MXPA99007866A - Oxazolidines as 5-ht2a-antagonists - Google Patents

Abstract

The invention relates to novel oxazolidine derivatives of formula (I), wherein R1, R2 and R3 have the meaning cited in Claim 1. The invention further relates to the salts thereof and to a method for the production of the inventive compounds. The compounds of formula (I) act as 5-HT2A antagonists having a reuptake-inhibiting, antidepressant or anxiolytic effect and can be used in the production of medicaments.

Description

OXAZO IDINONES AS ANTAGONISTS OF 5-HT2A DESCRIPTION OF THE INVENTION The invention relates to the compounds of formula I wherein R1 represents H, CN, Hal or OA, R ~, R3 independently represents H, CN, Hal or OA, R2 and R3 together also represent ethylenedioxy, A represents H, CF3 or alkyl of 1 to 6 carbon atoms and Hal represents F, Cl, Br, I, and their salts. European Patent No. 0 443 197 discloses 5- [(2-oxo-benzimidazolin-1-yl) -piperidino-methyl] -oxazolidin-2-ones having an effect on the central nervous system. European Patent No. 0 683 166 describes, for example, indolepiperidines which are REF .: 30968 find alkylated in the nitrogen with respect to indolalquilo. European Patent No. 0 635 505 discloses the derivatives of 3-phenyl-5- [(4-RX-piperidino) -alkyl] -oxazolidin-2-one, in which R represents phenyl and X is -0-, -S-, -SO- or -S0, which have an effect on the central nervous system. European Patent No. 0 722 942 describes the derivatives of indolpiperidine with a tricyclic moiety that exert an effect on the central nervous system. In the world patent n ° 95/33721 the derivatives of 4-aryl-l- (indane-, dihydrobenzofuran or dihydrobenzothiophene-methyl) -piperidine are described which influence the serotoninergic and dopaminergic transmission and inhibit the reabsorption of 5-HT. The aim of the invention was to develop new compounds with valuable properties, in particular, compounds that can be used in the manufacture of medicines. It was found that the compounds of formula I and their salts are well tolerated and possess particularly valuable pharmacological properties, since they exert an effect on the central nervous system mainly as dopamine antagonists and inhibitors of 5-HT reabsorption, since they influence serotonergic transmission and on dopaminergic transmission. In particular, they have affinity for the 5-HTiñ and / or 5-H: ^ receptors. The compounds of formula I inhibit the binding of tritiated ligands of the serotonin receptors to the hippocampal receptors (Cossery et al., European J. Pharmacol 140 (1987), pages 143-155) and inhibit serotonin reuptake (Sher an et al., Life, Sci. 23 (1978), pp. 1863-1870). In particular, the 5-HT receptors;?, And D; . In addition, modifications occur in the accumulation of DOPA in the striatum and in 5-HTP in the nuclear raphe (Seyfried et al, European J. Pharmacol 160 (1989), pp. 31-41). The antagonist action 5-HTi? it is tested in vitro, for example, by inhibition of the nullification of the electrically induced contraction caused by 8-OH-DPAT in the coballo ileum (Fozard and Kilbinger, Br. J. Pharmacol 86 (1985) 601P). The inhibition of the accumulation of 5-HTP reduced by 8-OH-DPAT serves to prove in-vivo the action of 5-HT? A antagonist (Seyfried et al., European J. Pharmacol., 160 (1989), page 31). -41).

As an in vivo confirmation of the inhibition of serotonin reuptake, synaptic inhibition of absorption (Wong et al Neuropsychopharmacol. _8 (1993), pp. 23-33) and antagonism of p-chloroamphetamine (Fuller et al. ., J. Pharmacol. Exp. Ther. 212 (1980), pp. 115-119). Finally, pharmacological tests can also be carried out analogously to the methods described in World Patent No. 95/33721. Therefore, the compounds of formula I are suitable both in veterinary medicine and in medicine for the treatment of functional disorders of the central nervous system. They can be used for the prophylaxis of and the fight against the sequelae of a cerebral infarct (Cerebri apoplexy) such as a stroke attack and cerebral ischemia, as well as for the treatment of the secondary extrapyramidal motor effects of neuroleptics and for the treatment of Morbus Parkinson. However, they are particularly suitable as anxiolytic active substances, antidepressants, antipsychotics and / or for the treatment of behaviors in situations of tension (OCD obsessive-compulsive disorders), anxiety states, panic attacks, depression, psychosis, schizophrenia, obsession, Alzheimer's, migraine, anorexia, sleep disorders, tardive dyskinesia, learning disorders, age-dependent memory disorders, eating disorders such as bulimia, narcotic abuse and / or disorders of sexual function. Accordingly, the compounds of formula I and their acid-addition salts, which are physiologically acceptable, can be used as anxiolytic, antidepressant, antipsychotic, neuroleptic and / or anti-hypertensive active substances, and also to exercise an positive influence on behaviors in situations of stress, - eating disorders such as bulimia, tardive dyskinesia, learning disorders and age-dependent memory disorders. They can also be used as intermediate products for the production of other active substances of medicines. Therefore, the compounds of formula I and their physiologically acceptable acid-addition salts are the subject of the present invention, based on the foregoing, the compounds of formula I and also an object of the present invention are subject to the present invention. Process for preparing the compounds of formula I which is characterized in that a) a compound of formula II is reacted wherein R1 has the meaning indicated in claim 1 and L represents Cl, Br, I or a free or functionally modified OH group in a reactive form, with a compound of formula III wherein R "and R ~ have the meanings indicated in claim 1, or a compound of formula IV is reacted wherein R1, R2 and R3 have the meanings indicated in claim 1, with a compound of formula V wherein L and L 'independently represent Cl, Br, I or a free or functionally modified OH group in a reactive form, or c) a compound of formula VI is hydrogenated (SAW), wherein R ~, R: and R ~ have the meanings indicated in claim 1, and / or a base of formula I is transformed into one of its salts by treatment with an acid. The remains R, R ~, R3 and L that appear in this text have the meanings indicated for formulas I, II, III, IV and V, unless otherwise indicated. Also the subject of the present invention are medicaments of formula I and their physiologically acceptable salts with a 5-HT.i.-antagonist, S-HT.sub.-antagonist and 5-HT reuptake inhibitor action. The subject of the present invention are the compounds of formula I, according to claim 1, and also their enantiomers and salts. The meanings of all the remains that appear repeatedly, such as A, are independent of each other. The alkyl radical has from 1 to 10, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. Therefore, the alkyl radical represents, in particular, for example methyl, then ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or terbutyl, then also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 -, 2 -, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-, or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1- ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, then also fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-trichloroethyl or pentafluoroethyl. A-0- represents hydroxy or alkoxy, in particular, methoxy, ethoxy, propoxy or butyloxy. Both the compounds of formula I and the starting materials for their preparation are prepared according to methods known per se, as described in the literature (for example, in certain works such as those of Houben-eyl, "Methoden der organischen Chemie" "(Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods that are not detailed in this text. In the compounds of formula II L represents Cl, Br, I or a group of free or esterified and reactive OH; the same independently represent L and L 'in the compounds of formula V. When L represents an esterified and reactive OH group, said group is preferably trichloromethoxy, alkoxy such as, for example, methoxy, ethoxy, propoxy or butoxy, then phenoxy, alkylsulfonyloxy having from 1 to 6 carbon atoms (preferably ethylsulfonyloxy) or arylsulfonyloxy having from 6 to 10 carbon atoms (preferably phenylsulfonyloxy or p-tolylsulfonyloxy, then also 2-naphthalenesulfonyloxy). In the compounds of formula V L represents, in particular, Cl, 1-imidazolyl, ethoxy, trichloromethoxy, phenoxy or nitrophenoxy. If desired, the starting materials can be prepared in itself, but in such a way that instead of isolating them from the reaction mixture they are directly reacted to form the compounds of formula I. Otherwise, it is also possible to carry out the reaction in stages. The compounds of formula I can be obtained preferably by reaction of compounds of formula II with compounds of formula III. The paxtide compounds of formulas II and III are known in part. If they are not known, they can be prepared according to methods known per se. The primary alcohols of formula II can be obtained, for example, by reduction of the corresponding carboxylic acids or their esters. The corresponding halides of formula II are obtained by treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogenated compounds. The 3- (4-piperidyl) -indoles of formula III can be obtained, for example, by reaction of 4-piperidinones with the indole or its derivatives correspondingly substituted with R ~ and / or R ~, and then by treatment with hydrogenation In general, the reaction of the compounds of formula II with the compounds of formula III is carried out in an inert solvent and in the presence of an acid capturing agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or of another salt of a weak acid and an alkali metal or alkaline earth metal, preferably a salt of potassium, sodium, calcium or cesium. It may also be convenient to add an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. The reaction time depends on the conditions employed and is between a few minutes and 14 days, and the reaction temperature ranges from about 0 ° to 150 °. In general, the latter is between 20 ° and 130 °.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; the ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether (methyl glycol), ethylene glycol monoethyl ether (ethyl glycol) or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon sulfide; carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned. The compounds of formula I can also be prepared preferably by reacting compounds of formula IV with compounds of formula V. Preferred compounds of formula V are dialkyl carbonates such as dimethyl carbonate, dichloromethyl or diethyl, esters of chloroformic acid such as methyl or ethyl chloroformate, N, N'-carbonyldiimidazole or phosgene The starting compounds of formulas IV and V are known in part, and if they are not known they can be prepared in accordance to methods known per se The reaction is carried out in the solvents and at the temperatures described above The compounds of formula VI can be reduced to compounds of formula I. For this purpose, catalytic hydrogenation with, for example, palladium is preferably used. on activated carbon and hydrogen The starting compounds of formula VI are known in part, if they are not known, they can be prep Plow according to known methods. The reduction is carried out in the solvents and at the temperatures described above. It is also possible to transform a compound of formula I, in which R 1 represents OH, into an ether of formula I, in which R "represents alkoxy, by alkylation. A base of formula I can be converted into its salt by the addition of a acid, for example, by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and then concentrating by evaporation For this reaction it is necessary to take into account, in particular, the acids that form salts acceptable from the point of Thus, inorganic acids may be used, such as, for example, sulfuric acid, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfuric acid, and also organic acids, in particular, mono- or polybasic aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic, sulfonic and sulfuric acids For example, formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, alic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid and naphthalene sulphonic acid, lauryl sulfuric acid. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I.

By virtue of their molecular structure, the compounds of formula I of the invention can exhibit chiral centers, whereby two enantiomeric forms can exist. Thus, these compounds can be presented in racemic or optically active form. Since racemates or stereoisomers of the compounds of the invention may have a different pharmaceutical activity, sometimes the use of the enantiomers is preferred. In these cases, the final product or intermediate products can be separated into their enantiomers, using physical or chemical methods known to those skilled in the art, or the synthesis can be carried out using enantiomeric compounds. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separation agent. As the separation agent, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, of amino acids suitably protected in nitrogen, are suitable. (for example, N-benzoylproline or N-benzenesulfonylproline) or the various optimally active camphorsulfonic acids. It is also convenient to separate the enantiomers by chromatography using an optimally active separation agent (for example, dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatives of methacrylate polymers which have been fixed on silica gel) . As the mobile phase, aqueous or alcoholic mixtures of solvents such as, for example, those of hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3, are used in this case. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I. Another object of the present invention is the use of the compounds of formula I and / or of its physiologically acceptable salts in the preparation of pharmaceutical preparations, in particular by non-chemical methods. In this way, these compounds can be brought into a suitable dosage form together with at least one excipient or auxiliary solid, liquid and / or semi-liquid product and optionally in combination with one or more different active substances.

Also the subject of the invention are pharmaceutical preparations containing at least one compound of formula I and / or one of its physiologically acceptable salts. These preparations can be used in medicine and veterinary medicine as medicines. Among the excipients, there may be named organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and which do not react with the new compounds, for example, water, vegetable oils, benzylic alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose and starch, magnesium stearate, talc, petrolatum. For oral administration, tablets, pills, capsules, powders, granules, syrups, juices or drops are mainly used for administration by rectal administration of suppositories, for parenteral application, solutions, preferably oily or aqueous solutions. , also suspensions, emulsions or implants, and for topical application ointments, creams or powders. The new compounds can also be freeze-dried and the lyophilized products thus obtained can be used, for example, for the preparation of injectable preparations. The aforementioned preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, flavors and / or one or more substances different active ingredients, such as one or more vitamins. In general, the compounds of formula I of the invention are administered analogously to commercially available preparations for the claimed indications (for example, imipramine, fluoxetine, clomipramine), preferably in doses between 0, 1 mg and 500 mg, in particular between 5 and 300 mg per dosage unit. The daily dose is preferably comprised between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg of body weight. However, the particular dose for each patient depends on different factors, for example, the activity of the special compound used, age, body weight, general health, sex, diet, timing and the manner of administration, the rate of excretion, the combination of medications and the severity of the disease to which the therapy is applied. Oral administration is preferred. All temperatures indicated in this text are given in ° C. In the following examples, the expression "is worked or treated in the usual manner" means the following: if necessary, water is added, the pH is possibly adjusted to values between 2 and 10 according to the constitution of the final product, extracted with ethyl acetate or dichloromethane, the phases are separated, the organo-phase is dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel, also used to carry out the separation of the isomers described below, and / or by recrystallization. The Rf values are given on silica gel. Mobile phase: ethyl acetate / methanol 9: 1. Mass spectrometry (EM) The (electronic impact ionization): M "FAB (fast atom bombardment); "Fast Atom Bombardment"): (M + H) ~ Example 1 To a solution of 5- (ethanesulfonyloxymethyl) -3-p-methoxyphenyl-oxazolidin-2-one [obtained by the reaction of 2,3-epoxypropanol with N-benzyl-p-methoxyaniline to give 1- (N-benzyl) -p-methoxy-anilino-propan-2,3-diol, then by hydrogenolysis of the latter to obtain 1-p-methoxyanilinopropan-2,3-diol, reaction with diethyl carbonate to obtain 5-hydroxymethyl-3- p-methoxyphenyl-oxazolidin-2-one and finally by reaction with CHSO-Cl) in acetonitrile equimolar amounts of 4- (3-indolyl) -piperidine ("A"), potassium iodide and potassium carbonate are added Then it is heated at reflux for 16 hours and finally the reaction mixture is worked in the usual way, 3- (methoxyphenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] -oxazolidin-2 is obtained. Ona, melting point 151-153 ° Analogously obtained by reaction of "A" with (5S) -5- (methanesulfonyloxymethyl) -3-p-methoxyphenyl-oxazolidin-2-one (5S) - (- ) -3- (4-methoxy phenyl) -5- [4- (3-indoli l) -1- piperidinyl-methyl] -oxazolidin-2-one, hydrochloride, melting point 234-236 °, aD20 = -56 ° (c = 1, methanol); (5S) -5- (methanesulfonyloxymethyl) -3-p-chlorophenyl-oxazolidin-2-one (5S) - (-) -3- (4-chlorophenyl) -5- [4- (3-indolyl) - 1- piperidinyl-methyl] -oxazolidin-2-one, melting point 188-189 °, -y '= -28 ° (c = 1, DMSO); hydrochloride, melting point 260-263 °; with 5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one the 3- (4-cyanophenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one; with 5- (methanesulfonyloxymethyl) -3-phenyl-oxazolidin-2-one 3-phenyl-5- [4- (3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one; with 5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one the 3- (4-fluorophenyl) -5- [4- (3-indolyl) -1- piperidinylmethyl] oxazolidin-2-one. Analogously, it is obtained, by reaction of 4- (5H-1, 3-dioxolo [4, 5-f] -indol-7-yl) -piperidine ("B") with (5S) -5- (methanesulfonyloxymethyl) -3-p-methoxyphenyl-oxazolidin-2-one (5S) - (-) -3- (4-methoxy-phenyl) -5- [4- (5H-1, 3-dioxolo [4, 5-f] -indol-7-yl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 232-234 °, ayr = -50.5 ° (c = 1, methanol); with (5s) -5- (methanesulfonyloxymethyl) -3-p-chlorophenyl-oxazolidin-one (5S) - (-) -3- (4-chlorophenyl) -5- [4- (5H-1, 3- dioxole [4, 5-f] -indol-7-yl) -1-piperidinylmethyl] -oxazolidin-2-one.

Analogously, it is obtained by reaction of 4- (5-fluoro-3-indolyl) -piperidine ("C"), with (5S) -5- (methanesulfonyloxymethyl) -3-p-methoxyphenyl-oxazolidin-2-one , (5S) - (-) -3- (4-methoxyphenyl) -5- [4- (5-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 233 -234 °, a; ~ = -58.5 ° (c = 1, DMSO); with 5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one, 3- (4-cyanophenyl) -5- [4- (5-fluoro-3-indolyl) -1- piperidinylmethyl] -oxazolidin- 2-one, hydrochloride, melting point 290-292 °; with (5S) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one, (5S) - (-) - 3 - (4-cyanophenyl) -5- [4- (5-fluoro- 3- indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 203-204 °, aD20 = -36.5 ° (c = 1, DMSO); (5R) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one (5R) - (+) - 3 - (4-cyano-phenyl) -5- [4- (5-fluoro-3 - indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 286-287 °, aD20 = + 41.5 ° (c = 1, DMSO).

In an analogous way, it is obtained, by reaction of 4- (5-cyano-3-indolyl) -piperidine ("D"), with 5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one, the 3- (4-cyanophenyl) -5- [4- (5-cyano-3-indolyl) -1- piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 290 °; with (5S) -5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one, (5S) - (-) - 3- (4-fluorophenyl) -5- [4- (5-cyano- 3- indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 252-253 °; with (5S) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one, (5S) - (-) - 3 - (4-cyano-phenyl) -5- [4- (5-cyano- 3- indolyl) -lpiperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 270-271 °, ar 20 = -38.7 ° (c = 1, DMSO); with (5R) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one, (5R) - (+) - 3 - (4-cyanophenyl) -5- [4- (5-cyano- 3- indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 270-272 °, aD2 '= + 37.7 ° (c = 1, DMSO); with 5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one, 3- (4-fluorophenyl) -5- [4- (5-cyano-3-y, ndolyl) -1- piperidinyl ethyl] -oxazolidin-2-one, hydrochloride, melting point 264-268 °; with 5- (methanesulfonyloxymethyl) -3-phenyl-oxazolidin-2-one, 3-phenyl-5- [4- (5-cyano-3-indolyl) -1- piperidinylmethyl] -oxazolidin-2-one, 'hydrate of hydrochloride, melting point 183-185 °; with (5R) -5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one, (5R) - (+) - 3 - (4-fluorophenyl) -5- [4- (5-cyano- 3- indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 184-188 °, r "= + 27.2 ° (c = 1, DMSO). Analogously, by reaction of 4- (6-fluoro-3-indolyl) -piperidine ("E"), with (5S) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one, (5S) - (- ) -3- (4-cyanophenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, mp 287-288 °, ac2 '"' = -38.4 ° (c = 1, DMSO); with 5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one, 3- (4-fluorophenyl) -5- [4- (6-fluoro-3-indolyl) -1- piperidinylmethyl] -oxazolidin- 2-one, hydrochloride, melting point 257-259 °; (5R) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one (5R) - (+) - 3 - (4-cyanophenyl) -5- [4- (6-fluoro-3) - indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, mp 288-290 °, ar "= + 38.8 ° (c = 1, DMSO), with 5- (methanesulfonyloxymethyl) -3- fenii-oxazolidin-2-one, 3-phenyl-5- [4- (6-fluoro-3-indolyl) -1- piperidinylmethyl] -oxazolidin-2-one, hydrochloride, melting point 234-236 °.

Example 2 To a solution of 1- [4- (3-indolyl) -piperidin-1-yl] -3- (4-methoxy-anilino) -propan-2-ol in dichloromethane equimolar amounts of trichloromethyl carbonate are added and then it is stirred for 5 hours. After working the reaction mixture in a usual manner, 3- (4-methoxyphenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, melting point 151-153 ° is obtained. .

Example 3 By a solution of 5- [4- (3-indolyl) -3,6-dihydro-2H-pyridin-1-ylmethyl] -3- (4-methoxyphenyl) -oxazolidin-2-one [obtained by dehydration of 3- (4-methoxyphenyl) -5- [4- (3-indolyl) -4-hydroxy-1-piperidinylmethyl] -oxazolidin-2-one which in turn is prepared by the reaction of 3- (4-methoxyphenyl) -5- [4-Oxo-l-piperidinylmethyl] -oxazolidin-2-one with indole] in methanol is passed through hydrogen for 1 hour and in the presence of palladium (10% on activated charcoal). After removing the catalyst and working the reaction mixture in a usual manner, 3- (4-methoxyphenyl) -4- [4- (3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, melting point is obtained. 151-153 °. The following examples refer to pharmaceutical preparations: Example A: vials for injections The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 1 of double-distilled water is adjusted to 6.5 with 2 JST hydrochloric acid, then filtered under sterile conditions, the bottles are filled with the solution, lyophilized and the bottles are closed under sterile conditions. Each bottle for injection contains 5 mg of the active substance. Example B: suppositories A mixture composed of 20 g of an active substance of formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, then the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of active substance Example C: solution A solution is prepared with 1 g of an active substance of formula I, 9.38 g of NaHiPO ^ x 2H, 0.28.48 g of NaH-PO, x 12 H, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water, the pH is adjusted to 6.8, the volume is brought to 1 1 and sterilized by irradiation Example D: ointment Under aseptic conditions 500 mg of an active substance of formula I are mixed with 99.5 g of petrolatum Example E: tablets A mixture composed of 1 kg of an active substance of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets, such that each tablet contains 10 mg of the active substance.

Example F: Dragees The tablets are formed analogously to that described in Example E and are then coated in a usual manner with a bath of sucrose, potato starch, talc, tragacanth and dye. Example G: capsules With 2 kg of an active substance of formula I, hard gelatine capsules are filled, so that each capsule contains 20 mg of the active substance. Example H: ampoules A solution of 1 kg of an active substance of formula I in 60 1 of bidistilled water is filtered under sterile conditions. The ampoules are filled with this solution and then lyophilized and closed under sterile conditions. Each ampoule contains 10 mg of the active substance.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compounds of formula I where R: represents H, CN, Hal or OA, R:, R2 independently represent H, CN, Hal or OA, R2 and R ~ together also represent methylenedioxy, A represents H, CF3 or alkyl of 1 to 6 carbon atoms and Hal represents F, Cl, Br, I, and their salts.

2. Enantiomers of the compounds of formula I, according to claim 1.

3. Compounds of formula I, according to claim 1 or 2, a) (5S) - (-) - 3 - (4-chlorophenyl) -5- [4- (3-indolyl) -1- piperidinylmethyl] -oxazolidin-2- ona; b) 3- (4-cyanophenyl) -5- [4- (5-cyano-3-indolyl) -1- piperidinylmethyl] -oxazolidin-2-one; c (5S) - (-) - 3 - (4-cyanophenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one; d (5R) - (+) - 3 - (4-cyanophenyl) -5- [4- (5-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one; e) (5R) - (+) - 3 - (4-cyanophenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one; f) 3-phenyl-5- [4- (5-cyano-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one; g) 3-phenyl-5- [4- (6-fluoro-3-indolyl) -1- piperidinylmethyl] -oxazolidin-2-one; and the salts of these compounds.

4. Process for preparing compounds of formula I, according to claim 1, characterized in that a) is reacted with a compound of formula II wherein R ~ has the meaning indicated in claim 1 and L represents Cl, Br, I or a group of OH free or functionally modified in a reactive form, with a compound of formula III wherein R ~ and R ~ have the meanings indicated in claim 1, or b) is reacted with a compound of formula IV wherein R ~, R * and R "have the meanings indicated in claim 1, with a compound of formula V wherein L and L 'independently represent Cl, Br I or a group of free or functionally modified OH in a reactive form, or c) a compound of formula VI is hydrogenated wherein R ~, R- and R3 have the meanings indicated in claim 1, and / or a base of formula I is transformed into one of its salts by treatment with an acid.

5. Process for obtaining pharmaceutical preparations, characterized in that a compound of formula I, according to claim 1, and / or one of its physiologically acceptable salts or one of its enantiomers is brought into a suitable dosage form, together with less an excipient or solid, liquid or semi-liquid auxiliary product and, optionally, in combination with one or more different active substances.

6. Pharmaceutical preparation characterized in that it contains at least one compound according to claim 1 or 2 and / or one of its salts acceptable from the physiological point of view.

7. Compounds of formula I, according to claim 1, and their physiologically acceptable salts to combat the sequelae of a stroke and cerebral ischemia, and to treat the behaviors in situations of stress (OCD), the states of anxiety, panic attacks, depression, psychosis, schizophrenia and Morbus Parkinson.

8. Medicament of formula I, according to claim 1, and its physiologically acceptable salts as 5-HT antagonists; A with an inhibiting effect of 5-HT reabsorption.

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

10. Use of the compounds of formula I, according to claim 1, and / or of their physiologically acceptable salts to combat the sequelae of a stroke and cerebral ischemia, and to treat the behaviors in situations of stress (OCD), anxiety states, panic attacks, depression, psychosis, schizophrenia and Morbus Parkinson.