WO2006010968A1

WO2006010968A1 - New aryloxy acetic acid amide derivatives

Info

Publication number: WO2006010968A1
Application number: PCT/HU2005/000081
Authority: WO
Inventors: György KESERÛ; István VÁGÓ; Sándor FARKAS; Csilla HORVÁTH; Attila Bielik; István BORZA; Csaba WÉBER; Sándor KOLOK; József Nagy
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 2004-07-29
Filing date: 2005-07-21
Publication date: 2006-02-02
Anticipated expiration: 2007-01-29
Also published as: HU0401526D0; HUP0401526A2

Abstract

The new aryloxy acetic acid amide derivatives of formula (I) where R1 and R2 are the same or different and can be hydrogen atom or C1-4 alkanoylamido group optionally substituted by halogen atom or C1-4 alkyl-sulfonylamido group or N'-( C1-4 alkyl)-ureido group C1-6 alkoxy-carbonyl-amido or di-( C1-4 alkyl)-amino group with the proviso that only one of them can be hydrogen atom, or R1 and R2 form together a -NH-CO-NH-, -NH-N=CH- or -NH-CO-O- chain attached to two neighbouring carbon atoms of the benzyl group, R3 and R4 mean the same or different C1-4 alkyl groups which are substituted by phenyl group, or R3 and R4 mean together a C4-6 alkylene chain which can be interrupted optionally by a nitrogen atom and which can contain a C-C double bound and which C4-6 alkylene chain can substituted by one or two substituents from the following hydroxy group, phenyl or phenoxy group optionally substituted by a C1-4 alkyl or trifluoro methyl group, =CH-phenyl group which can be substituted by halogen atom or C1-4 alkyl group, C1-4 alkyl group optionally substituted by hydroxy groµp and one or two phenyl groups which can be substituted by halogen atom or C1-4 alkyl group, C1-4 alkyl amino group which is substituted by a phenyl or naphtyl group which can be substituted optionally by a halogen atom or a C1-4 alkyl group, as well as their salts formed with organic or inorganic acids or bases and solvates of these compounds are functional antagonists of NMDA receptors, which target the NMDA receptors primarily via binding to the ifenprodil binding site. Furthermore objects of the present invention are the pharmaceutical compositions containing new aryloxy acetic acid amide derivatives of formula (I) or optical antipodes or racemates or the salts thereof as active ingredients and processes for producing these compounds and pharmaceutical compositions.

Description

New aryloxY acetic acid amide derivatives

The invention relates to new aryloxy acetic acid amide derivatives of formula (I)

where

R and R are the same or different and can be hydrogen atom or

C_1-4 alkanoylamido group optionally by halogen atom substituted or

C_1-4 alkyl-sulfonylamido group or

N'-( C_1-4 alkyl)-ureido group C_1-6 alkoxy-carbonyl-amido or di-( Ci_-4 alkyl)-amino group with the proviso that only one of them can be hydrogen atom, or R¹ and R² form together a -NH-CO-NH-, -NH-N=CH- or -NH-CO-O- chain attached to two neighbouring carbon atoms of the benzyl group, R³ and R⁴ mean the same or different C_1-4 alkyl groups which are substituted by phenyl group, or R³ and R⁴ mean together a C_4-6 alkylene chain which can be interrupted optionally by a nitrogen atom and which can contain a C-C double bound and which C_4-6 alkylene chain can substituted by one or two substituents from the following hydroxy group, phenyl or phenoxy group optionally substituted by a C_1-4 alkyl or trifluoro methyl group,

=CH- group, substituted by phenyl group which can be substituted by halogen atom or C_1-4 alkyl group, C_1-4 alkyl group optionally substituted by hydroxy group and one or two phenyl groups which can be substituted by halogen atom or C_1-4 alkyl group,

C_1-4 alkyl amino group which is substituted by a phenyl or naphtyl group which can be substituted optionally by a halogen atom or a C_1-4 alkyl group, as well as their salts formed with organic or inorganic acids or bases and solvates of these compounds which are antagonists of NMDA receptor or are intermediates for preparing thereof. Background of the invention. N-methyl-D-aspartate (NMDA) receptors are ligand-gated cation-channels embedded in the cell membranes of neurons. Overactivation of NMDA receptors by glutamate, their natural ligand, can lead to calcium overload of cells. This triggers a cascade of intracellular events that alters the cell function and ultimately may lead to death of neurons [TINS, 10, 299- 302 (1987)]. Antagonists of the NMDA receptors may be used for treating many disorders that are accompanied with excess release of glutamate, the main excitatory neurotransmitter in the central nervous system.

The knowledge on the NMDA receptor structure, function and pharmacology has expanded owing to recent achievements of the molecular biology. The NMDA receptors are heteromeric assemblies built up from at least one NRl subunit and at least one of the four different NR2 subunits _. (NR2A-D). Both spatial distributions in the CNS and the pharmacological sensitivity of NMDA receptors built up from various NR2 subunits are different. Particularly interesting of these is the NR2B subunit due to its restricted distribution (highest densities in the forebrain and substantia gelatinosa of the spinal cord). Compounds selective for this subtype are available [Curr. Pharm. Des., 5, 381-404 (1999)] and have been proved to be effective in animal models of stroke [Stroke, 28, 2244-2251 (1997)], traumatic brain injury [Brain Res., 792, 291-298 (1998)], Parkinson's disease [Exp. Neurol, 163, 239-243 (2000)], neuropathic and inflammatory pain [Neuropharmacology, 38, 611-623 (1999)]. Moreover, NR2B subtype selective antagonists of NMDA receptors are expected to possess little or no untoward side effects that are typically caused by the non-selective antagonists of NMDA receptors, namely psychotomimetic effects such as dizziness, headache, hallucinations, dysphoria and disturbances of cognitive and motor function.

NR2B subtype selective NMDA antagonism can be achieved with compounds that specifically bind to, and act on, an allosteric modulatory site of the NR2B subunit containing receptors. This binding site can be characterised by displacement (binding) studies with. specific radioligands, such as [125I]-ifenprodil [J.Neurochem., 61, 120-126 (1993)] or [3H]-Ro 25,6981 [J. Neurochem., 70, 2147-2155 (1998)]. Since ifenprodil was the first, though not sufficiently specific, known ligand of this receptor, it has also been termed ifenprodil binding site. The patent document WOOl/30330 discloses a method to treat pain utilizing 2- methyl- or -ethyl-piperidino-benzimidazole derivatives as NMDA NR2B antagonists.

Aralkyl- and aralkenyl-piperidino-derivates are described as NMDA receptor antagonists in the published patent application WO99/48891. The published PCT application WO 99/21539 discloses a method for treating disease-related or drug-induced dyskinesias using NMDA receptor antagonists. The used compounds consist of a substituted piperidine ring and a substituted aryl or heteroaryl group, which are coupled by a (hetero) alkylene chain or a direct chemical bound.

6-{3-[4-(4-Fluorobenzyl)-piρeridin-l-yl]-propionyl}-3H-benzoxazol-2-one derivatives are published as excitatory amino acid antagonists in the PCT application WO98/18793.

A large number of 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists are disclosed in the PCT application WO 97/23216. Another group of compounds of this type act on the glutamate receptor and on the glutamate receptor dependent ion chanel as disclosed in the published German patent application DE 4410822. Summary of the invention

Surprisingly it was found that the new aryloxy acetic acid amide derivatives of formula (I) of the present invention are functional antagonists of NMDA receptors, which target the NMDA receptors primarily via binding to the ifenprodil binding site. Therefore, they are believed to be NR2B subtype specific antagonists. Experimental protocols Expression of recombinant NMDA receptors

To prove NR2B selectivity of our compounds, we tested them on cell lines stably expressing recombinant NMDA receptors with subunit compositions of NRl(-3)/NR2A. cDNAs of human NRl(-3) and NR2A subunits subcloned into inducible mammalian expression vectors were introduced into HEK 293 cells lacking NMDA receptors using a cationic lipid-mediated transfection method [Biotechniques, 1997 May ;22(5),: 982-7; Neurochemistry International, 43j 19-29. (2003)]. Resistance to neomycin and hygromycin was used to screen for clones possessing both vectors and monoclonal cell lines were established from the clones producing the highest response to NMDA exposure. Compounds were tested for their inhibitory action on NMDA evoked cytosolic calcium elevations in fluorescent calcium measurements. Studies were performed 48-72 h after addition of _.the inducing agent. Ketamine (500 μM) was also present during the induction in order to prevent cytotoxicity. Assessment of NMDA antagonist potency in vitro by measurement of intracellular calcium concentration with a plate reader fluorimeter in cells expressing recombinant NMDA receptors

Measurements of [Ca²⁺]i were carried out on EcR HEK293 cells stably expressing the murine NRla/NR2B NMDA receptor subunit combinations. Cells were grown in standard 96- well microplates and before the measurement were loaded with a fluorescent Ca²⁺-sensitive dye, fluo-4/AM (2μM) for 60-90min. To facilitate dye retention, the loading medium also contained 2 mM probenecid (an anion-transport inhibitor). To stop dye loading cells were washed twice with extracellular medium (14OmM NaCl, 5mM KCl, 2mM CaCl₂, 5mM HEPES, 5mM HEPES-Na, 2OmM glucose, lOμM glycine, pH=7.4), containing 2mM probenecid and 400μM DL-AP5 (an NMDA-antagonist to prevent deleterious receptor activation during the washing step). After washing, the test compounds (diluted in extracellular medium from a DMSO stock solution, final DMSO concentration was <0.1%) were added to the cells. Cytosolic calcium measurements were carried out with a plate reader fluorimeter (Fluoroskan Ascent, Labsystems): after recording baseline fluorescence (5min.), elevation of [Ca²⁺]i was induced by application of lOOμM NMDA and the fluorescence was recorded for an additional 5 min. Inhibitory potency of the test compounds was assessed by measuring the reduction in the calcium elevation in the presence of different concentrations of the compounds. AU treatments on a single plate were measured in multiple wells. The average value of all wells of a treatment was used for analysis.

Dose-response curves and ICso-values were calculated by using data derived from at least three independent experiments. Inhibitory potency of a compound at a single concentration point was expressed as percent inhibition of the NMDA response. Sigmoidal concentration-inhibition curves were fit to the data and IC₅₀ values were determined as the concentration that produces half of the maximal inhibition caused by the compound.

Table A.

ICsn values of most active compounds measured by fluorimetric method in cells expressing recombinant NMPA receptors.

Disorders which may be beneficially treated with NMDA antagonists acting at NR2B site, as reviewed recently by Loftis [Pharmacology & Therapeutics, 97j 55-85 (2003)] include schizophrenia, Parkinson's disease, Huntington's disease, excitotoxicity evoked by hypoxia and ischemia, seizure disorders, drug abuse, and pain, especially neuropathic, inflammatory and visceral pain of any origin [Eur. J. Pharmacol., 429, 71-78 (2001)].

Due to their reduced side effect liability compared to non-selective NMDA antagonists, NR2B selective antagonists may have utility in diseases where NMDA antagonists may be effective, such as amyotrophic lateral sclerosis [Neurol. Res., 2I₁ 309-12 (1999)], withdrawal syndromes of e.g. alcohol, opioids or cocaine [Drug and Alcohol Depend., 5S⁾ ₁ 1-15 (2000)], muscular spasms [Neurosci. Lett., 73J₁ 143-148 (1987)], dementia of various origins [Expert Opin. Investig. Drugs, 9_j 1397-406 (2000)], anxiety, depression, migraine, hypoglycemia, degenerative disorders of the retina (e.g. CMV retinitis), glaucoma, asthma, tinnitus, hearing loss [Drug News Perspect 1I₂523-569 (1998) and WO 00/00197 international patent application]. Accordingly, effective amounts of the compounds of the invention may be beneficially used for the treatment of traumatic injury of brain or spinal cord, tolerance and/or dependence to opioid treatment of pain, withdrawal syndromes of drugs of abuse e.g. alcohol, opioids or cocaine, ischemic CNS disorders, chronic neurodegenerative disorders, such as e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, pain and chronic pain states, such as e.g. neuropathic pain.

Detailed description of the invention

The new aryloxy acetic acid amide derivatives of formula (I) - wherein the meaning of R , R , R and R are as defined in claim 1 - and/or their salts formed with organic or inorganic acids or bases and solvates of these compounds can be prepared by reacting an aryloxy acetic acid of formula (II)

(II)

or a reactive derivative of it - where R¹ and R² have the same meaning as defined in- claim 1 with an secondary amine of formula (III)

(III)

- where R³ and R⁴ have the same meaning as defined in claim 1 - and the obtained compounds of formula (I) - where R¹, R², R³ and R⁴ are as defined in claim 1 - are transformed in given case into an other compound of formula (I) by introducing further substituents and/or modifying and/or removing the existing ones, and/or formation of salts with acids and/or bases and/or liberating the carboxylic acid amide derivative of formula (I) from the obtained salts by treating with a base and/or acid and/or by forming solvates from them.

A preferably method is when the reactive derivative of the aryloxy acetic acid of formula (II) is formed in situ by using of a carbodiimide e.g. by using l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide (EDC) as carbodiimide.

For example the process for producing of compounds of formula (I) can be carried out as follows:

0.25 mmol of an aryloxy acetic acid of formula (II) is solved in 1 ml of dimethylformamide. 0.2 mmol of compound of formula (III) in 1 ml of dimethylformamide, 0.25 mmol of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) in 0.5 ml of dimethylformamide and 0.04 mmol of 4-(dimethylamino)pyridine in 0.5 ml of dichloromethane were added and the mixture was vigorously shaken for 12 hours. The mixture was diluted with 2 ml of dichloromethane, and extracted with 4 ml of IM HCl three times, 4 ml of water three times, 4 ml of 8 % NaHCO₃ three times and 4 ml of water three times. The organic solution was concentrated to yield the final product (I).

The forming of salts can be performed by known methods, by treating the aryloxy acetic acid amide derivative of formula (I) with acids or bases. From an obtained salt the free aryloxy acetic acid amide derivative of formula (I) can be freed, too by using known methods. Characterization and Purification Methods Compounds of the present invention were characterized by high performance liquid chromatography coupled to mass selective detector (LC/MS) using HP 1100 Binary Gradient chromatography system with Microplate Sampler (Agilent, Waldbronn), controlled by ChemStation software. HP diode array detector was used to acquire UV spectra at 225 and 240 nm. All experiments were performed using HP MSD (Agilent, Waldbronn) single quadruple spectrometer equipped with an electrospray ionisation source to determine the structure.

The synthesized products were dissolved in 1 ml DMSO (Aldrich, Germany). 100 μl of each solution was diluted with DMSO to 1000 μl volume. Analytical chromatographic experiments were_. performed on Discovery RP C-16 Amide, 5 cm X 4.6 mm X 5 μm column from Supelco (Bellefonte, Pennsylvania) with a flow rate of 1 ml/minute for qualification. The obtained compounds were characterized by their k' value (purity, capacity factor), k' factors are evaluated by the following formula: k' = (t_R- to) /t_o where k'= capacity factor, t_R = retention time and to = eluent retention time. .

The A eluent was water containing 0.1% trifluoroacetic acid (TFA) (Sigma, Germany), the B eluent was 95% acetonitrile (Merck, Germany) containing 0.1% TFA and 5% A eluent. Gradient elution was used, starting with 100% A eluent and processing to 100% B eluent over a period of 5 minutes. Semipreparative separation of the compounds of the present invention - purity below

85% - was carried out using the same high performance chromatography system. The separation was performed on Discovery RP C-16 Amide, 20 cm X 10 mm X 5 μm semipreparative column from Supelco (Bellefonte, Pennsylvania) with a flow rate of 3 ml/minutes. The fraction collection was based on mass selective separation. Gradient elution was used, starting with 80% A eluent and processing to 65% B eluent over a period of 35 minutes for those compounds where the capacity factor was more than 2.5. The gradient elution was changed, starting with 100 % A eluent and processing to 55% B eluent in 30 minutes for those compounds where the capacity factor was less than 2.5. The collected fractions were qualified by the above detailed analytical method and the solvent was evaporated by Speed Vac (Savant, USA). The synthesis of compounds and pharmaceutical compositions according to the invention is illustrated by the following not limiting Examples. Example 1 5-{2-r4-(4-ChIoro-phenoxy)-piperidm-l-yl]-2-oxo-ethoxy)-3H-benzooxazol-2-one (3b-12)

52 mg (0.25 mmol) (2-Oxo-2,3-dihydro-benzooxazol-5-yl)-oxy-acetic acid is solved in 1 ml of dimethylformainide. 55 mg (0.26 mmol) of 4-(4-chloro-phenoxy)-piperidine in 1 ml of dimethylformamide, 0.25 mmol of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide [EDC] in 0.5 ml of dimethylformamide and 0.04 mmol of 4-(dimethylamino)-pyridine in 0.5 ml of dichloromethane were added and the mixture was vigorously shaken for 12 hours. The mixture was diluted with 2 ml of dichloromethane, and extracted with 4 ml of IM HCl three times, 4 ml of water three times, 4 ml of 8 % NaHCO₃ three times and 4 ml of water three times. The organic solution was concentrated to yield 49 mg 5-{2-[4-(4-chloro-phenoxy)-piperidrn-l-yi]-2- oxo-ethoxy}-3H-benzooxazol-2-one. (k'=3.098)

Using the procedure described above we prepared the following compounds of formula (I). Here and in the following tables Ph means phenyl group. MW_C is the calculated, and MW_n, the measured molecular weight.

Table Ia

Using the procedure described above we prepared the following narrower group of compounds of formula (T), covered in the following tables, characterised by the formula (IA), where the dotted bond means a simple C-C bond and A is a -CH₂- group:

Table 2a

Compounds of formula (IA), where the dotted bond means a double C-C bond and A -CH= group:

Table 2b

Compounds of formula (IA), where the dotted bond means a simple C-C bond and A an -NH- group:

Table 3a

Compounds of the formula (IA), where the dotted bond means a simple C-C bond and A is a -CH₂- group:

Table 3b

Compounds of formula (IA), where the dotted bond means a double C-C bond and A is a -CH= group:

Table 4a

Compounds of formula (IA), where the dotted bond means a simple. C-C bond and A is an -NH- group:

Table 4b

Example 2

Preparation of pharmaceutical compositions; a) Tablets:

0.01-50 % of active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of. polyvinyl pyrrolidone, 1-5 % of talc, 0.01-3 % of magnesium stearate, 1-3 % of colloid silicon dioxide and ^•2-7 % of ultraamylopectin are mixed, then are granulated by wet granulation and pressed to tablets. b) Dragees, filmcoated tablets;

The tablets made according to the method described above are coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragees are polished by a mixture of beeswax and carnuba wax. c) Capsules:

0.01-50 % of active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I), 1-5 % of sodium lauryl sulfate, 15-50 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of magnesium stearate are thoroughly mixed, the mixture is passed through a sieve and filled in hard gelatin capsules. d) Suspensions:

Ingredients: 0.01-15 % of active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol, 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.

To solution of nipagin and citric acid in 20 ml of distilled water, carbopol is added in small portions under vigorous stirring, and the solution is left to stand for 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavor are added with stirring. To this carrier the active ingredient is added in small portions and suspended with an immersing homogenizator. Finally the suspension is filled up to the desired final volume with distilled water and the suspension syrup is passed through a colloid milling equipment. e) Suppositories:

For each suppository 0.01-15% of active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I) and 1-20% of lactose are thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol 4) is melted, cooled to 35 ⁰C and the mixture of active ingredient and lactose is mixed in it with homogenizator. The obtained mixture is mould in cooled forms. f) Lyophilized powder ampoule compositions:

A 5 % solution of mannitol or lactose is made with bidistilled water for injection use, and the solution is filtered so as to have sterile solution. A 0.01-5 % solution of the active ingredient selected from the new aryloxy acetic acid amide derivatives of formula (I) is also made with bidistilled water for injection use, and this solution is filtered so as to have sterile solution. These two solutions are mixed under aseptic conditions, filled in .1 ml portions into ampoules, the content of the ampoules is lyophilized, and the ampoules are sealed under nitrogen. The contents of the ampoules are dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.

Claims

What we claim is;

1. New aryloxy acetic acid amide derivatives of formula (I)

where R¹ and R² are the same or different and can be hydrogen atom or

C_1-4 alkanoylamido group optionally substituted by halogen atom or C_1-4 alkyl-sulfonylamido group or N'-( C_1-4 alkyl)-ureido group C_1-6 alkoxy-carbonyl-amido or di-( Ci_-4 alkyl)-amino group with the proviso that only one of them can be hydrogen atom, or R¹ and R² form together a -NH-CO-NH-, -NH-N=CH- or -NH-CO-O- chain attached to two neighbouring carbon atoms of the benzyl group,

R³ and R⁴ mean the same or different C_1-4 alkyl groups which are substituted by phenyl group, or

R³ and R⁴ mean together a C_4-6 alkylene chain which can be interrupted optionally by a nitrogen atom and which can contain a C-C double bound and which C_4-6 alkylene chain can substituted by one or two substituents from the following hydroxy group, phenyl or phenoxy group optionally substituted by a C_1-4 alkyl or trifluoro methyl group,

=CH-phenyl group which can be substituted by halogen atom or C_1-4 alkyl group, Ci-₄ alkyl group optionally substituted by hydroxy group and one or two phenyl groups which can be substituted by halogen atom or C_1-4 alkyl group, C_1-4 alkyl amino group which is substituted by a phenyl or naphtyl group which can be substituted optionally by a halogen atom or a C_1-4 alkyl group, as well as their, salts formed with organic or inorganic acids or bases and solvates of these compounds.

2. Compounds of formula (I) as claimed in claim 1, where R³ and R⁴ mean the same or different Ci_-4 alkyl groups which are substituted by phenyl group and R and R . have the same meaning as defined in claim 1.

3. Compounds of formula (I) as claimed in claim 1, where R³ and R⁴ mean together a C_4-6 alkylene chain which can be interrupted optionally by a nitrogen atom and which can contain a C-C double bound and which C_4-6 alkylene chain can substituted by one or two substituents from the following hydroxy group, phenyl or phenoxy group optionally substituted by a Ci_-4 alkyl or trifluoro methyl group,

=CH-phenyl group which can be substituted by halogen atom or Ci_-4 alkyl group, Ci-₄ alkyl group optionally substituted by hydroxy group and one or two phenyl groups which can be substituted by halogen atom or C_1-4 alkyl group, Ci_-4 alkyl amino group which is substituted by a phenyl or naphtyl group which can be substituted optionally by a halogen atom or a Ci_-4 alkyl group, and

R and R have the same meaning as defined in claim 1.

4. Compounds of formula (I) as claimed in claim 1, where R¹ and R² are the same or different and can be hydrogen atom or

Ci_-4 alkanoylamido group optionally by halogen atom substituted or . Ci_-4 alkyl-sulfonylamido group or

N'-( Ci_-4 alkyl)-ureido group

C_1-6 alkoxy-carbonyl-amido or di-( Ci_-4 alkyl)-amino group with the proviso that only one of them can be hydrogen atom, and R³ and R⁴ have the same meaning as defined in claim 1.

5. Compounds of formula, (I) as claimed in claim 1, where

R¹ and R² form together a -NH-CO-NH-, -NH-N=CH- or -NH-CO-O- chain attached to two neighbouring carbon atoms of the phenyl group, and R³ and R⁴ have the same meaning as defined in claim 1.

6, A member of the following group of compounds of formula (I) as claimed in claim

1

5-{2-[4-(4-methyl-benzyl)-piperidin-l-yl]-2-oxo-ethoxy}-l,3-dihydiO-benzoimidazol-2-one, N-(4-{2-[4-(4-methyl-benzyl)-ρiperidin-l-yl]-2-oxo-ethoxy}-ρhenyl)-methanesulfonamide, N-(4-{2-[4-(4-chloro-benzyl)-piperidin-l-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide, . 5- { 2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-2-oxo-ethoxy} - 1 ,3-dihydro-benzoimidazol-2-one and

5-{2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-2-oxo-ethoxy}-3H-benzooxazol-2-one.

7. Pharmaceutical compositions having an NR2B subtype specific NMDA antagonist effect, c h a r a c t e r i z e d b y comprising a biologically effective dose of a new aryloxy acetic acid amide derivative of formula (I) - wherein the meaning of R¹, R², R³ and. R⁴ are as defined in claim 1 - and/or pharmaceutically acceptable salts thereof formed with acids or bases as active ingredient and carriers, filling materials and the like usually applied in pharmaceuticals.

8. Process for preparing of new aryloxy acetic acid amide derivatives of formula (I) - wherein the meaning of R¹, R², R³ and R⁴ are as defined in claim 1 - and/or their salts formed with organic or inorganic acids or bases and solvates of these compounds c h a r a c t e r i z e d b y reacting an aryloxy acetic acid of formula (II)

(H)

or a reactive derivative of it - where R¹ and R² have the same meaning as defined in claim 1 with a secondary amine of formula (III)

/^R3

H-N

(III)

- where R³ land R⁴ have the same meaning as defined in claim 1 - and the obtained compounds of formula (I) - where R¹, R², R³ and R are as defined in claim 1 - are transformed in given case into an other compound of formula (I) by introducing further substituents and/or modifying and/or removing the existing ones, and/or by forming salts with acids and/or bases and/or by liberating the new aryloxy acetic acid amide derivative of formula (I) from the obtained salts by treating with a base and/or acid and/or by forming solvates from them.

9. Process as claimed in claim 8, c h a r a c t e r i z e d b y in situ forming the reactive derivative of the aryloxy acetic acid of formula (II) - where R and R have the same meaning as defined in claim 1 - by using of a carbodiimide.

10. Process as claimed in claim 8, c h a r a c t e r i z e d b y using l-[3- (dimethylamino)ρropyl]-3-ethylcarbodiimide (EDC) as carbodiimide.

11. Process for manufacturing pharmaceutical compositions having NR2B selective NMDA receptor antagonist effect, c h a r a c t e r i z e d b y mixing an aryloxy acetic acid amide derivative of formula (I) - wherein the meaning of R¹, R², R³ and R⁴ are as defined in claim 1 - or the pharmaceutically acceptable salts thereof as active ingredient and auxiliary materials, which are commonly used in practice, such as carriers, excipients, diluents, stabilizers, wetting or emulsifying agents, pH- and osmotic pressure-influencing, flavoring or aromatizing, as well as formulation-promoting or formulation-providing additives.

12. Method of treatment and alleviation of symptoms of the following diseases of mammals - including human - chronic neurodegenerative disorders, such as stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, injury of spinal cord, epilepsy, anxiety, depression, cerebral ischemia of any origin, muscular spasm, multiinfarct dementia, injury of brain, pain (e.g. posttraumatic or postoperative) and chronic pain states, such as neuropathic pain or cancer related pain, migraine, human immunodeficiency virus (HIV) related neuronal injury, hypoglycemia, amyotrophic lateral sclerosis (ALS), bacterial sclerosis, macula degeneration, degenerative disorders of the retina (e.g. CMV retinitis) asthma, tinnitus, aminoglycoside antibiotic-induced hearing loss, bacterial and viral infections, to decrease tolerance and/or dependence to drugs and alcohol, and for treatment of withdrawal syndrome of drugs and alcohol, psychosis, bladder incontinence, c h a r a c t e r i z e d b y administering effective amount/amounts of an aryloxy acetic acid amide derivative of formula (I) - wherein the meaning of R¹, R², R³ and R⁴ are as defined in claim 1 - and/or pharmaceutically acceptable salts thereof formed with acids or bases as active ingredient as such or suitably in the form of pharmaceutical composition manufactured with known auxiliaries usually applied, in pharmaceuticals to a mammal - including human - to be treated.

13. Use of an aryloxy acetic acid amide derivative of formula (I) - wherein the meaning of R , R², R³ and R⁴ are as defined in claim 1 - and/or optical antipodes or racemates and/or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical for the txeatment and alleviation of symptoms of the following diseases in a mammals, including humans: chronic neurodegenerative disorders, such as stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, injury of spinal cord, epilepsy, anxiety, depression, cerebral ischemia of any origin, muscular spasm, multiinfarct dementia, injury of brain, pain (e.g. posttraumatic or postoperative) and chronic pain states, such as neuropathic pain or cancer related pain, migraine, human immunodeficiency virus (HIV) related neuronal injury, hypoglycemia, amyotrophic lateral sclerosis (ALS), bacterial sclerosis, macula degeneration, degenerative disorders of the retina (e.g. CMV retinitis) asthma, tinnitus, aminoglycoside antibiotic-induced hearing loss, bacterial and viral infections, to decrease tolerance and/or dependence to drugs and alcohol, and for treatment of withdrawal syndrome of drugs and alcohol, psychosis, bladder incontinence.