2,3,4-tetrahydro-5-naphthyloxy) -2-hydroxypropyl] - 4-piperidyl} -ketone, m.p. 128-131 ° C {1- [3- (1-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone {1- [3- (1-naphthyloxy) -2- hydroxypropyl] -4-piperidyl} - (3,4-fluorophenyl) ketone {1- [3- (2-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-fluorophenyl) ketone.

Example 7 {1- [3- (3-Dimethylaminophenoxy) -2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone

250 g of {1- [3- (3-dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone are dissolved in 10 ml of dried pyridine. After the addition of 0.15 ml of acetic anhydride, the reaction mixture is heated under reflux for 3 hours. After cooling, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel using methylene chloride / ethanol (180: 75). 125 mg of {1- [3- (3-dimethylaminophenoxy) 18] are obtained

2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone as an oil.

The following are produced in an analogous manner:

2- (4 - ((4-fluorobenzyl) -piperidino) -2-acetoxypropoxy] -naphthalene {1- (3- (1-naphthyloxy) -2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- [3- (2-naphthyloxy) -2-acetoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- [3- (1-naphthyloxy) -2-acetoxypropyl] -4-piperidyl} - (3,4-difluorophenyl) -ketone.

Example 8 {1- [3- (3-Dimethylaminophenoxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone

250 g of {1- [3- (3-dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone are dissolved in 10 ml of ethylene glycol dimethyl ether, mixed with 20 mg of sodium hydride (90%) and cooled. in an ice bath. After the addition of 106 mg of methyl iodide, the reaction mixture is stirred for 4 hours cold and for one hour at room temperature. After concentrating the reaction mixture, the organic phase is chromatographed on silica gel with methylene chloride / ethanol (1800: 75). 150 mg of {1- [3- (3-dimethylaminophenoxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone are obtained in the form of an oily liquid.

The following are produced in an analogous manner:

2- [4 - ((4-fluorobenzyl) -piperidino) -2-methoxypropoxy] -naphthalene {1- (3- (1-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- [3- (2-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- (3- (1-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) -ketone.

Example 9 (4-Fluorophenyl) - {1- (3- (1,2,3,4-tetrahydro-5-naphthyloxy) propyl] -4-piperidyl} ketone

A solution of 200 mg of 1,2,3,4-tetrahydro-5-naphthol in 25 ml of tetrahydrofuran p.a. 700 mg of (4-fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone, 700 mg of triphenylphosphine and 0.45 ml of diethyl azodicarboxylic acid are added and the reaction mixture is heated with stirring for 20 minutes. at a bath temperature of 80 [deg.] C. The solution is then treated with 50 ml of water and extracted with ethyl acetate, and after drying, the organic phase is concentrated and the residue is chromatographed on silica gel with methylene chloride / ethanol (9: 1). 264 g of (4-fluorophenyl) - {1- [3- (1,2,3,4-tetrahydro-5-naphthyloxy) -propyl] -4-piperidyl} ketone are obtained.

(4-Fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone is obtained according to methods known in the literature by alkylation of 4- (4-fluorobenzoyl) -piperidine with 3-bromo-1-propanol and potassium carbonate in dimethylformamide.

The following are produced in an analogous manner:

(4-Fluorophenyl) - {1- [3- (indan-4-yloxy) -propyl] -4-piperidyl} -ketone, m.p. 70-72 ° C (4-Fluorophenyl) - {1- [3- (indan-5-yloxy) -propyl] -4-piperidyl} -ketone, m.p. 49-52 ° C (3,4-Fluorophenyl) - {1- [3- (indan-5-yloxy) -propyl] -4-piperidyl} -ketone {1- [3- (4-benzylphenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, m.p. 105-107 ° C (4-fluorophenyl) - {1- (3- (1,2,3,4-tetrahydro-6-naphthyloxy) -propyl] -4-piperidyl} -ketone.

H, 11.191

Claims (4)

1. 1,4-disubstituted piperidine derivatives of the general formula I R ¹ —Z — x — NB ω. wherein R 1 is C 1 -C 4 alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, carboxyl, C 1 -C 4 alkoxy, formyl, phenoxy, benzyl. a group, -NR ⁵ or SO ₂ NR ⁵ R ⁶ substituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, or an unsubstituted benzothiophene group, a substituted or unsubstituted benzofuran group, a substituted or unsubstituted tetrahydroquinoline group, a substituted or unsubstituted tetrahydroisoquinoline group, a substituted or unsubstituted tetraline group, a substituted or unsubstituted dietronanediol group, a substituted or unsubstituted tetralin group, And substituted or unsubstituted unsubstituted unsubstituted a substituted naphthoquinone group, wherein R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a C 1 -C 4 alkyl group, a phenyl group, a C 1 -C 6 alkanoyl group, or, together with a nitrogen atom, a five-membered or six-membered, saturated or unsaturated a heterocycle which may be substituted one or more times by an alkyl group having from 1 to 4 carbon atoms or by a phenyl group and may contain another oxygen, nitrogen or sulfur atom, Z represents an oxygen atom, a sulfur atom, an SO group or an SO2 group, X is - (CH 2) m -CR ² R ³ - (CH 2) p or - (CH ₂ ) _m -CHR 2 - (CH ₂ ) g -CHR 3 - (CH ₂ ) p -a B is = CH-R ⁴ where m, p and p are 0, 1, 2 or 3, R ² and R ³ are the same or different and represent a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or an alkanoyloxy group having 1 to 6 carbon atoms, and R ⁴ represents a straight or branched alkyl group having 1 to 6 carbon atoms, a group of formula or optionally an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, halogen, hydroxy, -CF 3, or -O-CF 3 substituted phenyl, benzyl, benzoyl, α-hydroxybenzyl, pyridinyl or naphthyl group, wherein the substituents may be the same or different, one to three times, wherein Y represents an oxygen atom, a sulfur atom or an NH- group, and physiologically acceptable salts thereof. 2. A compound according to claim 1, which is {1- [3- (1-naphthyloxy) -phenyl] -4-piperidinyl} - (4-fluorophenyl). ) -ketone {1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (2-nitro-1-naphthyloxy) -propyl] " 4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (1-nitro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- ( 2,4-dinitro-1-naphthyloxy) propyl] -4-piperidinyl} - (4-fluorophenyl) ketone (4-fluorophenyl) - {1- [3- ( 5-isoquinolyloxy) -propyl] -4-piperidyl} -ketone {1- [3- (1-bromo-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3] - (4-Chloro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (1-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4 -fluorophenyl) -ketone {1- [3- (2-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) -ketone 1- {1- [3- (1-Naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -methanol 1- {1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -methanol 1-Naphthyl- {3- [4- (4-fluorobenzyl) -1-piperidyl] -propyl} -ether 2-naphthyl- {3- [4- (4-fluorobenzyl) -1-piperidyl] -propyl} -ether {1- [3- (1-bromo-2-naphthyloxy) -propyl] -4-piperidyl} - ( 4-Fluorophenyl) ketone {1- [3- (4-chloro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone 4- {3- [4- (4-fluorobenzoyl) -1-piperidyl] -propoxy} -indan-1-one 5- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] -propoxy} -3,4-dihydro-naphthalen-1 (2H) -one {1- [3- (7,8-dihydro-2) -naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone {1- [3- (7,8-dihydro-2-naphthyloxy) -propyl] -4-piperidyl} - (3,4- Difluorophenyl) ketone {1- [3- (7,8-dihydro-2-naphthyloxy) -propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone 7- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] propoxy} -2H-chromen-2-one 7- {3- [4- (4-fluorobenzoyl) -1-piperidinyl] propoxy} -4-methyl-2H-chromen-2-one 4- {3- [4- (4-Fluorobenzoyl) -1-piperidyl] -propoxy} -2H-chromen-2-one {1- [3- (6-bromo-2-naphthyloxy) -propyl] -4- piperidyl} - (4-fluorophenyl) -ketone {1- [3- (2-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) -ketone (4-fluorophenyl) - {1- [3] - (1-oxo-1,2,3,4-tetrahydro-5-naphthyloxy) -2-hydroxypropyl] -4-piperidyl] ketone {1- [3- (1-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-Dimethoxyphenyl) ketone {1- [3- (1-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-fluorophenyl) ketone {1- [3- (2- naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3,4-fluorophenyl) ketone [2- (4 - ((4-fluorobenzyl) -piperidino) -2-methoxypropyl] naphthalene {1- [3- (1-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone {1- [3- (2-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) {1- [3- (1-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (3,4-dimethoxyphenyl) ketone (4-fluorophenyl) - {1- [3- (1,2, 3,4-tetrahydro-5-naphthyloxy) -propyl] -4-piperidyl} -ketone (4-fluorophenyl) - {1- [3- (indan-4-yloxy) -propyl] -4-piperidyl} -ketone ( 4-fluoro-phenyl) - -1- {[3- (indan 5-yloxy) -propyl] -4-piperidyl} -ketone (3,4-difluorophenyl) - {1- [3- (indan-4-yloxy) -propyl] -4-piperidyl} -ketone (4-fluorophenyl) - {1- [3- (1 _l 2,3,4-tetrahydro-6-naphthyloxy) propyl] -4-piperidyl} -ketone. Compound-based medicament according to claims 1 and 2. A process for the preparation of the compounds of the formula I according to claim 1, characterized in that it comprises: a) reacting a compound of formula II R ¹ -ZH (II) in which R 1 and Z are as defined above with a compound of formula III A - X - N (m). in which X and B are as defined above, and A represents a leaving group or a radical b) reacting a compound of formula IV AXZ - ^R1 (IV) in which X, Z and R '? and A is a leaving group, with an amine of formula V H - N B (V) wherein B is as defined above, or is c) reacting an epoxide of the formula VI in which R ¹ , Z m is as defined above with an amine of the formula V H - N B wherein B is as defined above, or is d) reacting a compound of formula VII HO-X-NB (VH) in which X and B are as defined above, according to Mitschunobu with a compound of the formula R ^-OH in which R ”* is as defined above, and then the carbonyl group is reduced or hydroxyl the group esterifies or etherifies, or physiologically acceptable salts are formed and / or the isomers are separated.