WO1994005663A1 - Novel isoindolinone derivative, its preparation and pharmaceutical compositions containing same - Google Patents

Abstract

Novel isoindolinone derivative of formula (I), in a racemic form or in the form of its enantiomers, its preparation and pharmaceutical compositions containing same. In general formula (I), R is an optionally substituted alkyl radical. The novel product of formula (I) is useful in as an anxiety-relieving, hypnotic, anticonvulsant, antiepileptic and myorelaxant therapeutic agent.

Description

 NEW ISOINDOLINONE DERIVATIVE. ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS

WHO THE CQNTIFN ^ T

The present invention relates to a new derivative of the isoindolinone of formula:

sous forme racémique ou sous forme de ses énantiomères, ainsi que ses sels, sa prépa¬ ration et les compositions pharmaceutiques qui le contiennent- Dans la formule générale (I), R représente un radical alcoyle contenant 1 à 10 atomes de carbone éventuellement substitué par un ou plusieurs atomes ou radicaux choisis parmi les atomes d'halogène et les radicaux phényles, hydroxy, amino, alcoylamino contenant 1 à 4 atomes de carbone, dialcoylamino dont chaque partie alcoyle contient 1 à 4 atomes de carbone ou carboxy.

in racemic form or in the form of its enantiomers, as well as its salts, its preparation and the pharmaceutical compositions which contain it- In the general formula (I), R represents an alkyl radical containing 1 to 10 carbon atoms optionally substituted by one or more atoms or radicals chosen from halogen atoms and phenyl, hydroxy, amino, alkylamino radicals containing 1 to 4 carbon atoms, dialkoylamino in which each alkyl part contains 1 to 4 carbon atoms or carboxy.

The product of formula (I) has remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant properties.

In European patent EP 0 274 930, derivatives of isoin¬ dolinone of the general formula have been described:

dans laquelle, plus particulièrement, A forme avec le cycle pyrrole un noyau isoindo- Une, Het représente un radical naphtyridinyle substitué par un atome d'halogène, Y représente un radical CO et Rj représente un radical alcoyle contenant 1 à 10 atomes de carbone non substitué ou substitué, qui présentent des propriétés thérapeutiques remarquables.

in which, more particularly, A forms with the pyrrole ring an isoindo- A ring, Het represents a naphthyridinyl radical substituted by a halogen atom, Y represents a CO radical and Rj represents an alkyl radical containing 1 to 10 carbon atoms not substituted or substituted, which have remarkable therapeutic properties.

Among these products, that for which A forms with the pyrrole ring an isoindoline ring, Het represents a radical (chloro-7 naphthyridine-1.8 yl) -2, Y represents a radical CO and R represents a methyl-3 butyl radical, in racemic form or in the form of its enantiomers, in particular the dextrorotatory isomer manifests a particularly potent activity associated with low toxicity.

The products of general formula (II) in which R represents an alkyl radical substituted by a tertiary hydroxy radical, and in particular the product of formula:

sous forme racémique ou sous forme de ses énantiomères manifeste, de façon surpre¬ nante et inattendue, une activité au moins aussi intéressante que celle du produit correspondant pour lequel R} représente un radical méthyl-3 butyle. Les produits de formule générale (I), qui sont des esters du produit de formule (m) permettent de modifier ou de moduler les propriétés du produit de formule (m) au niveau par exemple de la solubilité ou du contrôle de la libération.

in racemic form or in the form of its enantiomers manifests, surprisingly and unexpectedly, an activity at least as interesting as that of the corresponding product for which R} represents a 3-methyl-butyl radical. The products of general formula (I), which are esters of the product of formula (m) make it possible to modify or modulate the properties of the product of formula (m) in terms of, for example, solubility or release control.

According to the present invention, the product of general formula (I) can be obtained by esterification of a product of general formula (m) using an acid of general formula:

R-CO-OH (IV)

in which R is defined as above, optionally in the form of a halide or anhydride.

When an acid of general formula (IV) is used, the esterification is generally carried out in the presence of a condensing agent chosen from carbodiimides such as dicyclohexylcaιtx> di_mide or reactive carbonates such as 2-dipyridyl carbonate and d an activating agent chosen from tertiary amines such as dialkoylanilines (dimethylaniline) or aminopyridines (dimethylamino-pyridine or pyrroUdino-4 pyridine) by operating in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tbutyl ether or dioxane, esters like ethyl acetate, nitriles like acetonitrile, aUphatic hydrocarbons like pentane, hexane or heptane, halogenated aUphatic hydrocarbons like dichloromethane, 1-dichloro , 2 ethane or chloroform and aromatic hydrocarbons such as benzene, toluene or xylenes, at a temperature between 0 and 90 ° C, preferably close to 25 ° C.

When the acid of general formula (EU) is used in the form of halide, preferably chloride, the esterification is generally carried out in the presence of an activating agent chosen from tertiary amines such as dialkoylanilines (dimethylaniline ) or the aminopyridines (4-dimethylamino pyridine, 4-pyridino-pyridine) by operating in an organic solvent chosen from ethers such as tetrahydrofuran, diisopropylther, methyl tbutyl ether or dioxane, esters such as ethyl acetate, nitriles such as acetonitrile, aUphatic hydrocarbons such as pentane, liexane or heptane, halogenated aUphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene or xylenes, at a temperature between 0 and 90 ° C, preferably around 25 ^β C. When using the acid of general formula (IV) in the form of anhydride , the esterification is generally carried out in the presence of a base which is preferably an organic nitrogenous base such as an aUphatic tertiary amine such as triethylamine, pyridine or an aminopyridine such as 4-dimethylamino pyridine or pyrroUdino-4 pyridine, by operating in an inert organic solvent chosen from ethers such as tetrahydrofuran, diisopropyl ether, methyl tbutyl ether or dioxane, nitriles such as acetonitrile, esters such as ethyl acetate, aUphatic hydrocarbons such as pentane , heptane or hexane, halogenated aUphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform and aromatic hydrocarbons such as benzene, toluene or xylenes at a temperature between 0 and 90 ° C, preferably around 25 ° C.

For the implementation of these methods, depending on the nature of the substituents optionally carried by the radical R, it may be necessary to protect these substituents with appropriate protective groups which will be removed later once the esterification reaction is complete.

sous forme racémique.The product of formula (III), in racemic form, can be obtained by hydration of the product of formula:

in racemic form.

As organic solvent, an ether such as tetra¬ hydrofuran or dioxane is preferably used. As the acid, a mineral acid such as sulfuric acid is preferably used.

Generally, hydration is carried out at a temperature between 0 and 50 ° C and, preferably, close to 20 ° C.

The enantiomers of the product of formula (m) can be obtained: - either by separation on an appropriate chiral phase of the enantiomers constituting the product of racemic formula (m),

- Either by separation on the appropriate chiral phase of the enantiomers constituting the product of racemic formula (V), followed by the hydration of each of the enantiomers obtained. Generally, the separation of the enantiomers constituting the product of racemic formula (m) is carried out by high performance liquid chromatography on a column of siUce coated with ceulose trisphenylcarbamate, eluting with a suitable solvent such as an ethanol-hexane mixture. Preferably, a phase prepared under the conditions described in J. Amer is used. Chem. Soc., Ifl & 5357 (1984).

Generally, the separation of the enantiomers constituting the product of racemic formula (V) is carried out by high performance liquid chromatography on a Pirkle type phase modified by eluting with a suitable solvent such as a hexane-methylene chloride mixture. As the chiral phase, use is preferably made of a phase in which the chiral selector, which is preferably 3,5-dinitro-benzoyl-L-leucine, is separated from the silica by an aminoalkanoyl arm containing 3 to 14 fixed carbon atoms. on the amino functions of an aminopropyl silica and of which the free silanol functions are blocked by trialkylsilyl radicals. This chiral phase, which constitutes another object of the present invention, can be defined by the following structure:

dans laqueUe les symboles R', identiques ou différents, et R₂, identiques ou différents, représentent des radicaux alcoyles contenant 1 à 10 atomes de carbone, G représente un groupement électro-attracteur et n représente un nombre entier compris entre 3 et 13 inclusivement.

in which the symbols R ', identical or different, and R ₂ , identical or different, represent alkyl radicals containing 1 to 10 carbon atoms, G represents an electron-attracting group and n represents an integer between 3 and 13 inclusive .

Preferably, one of the symbols R 'represents an alkyl radical containing 7 to 10 carbon atoms and the other two represent an alkyl radical containing 1 or 2 carbon atoms and preferably a methyl radical, the symbols R ₂ are identical and represent a methyl or ethyl radical, G represents a benzoyl radical optionally substituted, preferably, by one or more nitro radicals such as the 3,5-dinitro-benzoyl radical and n is equal to 10.

The new chiral phase according to the invention can be prepared by action on an aminopropyl silica of the anhydride of an aminoalkanoic acid containing 3 to 14 carbon atoms whose amino function is protected by a protective group such as the tertbutoxycarbonyl radical, followed blocking part of the silanol functions with Si (R ') radicals as defined above, then, after elimination of the protective group for the amino function, of amidification by means of L-leucine, the amino function of which is protected by an electron-withdrawing group G as defined above, and finally by blocking the residual silanol functions with Si (R * 2) ₃ radicals as defined above.

Generally, the action of the anhydride of a protected aminoalkanoic acid on the aminopropyl site is carried out by operating in an anhydrous organic solvent such as dimethylformamide at a temperature in the region of 20 ° C.

The blocking of the silanol functions by —Si (R ′) groups as defined above is carried out by the action of a halotrialkylsilane on the aminopropyl silica grafted with aminoalkanoyl residues by operating in a solvent organic such as methylene chloride in the presence of a basic agent such as pyridine.

The removal of the protective groups from the aminoalkanoyl residues is generally carried out, when the protective group is a tert-butoxycarbonyl radical, by the action of trifluoroacetic acid in an organic solvent such as methylene chloride.

Amidification by means of L-leucine, the amino function of which is protected, is carried out in the presence of a condensing agent such as N-ethoxycarbonyl 2-ethoxy-1,2-dihydro-quinoline, operating in an anhydrous organic solvent. such as dimethylformamide.

The blocking of the residual silanol functions by -Si (Rχ) radicals as defined above is generally carried out by means of trialtylsdlylimidazole by operating in an organic solvent such as methylene chloride.

The hydration of each of the enantiomers obtained is carried out under the conditions described above for the hydration of the corresponding racemic product

The product of formula (V) can be obtained by dealkoxycarbonylation of a product of general formula:

dans laqueUe R représente un radical alcoyle droit ou ramifié contenant 1 à 4 atomes de carbone par action du chlorure de Uthium dans un solvant organique tel que le diméthylsulfoxyde à une température comprise entre 0 et 50°C.

in which R represents a straight or branched alkyl radical containing 1 to 4 carbon atoms by the action of uthium chloride in an organic solvent such as dimethyl sulfoxide at a temperature between 0 and 50 ° C.

The product of general formula (Vu) can be obtained by the action of an ester of general formula:

dans laqueUe R est défini comme précédemment sur la chloro-3 (chloro-7 naphtyri- dine-1,8 yl-2)-2 isoindolinone-1 en opérant en présence d'une base minérale forte teUe que l'hydrure de sodium dans un solvant organique anhydre tel que le diméthyl- formamide.

in which R is defined as above on chloro-3 (chloro-7 naphthyridin-1,8 yl-2) -2 isoindolinone-1 by operating in the presence of a strong mineral base such as sodium hydride in an anhydrous organic solvent such as dimethylformamide.

The ester of general formula (VHI) can be obtained under the conditions described by V.B. RAO et al., J. Amer. Chem. Soc., 5732 (1985). Chloro-3 (chloro-7 naphthyridine-1,8 yl-2) -2 isoindolinone-1 can be prepared under the conditions described in European patent EP 0274930.

The product of formula (I), in the form of a racemic and its enantiomers, in particular the dextrorotatory enantiomer, optionally in the form of salts, have particularly advantageous pharmacological properties which make them useful as anxiolytics, hypnotics, anti-convulsants, antiepileptics and muscle relaxant. In mice, they have been shown to be active at doses generally between 0.05 and 10 mg / kg, and preferably between 0.1 and 5 mgflcg, orally with respect to convulsions induced by pentetrazol according to a technique similar to that of Everett and Richards, J. Pharmacol., £ 402 (1944). The new product of formula (I) and its salts have a low toxicity.

Their LD50 is greater than 300 mg kg orally in mice.

For medicinal use, use may be made of the new product of formula (I) as it is or in the form of a pharmaceutically acceptable salt, that is to say non-toxic at the doses of use. As pharmaceutically acceptable salts, there may be mentioned the addition salts with mineral acids such as hydrochlorides, sulfates, nitrates, phosphates or organic acids such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isethionates, theophylline- acetates, saUcylates, phenolphthalein, methylene-bis-β-oxynaphthoates or substitution derivatives of these compounds.

The following examples illustrate the present invention.

EXAMPLE 1

To a solution containing 3.0 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindolinone-1- (RS) and 0.65 cm3 of N, N-dimethylaniline in 10 cm 3 of chloroform is added, at a temperature in the region of 0 ° C., a solution of 0.17 cm 3 of acetyl chloride in 1.0 cm 3 of chloroform. The reaction mixture is stirred for 6 hours at a temperature in the region of 50 ° C, then is hydrolyzed by addition of 25 cm3 of an IN aqueous solution of sulfuric acid while maintaining the temperature in the region of 25 ° C. The heterogeneous environment obtained is extracted with 2 times 20 cm3 of dichloromethane. The combined organic phases are washed successively with 25 cm3 of water, 25 cm3 of a 10% aqueous solution of sodium hydrogencarbonate and 25 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure to a temperature close to 40 ° C. The residue obtained is purified by chromatography on siUce [eluent: ethyl acetate-cyclohexane- * 4iethylamine (49.9-49.9-0.2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. 0.27 g of [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindoUnyl-1] -1 (5 methyl 5 oxo) acetate is thus obtained after crystallization from ethyl acetate. -2) hex-5 yle- (RS) melting at 133 ° C.

(7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindolinone-1- (RS) can be prepared as follows:

To a suspension of 2.0 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-oxo-2 hexene-5 yl-1) -3 isoindolinone-1 - (RS) in 20 cm3 of 1,4-dioxane, 20 cm3 of an aqueous solution of 35% sulfuric acid (pv) are added at a temperature in the region of 20 ° C. The yellow solution obtained is stirred for 12 hours and then 20 g of crushed ice are added. The pH of the reaction mixture is brought to around 7 by addition of an aqueous solution of IN sodium hydroxide. Then extracted with 3 times 100 cm3 of ethyl acetate. The combined organic phases are washed with 2 times 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. After recrystallization of the residue obtained from acetonitrile, 1.2 g of (chloro-7 naphthyridine-i, 8 yl-2) -2 (methyl-5-hydroxy-5-oxo-2 hexyl) -3 isoindolinone-1 are obtained. (RS) melting at 140 ° C.

(7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-oxo-2 hexene-5 yl-1) -3 isoindolinone-1- (RS) can be prepared as follows:

To a solution of 9.3 g of [(chloro-7 naphthyridin-1,8 yl-2) -2 oxo-3 isoin-doUnyl-1] -2 methyl-6 oxo-3 heptene-6 oate of ethyl ( mixture of forms A and B) in 60 cm3 of dimethylsulfoxide, 11.5 g of Uthium chloride and 4.6 cm3 of water are added at a temperature in the region of 25 ° C. The reaction mixture is heated at reflux for 20 minutes, cooled to a temperature in the region of 30 ° C, diluted with 60 cm3 of water and then cooled to a temperature in the region of 5 ° C. The precipitated soda is separated by filtration, washed successively with 2 times 25 cm 3 of water, 1 time 20 cm 3 of ethanol and 2 times 25 cm 3 of dusopropyl ether. 7.2 g of (chloro-7 naphthyridine-1,8 yl-2) -2 (methyl-5 oxo-2 hexene-5 yl-1) -3 isoindolinone-1 are thus obtained, after air drying. - (RS) melting at 184 ° C. [(Chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-6 oxo-3 heptene-6 ethylate (mixture of forms A and B) can be prepared as follows :

1.7 g of oily suspension (50% by weight) of sodium hydride are added to 100 cm3 of anhydrous dimethylformamide, under an argon atmosphere, at a temperature close to 10 ° C. Then added 9.8 g of methyl 6-oxo-3 heptene-6 oate ethyl in 25 cm3 of anhydrous dimethylformamide. The suspension obtained is stirred for 30 minutes, allowing the temperature to rise to about 20 ° C., then 11.6 g of chloro-3 (chloro-7 naphthyridine-1.8 yl-2) -2 isoindolinone-1 are added. The reaction mixture is stirred for 4 hours at a temperature in the region of 20 ° C. and then poured into 250 cm3 of water. The aqueous phase, acidified by addition of 25 cm3 of an aqueous solution of IN hydrochloric acid, is extracted with 2 times 200 cm3 of dichloromethane. The combined organic phases are washed with 2 times 50 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40 ° C. The oily residue obtained is purified by sitice chromatography [eluent: ethyl acetate-cyclohexane (30 70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40 ° C. 9.4 g of [(7-chloro-naphthyridine-1,8 yl- 2) -2 oxo-3 isoindolinyl-l] -2 methyl-6-oxo-3 heptene are thus obtained, after crystallization from dϋsopropyl ether -6 ethyl oate (mixture of forms A and B) melting at 125 ° C.

6-methyl-3-oxo-heptene-6-ethylate may be prepared according to the method described by V.B. RAO and coU., J. Amer. Chem. Soc., LfiZ, 5732 (1985).

Chloro-3 (chloro-7 naphthyridine-1,8 yl-2) -2 isoindolinone-1 can be prepared according to the method described in European patent EP 0274930.

EXAMPLE 2

To a solution containing 1.0 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindolinone-1- (RS) and 0.6 g of 4-dimethylamino pyridine in 5 cm 3 of chloroform is added, at a temperature in the region of 0 ° C., a solution of 0.6 cm 3 of acetyl chloride in 3.0 cm 3 of chloroform. The reaction medium is stirred for 5 hours at a temperature in the region of 50 ° C and then, after returning to a temperature in the region of 25 ° C, washed successively with 15 cm3 of a 2N aqueous solution of sulfuric acid, 15 cm3 of water , 15 cm3 of a 10% aqueous solution of sodium bicarbonate and 15 cm3 of water. The organic phase collected is dried over magnesium sulfate and concentrated dry under reduced pressure at a temperature close to 40 ° C. The residue obtained is purified by chromatography on silica [eluent: ethyl acetate-cyclohexane-diethylamine (49.9-49.9-0.2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. 0.15 g of [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -l (methyl-5 oxo) acetate is thus obtained after crystallization from ethyl acetate. -2) hex-5 yle- (RS) melting at 132 ° C.

EXAMPLE 3

To a solution of 0.6 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindoUnone-1- (RS) and 0.21 cm3 of acetic anhydride in 10 cm3 of dichloromethane, 0.36 cm3 of triethylamine and 0.04 g of 4-dimethylamino-pyridine are added successively, at a temperature close to 0 ° C. The reaction medium is stirred for 16 hours at a temperature in the region of 50 ° C and then, after returning to a temperature in the region of 25 ° C, washed successively with 10 cm3 of a 1N aqueous solution of sodium hydroxide and 15 cm3 of water. The organic phase collected is dried over magnesium sulphate and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue obtained is purified by chromatography on silica [eluent: ethyl acetate-cyclohexane-diethylamine (49.9-

49.9-0.2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. 0.32 g of [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindol_nyl-1] -l (methyl-5 oxo) acetate is thus obtained after crystallization from ethyl acetate. -2) hex-5 yle- (RS) melting at 132 ° C.

EXAMPLE 4

To a solution of 0.14 cm3 of glacial acetic acid in 5 cm3 of dichloromethane is added, at a temperature in the region of 10 ° C, 0.5 g of dicyclohexylcarbodiimide. After stirring the reaction mixture for 10 minutes at this same temperature, a solution of 1.0 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-5-oxo-2-hexyl) is successively introduced ) -3 isoindolinone-1- (RS) in 5 cm3 of dichloromethane and 0.06 g of 4-dimethylamino pyridine. Stirring is continued for 24 hours at a temperature in the region of 25 ° C and then for 1 hour in the vicinity of 50 ° C. The precipitated product is separated by filtration and the filtrate is washed successively with 25 cm3 of water, 20 cm3 of a solution aqueous with 5% acetic acid and 20 cm3 of water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue obtained is purified by chromatography on silica [eluent: ethyl acetate-cyclohexane-diethylamine (49.9-49.9-0.2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. 0.11 g of [(chloro-7 naρhtyridine-1,8 yl-2) -2 oxo-3 isoindotinyl-1M (methyl-5 oxo-2) is thus obtained after crystallization from ethyl acetate. hex-5 yle- (RS) melting at 132 ° C.

EXAMPLE?

The procedure is as in Example 1 but starting with 1.0 g of (7-chloro-naphthyridin-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindoUnone-l- (RS), 0.90 cm3 of N "N-dimethylaniline and 0.88 cm3 of trimethylacetyl chloride. The residue obtained is purified by chromatography on a sitice [eluent: ethyl acetate-cyclohexane-diethylamine (49.9-49.9-0.2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. 0.05 g of [(chloro-7 naphthyridine-1,8 yl-2) -2-oxo-3 isoindolinyl-1] -l (5-methyl-oxo-trimethylacetate) is thus obtained after threshing in diisopropyl ether 2) hex-5 yle- (RS) melting at 152 ° C.

EXAMPLE S

The procedure is as in Example 3 but starting with 0.5 g of (+) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindoUnone-1, 0.12 cm3 of acetic anhydride, 0.3 cm3 of triethylamine and 0.03 g of 4-dimethylamino pyridine. The residue obtained is purified by chromatography on siUce [eluent: ethyl acetate-cyclohexane-diethylamine (49.9-49.9-0.2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the region of 40 ° C. After recrystallization from 10 cm3 of ethyl acetate, 0.110 g of (+) - (7-chloro-naphthyridine-1.8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-2-hexyl) is thus obtained. 3 isoindolinone-1 melting at 127 ° C. [α] ²⁰ D = ⁺¹²⁷ ° ± 3 (c = 0.507; dimethylformamide). (+) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindolinone-1 can be prepared according to the following method: Starting from 0.86 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindoUnone-1- (RS), they are separated by Uquide chromatography high-performance on 350 g of support consisting of siCe coated with trisphenylcarbamate of ceUulose prepared according to J. Amer. Chem. Soc., J ”5357 (1984) and contained in a column 19 cm long and 6 cm in diameter with as mobile phase the ethanol-hexane mixture (1-1 by volume) at a flow rate of 30 cm3 / minute, eluting successively:

- 0.38 g of (-) - (chloro-7 naρhtyridine-1,8 yl-2) -2 (5-methyl-5-hydroxy-2-oxo-hexyl) -3 isoindolinone-1 melting at 178 ° C whose power rotary is [α] ² ^ = -105 ° ± 2 ° (c = 0.75; chloroform), then

- 0.41 g of (+) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-hydroxy-oxo-hexyl) -3 isoindolinone-1 melting at 178 ° C including the rotary power is [α] ^ = + 104 ° ± 2 °

(c = 0.81; chloroform).

The present invention also relates to the drugs which contain the products of formula (I) in the pure state or in the form of compositions in which they are combined with an adjuvant, a diluent and / or a coating which are compatible and pharmaceutically acceptable. These drugs can be used orally, rectally, parenterally or percutaneously.

As solid compositions for oral administration, tablets, pills, powders (generally in gelatin capsules) or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate. As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products. The compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or organic injectable esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, 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 which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax. The compositions for percutaneous administration are creams, pom¬ mades, lotions and Uniments, in which the active product is associated with liquid or pasty excipients, preferably in combination with a vehicle promoting percutaneous migration.

The medicaments and compositions according to the invention are particularly useful in human therapy for their anxiolytic, hypnotic, anticonvulsant, anti-epileptic and muscle relaxant action.

In human therapy, the doses depend on the desired effect and on the duration of the treatment; They are generally between 10 and 500 mg per day orally for an adult. In general, the doctor will determine the dosage that U considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

The following example, given without limitation, illustrates a composition according to the invention.

EXAMPLE

Tablets containing 10 mg of active product having the following composition are prepared according to the usual technique:

- acetate of [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-l] -l (methyl-5 oxo-2) hex-5 yl- (RS) 0.01 g - starch 0.200 g

- precipitate siCe 0.036 g

- magnesium stearate 0.004 g

Claims

 REVENPICAΉQNS 1 - New isoindolinone derivative of formula

in which R represents an alkyl radical containing 1 to 10 carbon atoms optionally substituted by one or more atoms or radicals chosen from halogen atoms and phenyl, hydroxy, amino, alkylamino radicals containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 to 4 carbon or carboxy atoms in racemic form or in the form of its enantiomers, as well as its salts. 2 - Process for preparing the product according to claim 1 under a racemic farm, characterized in that the esterification of a product of formula is carried out:

in racemic form or in the form of its enantiomers, by means of an acid of general formula: R-CO-OH in which R is defined as above, optionally in the form of a halide or anhydride and, if necessary, optionally separates the product obtained into its enantiomers. 3 - Process according to claim 2 characterized in that the esterification by means of the acid is carried out in the presence of a condensing agent and an activating agent by operating in an organic solvent at a temperature between 0 and 90 ° C. 4 - Process according to claim 3 characterized in that the condensing agent is chosen from carbodiimides and reactive carbonates and the activating agent is chosen from dialkoylanilines and aminopyridines. 5 - Method according to one of claims 3 or 4 characterized in that the solvent is chosen from ethers, esters, nitriles, aUphatic hydrocarbons, halogenated aUphatic hydrocarbons and aromatic hydrocarbons. 6 - Process according to claim 2 characterized in that the ester-f ication by means of the acid in the form of acid dlialogénide is carried out in the presence of an activating agent by operating in an organic solvent at a temperature included between 0 and 90 ° C. 7 - Process according to claim 6 characterized in that the activating agent is chosen from tertiary amines. 8 - Process according to claim 6 characterized in that the solvent is chosen from ethers, esters, nitriles, aUphatic hydrocarbons, halogenated aUphatic hydrocarbons and aromatic hydrocarbons. 9 - Process according to claim 2 characterized in that the esterification by means of the acid in the form of anhydride is carried out in the presence of a base by operating in an organic solvent at a temperature between 0 and 90 ° C. 10 - Process according to claim 9 characterized in that the base is chosen from nitrogenous organic bases. 11 - Process according to claim 9 characterized in that the solvent is chosen from ethers, esters, nitriles, aUphatic hydrocarbons, halogenated aUphatic hydrocarbons and aromatic hydrocarbons. 12 - Pharmaceutical composition characterized in that it contains at least one product according to claim 1 in racemic form or in the form of its enantiomers in association with one or more pharmaceutically acceptable diluents or adjuvants inert or therapeutically active.