FR2779144A1 - NOVEL 8-AMINO-1,4-BENZOXAZINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

The invention concerns compounds of formula (I) wherein: R1 and R2 independently represent a hydrogen, an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl group, or a (CH2)p-O-(CH2)q-R5 group or R1 and R2 together form a cycloalkyl group; R3 and R4 independently represent a hydrogen, an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl group, or a CH(CH2-OH)2 or (CH2)p-O-(CH2)q-R5; T1, T2, T3, T4 independently represent a hydrogen, a halogen or an alkyl, hydroxy, alkoxy, cyano, amino, acyl group, or a O-(CH2)r-CO-R6 group.

Description

The present invention relates to novel 8-amino-1,4-

  benzoxazine compounds, their process of preparation and the pharmaceutical compositions containing them, as well as their

  use in the treatment of pathologies associated with the presence of free radicals.

  According to Hartman's radical theory of aging (J. Gerontol., 1956, 11, 298), the successive oxidative aggressions create oxidative stress conditions which reflect an imbalance in the body between the radical-producing systems and the systems. protectors against these species (RE PACIFICI, KJA DAVIES, Gerontology, 1991, 37, 166). Different defense mechanisms can act synergistically and control the action of free radicals. These mechanisms can be enzymatic, as is the case for systems involving superoxide dismutase, catalase, and glutathione peroxidase, or non-enzymatic enzymes, as in the case of vitamin E and C intervention. case, especially with age, these natural protections become less and less effective, especially because of the numerous oxidative inactivation

  enzymes (A. CASTRES de PAULET, Ann Biol Clin, 1990, 48, 323).

  Oxidative stress conditions may have been associated with senescent-related conditions such as atherosclerosis, cataract, insulin-dependent diabetes, or cancer (M. HAYN et al., Life Science, 1996, 59, 537). The central nervous system is particularly sensitive to oxidative stress because of its high oxygen consumption, the relatively low level of its antioxidant defenses (SA BENKOVIC et al., J. Comp., Neurol., 1993, 338, 92 D. HARTMAN, Drugs Aging, 1993, 3, 60). The successive oxidative aggressions therefore constitute one of the etiological factors of cerebral aging and associated diseases such as Alzheimer's disease and chronic neurodegenerative diseases, neurodegenerations

  basal ganglia (Parkinson's disease, Hungtington, ...), or Down's syndrome.

  The compounds of the present invention possess an original structure characterized by the

  presence of an amino group variously substituted at the 8-position of a 5-acyl-1,4-ring

  benzoxazine. Similar oxygenated derivatives at position 8 are described in WO 9518114, and other acylated 1,4-benzoxazine structures have been used as intermediates in the synthesis of cholecystokinin A-antagonist benzodiazepines (Chem Pharm Bull). ., 1994, 42,

2071; EP 360079).

  The compounds of the invention, in addition to being novel, possess valuable pharmacological properties. Their antioxidant nature, especially in the central nervous system, allows to consider their use to oppose the effects of oxidative stress,

  giving them a higher protective power than that of the compounds of the prior art.

  They are therefore useful in the treatment of affections related and / or maintained by the presence of reactive oxygen species, more particularly atherosclerosis, cancer, acute neurodegenerative diseases such as cerebral ischemia, epilepsy, diseases neurodegenerative diseases such as Alzheimer's disease, Pick's disease, basal ganglia neurodegenerations (Parkinson's disease, Hungtington, ...) or

Down syndrome.

  The present invention relates to the compounds of general formula (I):

R2 R

Ti () T2 o (I)

-3 / T4 T3

  R4 wherein: R1 and R2 independently represent a hydrogen atom, a linear or branched (C1-C6) alkyl group, a (C3-C8) cycloalkyl, a (C3-C8) linear -alkyl- (C1-C6) cycloalkyl or branched, optionally substituted aryl, optionally substituted linear or branched (CQ-C6) arylalkyl, or a (CH2) pO- (CH2) q-R5 group wherein: - p is an integer such that 1 <p <6 - q is an integer such that 0 <q <6 - R5 represents a hydrogen atom, a linear or branched (C-C6) alkyl group, (C3-C8) cycloalkyl, optionally substituted aryl, linear (C1-C6) acyl or branched, or R1 and R2 together with the carbon atom carrying them a cycloalkyl (C3-C8), -3 R3 and R4 independently represent a hydrogen atom, a linear (C1-C6) alkyl group or branched, (C 3 -C 8) cycloalkyl, linear or branched (C 3 -C 8) -alkyl- (C 3 -C 8) -alkyl, optionally substituted aryl, linear or branched (C 1 -C 6) arylalkyl or a (CH2) pO- (CH2) q-R5 group as previously defined, 5. T1, T2, T3, T4, independently represent a hydrogen atom, a halogen atom, an alkyl group (CI- C6) linear or branched, hydroxy, alkoxy (CQ-C6) linear or branched, cyano, amino (optionally substituted with one or two linear or branched (C 1 -C 6) alkyl groups, identical or different), acyl (C, - C6) linear or branched, or a group -O- (CH2) r-CO-R6 in which: - r is an integer such that O <r <6, - R6 represents a phenyl group optionally substituted by one or more atoms of halogen or linear or branched (C 1 -C 6) alkyl groups, linear or branched (C 1 -C 6) alkoxy, cyano, amino, it being understood that when several (CH 2) pO- (CH 2) q-R 5 groups are present on the molecule, they may be identical or different, their enantiomers, diastereoisomers, as well as their addition salts with an acid or a base

pharmaceutically acceptable.

  The term aryl means a phenyl or naphthyl group.

  The optionally substituted expression assigned to the terms aryl and arylalkyl means that these groups are substituted with one or more identical or different groups chosen from halogen, linear or branched (C 1 -C 6) alkyl, hydroxy, linear (C 1 -C 6) alkoxy or branched, amino, cyano, aminoalkyl (C 1 -C 6) linear or branched, carboxy, alkoxycarbonyl (C 1 -C 6)

linear or branched.

  Among the pharmaceutically acceptable acids, mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, -4-malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic,

  methanesulfonic, camphoric, etc ...

  Among the pharmaceutically acceptable bases, mention may be made of sodium hydroxide,

potassium hydroxide, etc.

  Preferably, the invention relates to the compounds of formula (I) for which R4 represents

a hydrogen atom.

  Preferably, in the compounds of formula (I), T1, T2, T3 and T4 represent each

a hydrogen atom.

  The subject of the present invention is also the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material: ## STR2 ##

HO 13

T4 T3

  in which G represents a hydrogen atom or a methyl group, and T1, T2, T3, T4 have the same meaning as in formula (I), which is treated electrochemically, by anodic electrolysis with controlled potential in the presence of a derivative of formula (III): R2 R

NH2-C-CH20H ()

  in which R1 and R2 have the same meaning as in formula (I), in alcoholic solution (for example methanol), and in the presence of a supporting electrolyte (for example a tetraethylammonium salt), to yield the compound of formula ( IV): -5- R2 Ri NH O

O1 IIT

0 U (V)

HO T2

O T

O T4 'T3

  in which R1, R2, T1, T2, T3, T4 have the same meaning as above, compound of formula (IV): which is optionally purified according to a conventional purification technique, 5. of which the enantiomers are optionally separated and and / or diastereoisomers according to standard separation techniques, and which, if appropriate, are converted into their addition salts with a pharmaceutically acceptable acid or base, which is subjected to controlled potential cathodic electrolysis, in solution. alcoholic (for example methanol), in the presence of a derivative of formula (V):

R3 NH2 (V)

  in which R3 has the same meaning as in formula (I), to yield the compound of formula (I / a)

R2 RI

NNH O Tl 0 - VT (I / a) T2

H T3

  in which R1, R2, R3, T1, T2, T3 and T4 are as defined above, which may optionally be chemically treated, with a compound of formula R4-Hal (Hal representing a halogen atom and R4, different of a hydrogen atom, being as defined in formula (I)), to give a compound of formula (I / b):

R2 R1

NH O 0> t T (FTb)

R3, T4 T

  R4 particular case compounds of formula (I) for which R1, R2, R3, T1, T2, T3 and T4 are as defined above, and R4, different from a hydrogen atom is as defined in the formula ( I), compounds of formula (I / a) and (I / b): which may be purified according to a conventional purification technique, from which the enantiomers and / or diastereoisomers may be separated according to conventional separation techniques, * and which, if appropriate, are converted into their addition salts with an acid or with a base

pharmaceutically acceptable.

  Electrolyses with controlled potential are realized by means of a three-electrode arrangement. The electrolysis cell consists of a set of ground glassware, the anode and cathode compartments being concentric and separated by a sintered glass wall. A potentiostat-galvanostat and an integrator complete the circuit. The working electrode may be, for example, a 10% iridium platinum canvas for anodic electrolysis, and a mercury layer for cathodic electrolysis. The auxiliary electrode may be for example a platinum plate, and the reference electrode a calomel electrode with a saturated solution of potassium chloride. The compounds of formula (IV): R2 Ri NH O

0 (IV)

HO I 2

O '

T4 T3

  In which: R1 and R2 independently represent a hydrogen atom, a linear or branched (C1-C6) alkyl group, a (C3-C8) cycloalkyl, a (C3-C8) cycloalkyl-(C -C) alkyl group; ) linear or branched, optionally substituted aryl, optionally substituted linear or branched (C1-C6) arylalkyl, or a (CH2) pO- (CH2) q-R5 group in which: - p is an integer such that 1 <p <6 q is an integer such that 0 <q <6 R5 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, (C3-C8) cycloalkyl, optionally substituted aryl or linear (C1-C6) acyl; or branched, or R1 and R2 together with the carbon atom carrying them a cycloalkyl group (C3-Cs), T1, T2, T3, T4, independently represent a hydrogen atom, halogen, a group linear or branched (C1-C6) alkyl, hydroxy, linear or branched (C1-C6) alkoxy, cyano, amino (optionally substituted by one or two linear (Ca-C6) alkyl groups

  or branched, identical or different), linear or branched acyl (C 1 -C 6), or a group -O-

  (CH2) r-CO-R6 wherein: - r is an integer such that O <r <6, - R6 represents a phenyl group optionally substituted by one or more linear halogen atoms or (C, -C6) alkyl groups or branched, linear or branched (C 1 -C 6) alkoxy, cyano, amino, with the proviso that R 1 and / or R 2 are different from a linear or branched (C 1 -C 3) alkyl group, a hydroxymethyl group and methoxymethyl, are new and also form part of the invention in the same way as the compounds of formula (I) of which they constitute synthetic intermediates, as well as their enantiomers, diastereoisomers and their possible addition salts with an acid or a pharmaceutically based

acceptable.

  The compounds of formula (II) as defined in the process above are known or readily available to those skilled in the art. They may for example be prepared by reaction between an aromatic carboxylic acid (VI / a), the ring is substituted by hydroxy groups, and an aromatic derivative (VI / b) suitably substituted: OG O HO

OH T

T2

HO T4

  (VI / a) (VI / b) or else also by reaction between a polyphenol derivative (VIVa) and an aromatic carboxylic acid (VII / b) optionally substituted with 1 to 4 groups Tl to T4 as defined in formula (I ):

OH O

HO HO t [T2

HO T T

HO 14 13

  (VII / a) (VII / b) in the presence of a Lewis acid, or phosphorus oxychloride, according to a scheme

  Friedel type reaction and Craft or Fries type.

  The invention also extends to pharmaceutical compositions containing as active ingredient at least one compound of formula (Ij alone or in combination with one or more

  non-toxic inert excipients or vehicles.

  Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, single or coated tablets, sublingual tablets, capsules, lozenges, suppositories, creams,

ointments, dermal gels, etc.

  The dosage varies with the age and weight of the patient, the nature and severity of the condition, and the route of administration. This can be nasal, rectal, parenteral or oral. In general, the unit dosage ranges from 0.1 to 500 mg for 1-in-1 treatment.

3 taken in 24 hours.

  The following examples illustrate the invention and do not limit it in any way. The structures of

  The described compounds have been confirmed by standard spectroscopic techniques.

  The preparations described below lead to starting materials used during the

  synthesis of the compounds of the invention.

  Preparation A: 4'-Fluoro-2,3,4-trihydroxybenzophenone Step a: 4'Fluoro-2-hydroxy-3,4-dimethoxybenzophenone To a suspension of 2 g of aluminum chloride and 1.80 g of sodium chloride 4-fluorobenzoyl in 3 cm3 of dichloromethane is added at 10 C and in 20 minutes 1.73 g of trimethoxybenzene dissolved in 3 cm3 of dichloromethane. After returning to ambient temperature, the suspension obtained is stirred for 22 hours. 100 cm3 of 0.1 molar hydrochloric acid are then added and the resulting reaction medium is extracted with 200 cm3 of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulphate, filtered, and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue obtained is

  recrystallized from diethyl ether to yield the expected product.

  Fusion point. 142 + 2 C Massive Spectrum (IC): m / z = 277 (MH ') Step b: 4'-Fluoro-2,3,4-trihydroxybenzophenone To a solution of 2.71 g of the compound described in the previous step in 140 cm3 of toluene is added 5.23 g of aluminum chloride. The reaction mixture is then stirred for 1 hour under reflux of toluene. After returning to ambient temperature, 300 cm3 of 0.1 hydrochloric acid

  molar are added and the resulting reaction medium is extracted with 400 cm3 of ethyl acetate.

  The combined organic phases are dried over anhydrous magnesium sulphate and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue obtained is

  recrystallized from toluene to yield the expected product.

  M.p. 3 ', 5'-Di-tert-butyl-4'-hydroxy-2,3,4-trimethoxybenzophenone To a suspension of 1.33 g of aluminum chloride in 3 cm3 of dichloromethane, the mixture is added at room temperature in 40 minutes, 1.73 g of trimethoxybenzene dissolved in 3 cm3 of dichloromethane. After 6 hours, 150 cm3 of 0.1 molar hydrochloric acid are added and the resulting reaction medium is extracted with 300 cm3 of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulphate, filtered, and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue is then taken up in 1 cm 3 of toluene and the solution obtained is deposited on a column of 70 g of silica gel (diameter 3.5

  cm, height 60 cm), eluted with toluene, to yield the expected product.

  M.p. solution of 2.0 g of 3 ', 5'-di-tert-butyl-4'-hydroxy-2,3,4-trimethoxybenzophenone in cm 3 of dichloromethane is added at room temperature and under a nitrogen atmosphere, 26 cm 3 of a molar solution of boron tribromide in dichloromethane. After 45 minutes, 100 cm3 of water are added and the resulting reaction medium is extracted with 500 cm3 of dichloromethane. The combined organic phases are dried over anhydrous magnesium sulphate and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C.

  Expected product is obtained after washing the residue with petroleum ether.

  Melting point: 136 + 2 C Mass spectrum (I.C.): m / z = 359 (MH +)

- 11 -

  EXAMPLE 1 [3- (tert-Butyl) -8- (phenethylamino) -3,4-dihydro-2H-1,4-benzoxazin-5-yl] phenyl) methanone Method A:

  The anodic electrolysis is carried out with a solution of 0.244 g of 3,4-dihydroxy-2-methoxy-

  benzophenone (described in J.Chem.Soc., Perkin Trans.2, 1996, 813), in 500 cm3 of methanol containing 0.6 g of S-tert-leucinol and 2.30 g of tetraethylammonium perchlorate as supporting electrolyte, under a nitrogen atmosphere, at 25 ° C., to a platinum electrode whose potential is set at + 0.4 V ecs At the end of the electrolysis, when the intensity of the current has become negligible (1 mA) in front of the intensity of the initial current (120 mA), 6.05 g of phenylethylamine are added to the resulting solution which is allowed to evolve. under a nitrogen atmosphere for half an hour. At the same time, the platinum electrode is replaced by a sheet of mercury. The cathodic electrolysis of the evolved solution is then carried out; the potential of the mercury layer is set at -0.9 V e.c.s. At the end of the electrolysis, when the intensity of the current has become negligible (0.5 mA) before the intensity of the initial current (80 mA), 100 cm3 of a solution of acetoacetic acid molar buffer are added to reaction medium, and the resulting solution is concentrated at 100 cm3, under reduced pressure (2.7 kPa), at a temperature of 40 C, and then extracted with 200 cm3 of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue is then taken up in 1 cm 3 of toluene and the solution obtained is deposited on a column of 30 g of silica gel (diameter 2 cm, height 60 cm) eluted with toluene. The expected product is obtained

  after recrystallization from a diethyl ether / pentane mixture (1/4).

  Melting Point: 108 + 2 C Mass Spectrum: m / z = 415 (MH +) Method B: Step a: 5-Benzoyl-3- (tert-butyl) -8a-hydroxy-3, 4.8,8a- tetrahydro-2H-1,4-benzoxazin-8-one 12 - This compound is part of the invention in the same way as the compound of Example 1 which it

  constitutes a synthesis intermediary.

  The anodic electrolysis is carried out with a solution of 0.244 g of 3,4-dihydroxy-2-methoxy-

  benzophenone (described in J.Chem.Soc., Perkin Trans. 2, 1996, 893), in 500 cm3 of methanol containing 0.6 g of S-tert-leucinol and 2.30 g of tetraethylammonium perchlorate as supporting electrolyte, under a nitrogen atmosphere, at 25 ° C., to a platinum electrode whose potential is set at + 0.4 V ecs At the end of the electrolysis, when the intensity of the current has become negligible (1 mA) before the intensity of the initial current (120 mA), 100 cm3 of a solution of acetoacetic acid molar buffer are added to the reaction medium. and the resulting solution is concentrated to 100 cm3, under reduced pressure (2.7 kPa), at a temperature of C, and then extracted with 200 cm3 of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulphate, filtered, and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue is then taken up in 1 cm 3 of dichloromethane and the solution obtained is deposited on a column of 40 g of silica gel (diameter 2.5 cm, height 60 cm), eluted with a toluene / acetone mixture (98/2 by volume). The expected product is obtained

  after recrystallization from a diethyl ether / pentane mixture (1/4 by volume).

  Endpoint: I 86 C (dec.) Mass Spectrum (IC): m / z = 328 (MH +) Step b: [3- (tert-Butyl) -8- (phenethylamino) -3,4-dihydro- 2H-1, 4-benzoxazin-5-yl] (phenyl) methanone 0.28 g of the compound described in the preceding stage is dissolved in 500 cm 3 of methanol containing 6.05 g of phenylethylamine. The resulting solution evolves under a nitrogen atmosphere for 30 minutes. Then 2.30 g of tetraethylammonium perchlorate are added and the cathodic electrolysis is carried out at 25 ° C. under a nitrogen atmosphere of the solution, at an electrode formed by a mercury layer whose potential is set at -0.9 V. e. cs At the end of the electrolysis, when the intensity of the current has become negligible (0.5 mA) before the intensity of the initial current (80 mA), 100 cm3 of a solution of acetoacetic acid molar buffer are added to the reaction medium and the resulting solution is concentrated at 100 cm3, under reduced pressure (2.7 kPa), at a temperature of 40 C, and then extracted with 200 cm3 of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and the solvent is evaporated to dryness under reduced pressure at a temperature in the region of 40 ° C. The residue is then taken up in 1 cm 3 of toluene and the resulting solution is deposited on a column of 30 g of silica gel (diameter 2.5 cm, height 60 cm), eluted with toluene. The expected product is obtained after recrystallization from a diethyl ether / pentane mixture (1/4 v / v), and has the same physicochemical characteristics as the compound obtained by Method A. EXAMPLE 2: [3- (tert-Butyl) - 8- (Isopentylamino) -3,4-dihydro-2H-1,4-benzoxazin-5-yl] (phenyl) methanone The expected product is obtained according to the process described in Example 1, Method A, in

  replacing phenylethylamine with isopentylamine.

  Melting point: 96 + 2 C (petroleum ether) Mass spectrum (CI): m / z = 381 (MH +) EXAMPLE 3: (8-Benzylamino-3-cyclopentyl-3,4dihydro-2H-1,4 benzoxazin-5-yl) (phenyl) methanone Method A: The expected product is obtained according to the process described in Example 1, Method A, replacing S-tert-leucinol with 1-amino-1-methylcylopentane and phenylethylamine by

benzylamine.

  Melting point: 125 ± 2 ° C (diethyl ether) Mass spectrum (IC): m / z = 399 (MH +) Method B: Step a: 5-Benzoyl-3-cyclopentyl-8α-hydroxy-3, 4.8 , 8a-Tetrahydro-2H-1,4-benzoxazin-8-one This compound is part of the invention in the same way as the compound of Example 3 which it

  constitutes a synthesis intermediary.

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  The expected product is obtained according to the process described in example 1, step a of method B, by replacing S-tert-leucinol with 1-amino-1-methylcyclopentane. The purification is carried out by chromatography on silica gel using a dichloromethane / methanol mixture (98/2, v / v). Melting point: 208 C (dec) (diethyl ether) Mass spectrum (IC): m / z = 326 (MHW) Step b: (8-Benzylamino-3-cyclopentyl-3,4-dihydro-2H-1, 4- benzoxazin-5-yl) (phenyl) methanone The expected product is obtained according to the method described in example 1, stage b of method B, by replacing the phenylethylamine by benzylamine, using as starting material the

  compound described in the previous stage.

  M.p. Benzoxazin-5-yl] (phenyl) methanone The expected product is obtained according to the method described in Example 1, Method A, replacing S-tert-leucinol with 1-amino-1-methylcyclopentane and phenylethylamine with 1 isobutylamine. Fusion point. 103 + 2 C (pentane) Mass Spectrum (IC): m / z = 365 (MH +) EXAMPLE 5 (8-Benzylamino-3,3-diphenyl-3,4-dihydro-2H-1,4-benzoxazin) 5-yl) (phenyl) methanone Method A: The title product is obtained according to the method described in Method A of Example 1, replacing S-tert-leucinol with 2-amino-2, 2-diphenylethanol and phenylethylamine by

benzylamine.

  Melting Point: 150 + 2 C (methanol) Mass Spectrum (IC): m / z = 497 (MH +) Method B: Step a: 5-Benzoyl-3,3-diphenyl-8α-hydroxy-3,4 8,8a-Tetrahydro-2H-1,4-benzoxazin-8-one This compound is part of the invention in the same way as the compound of Example 5 which it

  constitutes a synthesis intermediary.

  The expected product is obtained according to the method described in example 1, step a of method B, replacing S-tert-leucinol with 2-amino-2,2-diphenylethanol. The purification is carried out by chromatography on silica gel using a dichloromethane / methanol mixture

(98/2, v / v).

  Melting point: 230 C (dec) (diethyl ether) Mass spectrum (IC): m / z = 424 (MH +) Step b: (8-Benzylamino-3-diphenyl-3,4-dihydro-2H-1, 4-benzoxazin-5-yl) (phenyl) methanone The expected product is obtained according to the method described in example 1, stage b of method B, using as starting material the compound described in the previous stage and replacing the

  phenylethylamine by benzylamine.

  Melting point: 150 + 2 C (methanol) Mass spectrum (CI): m / z = 497 (MH +) EXAMPLE 6: [3,3-Diphenyl-8- (isopentylamino) -3,4-dihydro2H-1, 4-Benzoxazin-5-yl] (phenyl) methanone The expected product is obtained according to the method described in Example 1, Method A, replacing S-tert-leucinol by 2-amino-2,2 -diphenylethanol and phenylethylamine by isopentylamine. Melting point: 110 + 2 C (petroleum ether) Mass spectrum (IC): m / z = 477 (MH +) EXAMPLE 7: (8-Benzylamino-3,3-dimethyl-3,4-dihydro-2H- 1,4-Benzoxazin-5-yl) (phenyl) methanone The expected product is obtained according to the process described in Example 1, Method A, replacing S-tert-leucinol with 2-amino-2,2-benzene. dimethylethanol and phenylethylamine by the

benzylamine.

  Melting point: 132 2 C (ethyl ether / 50/50 petroleum ether) Mass spectrum (CI): m / z = 373 (MH +) EXAMPLE 8: 13,3-Dimethyl-8 (isopentylamino) -3,4- dihydro-2H-1,4-benzoxazin-5-yl (phenyl) methanone The expected product is obtained according to the process described in Example 1, Method A, replacing S-tert-leucinol with 2-amino-2,2 dimethylethanol and phenylethylamine by isopentylamine. Melting point: 100 + 2 C (petroleum ether) Mass spectrum (I.C.): m / z = 353 (MH +)

  EXAMPLE 9: {8 - [(2-Hydroxyethyl) amino)] - 3,3-di (hydroxymethyl) -3,4-dihydro-2H-1,4-

  Benzoxazin-5-yl} (phenyl) methanone The expected product is obtained according to the process described in Example 1, Method A, replacing S-tert-leucinol with tris (hydroxymethyl) aminoethane and phenylethylamine with ethanolamine. . Melting point: 178 ± 2 ° C (ethyl acetate) Mass spectrum (I.C.): m / z = 359 (MH +)

- 17- 2779144

-17-

  EXAMPLE 10: {3-Hydroxymethyl-3-methyl-8 - [(2-hydroxyethyl) amino] -3,4-dihydro-2H-

  1,4-Benzoxazin-5-yl} (phenyl) methanone The expected product is obtained according to the method described in Example 1, Method A, replacing the sterl-leucinol with 2-amino-2-methyl-1, 3-propanediol and phenylethylamine with ethanolamine. M.p.

  EXAMPLE 11: [8 - {[2-Hydroxy-1- (hydroxymethyl) ethyl] amino} -3 (hydroxymethyl) -3,4-

  Dihydro-2H-1,4-benzoxazin-5-yl] (phenyl) methanone Method A: The title product is obtained according to the method described in Example 1, method A, in

  replacing S-tert-leucinol and phenylethylamine with 2-amino-1,3-propanediol.

  Melting point: 164 ± 2 ° C (chloroform) Mass spectrum (I.C.). m / z = 359 (MH +) Method B:

  Step a: 5-Benzoyl-3-hydroxymethyl-8α-hydroxy-3,8,8,8a-tetrahydro-2H-1,4-benzoxazin-8-

  This product is part of the invention in the same way as the compound of Example 11 which it

  constitutes a synthesis intermediary.

  The expected product is obtained according to the process described in example 1, step a of method B,

  replacing S-tert-leucinol with 2-amino-1,3-propanediol.

  M.p. } -3 (hydroxymethyl) -3,4-dihydro-2H-1,4-benzoxazin-5-yl] (phenyl) methanone The expected product is obtained according to the method described in example 1, stage b of method B. by substituting 2-amino-1,3-propanediol for phenylethylamine (50 molar equivalents), using as starting material the compound described in the previous stage. Melting point: 164 ± 2 ° C (chloroform) Mass spectrum (I.C.): m / z = 359 (MH +)

  EXAMPLE 12 (8-Benzylamino-3-cyclopentyl-3,4-dihydro-2H-1,4-benzoxazin-5y) [4-

  hydroxy-3,5-di- (tert-butyl) phenyl] methanone Method A: The title product is obtained according to the method described in Example 3, Method A, using 3 ', 5'-as the starting material. di-tert-butyl-2,3,4,4'tétrahydroxybenzophénone

(described in Preparation B).

  Method B: Step a .: 3-Cyclopentyl-5- [3,5-di- (tert-butyl) -4-hydroxybenzoyl] -3,8,8,8a-tetrahydro-2H-1,4-benzoxazin-8-one This compound is part of the invention in the same way as the compound of Example 12 which it

  constitutes a synthesis intermediary.

  The expected product is obtained according to the process described in example 3, stage a of method B, using as starting material 3 ', 5'-di-tert-butyl-2,3,4,4'- tetrahydroxy

(described in Preparation B).

  Step b: (8-Benzylamino-3-cyclopentyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl) [4-hydroxy-3,5-

di- (tert-butyl) phenyl] methanone

- 19- 2779144

  The expected product is obtained according to the process described in example 3, stage b of method B,

  using as starting material the compound described in the previous stage.

  EXAMPLE 13 [3- (tert-Butyl) -8- (phenethylamino) -3,4-dihydro-2H-1,4-benzoxazin-5-yl) (4-fluorophenyl) methanone Method A: The title product is obtained according to the method described in Example 1, Method A, using as starting material 4'-fluoro-2,3,4-trihydroxybenzophenone (described in US Pat.

preparation A).

Method B:

  Stadium a. 5- (4-Fluorobenzoyl) -3- (tert-butyl) -8α-hydroxy-3,8,8,8-tetrahydro-2H-1,4-4

  benzoxazin-8-one This compound is part of the invention in the same way as the compound of Example 13 which it

  constitutes a synthesis intermediary.

  The expected product is obtained according to the process described in example 1, stage a of method B, using 4'fluoro-2,3,4-trihydroxybenzophenone (described in US Pat.

preparation A).

  Step b: [3- (tert-Butyl) -8- (phenethylamino) -3,4-dihydro-2H-1,4-benzoxazin-5-yl) (4-fluorophenyl) methanone The expected product is obtained according to the process described in US Pat. example 1, stage b of method B,

  using as starting material the compound described in the previous stage.

-20 -

  PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION

  EXAMPLE 14 Cytotoxicity Test Cytotoxicity of the products of the invention was determined on hippocampal cells

HT-22.

  Murine HT-22 hippocampal cells in culture (100 μl / well DMEM / F12 / 2.5% FCS) are incubated for 48 h in the presence of 8 concentrations (5, 10, 25, 50, 75, 100, 250 μM) of agent studied. The cytotoxicity is then evaluated by the method for reducing 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) (MOSSMANN T., Immunol Methods, 1983, 65, 55). and assaying the activity of Lactate Deshydrogenase (LDH) in the culture medium (KOH JH and CHOI DW, J. Neurosci, Meth., 1987, 20, 83). The results are expressed by the MTD (Tolerated Maximum Dose) and the TC50: concentration representing% of maximum toxicity, induced by Menadione (50 gM) and untreated cells

(0% toxicity).

Results:

  Most of the compounds of the invention have TC50 and MTD greater than 250 μM.

  EXAMPLE 15: Protective test The protective power of the compounds of the invention was determined by a protection test

  against toxicity to L-homocysteic acid.

  HT-22 murine hippocampal cells in culture (100 fl / well DMEM / F12 / 2.5% FCS)

  are preincubated for 1h in the presence of 8 concentrations (up to the BAT) of the agent under study.

  The cell cultures are then exposed for 48 hours to 2 mM L-homocysteic acid in the absence or in the presence of reference antioxidants or test compounds. The

  cytotoxicity is then assessed by the method of reduction of 3- (4,5-dimethylthiazole) bromide

  2-yl) -2,5-diphenyltetrazolium (MTT) (MOSSMANN T., Immunol Methods, 1983, 65, 55) and by assaying the activity of Lactate Deshydrogenase (LDH) in the culture medium (KOH JH and CHOI DW, J. Neurosci, Meth., 1987, 20, 83). The results are expressed by the PC50: concentration representing 50% protection compared to the toxicity induced by 2mM homocysteic acid (0% protection) and compared to the maximum protection obtained in the presence of iM vitamin E. Results The compounds of the invention have shown a significant protective power at doses below the BAT: By way of example the PC50 of the compounds of Examples 3 and 7 are grouped in the following table:

PC50 ("M)

MTT LDH

  Example 3 6.9 7.1 Example 7 3.5 3.1 EXAMPLE 16 Pharmaceutical composition

  Preparation formula for 1000 tablets dosed at 10 mg.

  Composed of example 7 ............................................ .......

  .............................. 10 g Hydroxypropylcellulose ............... DTD: .................................................. ................... 2 g Wheat starch .......................... ........................... DTD: ..................... ......................... l10 g Lactose ............ DTD: ........ .................................................. ............... DTD: ......................... 100 g Magnesium stearate ... ................ DTD: ................................ ................................... 3 g Talc ............ .................................................. .... .TDD: ........................................... ..... 3 g..DTD: - 22 -

Claims (10)

  1. Compounds of formula (I): R2 R NNH O T2 T4 3T   R3 / R4 wherein R1 and R2 independently represent a hydrogen atom, a linear or branched (C1-C6) alkyl group, a (C3-C8) cycloalkyl, a (C3-C8) cycloalkyl- (C1-C8) alkyl; C6) linear or branched, optionally substituted aryl, optionally substituted linear or branched (C1-C6) arylalkyl, or a (CH2) pO- (CH2) q-Rs group in which - p is an integer such that l <p < Q is an integer such that O <q <6 - R5 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group, (C3-Cs) cycloalkyl, optionally substituted aryl, acyl (C, - C6) or R1 and R2 together with the carbon atom carrying them a cycloalkyl group (C3-C4), R3 and R4 independently represent a hydrogen atom, an alkyl group (C, -C6) linear or branched, cycloalkyl (C3-Cs), cycloalkyl- (C3-C8) -alkyl- (C, -C6) linear or branched, optionally substituted aryl, aryl (C, -C6) linear or branched optionally or a (CH2) pO- (CH2) q-R5 group as previously defined, AT1, T2, T3, T4, independently represent a hydrogen atom, a halogen atom, a (C6-C6) alkyl group, ) linear or branched, hydroxy, linear or branched (C 1 -C 6) alkoxy, cyano, amino (optionally substituted with one or two linear (C 1 -C 6) alkyl groups - 23 -   or branched, identical or different), linear or branched acyl (C 1 -C 6), or a group -O-   (CH2) r-CO-R6 wherein: - r is an integer such that O <r <6, - R6 represents a phenyl group optionally substituted with one or more halogen atoms or linear (C-C6) alkyl groups or branched, linear or branched (C 1 -C 6) alkoxy, cyano, amino, it being understood that when several (CH 2) pO- (CH 2) q-R 5 groups are present on the molecule, they may be identical or different, their enantiomers, diastereoisomers and their addition salts with an acid or a base pharmaceutically acceptable.   2. Compounds of formula (I) according to claim 1, such that T1, T T3 and T4 each represent a hydrogen atom, their enantiomers, diastereoisomers, as well as their salts.   addition to a pharmaceutically acceptable acid.   3. Compounds of formula (I) according to claim 1, such that R4 represents a hydrogen atom, their enantiomers, diastereoisomers, as well as their addition salts with a   acid or a pharmaceutically acceptable base.   4. Compound of formula (I) according to claim 1 which is (8-benzylamino-3-cyclopentyl)   3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone, as well as its addition salts with a   pharmaceutically acceptable acid.   5. Compound of formula (I) according to claim 1 which is (8-benzylamino-3,3-dimethyl-   3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone, as well as its addition salts with a   pharmaceutically acceptable acid.   6. Process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material: -24 OG O HO T (11) T2 HO T4 T3   in which G represents a hydrogen atom or a methyl group, and T1, T2, T3, T4 have the same meaning as in formula (I), which is treated electrochemically, by anodic electrolysis with controlled potential in the presence of a derivative of formula (III): wherein R1 and R2 have the same meaning as in formula (I), in alcoholic solution, and in the presence of a supporting electrolyte, for to the compound of formula (IV): R2 R NHII O O IJ (IV) HO 1T2 T4 13   in which R1, R2, T1, T2, T3, T4 have the same meaning as above, compound of formula (IV): to which it is optionally purified according to a conventional purification technique, from which the enantiomers and / or or diastereoisomers according to conventional separation techniques, A and which, if appropriate, are converted into their addition salts with a pharmaceutically acceptable acid or base, which is subjected to controlled potential cathodic electrolysis, in solution. alcoholic, in the presence of a derivative of formula (V): R3-NH2 (V)   in which R3 has the same meaning as in formula (I), to yield the compound of formula (I / a): R2 R <NHl O O T1 (J / a) OR3 I 1 (T2 H 3   Wherein R1, R2, R3, T1, T2, T3 and T4 are as defined above, which may optionally be chemically treated, with a compound of formula R4-Hal (Hal representing a halogen atom and R4, different from a hydrogen atom, being as defined in formula (1)), to give a compound of formula (I / b) R2XRI NH O Tl 0 1 (Ib) T2 R3 ---- NI 4 T I TT   R4 particular case compounds of formula (I) for which R, R2, R3, T, T2, T3 and T4 are as defined above, and R4, different from a hydrogen atom is as defined in the formula ( I), compounds of formula (I / a) and (I / b): which may be purified according to a conventional purification technique, from which the enantiomers and / or diastereoisomers may be separated according to conventional separation techniques. , and that, where appropriate, they are converted into their addition salts with an acid or a base pharmaceutically acceptable.   -26 - 7. Compounds of formula (IV): embedded image in which: R 1 and R 2 independently represent a hydrogen atom, a linear or branched alkyl (C 1 -C 6) alkyl, cycloalkyl group (C3-C8), linear or branched (C3-C8) cycloalkyl- (C1-C8) alkyl, optionally substituted aryl, optionally substituted linear or branched (C1-C6) arylalkyl, or (CH2) pO- (CH2) q-R5 wherein: - p is an integer such that 1 <p <6 - q is an integer such that 0 <q <6 - R5 represents a hydrogen atom, a (C, -C6) alkyl group ) linear or branched, (C3-C5) cycloalkyl, optionally substituted aryl, linear or branched (C1-C6) acyl, or R1 and R2 together with the carbon atom carrying a (C3-Cα) cycloalkyl group , T1, T2, T3, T4, independently represent a hydrogen atom, a halogen atom, a linear or branched (C1-C6) alkyl group, hydroxy, linear or branched (C1-C6) alkoxy, cyano, amino (optionally substituted by one or two linear (C1-C6) alkyl groups   or branched, identical or different), linear or branched acyl (C 1 -C 6), or a group -O-   (CH2) r-CO-R6 wherein: - r is an integer such that O <r <6, - R6 represents a phenyl group optionally substituted by one or more halogen atoms or linear (C1-C6) alkyl groups or branched, linear or branched (C 1 -C 6) alkoxy, cyano, amino, with the proviso that R 1 and / or R 2 are different from a linear or branched (C 1 -C 3) alkyl group, a hydroxymethyl group and a methoxymethyl group Their enantiomers, diastereoisomers and their possible addition salts with a pharmaceutically acceptable acid or base,   useful as synthetic intermediates for the compounds of formula (I).   8. A compound of formula (IV) according to claim 7 which is 5-benzoyl-3-cyclopentyl-8α   3,4,8,8a-tetrahydro-2H-1,4-benzoxazin-8-one, and its addition salts with   pharmaceutically acceptable acid.   9. Pharmaceutical compositions containing as active ingredient at least one compound according to   any one of claims 1 to 5, alone or in combination with one or more   inert, non-toxic, pharmaceutically acceptable excipients or carriers.   10. Pharmaceutical compositions according to claim 9 containing at least one principle   active agent according to any one of claims 1 to 5 useful as antioxidants in   the treatment of atherosclerosis, cancer, acute neurodegenerative diseases such as cerebral ischemia, epilepsy, chronic neurodegenerative diseases such as Alzheimer's disease, Pick's disease, neurodegeneration of the ganglia of the   base (Parkinson's disease, Hungtington), or Down syndrome.