MXPA96004201A

MXPA96004201A - New piperid derivatives

Info

Publication number: MXPA96004201A
Application number: MXPA/A/1996/004201A
Authority: MX
Inventors: Huth Andreas; Seidelmann Dieter; Turski Lechoslaw; Kruger Martin; Ottow Eckhard; Neuhaus Roland; Jones Jones Graham
Original assignee: Schering Ag 13353 Berlin De
Priority date: 1994-03-24
Filing date: 1996-09-20
Publication date: 1998-09-18

Abstract

Compounds of the formula I are described: R1-Z-X-N B as well as its production and use in pharmaceutical agents

Description

NEW DERIVATIVES OF PIPERIDINE DESCRIPTION OF THE INVENTION The invention relates to novel piperidine derivatives, process for their production and pharmaceutical agents containing those compounds. It is known that piperidine derivatives have pharmacological actions and are suitable, for example, for treating psychotropic and cerebral vascular problems. It has now been found, which is quite surprising that the piperidine derivatives according to the invention functionally influence the glutamate receptor or the ion channels dependent on the glutamate receptor. The object of the invention are the compounds of the formula I wherein R1 means substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted tetrahydroquinoline, substituted tetrahydroissquinoline or unsubstituted, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalase, substituted or unsubstituted indane, substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromen-2-one, substituted or unsubstituted naphthoquinone, Z means oxygen, sulfur, SO or SO2, X signifies - (CH2) m-CR2R3- (CH2) P or, - (CH2) m -CHR2- (CH2) a -CHR3_ (CH2) P-, B means ^ CH- ^. and m, p, g mean each 0, 1, 2 or 3, R2 and R3 are the same or different and mean hydrogen, hydroxy, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or alkanoyloxy with 1 to 6 carbon atoms, R "* means alkyl having from 1 to 6 carbon atoms or -CQ- | Y straight or branched chain or a phenyl, benzyl, benzoyl, a-hydroxybenzyl, pyridinyl or naphthoyl optionally with alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, halogen, hydroxy, -CF3 or -O-CFs, in? a. p- fti p-- SwWti-tiy & .ß p ßtáfe be equal or different in one to three places, and Y means oxygen, asuf eo -NH-, as well as their physiologically compatible salts and isomers.If R1 is substituted, the substituent may be the same or different in one to three places with alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, halogen, NO2, CF3, -OCF3, hydroxy, carbonyl, carbonyl, alkoxylated bonyl with 1 to 4 carbon atoms, formyl, alkylcarbonyl with 1 to 4 carbon atoms, phenyl, phenoxy, benzyl, R5 and R6 being the same 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 saturated or unsaturated 5- or 6-membered heterocycle, which may be substituted in one or more places with alkyl having 1 to 4 carbon atoms or phenyl and may contain another O, N or S atom.

For example, piperidine, pyrrolidine, morpholine, thiomorpholine, piperazine, N-methylp > iperazine, 2,6-dimethylmorpholine, phenylpiperazine such as saturated heterocycle and imidazole, pyrazole, pyrrole or triazole as unsaturated heter- nocycle. Halogen is defined as fluorine, chlorine, bromine or iodine. Alkyl is respectively a straight or branched chain alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl sec. pentyl, isopentyl, hexyl. The alkanoyl radical with 1 to 6 carbon atoms is in each case derived from straight or branched chain aliphatic carboxylic acids such as for example, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, pentyl, isopentyl, hexyl. The alkanoyl radical having 1 to 6 carbon atoms is each derived from straight or branched chain aliphatic carboxylic acids such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid. If R1 is substituted the substituent can be in any position. As radical R1, there may be mentioned by way of example: pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1-naphthyl, 2-naphthyl, isoquinolin-5-yl, isoquinolyl-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-l-naphthyl, chromen-2-on-7-yl, chromen-2-on-4-yl, 1-oxo-l, 2, 3 , 4-tetrahydro-5-naphthyl, 1-oxo-1, 2,3, 4-tetrahydro-6-naphthyl, 2-oxo-l, 2,3,4-tetrahydro-5-naphthyl, 2-oxo-l , 2,3, 4-tetrahydro-6-naphthyl, indan-4-yl, indan-5-yl, indan-l-one-4-yl, naphthoquinone. Oxygen can be considered a preferred meaning of Z, and alkylene with 14 carbon atoms which can be straight or branched chain and can be substituted in any position, can be cited as the preferred meaning of X. Especially preferred are the combinations with derivatives of hydrogenated or non-hydrogenated naphthyl. The physiologically acceptable salts are derived from inorganic or organic acids. Inorganic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids, such as for example aliphatic or aromatic mono- or dicarboxylic acids, such as formic acid, acetic acid; aleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example alkanesulfonic acids with 1 to 4 carbon atoms, such as methanesulfonic or benzenesulfonic acid, such as acid p-toluenesulfonic, optionally substituted with halogen or alkyl with 1 to 4 carbon atoms. If an acid function is contained, the physiologically acceptable salts of the organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkaline and alkaline earth salts, as well as N-methylglucamine, dimethylgluca ina, ethylgluca ina, lysine, and the like. , 6-hexandiamna, ethanolamine, glucosamine, sacrosine, serinol, tris (hydroxymethyl) aminomethane, aminopropanediol, base Sovak, l-amino-2, 3, 4-butanetriol. The compounds of formula I comprise all possible optical isomers and their mixtures. The production of the compounds of the formula I and their physiologically compatible salts takes place in a manner known in the art, by a) reacting a compound of the formula II Ri-ZH (II), in which R1 and Z have the previous meaning, with a compound of formula III AX -O (III) in which X and B have the meanings given above and A represents a starting group, or b) a compound of formula IV in which X, Z and Rl have the above meaning and A represents a group starting, which is reacted with an amine of the formula V in which B has the above meaning, or c) an epoxide of the formula VI Ri-Z-ÍCHs in which R1, Z and m have the above meaning, is reacted with an amine of the formula V or d) a compueto of formula VIII HO-X-N B (VII) wherein X and B have the above meaning, is reacted with a compound of the formula R ^ -OH according to Mitsunobu and then optionally a carbonyl group is reduced or a hydroxy group is esterified or the physiologically compatible salts are formed or the isomers are separated. The nucleophilic substitution of the group of paertide A according to the variants of processes a) and b) is carried out under basic conditions according to the usual methods in a solvent which is inert under the reaction conditions. Suitable starting groups A, for example, are suitable chlorine, bromine or iodine or organic sulphonic acid radicals such as the alkanesulfonic acid radical, for example mesylate, triflate or the radical of an aromatic sulfonic acid, for example toluenesulfonic acid or bromobenzenesulfonic acid. . As inert organic solvents, polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or alcohols such as tanol, methanol or cyclic ethers such as dioxane, tetrahydrofuran, halogenated hydrocarbons are suitable. aromatic hydrocarbons or mixtures of the mentioned solvents. Suitable bases are inorganic and organic bases. Examples of organic bases are alkaline or alkaline earth hydroxide, alkaline earth carbonates, alkaline earth hydrocarbonates, alkaline earth alloyholates. Examples of organic bases are tertiary organic amines. Examples of organic bases are tertiary organic amines, such as tyramine ina, triethylamine, N-alkylmorpholine, N-alkylpipoeridine, Hünig's base, 1,4-diazabicyclo (2, 2, 2) ocatane, 1,5-diazabicyclo (5,4,0) undec-5-ene. The reaction temperature can be between room temperature and the boiling temperature of the solvent. The reaction according to process c) takes place, e.o. in protic solvents, such as alcohols at elevated temperatures up to the boiling temperature. The reaction according to Mitsunobi (process d) is carried out in the presence of triphenylphosphine and ethyl ester of azodicarboxylic acid in an inert solvent at elevated temperatures or in the presence of an organic acid at room temperature (Synthesis, 1981, 1). The reduction of the carbonyl group can be carried out with reducing agents which are commonly used, for example with sodium borohydride, the corresponding hydroxy compound or with triethylsilane and trifluoroacetic acid at room temperature to a methylene compound.

If it is desired to esterify this, it is carried out in a manner known in the art by means of the reaction with an activated acid derivative, such as, for example, acid anhydride, acid halide or acid imidazolide. The optional esterification of the hydroxy group is carried out according to the usual methods in the presence of bases, for example by the reaction with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride. The compounds of the formula I can be isolated from the reaction mixture and purified in a manner known in the art. The acid addition salts can be converted in the same way to free bases and the latter to physiologically compatible acid addition salts, for example when mixing the solution with a concentrated solution of the desired acid. If the compounds of the formula I have one or more chiral atoms, the optically active compounds can be obtained starting from optically active starting compounds or in a manner known in the art from the race. The separation of enantiomers can be carried out, for example, by means of chromatography on optically active vehicles. By means of the reaction with optically active acids and then fractional crystallization.

The compounds of the formula I as well as their physiologically compatible salts can be used as pharmaceutical agents based on their functional effect on the glutamate receptor or the ion channels dependent on the glatamate receptor. The pharmacological effectiveness of the compounds of the formula I was determined by the tests described below: Male NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 light / dark cycle hours, with free access to food and water) and its assignment to groups was random. The groups consisted of 5-16 animals. The observation of the animals took place between 0800 and 1300 hours. AMPA was sprayed into the left ventricle of free-moving mice. The applicator consisted of a cannula with a device made of stainless steel, which limits the injection depth to 3.2 mm. The applicator was connected to an injection pump. The hypodermic needle was inserted perpendicular to the surface of the skull according to the coordinates of Monte urro and Dukelo. The animals were observed until clonic or tonic seizures of up to 180 seconds occurred. The clonic movements, which lasted more than 5 seconds, were counted as seizures. The onset of clonic seizures was used as an extreme point for the determination of the seizure threshold. The dose that was necessary to increase or decrease the seizure threshold by 50% (THRDso) was determined in 4-5 experiments. The THRDeo limit and the confidence limit were determined in a regression analysis. The results of these tests show that the compound of formula I and its acid addition salts cause functional disturbances of the AMPA receptor. They are therefore suitable in the production of pharmaceutical agents for the preventive and symptomatic treatment of diseases, which are caused by a change in the function of the AMPA receptor complex. The treatment with the compounds according to the invention prevents or retards cell damage and functional problems that occur due to the disease and reduce the symptoms that occur in that way. The diseases that can be caused by the dysfunction of exitatory amino acids or changes of neurotransmission are part of, for example, neurodegenerative problems such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, dementia due to multiple infarctions, AIDS dementia. , AIDS encephalopathy, amyotrophic lateral sclerosis, olivopontocerebellar degeneration, epilepsy; cellular damage due to hypoglycemia, hypoxia, ischemia and problems of energy metabolism, neuronal damage. which are caused by brain damage, such as ischemia, brain trauma and asphyxia, if as psychosis, schizophrenia, anxiety conditions, fear attacks, migraines and vomiting. Also functional problems such as lack of memory (amnesia), problems in the learning process, surveillance symptoms and symptoms of deprivation after the pharmaceutical intake of diagnostic agents such as pharmaceutical agents based on sedatives, hallucinogens, alcohol, cocaine and opium in the dysfunction of glutamatergic neurotransmission. The indications can be shown by commonly used pharmacological tests. The invention also comprises the pharmaceutical agents containing the aforementioned compounds, their production as well as the use of the compounds according to the invention for the production of pharmaceutical agents, which are used for the treatment and prophylaxis of the aforementioned diseases. The pharmaceutical agents are produced in accordance with the processes known in the art, by placing the active ingredient with suitable vehicles, adjuvants and / or additives in the form of a pharmaceutical preparation, which is suitable for enteral or parenteral administration. The administration can be performed orally or subvlingually as solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs or emulsions or rectally in the form of suppositories or in the form of subcutaneously useful injection solutions. As auxiliaries for the desired pharmaceutical formulation, organic and inorganic carriers are known to those skilled in the art, such as for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. In addition, preservatives, stabilizers, humectants, emulsifiers or salts to change the osmotic pressure or buffers. The pharmaceutical preparations can be present in solid form, for example tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. As vehicle systems, auxiliaries such as bile acid salts or animal or vegetable phospholipids, but also their mixtures as well as liposomes or their components can be used. For oral use, tablets, coated tablets or capsules with talc and / or hydrocarbon vehicles or binders, such as for example lactose, corn starch or potato starch, are especially suitable. The use can also be carried out in liquid form such as, for example, a juice, to which a sweetener is optionally added. For parenteral use, solutions or suspensions for injection, especially aqueous solutions of active compounds in polyhydroxyethoxylated castor oil, are especially suitable. The dosage of the active ingredients may vary depending on the type of use, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dosage can be given as a single dose to be administered once or divided into 2 or more daily doses. The compounds are linked in a unit dose of 0.05 to 100 mg of active substance in a physiologically compatible vehicle. In general, a dose of 0.1 to 500 mg / day, preferably 0.1 to 50 mg / day is used. If the production of the starting compounds is not described, they are known or can be produced analogously to the known compounds or processes described herein. The following examples are to explain the production of the compounds of the formula I: Example 1 1-R3- (3-di? N-phenylamino-phenoxy? -propi-4-piperidyl) -1- (4-fIUQGQ phen) 1 -ketone, 265 mg of 3-dimethylaminophenyl are introduced into 20 ml of acetone, mixed with 265 mg of acetone. potassium carbonate and 824 mg of (4-flurophenyl) - [l- (3-methylsulfonyloxypropyl) -4-piperidyl] -ketone and refluxed under argon for 3 hours after the organic phase is concentrated by evaporation, chromatography on silica gel with methylene chloride and acetone = 1 + 1. 375 mg of. {l-l- [3- (dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -cetoma are obtained. , boiling point 48-50 [deg.] C. The (4-flurophenyl) -l- [l- (3-methylsulfonyloxypropyl) -4-piperidyl] -ketone is obtained according to the methods known in the literature by means of alkylation of 4- (4-fluorobenzoyl) -piperidine with 3-bromopropanol-1 and potassium carbonate in dimethylformamide and the subsequent reaction with methanesulfonic acid and triethylamine in methylene chloride. in: {. l- [3- (2-dimethylaminophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { 1-C3- (4-dimethylaminophenoxy) -propi1] -4-piperidyl} - (4-fluorophenyl) -ketone. { 1- [3- (3-morpholinophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 110-111 ° C. { 1- [3- (1-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 61-64 ° C. { 1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, mp 114-115 ° C. { 1- [3- (3-dibutylaminophenoxy) -propyl] -4-? iperidyl} - (4-fluorophenyl) -ketone, melting point. { 1- [3- (2-nitro-l-naphthyloxy) -propyl-4-piperidyl} - (4-fluorophenyl) -ketone. { l-C3- (1-nitro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, boiling point 137-138ßC. { 1- [3- (2, 4-dinitro-1-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone,. { 1- [3- (3-anilinophenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 75-78 ° C. { 1- [3- (l-bromo-2-naphthyloxy) -propi1] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 97-100 ° C. { l- [3- (4-Chloro-l-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { 1- C3- (3-acetyl inophenoxy) -propy1] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 108-111 ° C (4-fluorophenyl) -. { l- [3- (5-Isoquinolyloxy) -propyl] -4-piperidyl} -ketone, melting point 31-33 ° C (4-fluorophenyl) -. { 1- [3- (3-pyridyloxy) -propyl] -4-piperidyl} -ketone, melting point 52-55 ° C (4-fluorophenyl) -. { 1- [3- (N-methylanilino) -phenoxy) -propyl] -4-pi? eridyl} -ketone, melting point 75-77 ° C 4-. { 3- [4- (4-flurobenzoyl) -l-piperidyl] -propoxy} -indan-1-one, melting point 126-127 ° C 5-. { 3- [4- (flurobenzoyl) -l-piperidyl] -propoxy} -3,4-dihydronaphthalene-1 (2H) -one, (oil). { l- [3- (7,8-Dihydro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 72-74 ° C. { l- [3- (7,8-Dihydro-2-naphthyloxy) -propyl] -4- pipe idyl} - (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-y1) -phenoxy) -propyl] -4-piperidyl} -ketone (oil) (4-fluorofeni1) -. { 1- [3- (4-hydroxy-3, 5-di-te. -butyl-phenoxy) -propyl-4-piperidyl} -cetone 7-. { 3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy} -2H-chromen-2-one, melting point 128-129 ° C 7-. { 3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy} -4-methyl-2H-chromen-2-one, melting point 139-140 ° C 4-. { 3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy} -2H-chromen-2-one, melting point 132-133 ° C. { 1- [3- (6-Bromo-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 126-127ßC. { 1 [3- (2-naphthyloxy) -propi1] -4-piperidyl} - (4-fluorophenyl) -ketone, melting point 126-127 ° C. { l [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (3,4-dimethoxyphenyl) -ketone, melting point 107-108 ° C. Example 2 l-. { l-r 3 - (3-dimethylaminophenoxy-t > ropin-4-piperazidyl < -1- (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 15 ml of ethanol and 80 mg of sodium brohydrate, after 4 hours of stirring.The reaction solution is neutralized, it is mixed with water and then extracted with ethyl acetate. After the organic phase has dried, it is concentrated by evaporation, and the residue is chromatographed on silica gel with acetone plus methylene chloride = 1 +1. 154 mg of l-. { 1- [3 - (- Di-ethylane-phenoxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ethanol, mp 63-64"were obtained, and the following are also produced: l-. {L- [3- (1-naphthyloxy) -propyl] -4-piperidyl.} .l- (4-fluorophenyl) -methanol, l- { l- [3- (2-naphthyloxy) -propyl] -piperidyl}. -l- (4-fluoropheniD-ethanol, mp 136-137 °. EXAMPLE 3 (3-Dimethylaminophenyl-3T4-f4-fluorobenzyl) -l-PIPrisridi 11-propyl ether 2g of triethylsilane is added dropwise to a solution of 384 mg of. {L-l- [3- (3-dimethylaminophenoxy) - propyl] -4-piperidyl.} - (4-fluorophenyl) -ketone in 25 ml of trifluoroacetic acid The reaction mixture was stirred for 3 more days, then evaporated to dryness and the residue was taken up in ether and The mixture was stirred three times with 1N HCl, the combined extracts were made basic, extracted with ether, dried and concentrated by evaporation, 197 mg of (3-dimethylaminophenyl) -. {3- [4- (4-fluorobenzyl) -l- pipridyl] -propyl.} -ether were obtained Analogously, l-naphthyl- (3- (4- (4-fluorobenzyl) - l-piperidyl) -propyl) -ether 2-naphthyl- (3- (4- (4-fluorobenzyl) -l-piperidyl) -propyl) -ether, melting point 79-80 °. Example 4 fl-Ri-f3-dimethylaminophenyloxy) -butyl-l-4- piperldi1 \ - (4-fluorophenyl) -ketone 630 mg of (4-chlorobutyl) - (3-dimethylaminophenyl) -ether are stirred in 25 ml of dimethylformamide with 959 mg of 4- (4-fluorobenzoyl) -piperidine and 0.5ml of triethylamine a 100 ° in a bath for 8 hours under argon. After the solvent had been distilled, it was taken up in methylene chloride and washed each time with water and a saturated solution of common salt, the organic phase was dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 420 mg of 1- (1- (3-dimethylaminophenoxy) -butyl) -4-piperidyl) - (4-fluorophenyl) ketone were obtained. The (4-chlorobutyl) - (3-dimethylaminophenyl) ether required as the starting material is obtained by the etherification of 3-dimethylaminophenol with l-bromo-4-chlorobutane and potassium carbonate in dimethylformamide. Example 5 fl-Ri-f3-dimethylaminophenyloxy-ethyl-1-4-pyrididyl > (4- (4-enyl) -netone There were obtained 590 mg of (1- (1- (3-dimethylamino-enoxy) -ethyl) -4-? Iperidyl) - (4-fluorophenyl) -ketone (oil) from 590 mg of (2-chloroethyl) - (3-dimethylaminodenyl) -ether and 950 mg of 4- (fluorobenzoyl) -piperidine in a manner analogous to the process according to example 4.

Example 6 { 1-r3- < 3-dimethylamino enoxi -2-hydroxyproj11-4-piperidyl > - (4-fluorophenyl-ketone 380 mg of (3-dimethylaminophenyl) - (2,3-epoxypropyl) -ether was dissolved in 50 ml of methanol and mixed with 430 mg of 4-) 4-fluorobenzoyl) -piperidine. After 3 hours of heating, the solvent was distilled off, the residue was taken up in 50 ml of 1N hydrochloric acid and extracted several times with 1 chloroform. the aqueous phase was made alkaline with 2N sodium hydroxide in solution and then extracted with ethyl acetate. The combined phases of ethyl acetate were washed, dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 446 mg of (1- (3- (3-dimethylaminophenoxy) -2-hydroxypropyl) -4-piperidyl) - (4-fluorophenyl) were obtained. ) -cetone, p. F. 117-119 °. The (3-dimethylaminophenyl) - (2,3-epoxypropyl) -ether required as a starting material is obtained by the reaction of 3-dimethylaminophenol with epichlorohydrin and sodium hydride in dimethylformamide. Analogously, there were obtained: 3- (- (4-fluorobenzyl) -piperidino) -2- hydroxypropoxy) -dimethylaminoaniline, mp 85-87 °. (1- (3- (3-morpholinophenoxy) -2-hydroxypropyl) -4-piperidyl) - (4-fluorophenyl) -ketone 2-) 4- (4-fluorobenzyl) -piperidino-1-2-hydroxypropoxy) -naphthalene, pf 89-90 ° 1- (4- (4-fluorobenzyl) pi? Eridino) -2-hydroxy? Ropo i) -naphthalene, P.F. 104-105 ° (l- (3- (l-naphthyloxy) -2-hydroxypropyl) -4-piperidyl) -4-fluorophenyl (-ketone (1- (3- (2-naphthyloxy) -2-hydroxypropyl) -4 -piperidyl) - (4-fluorophenyl) -ketone, PF 136-137 ° (4-fluorophenyl) - (1- (3- (1-oxo-1, 2, 3, 4-tetrahydro-5-mafthyloxy) -2- hydroxypropyl) -4-piperidyl) -ketone, PF 128-131 ° (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-pipe? Idil ) - (3, 4-fluorophenyl) -ketone Example 7 { L-r3- (3-dimethylaminQfenQxl) -2-acetPXIpropyl1-4- pjperidylI-f4-luo-phenyl) -ketone 250 months of (l- (3- ( 3-dimethylaminophenoxy) -2- hydroxypropyl) -4-piperidyl) - (4-fluorophenyl) -ketone were dissolved in 10 ml of dry pyridine. Then O.ldml of acetic anhydride was added, and it was heated to reflux for 3 hours. After cooling, the reaction mixture was concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel with methylene chloride + ethanol = 1800 +75. 125mg of (1- (3- (3-dimethylaminophenoxy) -2-acetoxy-propyl) -4-piperidyl) -) 4-fluorophenyl) -ketone (as oil) was obtained. Analogously, there were obtained: 2- (4- (4-fluorobenzyl) -piperidino) -2-acetoxipropoxy) -naphthalene (1- (3- (1-naphthyloxy) -2-acetoxypropyl) -4-piperidyl) - (4-fluorophenyl) ) -ketone (l- (3- (2-naphthyloxy) -2-acetoxypropyl) -4-piperidyl) - (4-fluorophenyl) -ketone (1- (3- (l-naphthyloxy (-2-acetoxypropyl) -4 -piperidil) - (3, 4-difluorophenyl) -ketone Example 8. { l-r3- (3-D-methalaminophenoxy-2-ethoxypropyl-1-4-piperidyl- (4-fluorophenyl) -ketone 250 mg of (1- (3- (3-dimethylaminophenoxy) -2-hydroxypropyl) -4-piperidyl) were dissolved - (4-fluorophenylketone in lO l of ethylene glycol dimethyl ether, mixed with 20 mg of sodium hydride (90%) and cooled in an ice bath, 106 mg of emethyl iodide, the mixture of The reaction was stirred for 4 hours under cooling and for 1 hour at room temperature After the organic phase had been concentrated by evaporation, it was chromatographed on silica gel with methylene chloride + ethanol = 1800 + 75. 150 mg was obtained. (1- (3- (3-dimethylaminophenoxy) -2-methoxypropyl) -4-piperidyl) - (4-fluorophenyl) -ketone (oil) Analogously, 2- (4- (4-fluorobenzyl) -piperidino) was obtained. -2-methoxypropoxy) -naphthalene, (l- (3- (l-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-fluorophilnil l-r3- (1.2.3.4-tetrahydro-5-naphiloxH-propi11-4- plßridil1-ketone A solution of 200 mg of 1,2,3,4-tetrahydro-naphthol in 25 ml of tetrahydrofuran is mixed with 700 mg of (4-fluorophenyl) -l- (1- (3-hydroxypropyl) -4- piperidyl) -ketone, 700 mg of triphenylphosphine and 0.45 ml of diethyl ester of asodicarboxylic acid, and heated for 20 minutes at 80 ° in a bath, while stirring. The reaction solution was mixed with 50 ml of water and then extracted with ethyl acetate. Upon drying the organic phase was concentrated by evaporation, and the residue was chromatographed on silica gel with methylene chloride + ethanol = 9 + 1. 264 mg of (4-fluorophenyl) - (1- (3- (1, 2, 3, 4-tetrahydro = 5 = naphthyloxy) -propyl (-4-piperidyl) -ketone The (4-fluorophenyl (-l- (1- (3-hydroxy-ropy) -4-piperidyl) -ketone is obtained according to methods known in the art by alkylation of 4- (4-fluorobenzyl) -piperidine with 3-bromopropanol-1 and potassium carbonate in dimethylformamide. Analogously, (4-fluorophenyl) - ( - (3-indan-5-yloxy) -propyl) -4-pipe idyl) -ketone, melting point 70-72 ° (4-fluorophenyl) - (1- (3- (indane-5-yloxy) -propyl ) - 4-piperidyl) -ketone, melting point 49-52 ° (3,4-difluorophenyl) - * l- (3- (indane-4-yloxy) -propyl) -4-piperidyl) -ketone (l- (3- (4-benzylphenoxy) -propyl) -4-piperidyl) - (4-fluorophenyl) -ketone, mp 105-107 ° (4-fluorophenyl) - (1- (3- (1, 2, 3 , 4-tetrahydro-6- naft iloxy-propyl) -4-piperidyl) -ketone

Claims

CLAIMS 1.- Compounds of the formula I wherein R 1 means substituted or unsubstituted phenyl, substituted or unsubstituted pyridino, substituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzotenocene, substituted or unsubstituted benzofuran, substituted or unsubstituted tetrahydroquinoline, tetrahydroisoquinoline substituted or unsubstituted, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalene, substituted or unsubstituted indanone, substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromen-2-one, substituted or unsubstituted naphthoquinone, R5 and R6 equal or different mean hydrogen, alkyl having from 1 to 4 carbon atoms, phenyl, alkanoyl having from 1 to 6 carbon atoms or together with the nitrogen atom a saturated or unsaturated 5- or 6-membered heterocycle, which may be substituted in one or more places n alkyl with 1 to 4 carbon atoms or phenyl and may contain another 0, N or S atom. Z means oxygen, sulfur, SO or SO2, X means - (CH2) m-CR2R3- (CH2) po, - (CH2) m -CHR2- (CH2) a -CHR3- (CH2) -, B means "^ HR", and m, p, g mean each 0, 1, 2 or 3, R2 and R3 are the same or different and they mean hydrogen, hydroxy, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atom or alkanoyloxy with 1 to 6 carbon atoms, R4 means alkyl with 1 to 6 carbon atoms or -C0- | And straight or branched chain or a phenyl, benzyl, benzoyl, a-hydroxybenzyl, pyridinyl or naphthoyl radical optionally with alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, halogen, hydroxy, - CF3 or -O-CF3, in which the substituent may be the same or different in one to three places, and Y means oxygen, sulfur or -NH-, as well as their physiologically sharable salts and isomers.
2.- . { 1- [3- (1-naphthyloxy) -propyl] -4-piperidyl} - (4-flurophenyl) -ketone. { 1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} - (4-flurophenyl) -ketone. { l- [3- (2-Nitro-l-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { l- [3- (1-Nitro-1-naphthyloxy) -propyl] -4-pipe idyl} - (4-fluorophenyl) -ketone. { l-C3- (2,4-dinitro-l-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone (4-fluorophenyl) -. { l- [3- (5-Isoquinolyloxy) -propyl] -4-piperidyl} -Kettle. { 1- [3- (l-bromo-2-naphthyloxy) -propi1] -4-piperidyl} - (4-fluorophenyl) -ketone. { 1- [3- (4-chloro-1-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { l- [3- (l-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { l- [3- (2-Naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (4-fluorophenyl) -ketone l-. { 1- [3- (1-naphthyloxy) -propyl] -4-piperidyl} -1- (4-fluorophenyl) -methanol 1-. { 1- [3- (2-naphthyloxy) -propyl] -4-piperidyl} -l- (4-fluorophenyl) -methanol 1-naphthyl-. { 3- [4- (4-fluorobenzyl) -l-piperidyl] -propyl] -tetra-2-naphthyl-. { 3- [4- (4-fluorobenzyl) -l-piperidyl] -propyl] -ether. { 1- [3- (1-bromo-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { l- [3- (4-Chloro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -cetone 4-. { 3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy} -indan-l-ona 5-. { 3- [4- (fluorobenzoyl) -1-piperidyl] -propoxy} -3,4-dihydronaphthalene-1 (2H) -one. { l- [3- (7,8-Dihydro-2-naphthyloxy) -propyl] -4-piperidyl} - (4-fluorophenyl) -ketone. { 1- [3- (7,8-dihydro-2-naphthyloxy) -propi1] -4-piperidyl} - (3,4-difluorophenyl) -ketone. { 1- [3- (, 8-dihydro-2-naphidoyloxy) -propi1] -4-piperidyl} - (3,4-dlmethoxyphenyl) -ketone 7-. { 3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy] -2H-chromen-2-one 7-. { 3- [4- (4-fluorobenzoyl) -l-piperidyl] -propoxy] -4-methyl-2H-chromen-2-one 4-. { 3- [4- (4-fluorobenzoyl) -l-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) - [l- [3- (1-oxo-l), 2,3, 4-tetrahydro-5-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} -Kettle. { 1- [3- (1-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} - (3, 4-dimethoxypheni1) -ketone. { l- [3- (l-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) -piperifino) -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-dimethoxypheni1) -ketone (4-fluorophenyl) -. { 1- [3- (1,2,3,4-tetrahydro-5-naphthyloxy) -propyl] -4-piperidyl} -ketone (4-fluorophenyl) -. { l- [3- (Indan-4-yloxy) -propyl] -4-piepridyl} -ketone (4-fluorophenyl) -. { l- [3- (Indan-5-yloxy) -propyl] -4-piperidyl} -ketone (3, 4-difluorophenyl) -l. { l- [3- (Indan-4-yloxy) -propyl] -4-piperidyl} -ketone (4-fluoropheni1) -. { 1- [3- (1, 2, 3, 4-tetrahydro-6-naphthyloxy) -propyl] -4-piperidyl} ketone, according to claim 1.
3.- Pharmaceutical agents based on compounds according to claims 1 and 2.
4. Process for the production of compounds according to claim 1, characterized in that a) reacting a composed of the formula II R1-ZH (II), in which R1 and Z have the above meaning, with a compound of the formula III A-X-.T B (III) wherein X and B have the above-mentioned eignificants and A represents a starting group, or b) a compound of the formula IV AXZ-Ri (IV) in which X, Z and Rl have the above meaning and A represents a group starting, which is reacted with an amine of the formula V in which B has the above meaning, or c) an epoxide of the formula VI R1-Z- (CH2) m -CHA-CH2 (VI) in which R1, Z and m have the above meaning, is reacted with an amine of the formula V or d) a combination of formula VIII wherein X and B have the above meaning, is reacted with a compound of the formula R1-0H according to Mitsunobu and then optionally a carbonyl group is reduced or a hydroxy group is esterified or the physiologically compatible salts are formed or Separate the isomers.