WO1996002536A1

WO1996002536A1 - 4-hydroxy-3-phenyl-indeno(1,2-b)pyridine-2(1h)-one derivatives as nmda antagonists

Info

Publication number: WO1996002536A1
Application number: PCT/FR1995/000952
Authority: WO
Inventors: Jean-Claude Aloup; François Audiau; Michel Barreau; Dominique Damour; Arielle Genevois-Borella; Patrick Jimonet; Serge Mignani; Yves Ribeill
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1994-07-20
Filing date: 1995-07-17
Publication date: 1996-02-01
Also published as: EP0772612A1; FR2722786A1; JPH10504027A; AU2984695A; FR2722786B1; ZA955942B

Abstract

Derivatives of formula (I), wherein R is a methylene radical, N-alk, NH or an oxygen or sulphur atom, R1 and R2, which are the same or different, are a hydrogen or halogen atom or a hydroxy, alkoxy, alkyl, nitro, amino, monoalkylamino, dialkylamino, cyano, polyfluoroalkyl, polyfluoroalkoxy or phenoxy radical, R3 and R4, which are the same or different, are a hydrogen or halogen atom or an alkyl radical; tautomeric forms thereof, salts thereof, preparation thereof and drugs containing said derivatives.

Description

DERIVATIVES OF 4-HYDR0XY-3-PHENYL-INDEN0 (1,2-B) PYRIDINE-2 (1H) -0NE AS NMDA ANTAGONISTS

The present invention relates to compounds of formula:

their salts, their preparation and the drugs containing them.

In formula (I),

R represents a methylene, N-alk, NH radical or an oxygen or sulfur atom,

R- | and R2, which are identical or different, represent a hydrogen or halogen atom or a hydroxy, alkoxy, alkyl, nitro, amino, monoalkylamino, dialkylamino, cyano, polyfluoroalkyl, polyfluoroalkoxy or phenoxy radical,

R3 and R4, identical or different, represent a hydrogen or halogen atom or an alkyl radical,

alk represents an alkyl radical.

In the above definitions and those which will be cited below, unless otherwise stated, the alkyl and alkoxy radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain. 6/02536 PC17FR95 / 00952

The compounds of formula (I) can also be present in other tautomeric forms. These other tautomeric forms also form part of the invention.

The polyfluoroalkyl radicals are preferably the trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl radicals.

The polyfiuoroalkoxy radicals are preferably the trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy radicals.

The compounds of formula (I) for which R represents a methylene radical can be prepared by the action of ammonium acetate on a derivative of formula:

in which R represents a methylene radical, R-j, R2, R3 and R4 have the same meanings as in formula (I) and R5 represents an alkyl radical.

This reaction is generally carried out within acetic acid, at the boiling point of the reaction medium.

The derivatives of formula (II) can be obtained by the action of a 3-morpholino-1 H-indene substituted with R3 and R4, on a derivative of formula:

in which R- | and R2 have the same meanings as in formula (I), R5 represents an alkyl radical 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 trialkyamine (triethylamine for example), at a temperature in the region of 20 ° C.

The 3-morpholino-1 H-indenes substituted with R3 and R4 can be obtained by application or adaptation of the method described by A. T. BLOMQUIST et al., J. Org. Chem., 26, 3761 (1961) from the corresponding 1-indanones. The 1-indanones substituted with R3 and R4 can be obtained by application or adaptation of the methods described by M. OLIVIER et al., Bull. Soc. Chim. de France, 3092 (1973), R. SEKA et al., Chem. Ber., 75B, 1730 (1942) and in US patents 4,233,319, US 4,096,173 and EP 314,400.

The derivatives of formula (III) can be obtained by halogenation of the corresponding acid, by any known method making it possible to pass from an acid to an acid halide. One can for example react thionyl chloride or thionyl bromide, optionally in an inert solvent such as dichloromethane and optionally in the presence of a catalytic amount of dimethylformamide, at a temperature in the region of 20 ° C.

The corresponding acids can be obtained by application or adaptation of the method described by WG BENTRUDE et al., J. Am. Chem. Soc, 106, 106 (1984) from dialkyiphenylmalonates in which the phenyl is substituted by Rj and R2. Dialkyiphenylmalonates are commercially available or can be obtained by application or adaptation of the methods described by W. WISLICENUS, Ber., 27, 1091 (1894), WL NELSON et al., J. Am. Chem. Soc, 50, 2760 (1928) and D. IVANOFF et al., Bull. Soc. Chim. de France, 49, 20 (1931) from the corresponding alkylphenylacetates. The alkylphenylacetates are commercially available or can be obtained by application or adaptation of the methods described by PR AUSTIN et al., J. Am. Chem. Soc, 54, 655 (1932), W. MANN, Ber., 14, 1645 (1881), W. STAEDEL, Ber., 19, 1949 (1886) from the corresponding benzyl bromides which are themselves obtained by application or adaptation of the methods described by Y. HIRSHBERG et al., J. Chem. Soc, 1030 (1951) and F. KROHNKE, Chem. Ber., 83, 35 (1950) by halogenation of the corresponding toluenes.

The compounds of formula (I) for which R represents an N-alk, NH radical or an oxygen or sulfur atom can be prepared by cyclization of a derivative of formula:

in which R represents an N-alk radical, NH or an oxygen or sulfur atom, R-, R2, R3 and R4 have the same meanings as in formula (I) and Rg represents an alkyl radical.

This cyclization takes place in an inert solvent such as tetrahydrofuran, in the presence of lithium bis (trimethylsilyl) amide, at a temperature between 20 ° C and 60 ° C.

The derivatives of formula (IV) can be obtained by the action of a derivative of formula:

in which R represents an N-alk radical, NH or an oxygen or sulfur atom, R3 and R4 have the same meanings as in formula (I) and Rg represents an alkyl radical on a halide of formula:

in which R- | and R2 have the same meanings 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 (triethylamine for example), at the boiling temperature of the reaction medium.

The derivatives of formula (V) for which R represents an NH radical can be obtained by application or adaptation of the method described by PC UNANGST, J. Heterocyclic Chem., 20, 495 (1983) from 2-cyanoanilines substituted with R3 and R4. The 2-cyanoaniines are commercially available or can be obtained by application or adaptation of the methods described by TE NICKSON et al., Synthesis, 669 (1985); JB CAMPBELL et al., Synthetic Comm., 19, 2265 (1989); NV HARRIS et al., J. Med. Chem., 33, 434 (1990); DH KLAUBERT et al., J. Med. Chem., 24, 748 (1981); F. HUNZIKER et al., Eur. J. Med. Chem.-Chim. Ther., 16, 391 (1981); M. ADACHI et al., Synth. Comm., 20 (1), 71 (1990) and in patents EP 30156 and DE 1952896. The derivatives of formula (V) for which R represents an N-alk radical can be obtained by alkylation of the derivatives of formula (V) corresponding for which R represents an NH radical. This reaction is carried out by any alkylation method known to those skilled in the art making it possible to pass from an NH function to an N-alk function without affecting the rest of the molecule. Preferably, an alkyl halide is used, in the presence of an alkali metal hydride such as sodium hydride, in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or a mixture of these solvents , at a temperature close to 20 ° C.

The derivatives of formula (V) for which R represents an oxygen atom can be obtained by application or adaptation of the method described by K. GEWALD et al., J. F. Prakt. Chemie, 315, 779 (1973) from 2-cyanophenols substituted with R3 and R4. The 2-cyanophenols can be obtained by application or adaptation of the methods described by R.C. LAROCK, "Comprehensive Organic Transformation", ED VCH, page 483 (1989) from the corresponding 2-cyanoanilines.

The derivatives of formula (V) for which R represents a sulfur atom can be obtained by application or adaptation of the method described by D.E.L. CARRINGTON et al., J. Chem. Soc, 3903 (1971) from 2-cyanothiophenols substituted with R3 and R4. The 2-cyanothiophenols can be obtained by application or adaptation of the method described in patent EP 365397 from the corresponding 2-cyanophenols.

The derivatives of formula (VI) are marketed or can be obtained by halogenation of the corresponding phenylacetic acids by any known method making it possible to pass from an acid to an acid halide. One can for example react thionyl chloride or thionyl bromide, optionally in an inert solvent such as dichloromethane and optionally in the presence of a catalytic amount of dimethylformamide, at a temperature in the region of 20 ° C. Phenylacetic acids are commercially available or can be obtained by hydrolysis of the corresponding alkylphenylacetates, preferably either by means of a base such as an alkali metal hydroxide (soda or potash for example), in a water-alcohol mixture (ethanol for example), at a temperature between 20 and 30 ° C, either by means of a strong acid (hydrochloric or hydrobromic acid) in water, at reflux of the mixture.

It is understood by a person skilled in the art that, for the implementation of the methods according to the invention described above, it may be necessary to introduce groups protecting the amino and hydroxy functions in order to avoid reactions secondary. These groups are those that allow them to be eliminated without affecting the rest of the molecule. As examples of groups protecting the amino function, mention may be made of tert-butyl or methyl carbamates which can be regenerated by means of iodotrimethylsilane. As examples of protecting groups for the hydroxy function, mention may be made of trimethylsilyl, benzyl. Other protective groups which can be used are described by W. GREENE et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons.

The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.

The compounds of formula (I) comprising a basic residue can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.

The compounds of formula (I) comprising an acid residue can optionally be transformed into metal salts according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline earth, for example) on a compound of formula (I), in a solvent. The salt formed is separated by the usual methods.

These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, there may be mentioned addition salts with mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene- bis-β- oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate), the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium).

The compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulator sites of the NMDA receptor.

These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and the disease by PARKINSON. These compounds can also be used vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, traumas linked to the degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3 , 299-302 (1992) or retina (JL MONSINGER et al., Exp. Neurol., 113, 10-17 (1991), anxiety (KEHNE et al., Eur. J. Pharmacol., 193 , 283 (1991)), depression (TRULLAS et al. Eur. J. Pharmacol., 185, 1 (1990)), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), TOURETTE syndrome , hepatic encephalopathies, as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991)), anti-inflammatory drugs (SLUTA et al., Neurosci. Letters, 149, 99-102 (1993)) SORRELS et al., Brain Res., 572, 265 (1992)), antimigraine, antiemetics and to treat poisonings by neurotoxins or other NMDA receptor agonist substances, as well as neurological associated with viral diseases such as AIDS (LIPTON et al., Neuron, 7, 111 (1991)), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990)). These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and the inhibition of addiction and dependence on opiates. They can also be used in the treatment of deficits linked to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric-aminoaciduria, saturnine encephalopathy (intoxication chronic lead) and sulfite oxidase deficiency.

The affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to the method described. by T. CANTON et al., J. Pharm. Pharmacol., 44, 812 (1992). The [ ³ H] -DCKA (20 nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 30 minutes in 50 mM HEPES buffer, pH 7.5. The non-specific fixation is determined in the presence of 1 mM glycine. The 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

To a solution of 1.32 g of ethyl 3-phenylacetylaminobenzo [b] thiophene-2-carboxylate in 80 ml of tetrahydrofuran, 1.6 ml of a 1 M solution of lithium bis (trimethylsilyl) is added dropwise amide in tetrahydrofuran and the mixture is stirred overnight at a temperature in the region of 20 ° C. The reaction mixture is then heated at 55 ° C for 4.5 hours. The reaction mixture is cooled to a temperature in the region of 20 ° C., added with 10 ml of methanol and evaporated on a rotary evaporator. The evaporation residue is treated with 100 ml of ethyl acetate and 50 ml of 5N sodium hydroxide, and the aqueous phase is washed with ethyl acetate, added with 50 ml of methanol and brought to pH 1 with 1N hydrochloric acid. The precipitate formed is filtered, 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-phenyl-benzothieno [3,2-b] pyridine-2 (1H) -one is obtained in the form of a cream-colored solid melting at 330 ° C. with decomposition in the Maquenne block (Analysis% calculated C: 69.61, H: 3.78, N: 4.77, O: 10.91, S: 10.93,% found 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 as follows: to a solution of 3 g of ethyl 3-aminobenzo [bjthiophene-2-carboxylate in 70 ml of dioxane is added 3 , 78 ml of triethylamine and heated to reflux. 2 ml of phenylacetyl chloride dissolved in 20 ml of dioxane are then added over 30 minutes and the reflux is maintained for 4 hours. The reaction mixture is cooled to a temperature in the region of 20 ° C, filtered and evaporated 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, chromatography on a thin layer of silica gel, eluent: dichloromethane-cyclohexane (80-20 by volume)).

Ethyl 3-aminobenzo [b] thiophene-2-carboxylate can be prepared as described by D. E. L CARRINGTON, K. CLARKE and R. M. SCROWSTON, J. Chem. Soc. (C), 3903 (1971).

EXAMPLE 2

A mixture of 2 g of ethyl 3- (3-morpholino-1H-indene-2-yl) -3-oxo-2-phenylpropionate, 20 g of ammonium acetate and 80 is heated at reflux for 12 hours. ml of acetic acid. The reaction mixture is cooled to a temperature in the region of 20 ° C. and filtered, which leads to two fractions: the filtrate I and the solid I. The filtrate I is added with water and the precipitate formed is filtered, washed with water then with acetone to give a solid II (0.48 g). Solid I is washed with water, then with acetone to give a solid III

(0.88 g). Solids II and III are combined and, after recrystallization from a mixture of dimethylformamide and water, 1.16 g of 1H.5H-4-hydroxy-3-phenyl-indeno [1,2-b] pyridine are obtained. 2-one in the form of a beige solid melting above 260 ° C. (Analysis% calculated C: 78.53, H: 4.76, N: 5.09, 0: 11.62,% found C: 78, 4, H: 4.7, N: 5.2, 0: 11, 4).

The ethyl 3- (3-morpholino-1 H-indene-2-yl) -3-oxo-2-phenylpropionate can be prepared as follows: to 1.86 g of monoethyl phenylmalonate is added in portions 18 ml of thionyl chloride containing a drop of dimethylformamide. The mixture is kept for 18 hours at a temperature in the region of 20 ° C., then evaporated on a rotary evaporator. To the evaporation residue is added 40 ml of tetrahydrofuran and 1.25 ml of triethylamine. The precipitate formed immediately is removed by filtration and to the filtrate is added 1.25 ml of triethylamine and 1.7 g of 3-morpholino-1H-indene. The reaction mixture is stirred overnight at a temperature in the region of 20 ° C., then evaporated 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) to give 1.26 g of 3- (3-morpholino-1 H-indene -2-yl) -3-ethyl oxo-2-phenylpropionate

(Rf ≈ 0.45, chromatography on a thin layer of silica gel, eluent: cyclohexane-ethyl acetate (50-50 by volume)).

Monoethyl phenylmalonate can be prepared as described by W.G. BENTRUDE et al., J. Am. Chem. Soc, 106, 106 (1984).

3-Morpholino-1H-indene can be prepared as described by J. SCHOEN et al., Rocz. Chem., 45, 73 (1971) or by analogy with the method described by A.T. BLOMQUIST and E.J. MORICONI, J. Org. Chem., 26, 3761 (1961).

EXAMPLE 3

A mixture of 1.3 g of ethyl 3- (5-chloro-3-moφholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate, 15 g of, is refluxed for 2 hours. ammonium acetate and 60 ml of acetic acid, then the brown solution obtained is stirred overnight at a temperature in the region of 20 ° C. The suspension formed is filtered and the solid thus isolated is washed with distilled water, then with methanol. The gray solid is then crystallized from dimethylformamide (8.5 ml). 0.7 g of 1 H, 5H-8-chloro-4-hydroxy-3-phenyl-indeno [1,2-blpyridin-2-one is obtained in the form of a beige solid melting above 260 ° C. (Analysis % calculated C: 69.80, H: 3.90, Cl: 11.45, N: 4.52, O: 10.33,% found C: 69.7, H: 4.0, C 1: 11 , 5, N: 4.7).

Ethyl 3- (5-chloro-3-morpholino-1H-inden-2-yl) -3-oxo-2-phenylpropionate can be prepared as follows: a mixture of 5 is refluxed for 27 hours g of 6-chloroindan-1-one, 60 ml of toluene, 5.2 ml of morpholine and 75 mg of p.toluenesulfonic acid as collecting the water formed by means of a Dean-Stark apparatus. The reaction mixture is evaporated on a rotary evaporator and the evaporation residue containing 5-chloro-3-morpholino-1H-indene is added with 65 ml of tetrahydrofuran, 5.6 ml of triethylamine and a solution of phenylmalonate chloride of monoethyl in 25 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hours at a temperature in the region of 20 ° C., filtered and the filtrate is evaporated on a rotary evaporator. The evaporation residue is purified by chromatography on a silica column (400 g), first eluting with dichloromethane, then with a cyclohexane-ethyl acetate mixture (70/30 by volume). 1.6 g of ethyl 3- (5-chloro-3-moφholino-1 H-inden-2-yl) -3-oxo-2-phenylpropionate are obtained in the form of a greenish yellow solid melting at 175 ° C.

Monoethyl phenylmalonate chloride can be prepared as described by W.G. BENTRUDE et al., J. Am. Chem. Soc, 106, 106 (1984) from 4.2 g of monoethyl phenylmalonate. The monoethyl phenylmalonate chloride obtained is in the form of a yellow oil used as it is.

6-chloroindan-1-one can be prepared according to the method described by R. SEKA and W. KELLERMANN, Chem. Ber., 75, 1730 (1942).

EXAMPLE 4

The procedure is as in Example 3, but starting with 1.46 g of 3- (5-chloro-3- moφholino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate ethyl, 13.8 g of ammonium acetate and 60 ml of acetic acid. After returning to a temperature in the region of 20 ° C., the reaction mixture is added with 40 ml of distilled water, filtered and the brown solid obtained is washed with distilled water, then with ethyl ether and dried at 50 ° C. vacuum (1 mm Hg; 0.13 kPa). 0.65 g of 1 H, 5H-8-chloro-4-hydroxy-3- (3-phenoxyphenyl) -indeno [1, 2- b] pyridin-2-one is obtained in the form of a beige solid melting above 260 ° C (Analysis% calculated C: 71, 74, H: 4.01, Cl: 8.82, N: 3.49, 0: 11, 94,% found 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 as follows: as in Example 3 but from 5 g of 6-chloroindan-1-one to prepare the intermediate 5-chloro-3-morpholino-1H-indene on the one hand, and from 6.7 g of ( Monoethyl 3-phenoxyphenyl) malonate to prepare intermediate monoethyl (3-phenoxyphenyl) malonate chloride on the other hand. These two intermediates react under the conditions described in Example 3 and the crude product obtained is purified using two successive chromatographies: the first is carried out on a silica column (520 g), eluting with a dichloromethane-methanol mixture ( 99/1 by volume), the second on a silica column (500 g), eluting with a toluene-ethyl acetate mixture (5/1 by volume). 2 g of ethyl 3- (5-chloro-3-moφholino-1H-inden-2-yl) -3-oxo-2- (3-phenoxyphenyl) propionate are obtained in the form of a black solid used as such in the subsequent syntheses (Rf = 0.41, thin layer chromatography on silica gel, eluent: toluene-ethyl acetate (4/1 by volume)).

Monoethyl (3-phenoxyphenyl) malonate can be prepared as follows: 22.3 g of diethyl (3-phenoxyphenyl) malonate in 60 ml of absolute ethanol are stirred and cooled to around 5 ° C. a solution of 3.6 g of potassium hydroxide in 120 ml of absolute ethanol is added dropwise. Stirring is continued for 3 to 4 hours at a temperature between 10 and 20 ° C. The reaction mixture is evaporated on a rotary evaporator and the oily residue is poured onto 140 ml of ice water. Three extractions are carried out with ethyl ether (3 × 100 ml). The aqueous phase is acidified to pH 1 with an ice-cold solution of 10% hydrochloric acid and extracted with ethyl ether (3x100 ml). The ethereal solution is dried and evaporated on a rotary evaporator to give 6.9 g of monoethyl (3-phenoxyphenyl) malonate in the form of a thick yellow oil used as it is in subsequent syntheses (Rf≈ 0.14 (elongated spot), chromatography on a thin layer of silica gel, eluent: cyclohexane-ethyl acetate (80/20 by volume)).

Diethyl (3-phenoxyphenyl) malonate can be prepared in the following manner: under an inert atmosphere, to a stirred suspension of 3.3 g of 80% sodium hydride in 80 ml of diethyl carbonate is added dropwise a solution of 15.3 g of (3-phenoxyphenyl) ethyl acetate in 60 ml of diethyl carbonate. The agitation is continued for 48 hours at a temperature close to 20 ° C. The reaction mixture is neutralized with acetic acid and diluted with distilled water. The aqueous phase is extracted with ethyl ether (3 × 40 ml), the ethereal extracts are combined and washed with distilled water, dried and evaporated on a rotary evaporator. The evaporation residue is purified by chromatography on a silica column (600 g), eluting with a cyclohexane-ethyl acetate mixture (80/20 by volume). 16.7 g of diethyl (3-phenoxyphenyl Dmalonate) are obtained in the form of a yellow oil used as it is in subsequent syntheses (Rf≈ 0.57, chromatography on a thin layer of silica gel, eluent: cyclohexane-ethyl acetate (80/20 by volume).

Ethyl (3-phenoxyphenyl) acetate can be prepared according to the method described by 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 the pure state or in the form of a composition in which it is associated with any other product. pharmaceutically compatible, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sac charose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or 'paraffin oil. These compositions can include substances other than diluents, for example example of wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an NMDA receptor antagonist. These compounds are in particular useful for treating or preventing all ischemias and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo- pontocerebellar atrophy and PARKINSON's disease, vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral and spinal traumas, traumas linked to degeneration of the ear internal or retina, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathy, as an analgesic, anti-inflammatory, anti-anorexic, anti-migraine, antiemetic and to treat poisoning by neurotoxins or other substances agonists of the NMDA receptor, as well as neurological disorders associated with viral diseases such as AIDS, rabies, measles and tetanus. These compounds are also useful for the prevention of symptoms of drug and alcohol abstinence and the inhibition of addiction and dependence on opiates as well as for the treatment of deficits associated with mitochondrial abnormalities such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- Compound of formula (I) 50 mg

- Cellulose 18 mg

- Lactose 55 mg

- Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg - Talc; 10 mg

- Magnesium stearate 1 mg EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

- Compound of formula (I) 50 mg - Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg

- Carboxymethyl starch sodium 22 mg

- Talc 10 mg - Magnesium stearate 2 mg

- Colloidal silica 2 mg

- Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) q.s.p. 1 film-coated tablet finished at 245 mg

EXAMPLE C A solution for injection containing 10 mg of active product having the following composition is prepared:

- Compound of formula (I) 10 mg

- Benzoic acid 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

- Water q.s.p. 4 ml

Claims

1 - Compounds of formula:

in which

R represents a methylene radical, N-alk, NH or an oxygen or sulfur atom,

R-j and R2, which may be identical or different, represent a hydrogen or halogen atom or a hydroxy, alkoxy, alkyl, nitro, amino monoalkylamino, dialkylamino, cyano, polyfluoroalkyl, polyfluoroalkoxy or phenoxy radical,

alk represents an alkyl radical,

it being understood that the alkyl and alkoxy radicals and the alkyl and alkox portions contain 1 to 4 carbon atoms in a straight or branched chain,

their tautomeric forms and their salts.

2 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a methylene radical characterized in that ammonium acetate is reacted with a derivative of formula:

in which R represents a methylene radical, R- | , R2, R3 and R4 have the same meanings as in claim 1 and R5 represents an alkyl radical, isolates the product and optionally converts it to salt.

3 - Process for the preparation of the compounds of formula (I) according to revenbdication 1 for which R represents an N-alk, NH radical or an oxygen or sulfur atom characterized in that a derivative of formula is cyclized:

in which R represents an N-alk radical, NH or an oxygen or sulfur atom, R- |, R2, R3 and R4 have the same meanings as in claim 1 and Rg represents an alkyl radical, isolates the product and eventually transforms it into salt.

4 - Pharmaceutical compositions comprising as active principle at least one compound of formula (I) according to claim 1.