CZ277096A3 - 1,4-disubstituted derivatives of piperidine, process of their preparation and medicaments in which such derivatives are comprised - Google Patents

Abstract

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

Description

Technical field

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 receptors or glutamate receptor dependent ion channels.

The essence of the invention

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

R1-Z-X-N B-y (I).

in which

R ¹ denotes a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridine group, a substituted or unsubstituted naphthalene group, a substituted or unsubstituted quinoline group, a substituted or unsubstituted isoquinoline group, a substituted or unsubstituted indole group, a substituted or unsubstituted benzo group, a substituted or unsubstituted a uranium group, a substituted or unsubstituted tetrahydroquinoline group, a substituted or unsubstituted tetrahydroisoquinoline group, a substituted or unsubstituted tetraline group, a substituted or unsubstituted dihydronaphthalene group, a substituted or unsubstituted indane group, a substituted or unsubstituted tetralone group, a substituted tetralone group, or an unsubstituted naphthoquinone group,

Z represents an oxygen atom, a sulfur atom, an SO group or an SO2 group,

X denotes - (CH 2) _m -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 p are 0, 1, 2 or 3,

R and R are the same or different and are hydrogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 6 alkanoyloxy, and

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

-CO-Y or optionally C1-C4alkyl, C1-C4alkoxy, halogen, hydroxy, CF3 or -O-CF3 substituted phenyl, benzyl, benzoyl, alpha-hydroxy- benzyl, pyridinyl or naphthyl, the substituents may be the same or different, one to three times, and

Y represents an oxygen atom, a sulfur atom or an -NH- group.

as well as their physiologically acceptable salts.

The substituent may be one to three times, equally or differently substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, carboxyl, C 1 -C 4 alkoxycarbonyl in alkoxy, a formyl group, a (C 1 -C 4) alkylcarbonyl group, a phenyl group, a phenoxy group, a benzyl group or a formula group

• SO2 — N

Wherein R 5 and R 6 are the same or different and denote 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 5- or 6-membered 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, pyrrazole, pyrrole or triazole.

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

Alkyl is a straight or branched alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.

The (C 1 -C 6) alkanoyl moiety is in each case derived from straight or branched aliphatic carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid.

When the residue R ¹ is substituted, the substituent can be in any position. R @ ¹ radicals include pyridin-2-yl, pyridin-3-yl. a group, 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-one-7-yl, chromen- A 2-on-4-yl group,

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-4-yl, indan-5-yl, indan-1-on-4-yl and a naphthoquinone group.

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 may be straight or branched and may 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, 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 halogen or alkyl groups of 1 to 4 carbon atoms of substituted benzenesulfonic acids, for example acid p-toluenesulfonic acid.

When an acid function is present, suitable salts are physiologically acceptable salts with organic and inorganic bases, such as the well-soluble salts of alkali and alkaline earth metals, as well as N-methyl-glucamine, dimethylglucamine, ethylglucamine, lysine, 1,6- hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylaminomethane, 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 is carried out in a manner known per se by reacting them

a) reacting a compound of formula II

Or

(b) or

R ¹ ve se ve

A is reacted with a compound of formula IV

A - X - Z - R ¹ (IV), in which X, Z and the meanings given above have the meaning of a

A denotes a leaving group, with an amine of the formula (V) in which B is as defined above, (II).

wherein R ¹ and Z are as defined above, with a compound of formula III:

A — X — B (HI), in which X and B are as defined above, and denotes a leaving group

c) reacting the epoxide of formula VI

Λ

R-Z- (CH2) m-CH- (¾ (VI) diisocyanates having R ^1, Z am defined above, with an amine of formula V

H-N B (V) wherein B is as defined above, or is H

d) reacting a compound of formula VII

HO-X-NB \ _y (vn) in which influe ί X and B are as defined above, according Mitschunobu a compound of formula R ¹ - OH, in which R as defined above and thereafter as necessary reducing the carbonyl group or the hydroxyl group esterifies or etherifies, or physiologically acceptable salts are formed, or isomers separated.

The nucleophilic substitution of the leaving group A according to process variants a) and b) is 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, Hiinig bases, 1,4 -diazabicyclo [2.2.2] octane and 1,5-diazabicyclo [5.4.0] undec-5-ene.

The 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 azodicar boxylic acid ethyl ester in inert solvents at elevated temperature, or also in the presence of an organic acid at room temperature (Synthesis, 1981, 1).

Reduction of the carbonyl group can be carried out with 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 by a person known in the art 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 the formula I can also be isolated and purified from the reaction mixture in a known manner. The acid addition salts can be converted into the free bases by conventional methods, and these can 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 by starting from optically active starting compounds or from racemates in a manner known per se. The separation of enantiomers can be carried out, for example, by chromatography over optically active carriers, or by reaction with optically active acids followed by fractionated 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 to 22 g are maintained at controlled ratios (6θθ - 18θθ light / dark rhythm, free food and water) and randomized to grouping. Groups consist of 5 to 16 animals. Observation of the animals is performed between 8θθ and 13θθ hours.

AMPA is injected into the left ventricle 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 the injection pump. The injection needle is inserted perpendicularly to the surface of the skull according to the coordinates of Montemurro and Dukelow. 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 required to increase or decrease the seizure threshold by 50% (THRD?) Is determined in 4-5 experiments. THRD R2 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 a medicament 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 the disease and suppresses the resulting symptoms.

Diseases that may be caused by dysfunction of excitatory amino acids, possibly altered by glutamate-dependent neurotransmission, include, for example, neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzenheimer's disease, senile dementia, multi-infarct dementia, aids-dementia, encephalopathic dementia, olivopontocerebral degeneration, epilepsy; cell damage by hypoglycemia, hypoxia, ischemia and energy exchange disorders; neuronal damage that is 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 disorders (amnesia), learning disabilities, 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 their manufacture, as well as to the use of the compounds of the present invention in the manufacture of medicaments which can be used for the treatment and prophylaxis of the above diseases. The pharmaceutical compositions can also be prepared by methods known per se 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 optionally also subcutaneously usable injection solutions.

Suitable excipients for the desired dosage forms are those known to those skilled in the art for inert organic and inorganic carrier materials 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, suppositories, capsules and the like, or in liquid form, for example as solutions, suspensions or emulsions.

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

Especially suitable for oral administration are tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch. The use can also take place in liquid form, for example as a juice, to which optionally a sweetener is added.

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

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 a single dosage unit in an amount of 0.05 to 100 mg of active substance in a physiologically acceptable carrier. Usually a dose of 0.1 to 500 mg per day, preferably 0.1 to 50 mg per day is used.

If the preparation of the starting compounds is not 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-Dimethylamino-phenoxy) -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 to 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.

M.p. : 48-50 ° C.

(4-Fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone is obtained by alkylation methods known from the literature.

Of 4- (4-fluorobenzoyl) -piperidine with 3-bromo-1-propanol and potassium carbonate in dimethylformamide 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- (3-Dibutylarainophenoxy) -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, 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-pyridyloxy) -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. Mp 126-127 ° C

5- (3- (4- (4-fluoro-benzoyl) -1-piperidyl) -propoxy} -3,4-dihydronaphthalen-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, mp 128-129 ° C

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

4- (3- (4- (4-fluorobenzoyl) -1-piperidyl) -propoxy} -2H-chromen-2-one, mp 132-133 ° C) (1- [3- (6-bromo-2)) -naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone, mp 126-127 ° C {1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (3,4 -dimethoxyphenyl) ketone, mp 107-108 ° C.

Example 2

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

384 mg of {1- [3- (3-dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone are 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; it is concentrated and the residue is chromatographed on silica gel with acetone / methylene chloride (1: 1). 154 mg of 1- {1- [3- (3-dimethylaminophenoxy) -propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol are obtained.

M.p. Mp = 63-64 ° C.

The following are produced in an analogous manner:

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

Example 3 (3-dimethylaminophenyl) - {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether g 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, followed by stirring 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 are basified, extracted with diethyl ether and concentrated. 197 mg of (3-dimethylaminophenyl) - {3- [4- (4-fluorobenzyl) -1-piperidyl] -propyl} -ether is obtained as an oil.

The following are produced in an analogous manner:

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

2-naphthyl- {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether, m.p. 79-80 ° C.

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

630 mg of (4-chlorobutyl) - (3-dimethylaminophenyl) ether in 25 ml of dimethylformamide was stirred under argon atmosphere for 8 hours at a bath temperature of 100 DEG C. with 950 mg of 4- (4-fluorobenzoyl) -piperidine and 0.5 ml. ml of triethylamine. After distilling off the solvent, the residue is 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 required as 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

590 mg of {1- [1- (3-dimethylaminophenoxy)] was obtained from 590 mg of (4-chloroethyl) - (3-dimethylaminophenyl) ether and 950 mg of 4- (4-fluorobenzoyl) -piperidine. ethyl-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) -ethanol 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.

M.p. Mp = 117-119 ° C.

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:

and

3- [4 - ((4-fluorobenzyl) -piperidino) -2-hydroxypropoxy] -dimethylaminoaniline, m.p. 85-87 ° C {1- [3- (3-Morpholinophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone

2- [4 - ((4-fluorobenzyl) -piperidino) -2-hydroxypropoxy] -naphthalene, m.p. Mp 89-90 ° C

1- (4 - ((4-fluorobenzyl) -piperidino) -2-hydroxypropoxy] -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, mp 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 was heated to 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) -2-acetoxypropyl] -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-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 cool in an ice bath. After the addition of 106 mg of methyl iodide, the reaction mixture is stirred for 4 hours in the 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 as an oil.

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 N - (3,4-dimethoxyphenyl) ketone.

Example 9 (4-Fluoro-phenyl) - {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 azodicarboxylic acid diethyl ester are added and the reaction mixture is heated with stirring The solution was then treated with 50 ml of water and extracted with ethyl acetate, dried over the organic phase and concentrated and the residue was chromatographed on silica gel using methylene chloride / ethanol (9: 1). 264 mg 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 by methods known in the literature by alkylation

4- (4-fluorobenzoyl) -piperidine using 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.

Ή '.

< -3 and 30 * · 03 / ° 1 CZ —4 - < α i OC C3 05 / r— <3 □ 1 x O czx - ic -and < ΗΓΛ WHAT' O cn ΣΕ cn com> CG

nc <* C_. of

Claims (4)

PATENTOVÉ Claims 1. 1,4-Disubstituted piperidine derivatives of the general formula I-Z-Z-X-B (I). in which r! denotes a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridine group, a substituted or unsubstituted naphthalene group, a quinoline group, a substituted or unsubstituted isoquinoline group, a substituted or unsubstituted indole group, a substituted or unsubstituted benzothiophene group, a substituted or unsubstituted, substituted or unsubstituted a substituted or unsubstituted tetrahydroisoquinoline group, a substituted or unsubstituted tetralin group, a substituted or unsubstituted dihydronaphthalene group, a substituted or unsubstituted indane group, a substituted or unsubstituted tetralone group, a substituted or unsubstituted chromen-2-one group, and a stonite Z represents an oxygen atom, a sulfur atom, an SO group or an SC group> 2, X denotes - (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, and R are the same or different and denotes a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 Or (C 1 -C 6) alkanoyloxy; and R ⁴ denotes a straight or branched alkyl group having 1 to 6 carbon atoms, a group of the 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 a phenyl, benzyl, benzoyl, α-hydroxy-benzyl, pyridinyl or naphthyl group, the substituents may be the same or different, one to three times, wherein Y represents an oxygen atom, a sulfur atom or a -NH- group. as well as their physiologically acceptable salts. The 1,4-disubstituted piperidine derivatives according to claim 1 1 of formula I, which is {1- [3- (1-naphthyloxy) -propyl] -4-piperidyl} - (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-piperidyl} - ( 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) ) -keton 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-Fluoro-benzoyl) -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) {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-Fluoro-benzoyl) -1-piperidyl] -propoxy} -4-methyl-2H-chromen-2-one 4- {3- [4- (4-Fluoro-benzoyl) -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-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-fluorophenyl) -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-fluorophenyl) - {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- (1,2,3,4-tetrahydro-6-naphthyloxy) -propyl] -4-piperidyl} ketone. / A medicament for use as a compound according to claims 1 and 2. A process for the preparation of compounds of the formula I according to claim 1, characterized in that the process is carried out a) reacting a compound of formula II R ¹ - Z - Η (II), in which R 1 and Z are as defined above, with a compound of formula (III) - A — X — Ν Β (ΠΙ), in which X and B are as defined above and A denotes a leaving group or is b) reacting a compound of formula IV A - X - Z - R ^J (IV), in which X, Z and the meanings given above denote a leaving group, with an amine of the formula V 1 - V — Ν Β (V), in which B is as defined above, or is c) reacting an epoxide of the formula (VI): - Z - (CH 2) _{m -} CH - CH 2 (VI) » Η-N in which R ^1, Z am defined above, with an amine of the general Formula I / wherein B has the abovementioned meaning, or 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 ¹ - OH, in which R 2 is as defined above, and then the carbonyl group is reduced or hydroxyl the group esterifies or etherifies, or forms physiologically acceptable salts, or resolves isomers.