HUT75653A - 1,4-disubstituted piperidine derivatives acting on the glutamate receptor process for producing them and pharmaceutical compositions containing the said compounds - Google Patents

Description

The present invention relates to novel piperidine derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

Ά piperidine derivatives are known to have pharmacological effects and are suitable for e.g. psychotropic and cerebrovascular disorders. Surprisingly, it has now been found that the piperidine derivatives of the present invention functionally affect the glutamate receptor or its dependent ion channel.

The present invention thus relates to compounds of formula I and their physiologically tolerable salts and isomers; in this formula r! is optionally substituted phenyl, optionally substituted pyridine, optionally substituted naphthalene, optionally substituted quinoline, optionally substituted isoquinoline, optionally substituted indole, optionally substituted benzothiophene, optionally substituted benzofuran, optionally substituted tetrahydroquinoline, optionally substituted tetrahydroisoquinoline, a ···· ············································ · · · · · · ·

- 2 optionally substituted tetralin, optionally substituted dihydronaphthalene, optionally substituted indan, optionally substituted indanone, optionally substituted tetralone, optionally substituted chromen-2-one or optionally substituted naphthoquinone,

Z is oxygen, sulfur, -SO- or = SC> 2,

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 ,

B is CH-R ^4, and m, p, g is 0, 1, 2 or 3,

R ² and R ^{3 are the} same or different and are hydrogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 6 alkanoyloxy,

R ⁴ is a linear or branched C 1 -C 6 alkyl group, a group of formula (a) or optionally one to three identical or different substituents such as C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, Phenyl, benzyl, benzoyl, α-hydroxybenzyl, pyridinyl or naphthoyl containing CF ₃ or -O-CF ₂ ; and

Y is oxygen or sulfur or -NH-.

The ^R1 group is a tri-substituted with the following, the same or different groups selected from:

C 1-4 alkyl, C 1-4 alkoxy, halogen, nitro, hydroxy, -CF 3 or -O-CF ₂ , carboxyl, C 1-4 alkoxycarbonyl, formyl, ···· ······················································· ··

- C 3 -C 4 alkylcarbonyl, phenyl, phenoxy, benzyl,

-N (R ⁵ ) (R ⁶ ) or -SO ₂ -N (R ⁵ ) (R ⁶ ) wherein

R ⁵ and R ⁶ are the same or different and are selected from hydrogen, C 1-4 alkyl, phenyl or C 1-6 alkanoyl, or together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated hetero group which is mono- or polysubstituted It may be substituted with C 1-4 alkyl or phenyl and an additional 0, N or

It may contain an S atom.

The following are examples of the latter:

piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 2,6-dimethylmorpholine, phenylpiperazine ring (as a saturated heterocycle) and / or as the like. an imidazole, pyrazole, red or triazole ring (as an unsaturated heterocycle).

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

The alkyl group may be straight or branched, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, chair-butyl, pentyl, isopentyl and hexyl. The C 1 -C 6 alkanoyl group can be derived from straight or branched aliphatic carboxylic acids such as, e.g. formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid.

When R ^{1 is} substituted, the substituent may occupy any position. The following are referred to as R ¹ - groups:

Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1-naphthyl, 2-naphthyl. , isoquinolin-5-yl, isoquinolin-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-2-naphthyl, 7,8-dihydro-1-naphthyl, chromen-2-one -7-yl, chromen-2-one-4-yl, 1-oxo-1,2,3,4-tetrahydro-5-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 naphthoquinone.

Preferably Z is oxygen and X is preferably C 1-4 alkylene, which may be straight or branched and may be substituted at any position. Combinations with hydrated or non-hydrated naphthyl derivatives are particularly preferred.

The physiologically tolerable salts can be derived from inorganic and organic acids. Suitable inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or inorganic acids such as aliphatic mono- 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, e.g. C 1-4 alkanesulfonic acids such as methanesulfonic acid or benzenesulfonic acids optionally substituted with halogen or C 1-4 alkyl groups such as p-toluenesulfonic acid.

When an acid function is present, physiologically tolerable salts with organic and inorganic bases, such as e.g. highly soluble alkaline and

• »· · alkaline earth metal salts. As a base, e.g. the following may be mentioned: N-methylglucamine; dimethyl-glucamine; ethyl-glucamine; lysine; 1,6-hexadiamine; ethanolamine; glucosamine; sarcosine; serine; tris-hydroxymethyl aminomethane; amino-propane-diol; Sovak base; 1-amino-2,3,4-butane-triol.

The compounds of formula (I) include the possible optical isomers and mixtures thereof.

The compounds of formula (I) and their physiologically tolerable salts are prepared in a known manner by the following procedures:

a) reacting a compound of formula II, wherein R ¹ and Z are as defined, with a compound of formula III wherein X and B are as defined and A is a leaving group, or

b) reacting a compound of formula IV wherein X, R * - and Z are as defined and A is a leaving group - with an amine of formula V where B is as defined; or

c) reacting an epoxide of formula VI wherein R ¹ , Z and m are as defined, with an amine of formula V, wherein B is as defined; or

d) reacting a compound of formula VII, wherein X and B are as defined, according to Mitsunobu with a compound of formula R ¹ -OH, wherein R ¹ is as defined, and then reducing a carbonyl group if desired; Either a hydroxy group is esterified or etherified or physiologically tolerated salts are formed or the isomers are separated.

The nucleophilic displacement of the leaving group A is carried out in the usual manner according to a) and b) in an organic solvent inert under basic conditions. As a leaving group it is suitable e.g. a halogen atom (such as chlorine, bromine or iodine) or organic sulfonic acid ester residues such as an alkanesulfonic acid residue (e.g. mesylate, triflate) or an aromatic sulfonic acid residue (such as toluene sulfonic acid or bromobenzene-sulfonic acid residues).

Suitable inert organic solvents are polar solvents (such as dimethylformamide, dimethylacetamide, dimethylsulfoxide) or alcohols (such as ethanol, methanol) or cyclic ethers (such as dioxane, tetrahydrofuran), halogenated hydrocarbons, aromatic hydrocarbons or mixtures of the solvents listed above.

Suitable bases are inorganic and organic bases.

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

The reaction temperature can be selected from room temperature to the reflux temperature of the solvent.

Process c) e.g. in protic solvents such as alcohols (optionally up to reflux temperature) at elevated temperatures.

The Mitsunobi reaction - process d) can be carried out in the presence of triphenylphosphine and ethyl azodicarboxylic acid in inert solvents at higher temperatures or in the presence of an organic acid at room temperature (Synthesis 1, 1981). The reduction of the carbonyl group can be carried out using conventional reducing agents, e.g. sodium borohydride to the corresponding hydroxy compound or trimethylsilane and trifluoroacetic acid at room temperature to methylene carbonate.

If desired, the esterification may be carried out in a manner known per se with an active acid derivative, e.g. by reaction with an acid anhydride, an acid halide or an acid imidazolide.

Any etherification of the hydroxy group may be carried out in the conventional manner in the presence of a base, e.g. with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride.

The compounds of formula (I) can be isolated and purified from the reaction mixture in known manner. The acid addition salts can be converted into the free bases in the conventional manner and, if desired, the latter can be converted, if desired, into physiologically tolerable acid addition salts, e.g. by combining the solution with a concentrated solution of the desired acid.

When the compounds of formula (I) contain one or more chiral atoms, the optically active compounds may be prepared from optically active starting materials or from racemates in a known manner.

Enantiomers may be separated e.g. chroma on columns containing optically active carriers8 ········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - get - · · · · · · · · · · · · · · · · · · With reaction with an optic or optically active acids, followed by fractional crystallization.

The compounds of formula (I) and their physiologically tolerable salts can be used as medicaments by virtue of their functionally affecting the glutamate receptor or its dependent ion channel.

The pharmacological efficacy of the compounds of formula (I) is determined by the following assay.

Male NMRI mice weighing 18-22 g are housed under controlled conditions (6 to 18 hours light / dark rhythm, free food and water intake) and randomized. The groups consist of 5-16 animals. Groups were observed between 8 am and 1 pm.

AMPA is injected into the left brain ventricle of freely moving mice. The injection is performed by means of a device consisting of a brain cannula and an acid-proof steel structure attached thereto, which limits the injection depth to 3.2 mm. The device was connected to an injection pump. The needle was inserted perpendicular to the surface of the skull according to Montemurro-Dukelow coordinates. The animals were cloned or cloned. up to 180 seconds). Clonic movements that last for more than 5 seconds are considered as seizures. The onset of clonic seizures was considered as the end point for determining the seizure threshold. To raise or lower the seizure threshold by 50% The dose required to reduce the dose was determined using 4- THRD / q / 4-5 experiments. THRD ₅ q and confidence limits were determined by regression analysis.

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The results of these experiments indicate that the compounds of formula I and their acid addition salts influence the functional dysfunction of AMPA receptors. They are therefore suitable for the manufacture of a medicament for the symptomatic and preventive treatment of diseases resulting from changes in the function of the AMPA receptor complex.

Treatment with the compounds of the present invention prevents or inhibits. it delays the onset of cell damage and dysfunction as a result of the disease and reduces the symptoms that result.

Dysfunction and excitability of excitatory amino acids altered glutamatergic neurotransmission-mediated diseases include e.g. the next ones:

- neurodegenerative disorders, eg. Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, multiple infarction dementia, AIDS-related dementia, AIDS-derived encephalopathy, amyotrophic lateral sclerosis, olivopontocerebellar degeneration, epilepsy;

- cell damage caused by hypoglycemia, hypoxia, ischemia and disorders of energy metabolism;

- neuronal damage caused by brain damage such as stroke, brain trauma and asphyxia, and

- psychotic conditions, schizophrenia, panic disorder, pain, migraine and vomiting.

Some of the dysfunctions, such as memory disorders (amnesia), learning disabilities, insomnia, and withdrawal symptoms after chronic use of addictive substances (such as tranquillizers, hallucinogens, alcohol, cocaine and opiates), are also associated with glutamatergic neurotransmission.

The indication can be determined by standard pharmacological tests.

The present invention also relates to medicaments containing said compounds, to their preparation and to the use of the compounds according to the invention for the preparation of medicaments for the treatment and prevention of the listed diseases.

The drugs are prepared in a known manner by combining the active ingredient with suitable carriers, excipients and / or additives in the form of a pharmaceutical composition which can be enterally or parenterally administered. Administration can be in the form of a solid (capsule or tablet) orally or sublingually, or in the form of a solution, suspension, elixir or emulsion, or as a liquid. it may be administered rectally (in the form of a suppository) or optionally subcutaneously in the form of injection solutions. Suitable excipients for the pharmaceutical formulation of the desired form are inert inert organic and inorganic carriers known in the art, e.g. water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Optionally, preservatives, stabilizers, wetting agents, emulsifiers or salts (to change the osmotic pressure) or buffers may be added.

The pharmaceutical compositions may be in solid form (e.g., tablets, dragees, suppositories, capsules) or liquid (eg, solutions, suspensions or emulsions).

As excipients, surface-tensioning agents, e.g. salts of bile acids or animal or animal salts. phospholipids of vegetable origin, but mixtures thereof; liposomes and portions thereof may also be used.

In particular, tablets, dragees or capsules containing talc and / or carbohydrate carriers or excipients (such as lactose, corn or potato starch) are suitable for oral administration. The application may be in liquid form, e.g. as a drink to which optionally a sweetener is added.

Injectable solutions or suspensions are particularly suitable for parenteral administration, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil. The dosage of the active ingredient may vary depending on the route of administration, the age and weight of the patient, the type and severity of the disease being treated, and similar factors. The daily dose may be administered as a single dose or as a daily dose in divided doses of 2 or more times. The compounds are administered in dosage units of 0.05 to 100 mg of active ingredient in a physiologically tolerated vehicle. Generally, a dosage of 0.1 to 500 mg / day, preferably 0.1 to 50 mg / day, is used.

If the preparation of the starting compounds is not described, they are known or may be prepared in an analogous manner to known compounds or by methods described herein.

The following examples illustrate the preparation of compounds of formula (I).

Example 1

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

265 mg of 3-dimethylaminophenol are suspended in 20 ml of acetone, 265 mg of potassium carbonate and 824 mg of (4-fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl] are added. ketone and refluxed for 3 hours under argon. The organic phase is distilled off and the residue is chromatographed on silica gel with 1: 1 methylene chloride / acetone. 375 mg of the expected product are obtained; op 4 8 - 5 0 ⁰ C.

(4-Fluorophenyl) -1- [1- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone is prepared according to methods known in the art from 4- (4-fluorobenzoyl) piperidine. By alkylation of 3-bromopropan-1-ol with potassium carbonate in dimethylformamide and reaction of the product with methanesulfonic acid in the presence of triethylamine in methylene chloride.

The following compounds were prepared analogously:

{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, · * »· ··· · 1 · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·

- 13 Mp .: 110-111 ° C, {1- [3- (1-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone,

Mp: 61-64 ° C, {1- [3- (2-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone,

114-115 ° C, {1- [3- (3-dibutylamino-phenoxy) -propyl] -4-piperidyl} - (4-fluoro-phenyl) -ketone, {1- [3- (2-nitro) -1-naphthyloxy) propyl] -4-piperidin-1} - (4-fluorophenyl) ketone, {1- [3- (1-nitro-2-naphthyloxy) propyl] -4-piperidyl } - (4-fluorophenyl) ketone,

M.p. 137-138 ° C, {1- [3- (2,4-dinitro-1-naphthyloxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone, {1- [ 3- (3-phenylamino-phenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) ketone,

75-78 ° C, {1- [3- (1-Bromo-2-naphthyloxy) propyl] -4-piperidyl} - (4-fluoro ···· ···. «« • · · <«· · · · · · · · · · · · · · · · · · · ···

phenyl) ketone,

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) - {2- [3- (5-isoquinolyloxy) propyl] -4-piperidyl} ketone,

Mp: 31-33 ° C, (4-fluorophenyl) - {1- [3- (3-pyridyloxy) propyl] -4-piperidyl} ketone,

Mp: 52-55 ° C, (4-Fluorophenyl) - {1- [3- (3- (N-methylanilino) phenoxy) propyl] -4-piperidyl} ketone,

Mp: 75-77 ° C,

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

- {3- [4- (fluorobenzoyl) -1-piperidyl] propoxy} -3 ", 4-dihydronaphthalen-1 (2H) -one (oil), ···· ····

- 15 {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] -3-piperidyl} ketone (oil), (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,

Mp 139-140 ° C,

4- {3- [4- (4-Fluorobenzoyl) -1-piperidinyl] -propoxy} -2H-chromen-2-one,

Mp .: 132-133 ° C, · · · ·

- 16 {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, m.p.

Mp: 107-108 ° C.

Example 2

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

384 mg of {1- [3- (3-dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) ketone is added in portions at room temperature to a solution of 80 mg of sodium borohydride in 15 ml of ethanol contain. After stirring for 4 hours, the reaction mixture was neutralized, diluted with water and extracted with ethyl acetate. After removal of the organic phase by drying, the residue is evaporated and the product is chromatographed on silica gel with 1: 1 acetone: methylene chloride. 154 mg of 1- {1- [3- (3-dimethylaminophenoxy) propyl] -4-piperidyl} - (4-fluorophenyl) methanol are obtained; mp 63-64 ° C.

The following compounds were prepared analogously:

1- {1- [3- (1-naphthyloxy) propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol, 1- {1- [3- (2-naphthyloxy) ) -propyl] -4-piperidyl} -1- (fluorophenyl) methanol,

- ______ ____________._____________ .-. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

1 «·········· · · ··· · ·

- 17 ° C: 136-137 ° C. Example 3 (3-Dimethylaminophenyl) -3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether Triethylsilane is added dropwise to a solution of 384 mg of {1- / 3- Contains (3-dimethylaminophenoxy) propyl-4-piperidinyl} -4-fluorophenyl ketone in 25 ml trifluoroacetic acid. The reaction mixture was stirred for 3 days. After evaporation to dryness, the residue is taken up in ether and extracted three times with IN HCl. The combined extracts were basified to pH, extracted with ether, dried and evaporated. 197 mg (3-dimethyl-1-aminophenyl) - {3- [4- (4-fluorobenzyl) -1-piperidyl] propyl} ether are obtained as an oil.

The following compounds were prepared analogously:

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- [1- (3-benzyloxy-Dimeti1-aminophenyl) butyl} -4-piperidyl} - (4-fluorophenyl) ketone

(4-Chlorobutyl) - (3-dimethylaminophenyl) ether (630 mg) in formamide (25 ml) was stirred at 100 ° C for 8 hours under argon atmosphere with 950 ml of 4- (4-fluorobenzoyl) piperidine and • · · ·

——— · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · More More ·

- 18 after adding 0.5 ml of triethylamine. The solvent was distilled off and the residue was taken up in methylene chloride and washed once with water and once with brine. The organic phase is dried, filtered and evaporated. The residue was chromatographed on silica gel with 1: 1 acetone: methylene chloride to give 420 mg of the title compound.

The starting material (4-chlorobutyl) - (3-dimethylaminophenyl) ether was prepared by etherification of 3-dimethylaminophenol with 1-bromo-4-chlorobutane in the presence of potassium carbonate, dimethylformamide.

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

From 590 mg of (2-chloroethyl) - (3-dimethylaminophenyl) ether and 950 mg of 4-fluorobenzoylpiperidine in analogy to the procedure of Example 4, 590 mg of the title product are obtained in the form of an oil. .

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

(3-Dimethylaminophenyl) (2,3-epoxypropyl) ether (380 mg) was dissolved in methanol (50 mL) and 4- (4-fluorobenzoyl) piperidine (430 mg) was added. After heating for 3 hours, the solvent was distilled off, the residue was taken up in 50 ml of 1N HCl and extracted several times with chloroform. The aqueous phase was basified to pH 2N with sodium hydroxide and extracted with ethyl acetate. The combined ethyl acetate layers were washed, dried, filtered and evaporated. The residue was chromatographed on silica gel with 1: 1 acetone: methylene chloride. 446 mg of the expected product are obtained; mp 117-119 ° C.

The starting material (3-dimethylaminophenyl) - (2,3-epoxypropyl) ether was prepared by reacting 3-dimethyl-1-aminophenol with epichlorohydrin in the presence of sodium hydride in dimethylformamide.

The following compounds were prepared analogously:

(3- [4- (4-Fluoro-benzyl) -piperidino) -2-hydroxy-propoxy] -dimethyl-aminoaniline,

Mp: 85-87 ° C, {1- [3- (3-morpholinophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone, m.p.

2- [4- (4-fluoro-benzyl) piperidino) -2-hydroxy-propoxy] naphthalene,

Mp: 89-90 ° C, (1- [4- (4-fluorobenzyl) piperidino) -2-hydroxypropoxy] naphthalene, m.p.

Mp .: 104-105 ° C, {1- (3- [1-naphthoxy) -2-hydroxypropyl] -4-piperidyl} -4-fluorophenyl) ketone, m.p.

- 20 - {1- [3- (2-naphthyloxy) -2-hydroxypropyl] -3-piperidyl} - (4-fluorophenyl) ketone,

136-137 ° C, (4-Fluorophenyl) - {1- [3- (1-oxo-1,2,3,4-tetrahydro-5-naphthyloxy) -2-hydroxypropyl] -4-piperidinyl} methanone,

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-acetoxynophthyl] -4-piperidyl} - (4-fluorophenyl) ketone

250 mg of {1- [3- (3-dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} (4-fluorophenyl) ketone are dissolved in 10 ml of dry pyridine. After adding 0.15 ml of acetic anhydride, the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel with 1800: 75 methylene chloride: ethanol. 125 mg of the title compound are obtained in the form of an oil.

• · · ·

- 21 In an analogous manner, the following compounds were prepared:

2- [4- (4-Fluoro-benzyl) -piperidino-2-acetoxy-propyl] -naphthalene, {1- [3- (1-naphthyloxy) -2-acetoxy-propyl] -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 mg of {1- [3- (3-Dimethylaminophenoxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone are dissolved in 10 ml of ethylene glycol dimethyl ether, 20 mg (90%) sodium hydride are added and the mixture is cooled in an ice bath. After addition of 106 mg of methyl iodide, the reaction mixture was cooled for 4 hours and stirred at room temperature for 1 hour. After evaporation of the organic phase, the residue was chromatographed on silica gel with 1800: 75 methylene chloride: ethanol. 150 mg of the title compound are obtained in the form of an oil.

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- 22 In an analogous manner, the following compounds were prepared:

2- [4- (4-Fluoro-benzyl) -piperidino) -2-methoxy-propoxy] -naphthalene, {1- [3- (1-naphthyloxy) -2-methoxy-propyl] -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) -11- [3- (1,2,3,4-tetrahydro-5-naphthyloxy) propyl] -4-piperidinyl} ketone

200 mg 1,2,3,4-tetrahydro-5-naphthol in 25 ml p.a. dissolved in tetrahydrofuran, 700 mg of (4-fluorophenyl) -1- [1- (3-hydroxypropyl) -4-piperidyl] ketone, 700 mg of triphenylphosphine and 0.45 ml of azodicarboxylic acid are added to the solution. After stirring for 20 minutes at 80 DEG C., 50 ml of water are added to the reaction mixture, which is extracted with ethyl acetate, the organic phase is distilled off and the residue is chromatographed on silica gel with 9: 1 methylene chloride: ethanol 26. mg of the expected product is obtained.

(4-Fluorophenyl) -1- [1- (3-hydroxypropyl] -4-piperidyl] ketone can be prepared by methods known in the art from 4 · ·

- 23 - (4-Fluorobenzoyl) -piperidine by alkylation with 3-bromopropan-1-ol in the presence of potassium carbonate in dimethylformamide.

The following compounds may be prepared analogously:

(4-Fluorophenyl) - {1- [3- (indan-4-yloxy) -propyl] -4-piperidyl} ketone,

Mp 70-72 ° C, (4-fluorophenyl) -1- [3- (indan-5-yloxy) propyl] -4-piperidyl} ketone, m.p.

49-52 ° C, (3,4-difluorophenyl) {1- [3- (indan-4-yl-oxy) propyl] -4-piperidyl} ketone, {1- [3- (4-Benzyl-phenoxy) -propyl] -4-piperidyl} - (4-fluoro-phenyl) -ketone,

Mp .: 105-107 ° C, (4-Fluorophenyl) {1- [3- (1,2,3,4-tetrahydro-6-naphthyloxy) propyl] -4-piperidyl} ketone.

Claims (4)

PATENT CLAIMS 1.) Compounds of formula I and their physiologically tolerable salts and isomers; in which R ¹ is C 1-4 alkyl, -CF ₂ , -OCF 8, hydroxy, carboxyl, C 1-4 alkoxycarbonyl, formyl, phenoxy, benzyl, -NR ⁵ R® or - SO ₂ NR ⁵ R ⁶ substituted phenyl, optionally substituted pyridine, optionally substituted naphthalene, optionally substituted quinoline, optionally substituted isoquinoline, optionally substituted indole, optionally substituted benzothiophene, optionally substituted benzofuran- , optionally substituted tetrahydroquinoline, optionally substituted tetrahydroisoquinoline, optionally substituted tetralin, optionally substituted dihydronaphthalene, optionally substituted indane, optionally substituted indanone, optionally substituted tetralone, optionally substituted chromene-2- on or optionally substituted naphthoquinone ring, R ⁵ and R ^s are the same or different, are hydrogen atoms, with C 1-4 alkyl, phenyl or C 1-6 alkanoyl group or with the nitrogen atom a 5- or 6-membered saturated or unsaturated heterocyclic group can form a mono- or poly- It may be substituted with C 1-4 alkyl or phenyl and may contain an additional 0, N or S atom, Z is oxygen, 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 , B is CH-R ^4, and m, p, g is 0, 1, 2 or 3, R ² and R ^{3 are the} same or different and are selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy or C 1-6 alkanoyloxy, R ⁴ is a straight or branched C 1 -C 6 alkyl group, a group of formula (a) or optionally one to three identical or different substituents such as C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy. A phenyl, benzyl, benzoyl, α-hydroxybenzyl, pyridinyl or naphthoyl group containing -CF ₃ or -O-CF ₂ ; and Y is oxygen or sulfur or -NH-. 2.) {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, - 26 ···· ···· ·········································································································································································································································································· · · {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) ketone, 1- {1- [3- (1-naphthyloxy) propyl] -4-piperidyl} -1- (4-fluorophenyl) methanol, 1- {1- [3- (2-naphthyloxy) propyl] -4-piperidyl} -1- (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-Fluorobenzyl) -1-piperidyl] -propoxy} -indan-1-one. - 27 5- (3- [4- (fluorobenzoyl) -1-piperidyl] propoxy} -3,4-dihydronaphthalen-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-Fluoro-benzoyl) -1-piperidyl] -propoxy} -2H-chromen-2-one, 7- (3- [4- (4-Fluoro-benzoyl) -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-Fluoro-benzyl) -piperidino) -2-methoxy-propoxy] -naphthalene, ···· «··· '· · · · · · · · {1- [3- (1-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluoro) phenyl) ketone, {1- [3- (2-naphthyloxy) -2-methoxypropyl] -4-piperidyl} - (4-fluorophenyl) ketone, {1- [3- (1-naphthyl) (oxy) -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-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} methanone. 3.) Pharmaceutical compositions containing the compounds according to claim 1 or 2. 4.) A process for the preparation of the compounds according to claim 1, characterized in that a) reacting a compound of formula II, wherein R ¹ and Z are as defined, with a compound of formula III wherein X and B are as defined and A is a leaving group, or b) reacting a compound of formula IV, wherein X, R ¹ and Z are as defined and A is a leaving group, with an amine of formula V, wherein B is as defined, or ··· · -4 »* ···» * · «· · · · · · · · · · · · · · · · · · · · · · · · · · - 29 (c) reacting an epoxide of formula (VI) wherein R ¹ , Z and m are as defined, an amine of formula (V) in which B is as defined; or d) reacting a compound of formula VII, wherein X and B are as defined, according to Mitsunobu with a compound of formula R ¹ -OH, wherein R ¹ is as defined, and optionally reducing a carbonyl group; or esterifying or etherifying a hydroxy group or forming physiologically tolerable salts or separating the isomers.