HU226978B1 - New carboxylic acid amide compounds, process for their preparation and pharmaceutical compositions containing them and their use - Google Patents

Abstract

Carboxylic acid amides (I), their optical antipodes, racemates and salts are new. Carboxylic acid amides of formula (I), their optical antipodes, racemates and salts are new. [Image] (CHR 1>) m and (CHR 2>) 2CH 2-CH 2; V,U : H or halo, OH, CN, NO 2, amino or 1-4 alkylamino, arylamino, aralkylamino, 1-4C alkylsulfonamido or 1-4C alkanoylamido (all optionally substituted by one or more halo), arylsulfonamido, 1-4C alkylsulfonyloxy, carboxy, CF 3, CF 3O, 1-4C alkyl-SO 2-NH-CH 2, NH 2-(CH 2) 1 - 4 4-SO 2NH-, NH 2-(CH 2) 1-4-(CO)-NH, sulfamoyl, [NH 2-SO 2], formyl, [-CHO], aminomethyl, [CH 2-NH 2], hydroxymethyl, 1-4C alkyl, 1-4C alkoxymethyl, halogenmethyl, tetrazolyl group, or 1-4C alkoxy, 1-4C alkoxycarbonyl, 1-6C alkanoyloxy, phenyl or 1-4C alkoxy, optionally substituted by NH 2; or neighbouring V and U groups with one or more heteroatom and CH= and/or CH 2 groups : an optionally substituted 4-7 membered homo- or heterocyclic ring, preferably morpholne, pyrrole, pyrrolidine, oxo- orthioxo-pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazolidine, oxo- or thioxo-imidazole, imidazolidine, 1,4-oxazine, oxazole, oxazolidine, oxo or thioxo-oxazolidine, or 3-oxo-1,4-oxazine ring; W, X = CO, CH 2; : -CH(alkyl) where alkyl is 1-4C alkyl with the restriction that W and X cannot both be methylene at the same time; Y : O, 1-4C alkylene, 1-4C alkynylene, cycloalkylene, aminocarbonyl, -NH-, -N(alkyl), -CH 2O-, -CH(OH)-, OCH 2 where alkyl is 1-4C alkyl; Z' : H or halo, nitro, NH 2, 1-4C alkyl, 1-4C alkoxy, CN, CF 3, OH or carboxy; n : 0-3; R 1>, R 2>H or alkyl; or R 1> + R 2>optionally substituted 1-3 alkylene bridge. With the proviso when Z is H, Y is CH 2, both of m and n are 2, both of R 1> and R 2> are H, W is CO, X is CH 2 and V is H, then U is other than a 4-bromo-substituent; and when Z' is H, Y is CH 2, both of m and n are 2, both of R 1> and R 2> are H, both of W of W and X are CO and V is H, then U is other than 4-carboxyl or 4-ethoxycarbonyl. ACTIVITY : Analgesic; Anxiolytic; Cerebroprotective; Antidepressant; Ophthalmological: Antiparkinsonian; Antiaddictive; Neuroprotective; Nootropic; Anticonvulsant; Antidiabetic; Antiasthmatic; Auditory. In a mouse formalin test in which injection of formalin into the hind paw elicited biphasic pain, 2-{4-(4-fluoro-benzyl)-piperidin-1-yl]-2-oxo-N(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide (Ia) had an ED 5 0 of 0.46 mg/kg p.o., cf. greater than 20 mg/kg for a reference compound 6-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanesulfinyl}-3H-benzoxazolo-2-one. MECHANISM OF ACTION : (N-Methyl-D-aspartate) NMDA receptor antagonist.

Description

The present invention relates to novel carboxylic acid amide derivatives of formula (I)

(I)

wherein each is - (CHR ¹ ) m - and - (CHR ² ) n

-CH ₂ -CH ₂ -, the adjacent V and U groups optionally together with one or more other heteroatoms, same or different, and -CH = and / or -CH ₂ -, on a 4- to 7-membered homo- or heterocyclic ring preferably morpholine, pyridine, pyrrolidine, oxo or thioxopyrrolidine, pyrazole, pyrazolidine, imidazole, imidazolidine, oxo or thioxoimidazole or imidazolidine, 1,4-oxazine, oxazole, , oxazolidine, oxo or thioxooxazolidine, or 3-oxo-1,4-oxazine ring,

X is -CO-,

W is carbonyl, methylene, or -CH (alkyl) - wherein alkyl is C 1 -C 4 alkyl,

Y is oxygen or C 1-4 alkylene, C 2-4 alkynylene, cycloalkylene, -NH-CO-, -NH-, -N (alkyl) -, -CH ₂ -O- -CH (OH) -O-CH ₂ - where alkyl is C 1 -C 4 alkyl,

Z is hydrogen or halogen, nitro, amino, cyano, trifluoromethyl, hydroxy or carboxyl or a C 1-4 alkyl or alkoxy group, and salts thereof with acids or bases, and pharmaceutical compositions thereof, which contain these as active ingredients.

The invention also relates to processes for the preparation of the carboxylic acid amide derivatives of formula (I) and to the formulation of medicaments containing the therapeutically effective dose (s) of these compounds.

BACKGROUND OF THE INVENTION

N-methyl-D-aspartate (NMDA) receptors are cation channels modulated by ligands embedded in the cell membrane of nerve cells. NMDA receptors can be over-activated by their natural ligand, glutamate, which can lead to calcium overload in the cells. This initiates a process in the cell that affects cellular function and can even lead to neuronal death (TINS, 10, 299-302 (1987)). NMDA receptor antagonists are useful in the treatment of a number of diseases in which the major neurotransmitter, glutamate, is released in excess in the central nervous system.

Recent advances in molecular biology have significantly contributed to understanding the structure, function, and pharmacology of the NMDA receptor. The NMDA receptor is composed of a combination of multiple subunits: at least one NR1 subunit and one or more NR2A-D subunits form the receptor. The various NR2 subunit-containing receptors differ in both their distribution in the central nervous system and their pharmacology. Of particular interest is the NR2B subunit because of its limited distribution (highest density in the forebrain and in the substantia gelatinosa layer of the spinal cord). There are compounds which act selectively on this subunit [Curr. Pharm. Des., 5, 381-404. (1999)] which have been shown to be effective in stroke [Stroke, 28, 2244-2251. (1997)], Traumatic Brain Injury, Brain Slit 792, 291-298. (1998)], Parkinson's disease [Exp. Neurol., 163, 239-243. (2000)], Neuropathic and Inflammatory Pain (Neuropharmacology, 38, 611-623). (1999)] in symptomatic relief of animal models. Selective antagonists of the NMDA receptor subtype are expected to exhibit little or no side effects specific to non-selective NMDA receptor antagonists, namely psychotomimetic effects such as dizziness, headache, hallucinations, malaise, and cognitive and motor deficits. malfunctions.

The selective NMDA antagonist activity of the NR2B subtype can be achieved by compounds that specifically bind to and act on the allosteric interacting side of the receptor containing the NR2B subunit. This binding site is characterized by displacement (binding) experiments with specific radioligands, such as [ ^{125 I} ] -phenprodil [J. Neurochem., 1993, 61, 120-126] or [ ³ H] -Ro 25, 6981 [J. Neurochem., 70, 2147-2155 (1998)]. Because ifenprodil was the first, although not specific enough, its known ligand is also called the ifenprodil binding site.

Close structural analogs of the carboxylic acid derivatives of formula (I) are known in the art.

The Florida Center for Heterocyclic Compounds (Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL, 32611-7200, USA) sells three milligrams of the compounds of Formula I for biological assays: N- (4 -Bromophenyl) -4-benzyl-1-piperidineacetamide, 4- [2- (4-Benzyl-piperidin-1-yl) -2-oxo-acetylamino] -benzoic acid and 4- [2 - (4-benzyl-piperidin-1-yl) -2-oxo-acetilaminoj-benzoic acid ethyl ester.

Oxoethylamino derivatives are described as intermediates for thrombin inhibitors [Bioorg. Med. Chem. Letters, 9, 925 (1999)]. This publication does not report NMDA receptor antagonist activity.

N- (4-benzoylphenyl) -4-benzyl-1-piperidinylacetamide is disclosed as a selective neuropeptide Y receptor antagonist in U.S. Patent No. 6,048,900.

N- (2-formyl-6-methylphenyl) -4-benzyl-1-piperidineacetamide is disclosed as an intermediate of a carbostyril derivative in Australian Patent No. 6,395,229 which is used as an antiarrhythmic agent.

Aminoacetanilides are also known, [Rev. Chim. (Bucharest), 33 (7), 601 (1982); CA 97: 174467a] as topical anesthetics and anti-fibrillating agents.

HU 226 978 Β1

Piperidine derivatives and analogs substituted with NR2B-selective NMDA-antagonist phenols or phenol equivalents are described in WO90 / 14087, WO90 / 14088, WO97 / 23202, WO97 / 23214, 5

WO97 / 23215, WO97 / 23216, WO97 / 23458,

WO99 / 21539; WO000 / 25109; EP648,744;

US 5,436,255. Compounds containing the same biologically active 2-benzoxazolinone structure are disclosed in WO98 / 18793 and WO000 / 00197. Other NR2B-selective NMDA antagonists with a fused heterocyclic structure are described in WO2001 / 30330, WO2001 / 32171, WO2001 / 32174, WO2001 / 32177, WO2001 / 32179, WO2001 / 32615, WO2001 / 32634. 15

However, there is still a need for new NMDA antagonists at the NR2B receptor.

Surprisingly, it has been found that the novel carboxylic acid derivatives of formula (I) of the present invention are functional antagonists of NMDA receptors that act primarily on the ifenprodyl binding site of NMDA receptors. Therefore, these compounds are believed to be selective antagonists of the NR2B subtype.

The novel carboxylic acid derivatives of formula (I) of the present invention are potent and selective antagonists of the NMDA receptor, and more particularly are selective antagonists of the NRDA subtype of the NMDA receptor.

The novel carboxylic acid derivative of formula (I) is prepared according to the invention by:

a) a carboxylic acid of formula II

HOOC

(arc)

wherein each of the - (CHR ¹ ) m and - (CHR ² ) n groups is -CH ₂ -CH ₂ -, X, Y and Z are as defined in claim 1, or a reactive derivative thereof is represented by (V) with an amine of the general formula

V

NH ₂ (V)

wherein U and V are as defined for formula (I), or

c) for the preparation of compounds of formula I wherein W is -CH ₂ - or -CH (-alkyl) - wherein alkyl is C 1 -C 4 alkyl - a - (CHR ¹ ) m - and - Each of (CHR ² ) n - is -CH ₂ -CH ₂ - and X, V, U, Y and Z are as defined in claim 1 - a halogen derivative of formula (VII) / CHR ¹ ) _m , xN

X \,, (CHR ² ) _n

Q-CH \

I

R ³

(VII)

COOH (II)

- where U, V and W are as defined for formula (I) - or a reactive derivative thereof

(III) 50

wherein each of the - (CHR ¹ ) m - and - (CHR ² ) n - groups is -CH ₂ -CH ₂ -, Y and Z are as defined in claim 1, or

b) for the preparation of compounds of formula I wherein W is -CO- and each of - (CHR ¹ ) m - and - (CHR ² ) n - is -CH ₂ -CH ₂ -. , X, V, U, Y and Z are as defined in claim 1 - a carboxylic acid of formula IV

- where Q is halogen, R ³ is hydrogen or C 1 -C 4 alkyl, each of - (CHR ¹ ) m - and - (CHR ² ) n - is -CH ₂ -CH ₂ - and X is , Y and Z are as defined in claim 1, with an amine of formula (V)

V

NH ₂ (V)

- where U and V are as defined for formula (I) - and the resulting compounds of formula (I) - wherein - (CHR ¹ ) m - and - (CHR ² ) n - are each -CH ₂ -CH _{2 is a} group and X, W, V, U, Y and Z are as defined in claim 1, optionally converted to another compound of formula (I) by addition and / or modification of existing substituents and / or and / or salt formation with acids or bases and / or liberation from the resulting salt.

Preferably, the amide bond can be formed by preparing an active derivative of the general formula (II) or (IV).

The carboxylic acid of formula I1 is reacted with an amine of formula (III) or (V), preferably in the presence of a base.

Conversion of the carboxylic acid to the active derivative may be carried out in situ during the formation of the amide bond in a suitable solvent (e.g., dimethylformamide, acetonitrile, chlorinated hydrocarbons or hydrocarbons). The active derivatives may be chlorides (for example thionyl chloride from a carboxylic acid), mixed anhydrides (e.g. a carboxylic acid isobutyl ester prepared in the presence of a base such as triethylamine), active esters such as hydroxybenzothiazole or dicyclohexyl from carboxylic acid benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) base, prepared in the presence of, for example, triethylamine], acid azides (e.g., carboxylic acid hydrazide). The active derivatives can be prepared from 0 ° C to room temperature. The appropriate amine of formula (III) or (V) is added as the base or inorganic acid salt thereof to the resulting solution or suspension in the presence of a base such as triethylamine as needed to liberate the amine. The condensation reaction is followed by thin layer chromatography. The required reaction time is 6-20 hours. The reaction mixture may be worked up by various methods known per se.

Preferably, the amide bond formation can be accomplished by refluxing an amine of formula V with a halogen compound of formula VII in a suitable solvent, an organic base (e.g., triethylamine, pyridine, piperidine) or an inorganic base (e.g., sodium carbonate or potassium). carbonate) and sodium iodide. Suitable solvents may be an aprotic solvent (e.g. toluene, a chlorinated hydrocarbon) or a dipolar aprotic solvent (e.g. a ketone or acetonitrile or dimethylformamide). Reactions were monitored by TLC. The required reaction time is 20-50 hours. The reaction mixture may also be worked up by various methods known per se.

If the reaction mixture is a slurry, the precipitate is filtered off, washed with water and / or an organic solvent and recrystallized from a suitable solvent to give the pure product. If recrystallization does not yield a material of sufficient purity, for example, purification by column chromatography may be used. Column chromatography can be carried out using Kieselgel 60 adsorbent and various solvent mixtures such as toluene / methanol, chloroform / methanol or toluene / acetone as the eluent. If the reaction mixture is a solution after acylation or alkylation, it is evaporated and the residue is crystallized or purified by column chromatography as described above. The structure of the products was determined by IR, NMR and mass spectrometry.

The resulting carboxylic acid derivative of formula (I), regardless of the method of preparation, may optionally be converted into additional derivatives of formula (I) by introducing and / or modifying and / or removing existing substituents. The compounds of formula (I) in free base form can be converted into salts by treatment with acids and / or the salts of the compounds of formula (I) may be liberated by bases in salts. The carboxylic acid amide of formula (I) containing an acidic group can be converted to a base by its salt.

For example, the methoxy or benzyloxy derivatives, which may be in the Z position, provide phenol derivatives by removal of the methyl or benzyl group. Removal of the benzyl group can be effected, for example, by catalytic hydrogenation or hydrogen acetate solution in glacial acetic acid, and the removal of the methyl group by boron tribromide in dichloromethane. The compounds of formula (I) containing the free hydroxyl group can be converted into acyloxy derivatives by various acylating agents. The reactions may be carried out at room temperature in a chlorinated hydrocarbon with an acid chloride or an anhydride acylating agent in the presence of a base (e.g. triethylamine or sodium carbonate). The nitro group-containing carboxylic acid amide derivatives of formula (I) can be converted to amines by catalytic hydrogenation and the resulting amines can be further reacted to acid amides as described for the acylation of phenolic hydroxyl groups. The free hydroxyl groups may be esterified with acid anhydrides or acid chlorides in the presence of a base.

The carboxylic acids of formula (II) or (IV), the primary or secondary amines of formula (III) or (V) and the halogen compounds of formula (VII) are either commercially available or can be prepared by various known methods. The synthesis of some commercially available carboxylic acids of formula II or IV or halogen of formula VII is given in the Examples. By following these procedures, other commercially available carboxylic acids (II) or (IV) or a halogen compound (VII) can be prepared.

Experimental protocol

Determination of Functional NMDA-Antagonist Activity of Compounds in Primary Culture of Rat Cortical Neurons by Intracellular Calcium Concentration Measurement Using Fluorometric Methods Using a Plate Reader It is known that NMDA receptor subunits are expressed differently during postnatal development of neurons. Similarly, in cortical neuron culture, the composition of the NMDA receptor subunit varies with the age of culture [Eur. J. Neurosci., 10, 1704-1715 (1998)]. In accordance with the literature, our functional tests with our own immunocytochemical and selective NR2B antagonists also show that the NR1B subtype, which is essential for functional function, is predominantly found in the in vitro cultures used by us in 4-7 day old cultures. Therefore, the functional NMDA antagonist assay in these cells mainly reflects the activity expressed on receptors containing the NR2B subunit. because

It is known that NMDA receptors are permeable to calcium ions in the excitatory state, the extent of NMDA receptor activation and its inhibition by functional antagonists can be characterized by measuring the increase in intracellular calcium concentration in cells following administration of an agonist (NMDA). Because rat and human NMDA receptors have very high sequence similarity (99, 95, and 97% for NR1, NR2A, and NR2B subunits, respectively), there is little, if any, difference in their pharmacological sensitivity. Therefore, the results obtained on rat NMDA (cloned or natural) receptors can be well extrapolated to humans.

For intracellular calcium concentration measurements, primary neocortical cultures from 17-day Charles River rat embryos were used [for details on preparation of neocortical cell culture, see Johnson, Μ. I .; Bunge, RP (1992): Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson A., The Humana Press Inc., 13-38.]. After isolation, the cells are plated on standard 96-well tissue culture plates (plates) and the culture is maintained at 37 ° C in an atmosphere containing 95% air and 5% CO ₂ until use.

The cultures are used after 4-7 days for in vitro intracellular calcium concentration measurements. Prior to assay, cells were filled with fluorescent Ca ²⁺ indicator Fluo-4 / AM (2-2.5 μΜ). After loading, the cells are washed twice with standard solution (140 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 5 mM HEPES [4- (2-hydroxyethyl) -1-piperazinyl ethanesulfonic acid], 5 mM HEPES-Na). 20 mM glucose, 10 μg glycine pH 7.4}. Subsequently, the cells to be tested are dissolved in the previous solution (90 μΙ / well). Intracellular calcium concentration measurements were performed on a plate reader fluorimeter. Growth was induced by using 40 μΜ NMDA Fluo-4 fluorescence, indicating intracellular calcium concentration. The inhibitory effect of the compound at different concentrations is determined by measuring the decrease in calcium release. After the measurement, a standard calibration method [Meth. Cell. Biol., 40, 155-181 (1994)] for converting fluorescent data into calcium concentration values.

At a particular concentration, the compound's inhibitory activity is expressed as a percentage of the control NMDA response inhibition. Sigmoidal concentration-inhibition curves are fitted to the data and the IC _{50 is} determined, which represents half of the maximum inhibitory concentration that can be induced by the compound. Mean IC ₅₀ values are determined from at least three independent measurements.

Determination of Binding of Compounds to the NR2B Subunit by pH] -Ro 25.6981 Binding Assay The method is essentially similar to that described by Mutel et al. Neurochem., 70, 2147-2155 (1998)], except for the incubation temperature and radioligand concentration. Briefly, membranes were isolated from the forebrain of male Wistar rats. They are incubated for 2 hours at room temperature in the presence or absence of the test compound. Non-specific binding is determined by 10 μΜ Ro-25.6981 and is typically less than 7% of total binding. The concentration used in radioligand ^{(3H-Ro-25,6981)} 4 nM. IC ₅₀ values (50% inhibition concentrations) are determined from sigmoid curves fitted to concentration-displacement curves.

The biological activity of the compounds

Some of the compounds of the present invention exhibit IC ₅₀ values as determined by a functional NMDA antagonist and binding assay in Table 1, compared to the values of the most active reference compounds known.

The compounds of the present invention have IC ₅₀ values less than 50 μΜ, both in functional NMDA antagonist and in binding assays. Thus, the compounds and pharmaceutical compositions of the present invention are NR2B subunit specific NMDA antagonists. Some compounds are more potent than the known reference compounds (see Table 1).

Table 1

NMDA antagonist / binding activity of compounds on natural neurons / neuronal membranes isolated from rats

Compound Identification Number (Example Number) NMDA IC ₅₀ (μΜ) Ro-binding IC ₅₀ (μΜ) Code of the reference compound NMDA IC ₅₀ (μΜ) Ro-binding IC ₅₀ (μΜ) 70001623 (2) 0.0007 .0047 CI-1041 0.0066 0,004 70001824 (6) 0.0014 0.0044 Co 101 244 0.023 .0033 70001861 (7) 0.0024 .0055 EMD 95885 0,035 .0072 70001620 (3) .0032 0,018 CP 101.606 0.041 .0084 70001863 (8) 0,048 0.091 Co 111 103 0,060 .0084 70001844 (15) 0.113 0.214 Ro 25.6981 0.159 0.0059

HU 226 978 Β1

Table 1 (continued)

Compound Identification Number (Example Number) NMDA IC ₅₀ (μΜ) Ro-binding IC ₅₀ (μΜ) Code of the reference compound NMDA IC ₅₀ (μΜ) Ro-binding IC ₅₀ (μΜ) 70001843 (14) .533 0,972 ifenprodil 0.483 0,096 70001759 (4) 4.71 > 30

NMDA IC ₅₀ : IC ₅₀ for intracellular Ca ²⁺ concentration on cortical neurons. Ro binding IC50: IC50 determined by [ ³ H] -Ro 25.6981 binding on rat cerebral membrane.

Reference compounds are:

Cl-1041: 6- {2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -ethanesulfinyl} -3H-benzoxazol-2-one.

Co 101244: 1- [2- (4-Hydroxy-phenoxy) -ethyl] -4-hydroxy-4- (4-methyl-benzyl) -piperidine.

EMD 95885: 6- [3- (4-Fluoro-benzyl) -piperidin-1-yl] -propionyl] -2,3-dihydrobenzoxazol-2-one.

CP-101.606: (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol.

Co-111103: 1- [2- (4-hydroxyphenoxy) ethyl] -4- (4-fluorobenzyl) piperidine.

Ro 256981: R- (R *, S *) - 1- (4-Hydroxy-phenyl) -2-methyl-3- (4-benzyl-piperidin-1-yl) -1-propanol.

Ifenprodil: Erifro-2- (4-benzylpiperidino) -1- (4-hydroxyphenyl) -1-propanol.

Diseases that can be treated preferentially with NMDA antagonists include the traumatic brain [Neurol. 21: 330-338 (1999)] or spinal cord injury [Eur. J. Pharmacol., 175, 165-74 (1990)], nerve injury due to HIV infection [Annu. Port. Pharmacol. Toxicol., 1998; 38 159-77], amyotrophic lateral sclerosis [Neurol. 21: 309-12 (1999)] for the treatment of tolerance and dependence during opioid treatment [Brain. Slit., 731, 171-181 (1996)], withdrawal symptoms such as alcohol, opioids or cocaine (Drug and Alcohol Depend., 2000, 59, 1-15), muscle spasms, Neurosci. Lett., 73, 143-148 (1987)], dementia of various origins [Expert Opin. Investig. Drugs, 9, 1397-406 (2000)]. NMDA antagonists may also be used to treat the following conditions: cerebral ischemia of any origin (e.g. stroke, cardiac surgery), chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, pain (e.g., post-traumatic or postoperative), and chronic pain. such as neuropathic pain or cancer pain, epilepsy, anxiety, depression, migraine, psychosis, hypoglycemia, degenerative retinal disorders (such as CMV retinitis), glaucoma, asthma, tinnitus, aminoglycoside antibiotic-induced hearing loss -569 (1998) and WO 00/00197].

Accordingly, effective doses of the compounds of the present invention are useful in the treatment of traumatic brain or spinal cord injuries, nerve injuries due to HIV infection, amyotrophic lateral sclerosis, treatment tolerance or dependence with opioids, withdrawal symptoms such as alcohol, opioids or cocaine, ischemic CNS disorders, chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, pain and chronic pain conditions such as neuropathic pain or cancer pain, epilepsy, epilepsy, muscle spasms, dementia of various origins, hypoglycemia, degenerative disorders of the retina, glaucoma, asthma, tinnitus, hearing loss caused by an aminoglycoside antibiotic.

The compounds of the present invention and their pharmaceutically acceptable salts may be used alone or preferably in the form of pharmaceutical compositions. These preparations may be in solid, liquid or semi-liquid form and may include pharmaceutical excipients, such as carriers, additives, diluents, stabilizers, wetting or emulsifying agents, pH and osmotic pressure regulating or flavoring agents, and excipients that facilitate and facilitate formulation of the drug.

The dosage required to produce a therapeutic effect may vary widely and will in any case depend on the degree of disease, the severity of the disease being treated, the patient's weight and sensitivity to the active ingredient, the route of administration and the number of daily treatments. The dose of active substance to be used at any given time can be determined by the attending physician, in the light of the knowledge of the patient to be treated, and based on his / her expert knowledge.

Pharmaceutical formulations containing the active ingredient of the present invention generally contain from 0.01 to 100 mg of active ingredient per dosage unit. It is, of course, also possible for the amount of active ingredient in each formulation to go above or below the limit stated above.

Solid pharmaceutical compositions include tablets, dragees, capsules, cachets of powder, or freeze-dried formulations for injection. Liquid formulations include injection, infusion formulations, spoonfuls and drops. Ointments, balms, creams, shakes and suppositories are semi-liquid.

For ease of administration, it is desirable for pharmaceutical compositions to be comprised of dosage units that contain the amount of active ingredient to be administered simultaneously.

EN 226 978 Β1 get, or a small number of multiple, or half, third, quarter. Such dosage unit forms are, for example, tablets, which may be provided with a notch which facilitates halving or quartering the tablet to facilitate accurate dosage of the required active ingredient.

The tablets may also be coated with a layer insoluble in an acidic medium to render the active ingredient after the stomach, thereby rendering them enteric. A similar effect can be achieved by encapsulating the active ingredient.

For the preparation of oral preparations, for example, lactose or starch may be used as fillers. As binder or granulating material, for example, carboxymethylcellulose sodium, methylcellulose, polyvinylpyrrolidone or starch germ may be used. The disintegrant is preferably potato starch or microcrystalline cellulose, but also ultra-amylopectin or formaldehyde casein may be used. Examples of antiadhesive and lubricating agents are talc, colloidal silica, stearin, calcium and magnesium stearate.

For example, the tablet may be prepared by wet granulation followed by compression. The blended excipients, and optionally a portion of the disintegrant, may be granulated with an aqueous, alcoholic, or aqueous-alcoholic solution of the binders in a suitable apparatus and then dried. Next, other disintegrants, lubricants and anti-adhesives are added to the dried granulate and compressed into tablets. Optionally, the tablets are scored in half to facilitate dosing.

Tablets may also be prepared directly from the mixture of the active ingredient and suitable excipients by direct compression. The tablets may optionally contain protective, flavoring or coloring agents commonly used in the preparation of pharmaceuticals, such as sugar, cellulose derivatives (methyl or ethyl cellulose, sodium salt of carboxymethyl cellulose, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food colorings, food color lakes, flavorings, iron oxide pigments, etc. using pellets. When preparing a capsule, the mixture of active ingredients and excipients is filled into a capsule.

Liquid oral preparations include, for example, suspensions, syrups, elixirs, water, glycols, oils, alcohols, coloring and flavoring agents.

For rectal administration, the composition is prepared in the form of a suppository or enema. In addition to the active ingredient, the suppository contains a carrier mass, called adeps pro suppositorite. Suitable carriers are vegetable fats, such as hardened vegetable oils, triglycerides of C12-C18 fatty acids (preferably carriers known as Witepsol). The active ingredient is homogeneously distributed in the molten carrier mass and suppositories are prepared by molding.

For parenteral administration, the composition is prepared by injection. In preparing a solution for injection, the active compounds are optionally in the presence of solution mediators such as polyoxyethylene sorbitan monolaurate, monooleate, or mono-stearate (Tween 20, Tween 60, Tween 80) in distilled water and / or various organic solvents such as glycol. dissolved in ethers. The solution for injection may also contain various excipients, such as preservatives, such as ethylenediaminetetraacetate, as well as pH-adjusting and buffering agents, and optionally a local anesthetic such as lidocaine. The injection solution containing the active ingredient of the invention is filtered before being filled into an ampoule and then sterilized after filling.

If the active ingredient is susceptible to hydrolysis, it may be stabilized by the freeze-drying step.

The preparation of the compounds and compositions of the invention is illustrated in more detail by the following examples, which are not intended to limit the invention.

Example 1

2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide (4570001598) 1a ) [4- (4-Fluorobenzyl) -piperidin-1-yl] -oxo-acetic acid ethyl ester

2.3 g (10 mmol) of 4- (4-fluorobenzyl) piperidine hydrochloride [J. Med. Chem., 1992, 35, 4903] and triethylamine (4.5 mL, 32 mmol) in chloroform (80 mL) was added dropwise with a solution of ethyl oxalyl chloride (2.5 mL, 22 mmol) in chloroform (20 mL). Below 10 ° C and the reaction mixture is stirred at room temperature for 10 hours. Then 50 ml of 8% sodium bicarbonate solution are added, the organic phase is separated off and the aqueous phase is extracted three times with 25 ml of chloroform each time. The combined organic layers were dried over anhydrous sodium sulfate, evaporated, triturated with diisopropyl ether and filtered to give 2.1 g (72%) of the title compound. 72-74 ° C (diisopropyl ether).

1b) [4- (4-Fluorobenzyl) -piperidin-1-yl] -oxo-acetic acid

To a solution of 1.91 g (6.5 mmol) of ethyl ethyl ester of [(4-fluorobenzyl) piperidin-1-yl] oxoacetic acid in 15 ml of ethanol was stirred with 1.18 g (21.1 mmol) of potassium hydroxide A solution of 3 ml of water was added. The reaction mixture was stirred at room temperature for 6 hours, then cooled and acidified with hydrochloric acid. The precipitated solid was filtered and washed with water. 1.68 g (97.4%) of the title product are obtained. 152-154 ° C (ethanol-water).

c) 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide

3.2 g (12 mmol) of [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid, 1.4 mL (10 mmol) of triethylamine, 1.5 g (10 mmol) of 5-amino -1,3-dihydroindol-2-one [Tetrahedron, 24, 1376 (1957)], 3.8 g (10 mmol) of HBTU [O-benzthiazol-1-yl-N, N, N ', N'- a mixture of tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] and 100 ml of dimethylformamide was stirred at room temperature for 24 hours and then concentrated. To the residue were added 150 ml of 8% sodium bicarbonate solution and 150 ml

HU 226,978 Β1 chloroform was added. The organic layer was separated and the aqueous layer was extracted with chloroform (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, evaporated and the residue was purified by column chromatography using Kieselgel 60 adsorbent (Merck) and chloroform: methanol = 19: 1 as the eluent to give 2.67 g (68%) of the title product. 195-197 ° C (diethyl ether).

Example 2

2- [4- (4-Fluorobenzyl) piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1 H -benzoimidazol-5-yl) acetamide (4570001623)

2.5 g (9.6 mmol) of [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid (Example 1a), 1.1 mL (8 mmol) of triethylamine, 1.2 g (8 mmol) 5-amino-1,3-dihydrobenzimidazol-2-one [J. Amer. Chem. Soc., 80, 1657 (1958)], a mixture of HBTU (3.03 g, 8 mmol) and dimethylformamide (80 mL) was stirred at room temperature for 24 hours and then concentrated. To the residue was added 100 ml of 8% sodium bicarbonate solution, the precipitated product was filtered off and recrystallized from methanol. 1.51 g (48%) of the title product are obtained. M.p.> 260 ° C (methanol).

Example 3

2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1H-benzoxazol-6-yl) -acetamide (4570001620)

The title product was obtained from [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid (Example 1b) and 6-amino-3 H -benzoxazol-2-one [J. Chem. Soc., 321 (1938)]. Prepared according to the method described in Example 1b. M.p. 224-227 'C (diethyl ether).

Example 4

2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydrobenzoxazol-5-yl) -acetamide (4570001759)

The title product is obtained from 5-amino-3H-benzoxazol-2one [J. Chem., 10, 408 (1967)] and [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid as described in Example 1b. Prepared according to the method described in Example 1b. Mp 226-231 ° C (water).

Example 5

2- (4-Benzyl-piperidin-1-yl) -2-oxo-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide (4570001823)

The title product was prepared from (4-benzylpiperidin-1-yl) oxoacetic acid (prepared as in Example 1b) and 5-amino-1,3-dihydroindol-2-one by the method of Example 2. 115-118 ° C (water).

Example 6

2- (4-Benzyl-piperidin-1-yl) -2-oxo-N- (2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl) -acetamide (4570001824)

The title product was prepared from (4-benzylpiperidin-1-yl) oxoacetic acid (prepared as in Example 1a) and 5-amino-1,3-dihydrobenzimidazol-2-one according to the procedure described in Example 2. > 260 ° C (water).

Example 7

2- (4-Benzyl-piperidin-1-yl) -2-oxo-N- (2-oxo-2,3-dihydro-benzoxazol-6-yl) -acetamide (4570001861)

The title product is obtained from (4-Benzyl-piperidin-1-yl) -oxo-acetic acid (prepared as in Example 1a) and 6-amino-3H-benzoxazol-2-one. Prepared according to the method described in Example 1b. 190-193 'C (diethyl ether)

Example 8

5- {2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-ethylamino} -1,3-dihydrobenzimidazol-2-one (45,7000-1863)

8a) 2-Chloro-1- [4- (4-fluorobenzyl) piperidin-1-yl] ethanone

To a solution of 4- (4-fluorobenzyl) piperidine hydrochloride (4.6 g, 20 mmol) and triethylamine (5.9 mL, 42 mmol) in chloroform (160 mL) was added chloroacetyl (1.75 mL, 22 mmol). chloride (40 mL) was added dropwise with chloroform to keep the temperature below 10 ° C and the reaction mixture was stirred at room temperature for 10 hours. The resulting mixture was evaporated and to the residue was added 100 ml of 8% sodium bicarbonate solution. The precipitated product is filtered off and washed with water. 5.42 g (100%) of the title product are obtained. 85-87 ° C (water).

8b) 5- {2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-ethylamino} -1,3-dihydrobenzimidazol-2-one

5.4 g (20 mmol) of 2-chloro-1- [4- (4-fluorobenzyl) piperidin-1-yl] ethanone, 3.3 g (20 mmol) of potassium iodide, 5.6 mL of A mixture of triethylamine (6 mmol), 5-amino-1,3-dihydrobenzimidazol-2-one (6.0 g, 40 mmol) and toluene (200 mL) was heated to reflux for 20 hours. The reaction mixture was concentrated and 150 ml of water and 150 ml of chloroform were added to the residue. The organic layer was separated and the aqueous layer was extracted with chloroform (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, evaporated and the residue was purified by column chromatography using Kieselgel 60 adsorbent (Merck) and chloroform: methanol = 97: 3 as eluent. 3.7 g (48%) of the title product are obtained. M.p. 249-251 C (diethyl ether).

Example 9

6- {2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-ethylamino} -3H-benzoxazol-2-one (4570001944)

The title product was obtained from 2-chloro-1- [4- (4-fluorobenzyl) piperidin-1-yl] ethanone (Example 8a) and 6-amino-3H-benzoxazol-2-one in Example 8b. Prepared according to the method described in Example 1b. M.p. 202-205 'C (diethyl ether)

Example 10

- (4-Benzyl-piperidin-1-yl) -N- (1H-indazol-5-yl) -2-oxoacetamide (45 70001814)

The title product is prepared from 5-aminoindazole (Aldrich) and (4-benzylpiperidin-1-yl) oxoacetic acid (prepared as described in Example 1b) in the following manner. Prepared according to the method described in Example 1b. M.p. 204-209 C (diethyl ether).

HU 226 978 Β1

Example 11

1- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -N- (1H-indazol-5-yl) -2-oxo-acetamide (45 70001816)

The title product was prepared from 5-aminoindazole (Aldrich) and [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid (Example 1b) according to the procedure described in Example 2. M.p. 198-200 ° C (diethyl ether).

Example 12

2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) - acetamide (45 70001818)

The title product is obtained from 7-amino-4H-benzo [1,4] oxazin-3-one [J. Chem., 32, 1627 (1989)] and [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid (Example 1b) were prepared according to the procedure described in Example 2. M.p. 209-212 ° C (diethyl ether).

Example 13

N- (1H-Benzimidazol-5-yl) -2- [4- (4-fluorobenzyl) piperidin-1-yl] -2-oxoacetamide (4570001820)

The title product is obtained from (1H-benzimidazol-5-yl) amine [Synth. Commun., 29, 2435 (1999)] and [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid (Example 1b). Prepared according to the method described in Example 1b. 104-110 ° C (diethyl ether).

Example 14

1- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2- (1H-indazol-5-ylamino) -ethanone (4570001843)

The title product was prepared from 5-aminoindazole (Aldrich) and 2-chloro-1- [4- (4-fluorobenzyl) piperidin-1-yl] ethanone (Example 8a). Prepared according to the method described in Example 1b. 113-114 ° C (diethyl ether).

Example 15

2- (4-Benzyl-piperidin-1-yl) -2-oxo-N- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -acetamide (4570001844)

The title product is obtained from 7-amino-4H-benzo [1,4] oxazin-3-one [J. Chem., 32, 1627 (1989)] and (4-benzyl-piperidin-1-yl) -oxo-acetic acid (prepared as in Example 1b) were prepared by the method described in Example 2. 123-126 ° C (diethyl ether).

Example 16

- (4-Benzyl-piperidin-1-yl) -2- (1H-indazol-5-yl) -amino-ethanone (45 70001949)

16a) 2-Chloro-1- (4-benzyl-piperidin-1-yl) -ethanone The title product from 4-benzyl-piperidine and chloroacetyl chloride is prepared in the following way. Prepared according to the method described in Example 1b. M.p. 42-47 ° C.

16b) 1- (4-Benzyl-piperidin-1-yl) -2- (1H-indazol-5-yl) -amino-ethanone

The title product was prepared from 5-aminoindazole (Aldrich) and 2-chloro-1- (4-benzylpiperidin-1-yl) ethanone in Example 8b. Prepared according to the method described in Example 1b. 153-155 ° C (diethyl ether).

Example 17

1- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-ylamino) -ethanone ( 45 70002015)

The title product is obtained from 7-amino-4H-benzo [1,4] oxazin-3-one [J. Chem., 32, 1627 (1989)], and 2-chloro-1- [4- (4-fluorobenzyl) piperidin-1-yl] ethanone (Example 8a). Prepared according to the method described in Example 1b. 156-161 ° C (diethyl ether).

Example 18

2- [4- (4-Fluorobenzyl) piperidin-1-yl] -N- (5-methyl-2-oxo-2,3-dihydrobenzoxazo-6-yl) -2-oxoacetamide (4570002102 )

The title product was obtained from 6-amino-5-methyl-3H-benzoxazol-2-one (German Patent No. 4,40097) and [4- (4-fluorobenzyl) piperidin-1-yl] oxoacetic acid (Example 1b). 1c). Prepared according to the method described in Example 1b. 189-192.5 ° C (diethyl ether).

Example 19

2- (4-Benzyl-piperidin-1-yl) -N- (5-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl) -2-oxo-acetamide (4570002103)

The title product is prepared from 6-amino-5-methyl-3H-benzoxazol-2-one [DE 440097] and (4-benzyl-piperidin-1-yl) -oxo-acetic acid (prepared as in Example 1b). Prepared according to the method described in Example 1b. 195-196 ° C (diethyl ether).

Example 20

1- (4-Benzyl-piperidin-1-yl) -2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-ylamino) -ethanone (4570002104)

The title product is obtained from 7-amino-4H-benzo [1,4] oxazin-3-one [J. Chem., 32, 1627-30 (1989)] and 2-chloro-1- (4-benzylpiperidin-1-yl) ethanone (prepared as described in Example 16a). Prepared according to the method described in Example 1b. 172-175 ° C (diethyl ether).

Example 21

Manufacture of pharmaceutical preparations

(a) Tablets

0.01-50% active ingredient, 15-50% lactose, 15-50% potato starch, 5-15% polyvinylpyrrolidone, 1-5% talc, 0.01-3% magnesium stearate, -3% colloidal silica and 2-7% ultraamylopectin are mixed and tablets are made by wet granulation and compression.

b) Dragees, film-coated tablets

Tablets made in the above manner are coated in a known manner with an enteric or gastro-solvent film or a layer of sugar and dye and talc. The dragees are polished with a mixture of beeswax and carnauba wax.

c) Capsules

0.01-50% active ingredient, 1-5% sodium lauryl sulfate, 15-50% starch, 15-50% lactose, 1-3% colloidal silica and 0.01-3% magnesium stea

The mixture is thoroughly mixed and then sieved and filled into a hard gelatin capsule.

d) Suspensions

100 ml of suspension:

agent 1.00 g Sodium hydroxide 0.26 g Citric acid 0.30 g Nipagin (4-hydroxybenzoic acid- methyl ester, sodium salt) 0.10 g Carbopol 940 (Polyacrylic Acid) 0.30 g 96% ethanol 1.00 g raspberry Flavor 0.60 g Sorbitol (70% aqueous solution) 71.00 g Filled with distilled water To 100.00 ml

To a solution of nipagin and citric acid in 20 ml of distilled water, carbopol is added in small portions with vigorous stirring and the solution is allowed to stand for 10-12 hours. A solution of the above amount of sodium hydroxide in 1 ml of distilled water, an aqueous solution of sorbitol and finally a solution of raspberry aroma in ethanol are added dropwise with stirring. To this carrier, the active ingredient is added in small portions and suspended in a dip homogenizer. Finally, the suspension is made up to 100 ml with distilled water and the suspension syrup is passed through a colloidal mill.

e) Cones

0.01-15% of the active ingredient and 1-20% of lactose per suppository are thoroughly mixed, then 50-95% of the suppository base (e.g. Witepsol 4) is melted, cooled to 35 ° C and mixed with the active ingredient and lactose using a homogenizer. mixture. The resulting mixture is poured into chilled suppository molds.

(f) Lyophilized powder for solution for injection

A 5% solution of mannitol or lactose is prepared in double-distilled water for injection. The solution is filtered sterile. A solution of the active ingredient in a concentration of 0.01-5% is also prepared in double-distilled water for injection. This solution is also sterile filtered. The two solutions are mixed under aseptic conditions and filled into ampoules in 1 ml portions, the contents of the ampoules are lyophilized and they are sealed with nitrogen gas. Prior to administration, the contents of the ampoules are dissolved in water or 0.9% (physiological) sterile distilled aqueous sodium chloride solution.

Claims (8)

PATENT CLAIMS 1. Novel carboxylic acid derivatives of formula (I) - wherein each of - (CHR ¹ ) m - and - (CHR ² ) n - -CH ₂ -CH ₂ -, the adjacent V and U groups optionally together with one or more other heteroatoms, same or different, and -CH = and / or -CH ₂ -, on a 4- to 7-membered homo- or heterocyclic ring preferably morpholine, pyridine, pyrrolidine, oxo or thioxopyrrolidine, pyrazole, pyrazolidine, imidazole, imidazolidine, oxo or thioxoimidazole or imidazolidine, 1,4-oxazine, oxazole, , oxazolidine, oxo or thioxooxazolidine, or 3-oxo-1,4-oxazine ring, X is -CO-, W is carbonyl, methylene, or -CH (alkyl) - wherein alkyl is (C 1 -C 4) alkyl, Y is oxygen or C 1-4 alkylene, C 2-4 alkynylene, cycloalkylene, -NH-CO-, -NH-, -N (alkyl) -, -CH ₂ -O-, -CH (OH). ) -, -O-CH ₂ -, where alkyl is C 1 -C 4 alkyl, Z is hydrogen or halogen, nitro, amino, cyano, trifluoromethyl, hydroxy or carboxyl or a C 1-4 alkyl or alkoxy group and their salts with acids or bases. Compounds of formula (I) according to claim 1, wherein - (CHR ¹ ) m - and - (CHR ² ) n are each -CH ₂ -CH ₂ -, W is -CH ₂ -. , X is -CO-, and V, U, Y and Z are as defined in claim 1. Compounds of formula (I) according to claim 1, wherein - (CHR ¹ ) m - and - (CHR ² ) n are each -CH ₂ -CH ₂ -, W is -CO-, X is -CO-, and V, U, Y and Z are as defined in claim 1. 4. The following carboxylic acid derivatives of formula (I): 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide, 2- [ 4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1 H -benzoimidazol-5-yl) -acetamide, 2- [4- (4) -fluorobenzyl) piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-1H-benzoxazol-6-yl) acetamide, 2- [4- (4-fluorobenzyl) ) -piperidin-1-yl] -2-oxo-N- (2-oxo-2,3-dihydro-benzoxazol-5-yl) -acetamide, 2- (4-benzyl-piperidin-1-yl) -2-oxo-N - (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide, 2- (4-Benzyl-piperidin-1-yl) -2-oxo-N- (2-oxo-2,3-dihydro-1 H -benzoimidazol-5-yl) -acetamide, 2- (4-benzylpiperidin-1-yl) -2-oxo-N- (2-oxo-2,3-dihydrobenzoxazol-6-yl) oxoacetamide, 5- {2- [4- (4-Fluorobenzyl) piperidin-1-yl] -2-oxoethylamino} 1,3-dihydrobenzimidazol-2-one, 6- {2- [4- (4-Fluorobenzyl) piperidin-1-yl] -2-oxoethylamino} 3H-benzoxazol-2-one, 1- (4-Benzyl-piperidin-1-yl) -N- (1H-indazol-5-yl) -2-oxo-acetamide, HU 226 978 Β1 1- [4- (4-Fluorobenzyl) piperidin-1-yl] -N- (1H-indazol-5-yl) -2-oxoacetamide, 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2-oxo-N- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) - acetamide, N- (1H-benzimidazol-5-yl) -2- [4- (4-fluorobenzyl) piperidine-5 1-yl] -2-oxoacetamide, 1- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2- (1H-indazol-5-ylamino) -ethanone, 2- (4-Benzyl-piperidin-1-yl) -2-oxo-N- (3-oxo-3,4-dihydro-2 H -benzo [1,4] oxazin-7-yl) -acetamide, 1- (4 benzylpiperidin-1-yl) -2- (1H-indazol-5-yl) aminoethanone, 1- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-ylamino) -ethanone, 2- [4- (4-Fluorobenzyl) piperidin-1-yl] -N- (5-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl) -2-oxoacetamide, 2- (4-benzyl-1-piperidin-1-yl) -N- (5-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl) -2-oxoacetamide, 1- (4-Benzyl-1-piperidin-1-yl) -2- (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-ylamino) -ethanone. 5. Pharmaceutical compositions having a specific NMDA receptor antagonist action on the NR2B subunit, characterized in that the active ingredient is a carboxylic acid derivative of formula (I), wherein a- (CHR ¹ ) other - (CHR ² ) n - are each -CH ₂ -CH ₂ -. and W, X, V, U, Y and Z are as defined in claim 1, and / or salts thereof with pharmaceutically acceptable acids and bases containing a biologically effective dose of a conventional carrier, excipient, and other formulation excipients. became. 6. Process for the Carboxylic Acid Derivatives of Formula I (HI) wherein each of the - (CHR ¹ ) m - and - (CHR ² ) n - groups is -CH ₂ -CH ₂ -, Y and Z are as defined in claim 1 to 10, or b) for the preparation of compounds of formula I wherein W is -CO- and each of - (CHR ¹ ) m - and - (CHR ² ) n - is -CH ₂ -CH ₂ -, V, U, Y and Z are as defined in claim 1 - a carboxylic acid of formula IV Wherein each of the - (CHR ¹ ) m and - (CHR ² ) n groups is -CH ₂ -CH ₂ -, X, Y and Z are as defined in claim 1, or a reactive derivative thereof (V). ) with an amine of general formula (I) wherein each of the - (CHR ¹ ) m and - (CHR ² ) n groups is -CH ₂ -CH ₂ -, W, X, V, U, Y and Z are as defined in claim 1, and / or salts thereof with pharmaceutically acceptable acids or bases, characterized in that: a) a carboxylic acid of formula II (V) wherein U and V are as defined for formula (I), or c) for the preparation of compounds of formula I wherein W is -CH ₂ - or -CH (-alkyl) - wherein alkyl is C 1 -C 4 alkyl - a - (CHR ¹ ) m - and - Each of (CHR ² ) n - is -CH ₂ -CH ₂ -, and X, V, U, Y and Z are as defined in claim 1 - a halogen derivative of formula VII Q-CH ' I R ³ / / N x \ (CHR ¹ ) (CHR ² ) _n - '<K - where U, V and W are as defined in formula (I) - or a reactive derivative thereof with an amine of formula (II), 60 (VII) - where Q is halogen, R ³ is hydrogen or C 1 -C 4 alkyl, each of - (CHR ¹ ) m - and - (CHR ² ) n - is -CH ₂ -CH ₂ - and X is , Y and Z are as defined in claim 1, with an amine of formula (V) HU 226 978 Β1 NH ₂ ^ά 5 (V) - where U and V are as defined for Formula I and the resulting compounds of Formula I - wherein - (CHR ¹ ) m - and - (CHR ² ) n - are each -CH ₂ -CH ₂ -. and X, W, V, U, Y and Z are as defined in claim 1, optionally converted to another compound of formula (I), by the formation of additional substituents and / or modification of existing ones and / or removing them and / or forming salts with acids or bases and / or liberating the resulting salt. 7. A process for the preparation of a medicament having a selective NMDA receptor antagonist activity NR2B, characterized in that a carboxylic acid derivative of formula (I) wherein each of - (CHR ¹ ) m - and - (CHR ² ) n - -CH _{2 is} -CH ₂ - and X, W, V, U, Y and Z are as defined in claim 1 - 25 and / or salts thereof with pharmaceutically acceptable acids or bases in the customary carrier, filling and mixed with other formulation excipients to form a pharmaceutical composition. 8. A carboxylic acid amide derivative of formula (I) wherein each of - (CHR ¹ ) m - and - (CHR ² ) n - is -CH ₂ -CH ₂ - and X, W, V, U, Y and Z is the use as defined in claim 1 and / or a salt thereof with pharmaceutically acceptable acids or bases for the preparation of a medicament for the treatment or amelioration of the following diseases of a mammal, including man: traumatic brain or spinal cord injury, HIV nerve injuries due to infection, amyotrophic lateral sclerosis, tolerance to or dependence on opioid treatment, withdrawal symptoms such as alcohol, opioids or cocaine, ischemic CNS disorders, chronic neurodegenerative disorders such as Parkinson's disease, -disease, pain and chronic pain states such as neur opiate pain or cancer pain, epilepsy, anxiety, depression, migraine, psychosis, muscle spasms, dementia of various origins, hypoglycemia, degenerative retinal disorders, glaucoma, asthma, tinnitus, aminoglycoside antibiotic-induced hearing loss.