JPH10504027A - 4-hydroxy-3-phenyl-indeno (1,2-b) pyridin-2 (1H) -one derivatives as NMDA antagonists - Google Patents

Abstract

(57) [Summary] Formula (I) Wherein R is a methylene group, N-alkyl, NH or an oxygen atom or a sulfur atom, R ₁ and R ₂ are the same or different, and are a hydrogen atom or a halogen atom or a hydroxy group, an alkoxy group, an alkyl Group, nitro group, amino group, monoalkylamino group, dialkylamino group, cyano group, polyfluoroalkyl group, polyfluoroalkoxy group or phenoxy group, R ₃ and R ₄ are the same or different, and a hydrogen atom or a halogen atom or alkyl And tautomeric forms thereof, salts thereof, preparation thereof and drugs containing the above-mentioned derivatives.

Description

DETAILED DESCRIPTION OF THE INVENTION 4-Hydroxy-3-phenyl-indeno (1,2-b) pyridin-2 (1H) -one derivatives as NMDA antagonists , Their salts, their preparation and the pharmaceuticals containing them. In the formula (I), R represents a methylene group, an N-alk group or an NH group or an oxygen atom or a sulfur atom; ₁ And R _Two Are the same or different and are a hydrogen atom or a halogen atom or a hydroxyl group, an alkoxy group, an alkyl group, a nitro group, an amino group, a monoalkylamino group, a dialkylamino group, a cyano group, a polyfluoroalkyl group, a polyfluoroalkoxy group, or a phenoxy group And R _Three And R _Four Is the same or different and represents a hydrogen atom or a halogen atom or an alkyl group, and alk represents an alkyl group. In the preceding definitions and in the definitions mentioned below, unless otherwise stated, the alkyl and alkoxyl groups and the alkyl and alkoxyl moieties are from 1 to 4 straight or branched linear or branched groups. Contains carbon atoms. The compounds of the formula (I) can also exist in other tautomeric forms. These other tautomeric forms also form part of the invention. The polyfluoroalkyl groups are preferably a trifluoromethyl group, a pentafluoroethyl group or a 2,2,2-trifluoroethyl group. The polyfluoroalkoxy groups are preferably a trifluoromethoxy group, a pentafluoroethoxy group, a 2,2,2-trifluoroethoxy group or a 1,1,2,2-tetrafluoroethoxy group. Compounds of formula (I) in which R represents a methylene group include ammonium acetate and a compound of formula (I) Can be produced by reaction with a derivative of Here, R represents a methylene group; ₁ , R _Two , R _Three And R _Four Has the same meaning as in formula (I) and R _Five Represents an alkyl group. The reaction is generally carried out in acetic acid at the boiling point of the reaction mixture. The derivatives of formula (II) are represented by R _Three And R _Four 3-morpholino-1H-indene substituted by The compound can be obtained by a reaction with a derivative having the following. Where R ₁ And R _Two Has the same meaning as in formula (I), _Five Represents an alkyl group and Hal represents a halogen atom and preferably a chlorine atom. This reaction is generally carried out in an inert solvent such as tetrahydrofuran in the presence of a base such as a trialkylamine (eg triethylamine) at a temperature of about 20 ° C. R _Three And R _Four 3-morpholino-1H-indenes can be obtained by applying or improving the method described by AT Blomquist et al., Journal of Organic Chemistry (J. Org. Chem.), 26, 3761 (1961). To obtain the corresponding 1-indanone. R _Three And R _Four 1-Indanones have been described by M. Olivier et al., Bull. Soc. Chim. de France, 3092 (1973) and R. Seka et al., Chem. Ber., 75B, 1730 (1942) and by application or improvement of the methods described in U.S. Pat. No. 4,263,319, U.S. Pat. No. 4,096,173 and EP 314,400. Derivatives of formula (III) can be obtained by the corresponding acid halogenation by any known method which allows the conversion from acid to acid halide. For example, it is possible to react sulfinyl chloride or sulfinyl bromide, optionally in an inert solvent such as dichloromethane and optionally in the presence of a catalytic amount of dimethylformamide, at a temperature of about 20 ° C. Corresponding acids are those wherein phenyl is converted to R by the adaptation or modification of the method described by Bentrude et al., J. Am. Chem. Soc., 106, 106 (1984). ₁ And R _Two From dialkyl phenylmalonates substituted by The dialkyl phenylmalonates are commercially available or are available from W. Wislicenus, Ber., 27, 1091 (1894), Nelson et al., Journal of American Chemical Society (J. Am. Chem. Soc.), 50, 2760 (1928) and Ivanoff et al., Bull. Soc. Chim. De France, 49, 20 (1931) can be obtained from the corresponding alkyl phenylacetates by application or modification of the method described. The alkyl phenylacetates are commercially available or are available from Austin et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), 54, 655 (1932), W. Mann, 14, 1645 (1881) and W. Staedel, Ber., 19, 1949 (1886) can be obtained from the corresponding benzyl bromides by application or modification of the method. The benzyl bromides themselves are described in H. Hirshberg et al., Journal of Chemical Society (J. Chem. Soc.), 1030 (1951) and F. Krohnke, Chem. 83, 35 (1950) by halogenation of the corresponding toluenes by application or modification of the method described. Compounds of formula (I) in which R represents an N-alk (alkyl) group or an NH group or an oxygen atom or a sulfur atom are represented by the formula Can be produced by cyclization of a derivative of Here, R represents an N-alk (alkyl) group or an NH group or an oxygen atom or a sulfur atom; ₁ , R _Two , R _Three And R _Four Has the same meaning as in formula (I) and R ₆ Represents an alkyl group. This cyclization is carried out in an inert solvent such as tetrahydrofuran in the presence of bis (trimethylsilyl) lithium amide at a temperature between 20 ° C and 60 ° C. Derivatives of formula (IV) have the formula Wherein R represents an N-alk (alkyl) group or an NH group or an oxygen atom or a sulfur atom; _Three And R _Four Has the same meaning as in formula (I) and R ₆ Represents an alkyl group, which is represented by the formula Halide, where R ₁ And R _Two Has the same meaning as in formula (I), and Hal represents a halogen atom and preferably a chlorine atom. This reaction is generally carried out in an inert solvent such as dioxane in the presence of a base such as a trialkylamine (eg triethylamine) at the boiling point of the reaction mixture. Derivatives of the formula (V) in which R represents an NH group are described in Unangst, PC. Heterocyclic Chem., 20, 495 (1983). _Three And R _Four From 2-cyanoanilines substituted by The 2-cyanoanilines are commercially available, or Nixon et al., Synthesis, 669 (1985), JB Campbell et al., Synthetic Comm., 19, 2265 ( 1989), NV Harris et al. Med. Chem., 33, 434 (1990); DH. Klaubert et al. Med. Chem., 24, 748 (1981); F. Hunziker et al., Eur. J. Med. Chem.-Chim. Ther., 16, 391 (1981) and M. Adachi et al., Synth. Comm., 20 (1), 71 (1990), and by adapting or improving the methods described in EP 30156 and DE 1,952,896. Derivatives of formula (V) in which R represents an N-alk (alkyl) group can be obtained by alkylation of the corresponding derivatives of formula (V) in which R represents an NH group. This reaction is performed by any alkylation method known to those skilled in the art that allows for the conversion from an NH group to a Na-alk (alkyl) group without affecting the rest of the molecule. Conventionally, in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture of these solvents, preferably in the presence of an alkali metal halide such as sodium hydride, at a temperature of about 20 ° C. Made from alkyl halides. Derivatives of the formula (V) in which R represents an oxygen atom are described in K. Gewald et al., JF. Prakt. By adapting or adapting the method described by Chemie, 315, 779 (1973), R _Three And R _Four From 2-cyanophenols substituted by The 2-cyanophenols were obtained by adapting or improving the method described by Larock in "Comprehensive Organic Transformation", published by VCH, page 483 (1989). And the corresponding 2-cyanoanilines. Derivatives of the formula (V) in which R represents a sulfur atom can be obtained by applying or improving the method described by DEL. Carrington et al., Journal of Chemical Society (J. Chem. Soc.), 3903 (1971). , R _Three And R _Four From 2-cyanothiophenols substituted by The 2-cyanothiophenols can be obtained from the corresponding 2-cyanophenols by adapting or improving the method described in EP 365,397. Derivatives of formula (VI) are either commercially available or can be obtained by halogenation of the corresponding phenylacetic acids by any known method which allows the conversion from acid to acid halide. For example, a sulfinyl chloride or a sulfinyl bromide can be reacted at a temperature of about 20 ° C., optionally in an inert solvent such as dichloromethane, and optionally in the presence of a catalytic amount of dimethylformamide. The phenylacetic acids are commercially available or preferably in a water / alcohol (eg ethanol) mixture at a temperature between 20 ° C and 30 ° C, such as an alkali metal hydroxide (eg sodium hydroxide or potassium hydroxide). It can be obtained by hydrolysis of the corresponding alkyl phenylacetates, either with a base or with a strong acid (hydrochloric acid or hydrobromic acid) under reflux of the mixture in water. It is understood by those skilled in the art that in order to carry out the above-described method according to the invention, it may be necessary to introduce protecting groups for the amino and hydroxyl functions in order to avoid side reactions. These groups are groups that can be removed without affecting the rest of the molecule. Examples of amino functional protecting groups which may be mentioned are tert-butyl or methyl carbamate which can be regenerated with iodotrimethylsilane. Examples of protecting groups for a hydroxyl function which may be mentioned are the trimethylsilyl and benzyl groups. Other protecting groups that can be used are W. Greene et al., Protecting Groups in Organic Synthesis, Second Edition, 1991, John Wiley & Sons. Are described. The compounds of the formula (I) can be purified by customary known methods, for example by crystallization, chromatography or extraction. Compounds of formula (I) containing a basic residue can be reacted with such acids, optionally by the action of inorganic or organic acids in organic solvents such as alcohols, ketones, ethers or chlorinated solvents. It can be converted to addition salts. Compounds of formula (I) which contain an acidic residue can optionally be converted into metal salts according to methods known per se. These salts can be obtained by reacting a metal base (for example, an alkali metal or an alkaline earth metal) with a compound of the formula (I) in a solvent. The salt formed is separated off in the usual way. These salts also form part of the invention. Examples of pharmaceutically acceptable salts include addition salts with inorganic or organic acids (acetate, propionate, succinate, benzoate, fumarate, maleate, oxaloacetate, methane). Sulfonate, isethionate, theophylline acetate, salicylate, methylenebis (β-oxynaphthonate), hydrochloride, sulfate, nitrate, phosphate, etc., or alkali metals (sodium, potassium or lithium) or Salts with alkaline earth metals (calcium or magnesium) may be mentioned. The compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, and more specifically, they are ligands for the glycine regulatory site of the NMDA receptor. These compounds may therefore be used to treat any ischemia (such as focal or general ischemia) resulting from cerebrovascular accidents, cardiac arrest, arterial hypotension, cardiac or pulmonary surgery or severe hypoglycemia. ) Is useful for treatment or prevention. They are also useful in treating the effects of anoxia, whether it is perinatal, resulting from drowning or cerebrospinal injury. These compounds may also be used to treat or prevent the development of neurodegenerative diseases, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, olive pontine / cerebellar atrophy and Parkinson's disease. Can be. These compounds may also be used for epileptic and / or convulsive symptoms, such as brain or spinal cord trauma, inner ear (R. Pujol et al., Neuroreport, 3, 299-302 (1992)). Alternatively, trauma and anxiety related to degeneration of the retina (JL. Monsinger et al., Exp. Neurol., 113, 10-17 (1991)) (Kehne et al., European Journal of Pharmacology (Eur. J. et al.). Pharmacol.), 193, 283 (1991)), depression (Trullas et al., European Journal of Pharmacol. (Eur. J. Pharmacol.), 185, 1 (1990)), schizophrenia (Reynolds). , TIPS, 13, 116 (1992)), analgesics (Dickenson et al., Neurosc. Letters, 121, 263 (1991)) for the treatment of Jill de la Tourette syndrome and hepatic encephalopathy. Anti-inflammatory drugs (Sluta et al., Neurosci. Letters, 149, 99-102 (1993)), Anorexiatics (Sorrels et al., Brain Res., 572, 265 (1992)), as antimigraine and antiemetics, and poisoning with neurotoxins or other NMDA receptor antagonists and AIDS (Lipton et al., Neuron, 7, 111 (1991)), rabies, measles and tetanus (Bagetta et al., British Journal of Pharmacol., 101). , 776 (1990)) for the treatment of neurological diseases associated with viral diseases. These compounds are also useful for preventing drug and alcohol withdrawal symptoms and for preventing addiction and dependence on narcotics. They are also deficient in mitochondrial abnormalities such as mitochondrial myopathy, label syndrome, Wernicke's encephalopathy, Rett syndrome, homocysteinemia, hyperprolinemia, hydroxybutylaminouria, lead encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency. Can also be used in the treatment of The affinity of the compounds of formula (I) for the glycine moiety linked to the NMDA receptor is described by T. Canton et al. Pharm. According to the method described by Pharmacol., 44, 812 (1992), ^Three H] -DCKA was determined by examining the antagonism of specific binding. [ ^Three H] -DCKA (20 nM) is incubated for 30 minutes at 4 ° C. in 50 mM HEPES buffer at pH 7.5 in the presence of 0.1 mg of proteins. Non-specific binding is determined in the presence of 1 mM glycine. Bound radioactivity is separated by filtration on Whatman GF / B filters. The inhibitory activity of these products is less than or equal to 100 μM. The following examples illustrate the invention. Example 1 1.6 ml of a 1M solution of bis (trimethylsilyl) lithium amide in tetrahydrofuran is added dropwise to a solution of 1.32 g of ethyl 3-phenylacetylaminobenzo [b] thiophene-2-carboxylate in 80 ml of tetrahydrofuran and stirring is carried out. Perform overnight at a temperature of about 20 ° C. The reaction mixture is then heated at 55 ° C. for 4.5 hours. The reaction mixture is cooled to a temperature of about 20 ° C., 10 ml of methanol are added and evaporation to dryness is carried out on a rotary evaporator. The evaporation residue is treated with 100 ml of ethyl acetate and 50 ml of 5N sodium hydroxide solution, and the aqueous phase is washed with ethyl acetate, 50 ml of methanol are added and the pH is brought to 1 with 1N hydrochloric acid. The precipitate formed is filtered off, washed with water until neutral and recrystallized from 20 ml of dimethylformamide and 20 ml of water. After drying at 80 ° C., 0.68 g of 4-hydroxy-3-phenylbenzothieno [3,2-b] pyridin-2 (1H) -one is decomposed at 330 ° C. on a Maquenne block. Obtained in the form of a creamy solid that melts. (Elemental analysis; Calculated value% C: 69.61, H: 3.78, N: 4.77, O: 10.91, S: 10.93, Measurement value% C: 69.2, H: 3.7, N: 4.5, O: 10.9, S: 10.5) . Ethyl 3-phenylacetylaminobenzo [b] thiophene-2-carboxylate can be prepared by the following method. That is, 3.78 ml of triethylamine are added to a solution of 3 g of ethyl 3-aminobenzo [b] thiophene-2-carboxylate in 70 ml of dioxane and heating is carried out under reflux. A solution of 2 ml of phenylacetyl chloride in 20 ml of dioxane is then added over 30 minutes and reflux is continued for 4 hours. The reaction mixture is cooled to a temperature of about 20 ° C., filtered and evaporated to dryness on a rotary evaporator. The evaporation residue is purified by flash chromatography on silica, eluting with a mixture of dichloromethane and cyclohexane (80/20 by volume). The product thus isolated is recrystallized from ethanol to give 2.8 g of ethyl 3-phenylacetylaminobenzo [b] thiophene-2-carboxylate (Rf = 0.20, silica gel thin layer chromatography, developed Solvent: dichloromethane / cyclohexane (volume ratio 80/20)). Ethyl 3-aminobenzo [b] thiophene-2-carboxylate is available from D. EL. Carrington, K. Clarke and RM. Scrowston, Journal of Chemical Society (J. Chem. Soc. ) (C), 3903 (1971). Example 2 A mixture of 2 g of ethyl 3- (3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate, 20 g of ammonium acetate and 80 ml of acetic acid is heated under reflux for 12 hours. The reaction mixture is cooled to a temperature of about 20 ° C. and filtered. Filtration yields two fractions. That is, the filtrate I and the solid I. Water is added to filtrate I and the precipitate formed is filtered off and washed with water and then with acetone to give solid II (0.48 g). Solid I is washed with water and then with acetone to give solid III (0.88 g). After combining solids II and III and recrystallizing from a mixture of dimethylformamide and water, 1.16 g of 1 H, 5H-4-hydroxy-3-phenylindeno [1,2-b] pyridin-2-one Is obtained in the form of a beige solid melting above 260 ° C. (elemental analysis: calculated% C: 78.53, H: 4.76, N: 5.09, O: 11.62, measured% C: 78.4, H: 4.7, N: 5.2, O: 11.4). Ethyl 3- (3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate can be prepared in the following manner. That is, 18 ml of sulfinyl chloride containing one drop of dimethylformamide is added in small portions to 1.86 g of monoethyl phenylmalonate. The mixture is maintained at a temperature of about 20 ° C. for 18 hours and then evaporated to dryness on a rotary evaporator. 40 ml of tetrahydrofuran and 1.25 ml of triethylamine are added to the evaporation residue. The precipitate which forms immediately is removed by filtration and 1.25 ml of triethylamine and 1.7 g of 3-morpholino-1H-indene are added to the filtrate. The reaction mixture is stirred overnight at a temperature of about 20 ° C. and then evaporated to dryness on a rotary evaporator. The evaporation residue is purified by flash chromatography, eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), giving 1.26 g of 3- (3-morpholino-1H-inden-2-yl) -3. To give ethyl -oxo-2-phenylpropionate (R _f = 0.45, silica gel thin layer chromatography, developing solvent: cyclohexane / ethyl acetate (volume ratio 50/50)). Monoethyl phenylmalonate can be prepared as described by Bentrude et al., J. Am. Chem. Soc., 106, 106 (1984). 3-morpholino-1H-indene is described in J. Schoen et al., Rocz. Chem., 45, 73 (1971), or Blomquist and EJ Moriconi, Journal of Organic Chemistry (J. Org. Chem.), 26, 3761 (1961). Can be prepared by an analogous method to that described by Example 3 A mixture of 1.3 g of ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate, 15 g of ammonium acetate and 60 ml of acetic acid was refluxed for 2 hours. Heat and stir the resulting brown solution overnight at a temperature of about 20 ° C. The suspension formed is filtered and the solid thus isolated is washed with distilled water and then with methanol. The gray solid is subsequently crystallized from dimethylformamide (8.5 ml). 0.7 g of 1 H, 5H-8-chloro-4-hydroxy-3-phenylindeno [1,2-b] pyridin-2-one is obtained in the form of a beige solid melting above 260 ° C. (Elemental analysis; calculated% C: 69.80, H: 3.90, Cl: 11.45, N: 4.52, O: 10.33, measured% C: 69.7, H: 4.0, Cl: 11.5, N: 4.7). Ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate can be prepared in the following manner. That is, a mixture of 5 g of 6-chloroindan-1-one, 60 ml of toluene, 5.2 ml of morpholine and 75 mg of p-toluenesulfonic acid was heated under reflux for 27 hours, and the water formed was removed by Dean and Stark. Collect by instrument. The reaction mixture is evaporated to dryness on a rotary evaporator, and a solution of monoethyl phenylmalonate chloride in 65 ml of tetrahydrofuran, 5.6 ml of triethylamine and 25 ml of tetrahydrofuran is evaporated to a solution containing 5-chloro-3-morpholino-1H-indene. Add to residue. The reaction mixture is stirred for 48 hours at a temperature of about 20 ° C., filtered and the filtrate is evaporated to dryness on a rotary evaporator. The evaporation residue is purified by chromatography on a silica column (400 g), eluting first with dichloromethane and then with a mixture of cyclohexane and ethyl acetate (70/30 by volume). 1.6 g of ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate are obtained in the form of a greenish-yellow solid melting at 175 ° C. Can be Monoethyl phenylmalonate was obtained from 4.2 g of phenylmalonic acid as described by Bentrude et al., Journal of American Chemical Society (J. Am. Chem. Soc.), 106, 106 (1984). Can be prepared from monoethyl. The monoethyl phenylmalonate chloride obtained is in the form of a yellow oil, as is used. 6-Chloroindan-1-one is described in R. Seka and W. Kellermann, Chem. Ber., 75, 1730 (1942). Example 4 Preparation was as in Example 3, but 1.46 g of ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate , 13.8 g of ammonium acetate and 60 ml of acetic acid. After returning to a temperature of about 200 ° C., 40 ml of distilled water are added to the reaction mixture, filtration is carried out and the brown solid obtained is washed with distilled water and then with ethyl ether and at 50 ° C. under vacuum (1 mmHg). , 0.13 kPa). Beige solid in which 0.65 g of 1H, 5H-8-chloro-4-hydroxy-3- (3-phenoxyphenyl) indeno [1,2-b] pyridin-2-one melts at temperatures above 260 ° C. (Elemental analysis; calculated% C: 71.74, H: 4.01, Cl: 8.82, N: 3.49, O: 11.94, measured% C: 71.7, H: 3.9, Cl: 8.9, N : 3.4). Ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate can be prepared in the following manner. That is, the preparation is carried out as in Example 3, but on the one hand from 5 g of 6-chloroindan-1-one to prepare the intermediate 5-chloro-3-morpholino-1H-indene, and on the other hand the intermediate chloride ( It is carried out from 6.7 g of monoethyl (3-phenoxyphenyl) malonate to prepare monoethyl 3-phenoxyphenyl) malonate. These two intermediates are reacted under the conditions described in Example 3, and the crude product obtained is purified with the aid of two successive chromatographic separations. The first chromatography is on a silica column (520 g) eluting with a dichloromethane / methanol (99/1 by volume) mixture and the second chromatography is toluene / ethyl acetate (5/1 by volume). 2.) Performed on a silica column (500 g) where elution is performed on the mixture. This is the case when 2 g of ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate is used in the subsequent synthesis. (Rf = 0.41, silica gel thin layer chromatography, developing solvent: toluene / ethyl acetate (volume ratio: 4/1)). Monoethyl (3-phenoxyphenyl) malonate can be prepared in the following manner. That is, a solution of 3.6 g of potassium hydroxide in 120 ml of absolute ethanol is added dropwise to a solution of 22.3 g of diethyl (3-phenoxyphenyl) malonate in 60 ml of absolute ethanol, stirred and cooled to approximately 5 ° C. Stirring is continued at a temperature between 10 and 20 ° C. for 3 to 4 hours. The reaction mixture is evaporated to dryness on a rotary evaporator and the oily residue is poured onto 140 ml of ice-cold water. Three extractions (3 × 100 ml) are performed with ethyl ether. The aqueous phase is acidified to pH 1 with an ice-cold 10% hydrochloric acid solution and extracted with ethyl ether (3 × 100 ml). The ether solution is dried and evaporated to dryness on a rotary evaporator, and 6.9 g of monoethyl (3-phenoxyphenyl) malonate are obtained in the form of a thick yellow oil as is used in the subsequent synthesis. (R _f = 0.14 (tail spot), silica gel thin layer chromatography, developing solvent: cyclohexane / ethyl acetate (volume ratio 80/20)). Diethyl (3-phenoxyphenyl) malonate can be prepared by the following method. That is, a solution of 15.3 g of ethyl (3-phenoxyphenyl) acetate in 60 ml of diethyl carbonate was added dropwise under inert atmosphere to a stirred suspension containing 3.3 g of 80% sodium hydride in 80 ml of diethyl carbonate. Added. Stirring is continued at a temperature of about 20 ° C. for 48 hours. The reaction mixture is neutralized with acetic acid and diluted with distilled water. The aqueous phase is extracted with ethyl ether (3 × 40 ml) and the ether extracts are combined and washed with distilled water, dried and evaporated to dryness on a rotary evaporator. The evaporation residue is purified by chromatography on a silica column (600 g), elution being carried out with a mixture of cyclohexane / ethyl acetate (80/20 by volume). 16.7 g of diethyl (3-phenoxyphenyl) malonate are obtained in the form of a yellow oil as it is when used in a subsequent synthesis (R _f = 0.57, silica gel thin layer chromatography, developing solvent: cyclohexane / ethyl acetate (80/20 by volume)). Ethyl (3-phenoxyphenyl) acetate is described in K. Ogura et al., Bull. Chem. Soc. Jpn., 52, 2013 (1979). The medicaments according to the invention consist of a compound of formula (I) or a salt of such a compound, in pure form or in the form of a composition which is combined with any other compound which has no pharmaceutically effect. Compounds that have no pharmaceutically effect can be inert or physiologically active. The agents according to the invention can be used orally, parenterally, rectally or topically. Tablets, pills, powders (gelatin capsules or cachets) or granules can be used as solid compositions for oral administration. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silicon dioxide under a stream of argon. These compositions may also contain substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, colorants, coatings (sugar pills) or brighteners. Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs, including inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oils, are prepared for oral administration. It can be used as a liquid composition. These compositions may contain substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing agents. Sterile compositions for parenteral administration can be preferably suspensions, emulsions, or aqueous or non-aqueous solutions. Water, propylene glycol, some polyethylene glycols, vegetable oils, especially olive oil, injectable organic esters such as ethyl oleate, or other suitable organic solvents can be used as solvents or vehicles. These compositions may also include adjuvants, especially wetting agents, tonicity agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by sterile filtration, incorporating a sterilant into the composition, irradiation or heating. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other sterile injectable medium at the time of use. Compositions for rectal administration are suppositories or rectal capsules that contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides, or polyethylene glycols. Compositions for topical administration can be, for example, creams, lotions, eye drops, gargles, nasal drops or aerosols. In human therapeutics, the compounds according to the invention are particularly useful for the treatment and / or prevention of diseases requiring the administration of NMDA receptor antagonists. These compounds can be used for any ischemia and especially for cerebral ischemia, effects on anoxia, development of neurodegenerative diseases, Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis, olive / pontine / cerebellar atrophy For the treatment or prevention of infectious diseases and Parkinson's disease, in relation to epileptic and / or convulsive symptoms, trauma to the brain and spinal cord, trauma to degeneration of the inner ear or retina, anxiety, depression, schizophrenia, For the treatment of La Tourette syndrome or hepatic encephalopathy, as an analgesic, anti-inflammatory, anti-anorexic, anti-migraine or anti-emetics, as well as poisoning with neurotoxins or other NMDA receptor antagonists and AIDS It is particularly useful for the treatment of neurological diseases associated with viral diseases such as rabies, measles and tetanus. These compounds are also used to prevent drug and alcohol withdrawal symptoms and addiction and dependence on narcotics, as well as mitochondrial myopathy, Leber syndrome, Wernicke encephalopathy, Rett syndrome, homocysteinemia, hyperprolinemia, It is also useful in treating deficiencies related to mitochondrial abnormalities, such as hydroxybutylamino aciduria, lead encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency. The dosage depends on the desired effect, on the duration of the treatment and on the route of administration used, but they are generally between 10 mg and 100 mg per day for oral administration to adults in unit doses ranging from 5 mg to 50 mg. Is the amount of Generally, a physician will determine the appropriate dosage depending on age, weight, and any other factors specific to the patient being treated. The following examples illustrate the compositions according to the invention. Example A A gelatin capsule having the following composition containing 50 mg of active ingredient is prepared according to the usual techniques: 50 mg of the compound of formula (I) cellulose 18 mg lactose 55 mg colloidal silicic acid 1 mg sodium carboxymethyl starch 10 mg Example 1 A tablet having the following composition is prepared according to the usual techniques, comprising 50 mg of active ingredient: lactose 50 mg lactose 104 mg cellulose 40 mg polyvidone 10 mg Carboxymethyl starch sodium 22 mg ・ Talc 10 mg ・ Magnesium stearate 2 mg ・ Colloidal silicic acid 2 mg ・ Total amount of hydroxymethyl cellulose, glycerol and titanium oxide mixture (72 / 3.5 / 24.5) for one coated tablet (total 245 mg) Example C Injectable containing 10 mg of active ingredient having the following composition Solution is prepared: - formula (I) compound 10 mg-benzoate 80 mg, benzyl alcohol 0.06 ml, sodium benzoate 80 mg, 95% ethanol 0.4 ml & Sodium hydroxide 24 mg - Propylene glycol 1.6 ml & total water 4ml

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 471/04 104 C07D 471/04 104H 491/048 491/048 495/04 105 495/04 105A (81) Designated country EP (AT , BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN) , ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ, UG), AM, AU, BB, BG, BR, BY, CA, CN, CZ, EE, FI, GE, HU, IS, JP, KG, KP, KR, KZ, LK, LR, LT, LV, MD, MG, MN, MX, NO, NZ, PL, RO, RU, SG, I, SK, TJ, TM, TT, UA, US, UZ, VN (72) Inventor Barro, Michel France F-92230 Mongieron-Ri Marcel-Cieffere 11 (72) Inventor Damour, Dominique France F-75014 Paris Liuenri-Renyol 18 (72) Inventor Zinoujbois-Bolera, Ariel France-F-94 320 Teie-Avenille-Ocille-28 (72) Inventor Zimone, Patrick-France France-78450 Birprou-Aveny-Neumandie 13 (72) Inventor Mignyani, Sergey France-F 92290 Shyatone-Malabri-Aveneud-Rovanson14 (72) Inventor Libeille, Eve France-F-91360 Bilmoreson-Cyur-Orgieu-Plas-de-Aluetut 7

Claims (1)

[Claims] 1. formula In the formula, R represents a methylene group, an N-alk group or an NH group or an oxygen atom or a sulfur atom, and R ₁ and R ₂ are the same or different and are a hydrogen atom or a halogen atom or a hydroxyl group, an alkoxy group, an alkyl group, a nitro group. A group, an amino group, a monoalkylamino group, a dialkylamino group, a cyano group, a polyfluoroalkyl group, a polyfluoroalkoxy group or a phenoxy group, wherein R ₃ and R ₄ are the same or different, and a hydrogen atom or a halogen atom or an alkyl group Wherein alk represents an alkyl group; the alkyl and alkoxyl groups and the alkyl and alkoxyl moieties are understood to include from 1 to 4 straight or branched carbon atoms; Their tautomeric forms and their salts. 2. A process for the preparation of compounds of the formula (I) according to claim 1, comprising a compound of the formula Wherein R represents a methylene group, R ₁ , R ₂ , R ₃ and R ₄ have the same meaning as in claim 1 and R ₅ represents an alkyl group. Reacting and isolating the product and then optionally converting it to a salt. 3. A process for preparing compounds of formula (I) according to claim 1, wherein R represents an N-alk (alkyl) group or an NH group or an oxygen atom or a sulfur atom, Wherein R represents an N-alk or NH group or an oxygen or sulfur atom, R ₁ , R ₂ , R ₃ and R ₄ have the same meaning as in claim 1, and R ₆ is A process characterized by the cyclization of the derivatives of, which represent an alkyl group, and isolation of the product, and then optionally conversion to a salt. 4. Pharmaceutical compositions comprising at least one compound of formula (I) according to claim 1 as an active ingredient.