MXPA00009090A - 1-(3-heteroarylpropyl- or -prop-2-enyl)-4-benzylpiperidines used as nmda receptor antagonists - Google Patents

Abstract

The invention relates to piperidine derivatives of formula (I) and to the physiologically acceptable salts thereof, whereby X, Y, Z, R1, R2, R3 and R4 have the meanings cited in Claim 1. The inventive piperidine derivatives and the salts thereof can be used as excitatory amino-acid antagonists to combat neurodegenerative disorders including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntingdon's disease, cerebral ischaemia, infarcts or physchoses.

Description

PIPERIDINE DERIVATIVES The invention relates to piperidine derivatives of the formula I in which X is O, NR1, S or (CH2) n / Y is CH, Z is CH, where Y and Z together can also be C = C, R], R- and R- "each independently of the other are H or A, R < is H, Hal, A or OA, A is alkyl having 1-6 carbon atoms, REF .: 122403 Hal is F, Cl, Br or I and n is 1, 2 or 3, and their pharmaceutically acceptable salts.

Benzylpiperidine derivatives having a high affinity for binding to amino acid receptor sites are known, for example, from EP 0 709 384 Al.

The aim of the invention was to discover new compounds having useful properties, especially compounds that can be used for the preparation of medicines.

It has been found that the compounds of the formula I and their salts are only well tolerated but also have very useful pharmacological properties. In particular, they have a very high affinity for the binding of amino acid receptor sites, especially for their binding site of ifenprodil at the NMDA receptor (NMDA = N-met i 1-D- to spartate), which modulates the site of polyamine binding alloestéricamente.

The binding test for [3 H] -i-fenprodi 1 can be carried out by the method of Schoemaker et al., Eur. J. Pharmacol. 176, 249-250 (1990). The compounds are suitable for the treatment of neurodegenerative diseases, including cerebrovascular diseases. The new compounds can also be used as an analgesic or anxiolytic and in the treatment of epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischemias or infarcts. In addition, they are suitable for the treatment of psychoses caused by excessively high levels of amino acids.

The linkage test [3H] -CGP-39653 for the glutamate binding site of the NMDA receptor can be carried out, for example, by the method of M.A. Stills et al., Described in Eur. J. Pharmacol. 192, 19-24 (1991). The test for the glycine binding site of the NMDA receptor can be carried out by the method of M.B. Barón et al., Described in Eur. J. Pharmacol. 206, 149-154 (1991-).

Activity against Parkinson's disease, i.e. the enhancement of contralateral rotation induced by L-DOPA in hemipar kinsonian rats, can be detected by the method of U. Ungerstedt and G. Arbuthnott, Brain Res. 24., 485 (1970).

The compound is particularly suitable for the treatment or prophylaxis of attacks and for protection against and treatment of cerebral edema and low-supply states of the central nervous system, especially hypoxia or anoxia.

The referred activities, in addition, can be detected or verified by the methods such as those described in the following literature references: J.W. McDonald, F.S. Silverstein and M. V. Johnston, Eur. J. Pharmacol. 140, 359 (1987); R. Gilí, A.C. Foster and G.N. Woodruff, J. Neurosci. 1, 3343 (1987); J.B.

Bederson et al., Stroke, 17., 472-476 (1986); S. Brint et al., J. Cereb. Blood Flow Metab. 8. 474-485 (1988).

References in the literature listed above describe a variety of antagonists that are capable of blocking the different NMDA receptor binding sites:. Danysz, C.G. Parsons, I. Bresink and G. Quack, Drug, News & Perspective 8_, 261 (1995), K.R. Gee, Exp. Opin. Invest. Drugs 3_, 1021 (1994) and J.J. Kulagowski and L.L. Iversen, J. Med. Chem. 37, 4053 (1994).

The ifenprodil and eliprodil, of the formulas Illa and IV respectively, are capable of blocking the NMDA receptor int eract when using the polyamine modulator binding site (CJ Carter, KG Lloyd, B. Zivkovic and B. Scatton, J. Pharmacol Exp. Ther 253, 475 (1990)).

Since ifenprodil and eliprodil interact with the polyamine binding site on the NMDA receptor, the ant agonistic activity of the compounds of the invention can be determined using a binding test of [ΔH] -MK-801 (di zoci Ipina) .

In the presence of saturation concentrations of glycine and NMDA, spermine is still capable of increasing the binding of MK-801, which is inhibited by ifenprodil, eliprodil and, very effectively, by the compounds of the invention.

In addition, the compounds of the invention can be tested in a [3] -GABA (? ~ Aminobutyric) release test, in analogy to J. Dreijer, T. Honoré and A. Schousboe, J. Neurosci. 7, 2910 (1987), which is an in vitro model that describes the ant agonistic function in the cell.

The invention therefore provides the compounds of the formula I according to the claim 1 and / or its physiologically acceptable salts as antagonists for the receptors of exciting amino acids, such as glutamic acid or its salts.

The invention provides, in particular, the compounds of formula I according to claim 1 and / or their salts acceptable as exciting amino acid antagonists for combating neurodegenerative diseases, including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, disease of Parkinson 's disease and Huntington' s disease, cerebral ischemias,. heart attacks and psychoses.

The invention also provides the use of the compounds of the formula I according to claim 1 and / or their pharmaceutically acceptable salts for preparing a medicament for combating neurological or energetic diseases, including brain diseases, epilepsy, schizophrenia, Alzheimer's disease. , Parkinson's disease and Huntington's disease, cerebral ischemia, heart attacks and psychosis.

The compounds of the formula I can be used as an active ingredient of the medicaments in human and veterinary medicine.

The invention further provides a process for preparing the compounds of the formula I according to the rei indication 1 and its physiologically acceptable salts, characterized in that a) a compound of formula II wherein L is Cl, Br, I, OH or an esterified OH group reactivates, and X, Y, Z, R :, R2 and R3 are as defined in claim 1 is reacted with a compound of formula III wherein R * is as defined in claim 1 b) a compound of the formula I wherein X, R1, R2, R3 and R4 are as defined in. claim 1, and Y and Z together are C = C it is hydrogenated, or c) Water or L'H is removed from a compound of the formula I wherein X, R1, R3 and R4 are as defined in la-rei indication 1, Y is CH, Z is CH and R: is OH or L ', where L' is Cl, Br, I or a reactive esterified OH group, I d) a compound of formula I is converted by treatment with an acid into one of its salts.

Therefore, the invention provides in particular the compounds of formula I in which at least one of the stated radicals has one of the preferred definitions indicated above. Some preferred groups of compounds can be expressed by the following formulas la a le, corresponding to formula I and - in which the radicals not identified in more detail are as defined in formula I, but in which in the R * is H; in Ib R: it is H and X is 0, NR: or S in I c R1 is H, X is 0, NR: or S, R2 is H, R3 is H or A and R4 is Hal Alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms, and is preferably methyl, ethyl, trifluoromethyl, pentaf luoroethyl or propyl, and also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

The compounds of the formula I and also the starting materials for their preparation, on the other hand, are prepared by methods known per se, as described in the literature (eg in standard works such as Houben-Weyl, Methoden der organischen Chemie, Goerg-Thieme-See lag, Stuttgart) under the reaction conditions that are known and appropriate for the established reactions. In this context it is also possible to make use of variants that are known per se, but are not mentioned in greater detail here.

If desired, the initiator materials can also be formed in situ, such that they are not isolated from the reaction mixture, but instead they are immediately reacted further to give the compound of the formula I.

The compounds of the formula I can be obtained preferably by reacting the compounds of the formula II with the compounds of the formula III.

The initiator compounds of formula II are, in general, new. However, they can be prepared by methods that are known per se In the compounds of formula II, L is preferably Cl, Br, I, OH or a reactive modified OH group such as alkylsul phonoyloxy having 1-6 carbon atoms (preferably me tilsul foniloxy) or arylsul fonyloxy having 6- 10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy).

The reaction of the compounds of the formula II with the compounds of the formula III, in general, is carried out in an inert solvent, in the presence of an acid-binding agent, preferably an organic base, such as triethylamine, dimethylaniline, pyridine. or quinoline. It may also be advantageous to add a hydroxide, carbonate or bicarbonate of an alkali metal or alkaline earth metal, or another salt of a weak acid of alkali metals or ferrous alkali metals, preferably of potassium, sodium, calcium or cesium.

Depending on the conditions used, the reaction time falls between "several minutes and 14 days, the reaction temperature between approximately -30 ° and 140 °, normally between -10 ° and 90 ° and, in particular, between approximately 0 °. and approximately 70 °.

Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacet amide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters such as ethyl acetate, water or mixtures of the solvents are suitable.

Compounds of formula I may also be prepared in which Y and Z are each CH, preferably by hydrogenation of the compounds of formula I wherein Y and Z together are C = C.

For this purpose, it is preferred to employ catalytic hydrogenation with, for example, palladium on active carbon or hydrogen.

Examples of suitable catalysts for catalytic hydrogenation are noble metal catalysts and nickel and cobalt catalysts. The noble metal catalysts may be on supports (e.g. platinum or palladium on carbon, palladium on calcium carbonate or strontium carbonate), they may be oxide catalysts (e.g. platinum oxide), or they may be finely divided metal catalysts. Nickel catalysts and cobalt catalysts are judiciously used as Raney metals, also nickel on kieselguhr or pumice as support. The hydrogenation can be carried out at room temperature and atmospheric pressure or even at elevated temperature and / or increased pressure. It is preferred to operate at pressures between 1 and 100 bar and at temperatures between -80 and + 150 ° C, mainly between room temperature and 100 ° C. The reaction is carried out judiciously in an acid, neutral or basic range and in the presence of a solvent, such as water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dioxane-, acetic acid or THF; Mixtures of these solvents can also be used.

The compounds of the formula I in which Y and Z together are C = C, can be obtained preferably from the compounds of the formula I in which X, R, R3 and R are as defined in the rei indication Y is CH, Z is CH and R2 is OH or L r, where L 'is Cl, Br, I, OH or a reactive esterified OH group, eliminating water or L'H from these compounds The elimination is preferably carried out with aqueous acids, especially aqueous mineral acids.

L 'is, for example, preferably Cl, Br, I or a reactive modified OH group such as the fonolsylkyls having 1-6 carbon atoms (preferably me tilsul foniloxy) or arylsul fonyloxy having 6-10 carbon atoms (preferably phenyl or pt or 1 i ISJUI foni loxi).

Compounds in which R2 is OH or L 'can be obtained by reduction, for example, of compounds in which Y and R2 together form a carbonyl group. The reduction can be carried out as indicated by the catalytic hydrogenation or with complex metal hydrides.

Examples of complex metal hydrides which may be used are NaBH 4, diisobutylaluminium hydride or NaAl (OCH 2 CH 2 OCH 3) 2 H 2 and also diborane, with the addition if desired of catalysts such as BF 3, AlC13 or LiBr. Suitable solvents for this purpose are, in particular, ethers, such as diethyl ether, di-n-butyl ether, THF,. dioxane, diglyme or 1,2-dimethoxyethane, and hydrocarbons, such as benzene. For a reduction with NaBH-, the solvents which are mainly suitable are alcohols such as methanol or ethanol, and also water, and aqueous alcohols. According to these methods, the reduction is preferably carried out at temperatures between -80 and + 150 ° C, in particular between 0 and approximately 100 ° C.

The conversion of an OH group into a group OL 'is carried out by known and customary methods.

A base of the formula I can be converted to the associated acid addition salt using an acid by, for example, equivalent reaction amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporative concentration. Particularly preferred acids for this reaction are those which form the physiologically acceptable salts. For example, it is possible to use inorganic acids, examples being sulfuric acid, nitric acid, hydrohalide acids such as hydrochloric acid or hydrobromic acid, phosphoric acid, such as ortho-phosphoric acid, sulfamic acid and also organic acids, especially aliphatic, alicyclic acids , araliphatic, aromatic or monocyclic or polybasic heterocyclic, sulfonic or sulfuric carboxylic acid, examples being formic acid, acetic acid, propionic acid, pivalic acid, di and ethyl acetate, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylbenzene acid, benzene ulphonic acid, p-tol uensul fuonic acid, naft acid to lenmonosul phonic and naphthalendic acids ul phonic, and acid 1 a u r i 1 s u 1 f óni co. Salts with physiologically unacceptable acids, such as picrates, can be used to isolate and / or purify the compounds of the formula I The invention further provides the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation of pharmaceutical preparations, especially by a non-chemical route. In this case they could be carried out in an appropriate dosage form together with at least one solid, liquid and / or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more additional active substances.

The invention further provides pharmaceutical preparations comprising an effective amount of at least one of the compounds of the formula I and / or one of its physiologically acceptable salts.

These preparations can be used as medicines in human and veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (eg oral) or parenteral administration, topical application or administration in the form of an inhaled spray and which do not react with the new compounds, examples being water, oils vegetables, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose q starch, magnesium stearate, talc and petrolatum. Whole tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used in particular for oral administration, suppositories for rectal administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants , for parent administration, and ointments, creams or fine powders for topical application. The new compounds can also be lyophilized and the resulting lyophilizates are used, for example, for the preparation of injection preparations. The stated preparations can be sterilized and / or could include auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts- to influence the osmotic pressure, buffer substances, colorants, flavors and / or a plurality of additional active ingredients, such as one or more vitamins.

For administration as an atomization for inhalation it is possible to use sprays comprising the active substance either dissolved or suspended in a propellant or mixture of propellants (e.g. C02 or chlorofluorocarbons). In this case, the active substances are judiciously used in the micronized form with the possible presence of one or more additional physiologically compatible solvents, such as ethanol. Inhalation solutions can be administered using the customary inhalers.

The compounds of the formula I and their physiologically acceptable salts can be used as exciting amino acid antagonists to combat diseases, especially for combating neurodegenerative diseases, including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischemias, infarcts and psychoses.

In these treatments, the compounds of the invention can be administered in general, in analogy to other known compounds having a similar profile of action, such as ifenprodil, preferably in dosages of between about 0.05 and 500 mg, in particular between 0.5 and 500 mg. 100 mg per dosage unit. The daily dosage is preferably between about 0.01 and 2 mg / kg of body weight. The specific dosage for each patient, however, will depend on a wide variety of factors: for example, the efficiency of the specific compound used, age, body weight, general health, sex, diet, time and route of administration, the rate of excretion, the combination of the medication and the severity of the respective condition to which the therapy is applied. Parenteral administration is preferred.

Previous and later, all temperatures are indicated in ° C. In the following Examples, "customary processing" means: water is added if necessary, the mixture is adjusted to a pH of between 2 and 10 if necessary, depending on the construction of the final product, the mixture is extracted with ethyl acetate. ethyl or dichloromethane, the organic phase is separated, dried with sodium sulfate and concentrated by evaporation, and the residue is purified by chromatography on silica gel and / or by crystallization.

Ei emplo 1 A suspension of 5.5 g of 6- (3-cl oropropy1) -3H-benzoxazole-2 -one in 50 ml of ethanol is mixed with 5.7 g of 4- (4-fluorobenzyl) piperidine hydrochloride and 7.2 ml of triethyl . The mixture is stirred at reflux for one hour and subjected to the usual work-up to give 8.5 g of 6-. { 3- [4- (-fluorobenzyl) piperid-1-yl] propyl} -3H-benzoxa zol -2-one, p.f. 105-107 ° C.

Example 2 A solution of 6.7 g of 6-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] -1-hydroxypropyl} -3H-benzoxa zol-2 -one [obtained by hydrogenation of 6-. { 3- [4- (4-Fluorobenzyl) piperid-1-yl] -l-oxopropyl} -3H-benzoxazol-2-one, which can be obtained by reacting 4- (4-fluorobenz 1) pipe ridin and 6- (3-chloropropionyl) -3H-benzoxa zol-2 -one] in 70 ml of dioxane is heated to reflux with 7 ml of concentrated HCl for 1.5 h. The mixture is cooled and 8.5 g of NaHCO 3 and 70 ml of water are added. 30 ml of dichloromethane are added and the mixture is stirred for 30 minutes. The precipitate is separated, washed with acetone and ether and dried to give 5.7 g of 6-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} -3H-benzoxazol-2-one ("A"), m.p. 202-203.5 ° C; hydrochloride: p.f. 220-223 °.

The following compounds are obtained analogously 6- { 3 - [4- (4-Fluorobenzyl) piperid-1-yl] -2-methylpropenyl} -3H-benzoxazol-2-one, p.f. 156-160 °, hydrochloride: 230-235 6 -. 6 -. 6 -. { 3 - [4- (4-fluorobenzyl) piperid-1-yl] propenyl} -3H-benzothiazol-2-one, hydrochloride x H20, m.p. 95-99 ° (decomposition); - . 5 - . 5 - . 5 - . { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} -l, 3-dihydrobenzimidazol-2 -one, m.p. 218-220 °; hydrochloride: 243-245 °. - . { 3- [4- (4-f luorobenzyl) piperid-1-yl] propenyl} -l, 3-dihydroindol-2-one; 6- { 3- [4- (4-f luorobenzyl) piperid-1-yl] propenyl} -3,4-dihydro-1 H-qui nol in-2 -one.

Example 3 A solution of 2.56 g of "A" in 100 ml of methanol and 100 ml of THF is hydrogenated at room temperature with the addition of 1.2 g of Pd / C. The catalyst is separated and the mixture is subjected to the usual work-up to give 1.31 g of 6-. { 3 - [4 - (4-Fluorobenz 1) -perid-1-yl] propi 1} -3H-ben zoxa zol -2 -one, p.f. 105-107 °.

The following compounds are obtained analogously by hydrogenation: Of 6 - . { 3 - [4 - (4-F-luorobenzyl) piperid-l-yl] -2-methylpropenyl} -3H-benzoxazol-2-one 6- { 3- [4- (4-fluorobenzyl) piperid-1-yl] 2-methylpropyl} -3H-b e n z or ~ x "azol-2-one; Of 6- . { 3 - [4 - (4-f luorobenci 1) piperid-1-yl] propeni 1} -3H-benzoth azol-2 -one: 6 -. { 3 - [4- (4-Fluorobenzyl) piperid-1-yl] propyl} -3H-benzothiazol-2-one; of 5-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} -1, 3-dihydrobenzimidazol-2 -one: - . { 3 - [4 - (4-Fluorobenzyl) piperid-1-yl] propyl} -l, 3-dihydrobenzimidazol-2-one; of 5-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} -l, 3-dihydroindol -2 -one: 5 -. { 3 - [4- (4-fluorobenzyl) piperid-1-yl propyl} -l, 3-dihydroindol-2-one; Of 6- . { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} -3,4-dihydro-lH-quinolin-2-one: 6- { 3- [4- (4-fluorobenzyl) piperid-1-yl] propyl} -3, -dihydro-lH-quinolin-2-one.

The following examples refer to pharmaceutical preparations: Example A: Injection ampoules A solution of 100 g of the active substance of the formula I and 5 g of disodium acid phosphate in 3 1 of double distilled water is adjusted to a pH of 6.5 with 2N hydrochloric acid, filtered by sterilization, transferred to injection vials, Freeze-dried under sterile conditions and sealed by sterilization. Each vial contains 5 mg of active substance.

Example B: Suppositories A mixture of 20 g of the active substance of the formula I is melted together with 100 g of soy lecithin and 1400 g of cocoa butter and the mixture is poured into molds and allowed to cool. Each suppository contains 20 mg of active substance.

Example C: Solution A solution is prepared from 1 g of the active substance of the formula I, and 9.38 g of NaH2P04-2H20, 28.45 g of Na2HP04-12H2Ó and 0.1 g of benzalkonium chloride chloride in 940 ml of double distilled water. The pH is adjusted to 6.8, and the solution is made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment 500 mg of the active substance of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Tablets A mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are compressed into tablets in a customary manner, so that each tablet contains 10 mg of active substance.

Example F: Coated tablets The tablets are pressed as in Example E and then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules 2 kg of active substance of the formula I are filled into hard gelatine capsules in a customary manner, so that each capsule contains 20 mg of active substance.

Example H: Ampoules A solution of 1 kg of active substance of the formula The distilled double water is filtered by sterilization, filled in ampoules and lyophilized under sterile conditions and the ampoules are sealed by sterilization. Each vial contains 10 mg of active substance.

Example I: Atomization by inhalation 14 g of active substance of the formula I are dissolved in 10 1 of isotonic NaCl solution and the solution is filled into customary commercial atomization containers having a pump mechanism. The solution can be atomized in the mouth or nose. A spray jet (approximately 0.1 ml) corresponds to a dosage of approximately 0.14 mg.

It is stated that in relation to this date, the 'best. The method known to the applicant for carrying out said invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (9)

1. The piperidine derivatives of the formula I characterized because X is 0, NR :, S or (CH2) n, Y is CH, Z is CH, where Y and Z together can also be C = C, R1, R: and R3 each independently of the other are H or A, R- is H, Hal, A or OA, A is alkyl having 1-6 carbon atoms, Hal is F, Cl, Br or I and n is 1, 2 or 3 and its pharmaceutically acceptable salts

2- The compounds of the formula I, characterized in that they are according to claim 1: a) 6-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} 3H-benzol-2-one; b) 6-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propyl} -3H- benzol-2-one; c) 6-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} - 3H-benzothiazol-2-one; d) 5-. { 3- [4- (4-fluorobenzyl) piperid-1-yl] propenyl} 1,3-benzimidazol-2-one.

3. The process for preparing the compounds of the formula I according to claim 1 and their salts, characterized in that a) a compound of the formula II wherein L is Cl, Br, I, OH or an esterified OH group r e a c tzi v ame n t e, and X, Y, Z, R1, R2 and R3 are as defined in claim 1 is reacted with a compound of formula III eleven! wherein R4 is as defined in claim 1 b) a compound of the formula I wherein X, R1, R2, R3 and R4 are as defined in claim 1, and Y and Z together are C = C it is hydrogenated, c) Water or L'H is removed from a compound of the formula I wherein X, R1, R3 and R4 are as defined in claim 1, Y is CH, Z is CH and R "is OH or L ', wherein L' is Cl, Br, I or a reactive esterified OH group, I d) a compound of formula I is converted by treatment with an acid into one of its salts

4. The process for the preparation of a pharmaceutical preparation, characterized in that a compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts is brought into an appropriate dosage form together with at least one excipient or solid auxiliary , liquid or semi-liquid.

5. The pharmaceutical preparation, characterized in that an effective content of at least one compound of the formula I according to claim 1 and / or its physiologically acceptable salts.

6. The compounds of the formula I according to claim 1 and / or their physiologically acceptable salts, characterized in that they are used as exciting amino acid antagonists.

7. The compounds of the formula I according to claim 1 and their physiologically acceptable salts, characterized in that they are used as exciting amino acid antagonists to combat neurodegenerative disorders including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington, cerebral ischemia, heart attacks and psychosis.

8. The use of the compounds of the formula I according to claim 1 and / or their physiologically acceptable salts, characterized in that a medicament is prepared for combating neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischemia, heart attacks and psychoses.

9. The use of the compounds of the formula I according to claim 1 and / or their physiologically acceptable salts, characterized in that they combat neurodegenerative diseases including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease, cerebral ischemia, heart attacks and psychosis.