MXPA00000642A - Thiazolobenzoheterocycles, preparation and medicines containing same - Google Patents

Abstract

The invention concerns compounds of formula (I) in which:R1 represents a sulphur or selenium atom;R2 represents a hydrogen atom or an alkyl radical;-R3-R4-R5-R6- represents a chain of formula -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CO-, -CH2-CH2CH2CH(R8)-, -CH2-CH2-CH2-Se-, -CH2-CH2-Se-CH2-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-SO-, -CH2-CH2-CH2-SO2-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-N(R9)-, -CH2-CH2-CO-CH2-, -CH2-CH2CH(R8)-CH2-, -CH2-CH2-S-CH2-, -CH2-CH2-SO-CH2-, -CH2-CH2-SO2-CH2-, -CH2-C(alk)(alk')-S-CH2, -CH2-C(alk)(alk')-SO-CH2, -CH2-C(alk)(alk')-SO2-CH2, -CH2-CH(R10)-S-CH2-, -CH2-CH(R10)-SO-CH2-, -CH2-CH(R10)-SO2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or -CH2-CO-N(R9)-CH2-;R7 represents a polyalkyl or polyfluoroalkoxy radical;R8 represents a hydroxy radical;R9 represents a hydrogen atom or an alkyl or benzyl radical and R10 represents an alkyl radical, -CH2OH, -COOalk, -COOH or -CONH2, their isomers, racemic compounds, enantiomers, their salts, their methods of preparation and medicines containing them. Said compounds are anticonvulsant and interfere with glutamatergic transmission.

Description

TIAZO OBENZOHETEROCICLOS, ITS PREPARATION AND THE MEDICINES THAT CONTAIN THEM The present invention concerns compounds of the formula: Its isomers, racemates, enantiomers, its salts, its preparation procedures and the medicines that contain them.

In the formula Ri, represents a sulfur or selenium atom, R represents a hydrogen atom or an alkyl radical, REF.32232 ^^ ¿^^^^^^^^^ í ^^^^^^^^^ * ^^ -R3- R_- R5- Re- / represents a chain of formula -CH_- CH2- CH_- CH_-, -CH: - CH2- CH2- CO-, -CH; - CH; - CH2- CH (Re) -, - CH_- CH; - CH_- Se-, -CH2- CH; - Se- CH; -, - CH; - CH; - CH; - S-, - CH_- CH; - CH- SO-, -CH; - CH_- CH2- S0-, -CH2- CH2- CH2- O-, - 5 CH: - CH - CH; - N (R9) -, -CH; - CH; - CO- CH; -, -CH; - CH; - CH (RJ- CH--, -CH; - CH; - S- CH; , -CH; - CH2- SO- CH; -, -CH_- CH; - SO- CH_-, -CH_- C (alq) (alq ') - S- CH_, -CH; - C (alk) (alk) ') - SO- CH, CH-- C (alk) (alq') - SO, - CH2, -CH; - CH (R? 0) - S- CH; -, CH; - CH (Rm) - SO - CH; -, -CH; - CH (R? O) - SO; - CH2-, -CH; - CH; - 0- 10 CH: -, -CH-- CH; - N (RQ) - CH; - or -CH; - CO- N (Rq) "CH; -, R- represents a polyfluoroalkyl or polyfluoroalkoxy radical, R- represents a hydroxy radical, Rc represents a hydrogen atom or an alkyl or benzyl radical, R-, ,, represents an alkyl radical, -CH 2 OH, -COOalk, -COOH or -CONH;, Alk represents an alkyl radical, Alk 'represents an alkyl radical, S-A.X * -m ~ A ^. ^^. ^ .. - -, ^^ M ÍHG W * '"" • ^ -m-m-m-m' ^^ * ^ **? * - * > * In the above definitions and those which will be cited below, unless otherwise mentioned, the radicals and alkyl portions contain 1 to 6 carbon atoms in the right or branched chain.

The polyfluoroalkyl radicals include trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2-, tetrafluoroethyl, perfluoroethyl, perfluoropropyl, perfluorobutyl radicals.

The polyfluoroalkoxy radicals include trifluoromethoxy, perfluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2-, tetrafluoroethoxy, 2,2,3,3- pentafluoropropoxy, perfluoropropoxy, perfluorobutoxy radicals.

The preferred polyfluoroalkyl and polyfluoroalkoxy radicals are the trifluoromethyl, trifluoromethoxy and pentafluoroethoxy radicals.

The invention also concerns the addition salts of the compounds of formula (I) with the mineral or organic acids.

The compounds of formula (I) containing one or more Asymmetric centers have isomeric forms, these isomers and mixtures form part of the invention. The racemates and the enantiomers of these compounds also form part of the invention.

The compounds of formula (I) for which Ri represents a sulfur or seeleem atom, R_, represents a hydrogen atom, -R 2 -R, -R 5 -R b ~ represents a chain of formula -CH 2 -CH 2 -CH - CH; -, -CH "- CH; - CH; - CO-, -CH; - CH; -CH_- CH (Ro) -, -CH; - CH; - CH2- Se-, -CH; - CH; - Se- CH; -, -CH - CH - CH; - S -, - CH - CH; - CH - O -, - CH - CH - CH; - N (Rq) -, - CH; -CH; - CO- CH_-, -CH_- CH_- CH (Re) - CH; -, -CH2- CH2- S- CH; -, -CH_- C (alk) (alq ') - S- CH_- , -CH2- CH (R? O)) - S- CH; -, -CH_- CH-0- CH_-, -CH_- CH_- N (Rq) - CH2- or -CH- CO- N (R? ) - CH; -, R8 represents a hydroxy radical, R represents a hydrogen atom or an alkyl or benzyl radical and Ro represents an alkyl radical, COOalq or CONH can be prepared by the action of alkali metal thiocyanate or metal selenocyanate alkaline with a derivative of formula: - ^ || ^ ¡¡| In which R7, has the same meanings as in the formula (I) and -R3- R4- R5- e-, represents a chain of the formula -CH; - CH; - CH; - CH2-, -CH2- CH2 - CH; - CO-, -CH; - CH; - CH; - CH (R8) -, -CH2- CH2- CH; - Se-, -CH; - CH2- Se- CH; -, -CH- CH; - CH; - S ", -CH; - CH; - CH; - O", - CH; - CH; - CH; - N (R9) -, -CH; - CH; - CO- CH; , -CH2- CH2- CH (R8) - CH2-, -CH; - CH; - S- CH_-, - CH; - C (alk) (alq ') - S- CH; -, -CH; - CH (R?)) - S- CH; -, -CH_- CH_- O- CH; -, -CH; - CH: - N (R9) - CH2- or -CH; - CO "N (Rq)" CH; -, R8, represents a hydroxy radical, Rg, represents an atom of Hydrogen or an alkyl or benzyl radical and RJO represents an alkyl radical, COOalc or CONH2, ale and ale 'represent an alkyl radical.

This reaction is generally carried out in the presence of bromine, chlorine, chloramide or cupric chloride, in an organic solvent such as acetic acid, at a temperature between 15 ° C and the boiling temperature of the reaction medium. . As the alkali metal thiocyanate or alkali metal selenocyanate, it is preferable to use potassium thiocyanate or potassium selenocyanate.

The derivatives of formula (II) are new and as such form part of the invention. 25 • > - 1 ^^ ^^ a ^. ^^ »-.- .. j _ ^ _ ^ = L ^^^^^^^^^^^ _ s _ ^^ a ^ _ ^ _ = £ & ^^ ^ ^ = ^ = a ^^^^ = i = aa¿g The compounds of formula (I) for which R, represents an alkyl radical can be prepared by alkylation of a corresponding compound of formula (I) for which R; represents a hydrogen atom.

This alkylation is carried out by any method that allows to rent an imine function. Preferably, it is operated in the middle of a Ra-X derivative in which Ra represents an alkyl radical and X represents a reactive group such as a halogen atom (preferably chlorine, bromine or iodine) or a tosyloxy radical, in an inert organic solvent such as an aliphatic alcohol (1-6) (ethanol, propanol, butanol for example), a ketone (acetone, methylethyl ketone for example) or dimethylformamide, in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at a temperature between 20 ° C and the boiling temperature of the reaction medium.

The compounds of formula (I) for which R2 represents a hydrogen atom or an alkyl radical, -R3- Rj- R ^ -R ~, represents a chain of formula -CH; - CH- CH (RP) - CH; or -CH_- CH2- CH-CH (R8) - and R8, represents a hydroxy radical can also be obtained by reduction of a corresponding compound of formula (I) for which R2 represents a hydrogen atom or an alkyl radical and - - R- R¿- R-- R6- represents a chain of formula -CH: - CH- CO- CH; - Ó CH; - CH; - CH; - CO ".

This reaction is carried out by any method that allows to pass from a ketone to an alcohol. It is generally operated in sodium borohydride medium, in an alcohol such as methanol or ethanol, at a temperature between 0 and 25 ° C.

The compounds of formula (I) for which R; represents a hydrogen atom or an alkyl radical and -R- R- R- represents a chain of the formula CH2-CH; - CH; - SO, -CH; - CH_- CH-- SO--, -CH; - CH_- SO- CH; -, -CH; - CH; - SO; - CH; -, -CH-- C (alk)) (alq ') - SO- CH-, -CH; - C (alk ) (alq ') - SO; -, -CHCH (R: ") - SO- CH-- or -CH - CH (Rio) - SO-- CH- can be prepared by oxidation of a compound of formula (I) corresponding for which the chain - R - R - R - Re - represents a chain of formula --CH; - CH - CH - S -, - CH; - CH - S - CH -, - CH - C (alk) (alq ') - S- CH-- or -CH- CH (Rio) - S- CH- This oxidation is carried out according to the known methods of oxidation of the sulfur derivatives such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Mmonograph, 186, 252-263 (1990). For example, you operate by The action of an organic peracid, or a salt of such an acid (percarboxylic or persulphonic acid, particularly perbenzoic acid, 3-chloroperbenzoic acid, 4-nitroperbenzoic acid, peracetic acid, 5-pertrifluoroacetic acid) , performic acid, monoperphthalic acid) or mineral peracids or a salt of such an acid (for example periodic or persulphuric acid), in an inert solvent such as a chlorinated solvent (chloroform, dichloromethane for example), at a temperature between 0 and 25 ° C. It is also possible to use hydrogen peroxide or a periodate (sodium periodate, for example), in an inert solvent such as a lower aliphatic alcohol, water or a mixture of these solvents, at a temperature comprised between 0 and 20. ° C. Is It is equally possible to proceed in the medium of tert-butylhydroperoxide in the presence of titanium tetraisopropylate or oxonar (potassium peroxymonosulfate) in a lower aliphatic alcohol or a water-alcohol mixture, at a temperature of 25 ° C. twenty The compounds of formula (I) for which R;, represents a hydrogen atom or an alkyl radical, - R a - R - R "- R 0 - represents a chain of formula -CH - CH (R? O) -S - CH2 in which R ?, > Represents a radical -CH2OH, can be prepared by reduction of a compound of formula (I) corresponding to which R2 represents a hydrogen atom or an alkyl radical, -R3-R4-R5-Re- represents a chain of formula -CH2-CH (Rio) -S-CH in which Rio represents a radical - COOalq. This reaction is carried out by any known method which makes it possible to obtain an alcohol from the corresponding ester. Preferably, it is carried out in the sodium hydroboride medium, in an alcohol such as ethanol, at the boiling temperature of the reaction medium.

The compounds of formula (I) for which R represents a hydrogen atom or an alkyl radical, -R3-15 R, -R- R (, - represents a chain of formula -CH2-CH (Rjo) ~ S- CH - in which Ri represents a corresponding radical of formula (I) for which R- represents a hydrogen atom or an alkyl radical, -R; _ R, - Rt ~ Rp- represents a chain of formula -CH- CH ( Rio) - S- CH, in which Rio represents a radical -COOalq.

This reaction is carried out by any method that allows to pass from an ester to the corresponding acid. It is usually proceeded in the middle of an alkali metal hydroxide (soda for example), in an inert solvent such as an alcohol (methanol, ethanol for example), at a temperature comprised between 15 ° C and the boiling temperature of the reaction medium.

The derivatives of formula (II) for which the chain -Ri-R4-Rs ~ Re- represents a chain of formula -CH; -CH-CH- CH; - and R7 represents a polyfluoroalkyl or polyfluoroalkoxy radical can be obtained by of 1,4-dihalobutane on the lithium of a 4-polyfluoroalkylaniline or 4-polyfluoroalkoxyaniline whose amine function is protected, followed by the deprotection of NH.

This reaction is generally carried out in the tetrahydrofuran, at a temperature of -78 ° C. It is preferable to protect the amine function in the form of a tert-butyl carbamate; in this case, the deprotection is carried out in the trifluoroacetic acid medium, in an inert organic solvent such as a chlorinated solvent (chloroform, dichloromethane for example), at a neighboring temperature of 20 ° C. Preferably, 1- chloro-4-iodobutane is used. Lithium is obtained by the action of tert-butyllithium in pentane on a 4- polyfluoroalkylaniline or 4- polyfluoroalkoxyaniline whose amine function is protected, within tetrahydrofuran, at a temperature of -78 ° C.

The 4-polyfluoroalkylaniline and 4-polyfluoroalkoxyaniline are marketed or can be obtained by application or adaptation of the methods described in J. Org. Chem., 29, 1 (1964), and in patents US 3920444, US 2436100, DE 2606982, EP 205821 and EP 546391.

The derivatives of formula (II) for which -R 3 -R ~ R- Rc- represents a chain of formula -CH; - CH; - CH-- S-, - 10 CH- CH- CH- Se-, -CH - CH- CH- O-, -CH- CH; - CH- N (R9) -, -CH-- CH- S- CH-, -CH-- C (alk) (alq ') - S- CH -, -CH- CH (Rin) - S- CH; - in which Rio represents an alkyl radical, - CH-- CH-- Se- CH--, -CH- CH- O- CH-, -CH; - CH- N (Rq) - CH- can be obtained by reduction of a derivative of the formula: fifteen In which R ?, has the same meanings as in formula (I) and -R4- R5- Re- represents a chain of formula - CH-- CH- S-, -CH- CH- Se-, -CH2- CH- O-, -CH- CH- N (Rq) -, -CH- S- SH2-, -C (alq) (alk) ') - S- CH2, -CH (Rio) - S- CH- in which Rio represents an alkyl radical, -CH; - Se- CH_-, -CH- O- CH; -, -CH; - N ( R; -) - CH; - in which R has the same meanings as in formula (I).

This reaction is generally carried out in the medium of a reducing agent such as lithium tatrahydroaluminate, in an inert organic solvent such as tetrahydrofuran, at a neighboring temperature of 20 ° C or the borane-dimethylsulfide complex, in the of an inert solvent such as toluene, at the boiling temperature of the reaction medium.

The derivatives of formula (III) for which the chain - R 4 - R t, - R "- represents a chain of the formula -CH; - S - CH -, - C (alk) (alq ') - S - CH -, -CH (R10) -S-CH- in which Rio represents an alkyl radical or -CH- Se- CH- can be obtained by cyclization of a derivative of the formula: ^^? & ^ X s ^^^ In which the amino function is eventually protected and either RD represents a sulfur atom, Rc, Rd and R; they represent a hydrogen atom or an alkyl radical, and R- has the same meanings as in formula (I), or else Rc represents a selenium atom, Rc and Rd each represent a hydrogen atom and R = represents a alkyl radical.

Preferably, the amino function is protected in the form of tert-butyl carbamate. When Re represents a radical In the case of alkyl, the cyclization is generally carried out in the medium of trifluoroacetic acid, in an inert organic solvent such as a chlorinated solvent (chloroform, dichloromethane, for example), at a temperature of 20 ° C or in the medium of paratoluenesulfonic acid, in the breast of toluene, at the boiling temperature of the reaction medium. When Re represents a hydrogen atom, the cyclization is preferably carried out within the xylene by heating to the boiling temperature of the reaction medium. twenty The derivatives of formula (IV) for which Re represents an alkyl radical can be obtained by the action of sulfur or selenium after a derivative Hal-CRcRd- COOalq for which Hal represents a halogen atom, Rc and R-, have the same meanings as above the lithium of a 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-polyfluoroalkoxyaniline whose amine function is protected, preferably in the form of terbutyl carbamate, within the tetrahydrofuran, at a temperature varying from about -70. ° C to the vicinity of 20 ° C. The lithium of 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-polyfluoroalkoxyaniline whose amino function is protected can be obtained by the action of terbutyllithium on a 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-10. polyfluoroalcoxyaniline whose amino function is protected, within tetrahydrofuran, at a temperature of approximately -70 ° C. The derivatives of formula (IV) for which Re represents a hydrogen atom can be obtained by the hydrolysis of a derivative of formula (IV) Corresponding to which Re represents an alkyl radical. This hydrolysis is generally carried out in the soda medium, in ethanol, at a temperature comprised between 15 ° C and the boiling temperature of the reaction medium. twenty The 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-polyfluoroalkoxyaniline whose amino function is protected can be obtained by the action of iodo ethane on the lithium of a 4-polyfluoroalkylaniline or 4-25 polyfluoroalkoxyaniline whose amino function is protected in the sine of tetrahydrofuran, at a temperature ranging from about -70 ° C to about 20 ° C. The derivatives of formula (III) for which the chain -R_- R5-Rb- represents a chain of formula -CH-- N (R9) ~ CH- and the derivatives of formula (II) for which -R3-R- R ~ -RÓ_ represents a chain -CH; -CO- N (Rg) -CH; - can be obtained by the action of Chloracetyl chloride on an aniline of formula: In which R- and R have the same meanings as in formula (I), and separation of two derivatives.

This reaction is generally carried out in an inert organic solvent such as an ether (diethyl ether for example), in the presence of sodium bicarbonate, at a neighboring temperature of 20 ° C.

The anilines of formula (V) are obtained according to following reactive scheme: fifteen In these formulas, R- and R have the same meanings as formula (I) and BOC represents the radical tert-butoxycarbonyl. The operating conditions are defined in more detail in example 8.

The derivatives of formula (III) for which -R4-R5-RL- represents a chain -CH- O- CH-- can be obtained by application or adaptation of the method described by E. TESTA and L. FONTANELLA, II Farmacco, 1965, 20, 3233- 335 according to the following reactive scheme: In these formulas R- has the same meanings as in the formula (I), Me represents a methyl radical and Bu represents a butyl radical.

The derivatives of formula (III) for which the chain -R 4 -R- Re- represents a chain of the formula -CH 2 -CH; -S-, CH-- CH-- Se-, -CH-- CH- O- , -CH- CH2- N (R9) - can be obtained from a derivative of the formula: In which Rf represents a radical OH, SH, SeH or NH (Re), R7 and Rq have the same meanings as in the formula (I), by application or adaptation of the methods described in the examples and by X, HUANG, Synthesis, 851-852 (1984), WC LUMMA et al., J. Med. Chem. 24, 93-101 (1981) and EJ JACOBSEN et al., J. Med. Chem., 39, 158-175 (1996).

The derivatives of formula (VI) can be obtained by application or adaptation of the methods described by R. BELCHER et al., J. Chem. Soc, 3846 (1954); B. L. MYLARY, J. Med. Chem., 34, 108-122 (1991); D. W. COMBS et al., J. Med. Chem., 35, 172-176 (1992), .C. LUMMA et al., J. Med. Chem., 24, 93-101 (1981) and A.V. ZEIGER et al., J. Org. Chem., 42 (3), 542 (1977).

The derivatives of formula (II) for which -R- R- R 5 -R- represents a radical -CH- CH-CH-CO- can be obtained by decarboxylation after deprotection of a derivative of the formula: In which R7 has the same meanings as in the formula (I), Rg represents a p-toluenesulfonyl radical and Et 10 represents an ethyl radical.

This reaction is generally carried out in the hydrochloric acid medium in the acetic acid, at the boiling temperature of the reaction medium. The The deprotection is generally carried out in the medium of magnesium coils, in a mixture of tetrahydrofuran and methanol, at a neighboring temperature of 20 ° C.

The derivatives of formula (VII) can be obtained according to the following reaction scheme: In these formulas, R, has the same meanings as in the formula (I), R? represents a radical p-toluensssulfonyl, Et represents an ethyl radical and tBu a terbutyl radical. The operating conditions are defined more in detail in example 1.

The derivatives of formula (II) for which -R3-R4-R- Re- represents a radical -CH- CH- CH- CH (RH) - or -CH; - CH-CH (RK) -CH; and Ru represents a hydroxy radical can be obtained by reduction of a corresponding derivative of formula (II) for which R; represents a hydrogen atom or an alkyl radical and -R 3 -R 4 -R 5 -Re represents a chain of the formula -CH-CH-CO-CH- or -CH; - CH-CH- CO- This reaction is carried out by all methods that allow to pass from a ketone to an alcohol. The process is generally carried out in the sodium borohydride medium, in an alcohol such as methanol or ethanol, at a temperature between 0 and 25 ° C.

The derivatives of formula (II) for which -R3-R4-R5-R6- represents a radical -CH; -CH-CO- CH; - can be obtained by decarboxylation-deprotection of a derivative of the formula: In which R7, has the same meanings as in formula (I), tBu represents a tert-butyl radical and Et represents an ethyl radical.

This reaction is generally carried out in the hydrochloric acid medium in the acetic acid, at the boiling temperature of the reaction medium.

The derivatives of formula (VIII) can be obtained according to the following reaction scheme: In these formulas, R7 has the same meanings as in the formula (I), Et represents an ethyl radical and tBu a tert-butyl radical.

The derivatives of formula (II) for which - R 3 - R - R - Ru - represents a radical - CH - CH (Rio) _ S - CH 2 - for which Rio represents a radical - CONH 2 can be obtained by the action of ammonia on a derivative of corresponding formula (II) for which -R3- R- R5- Re- represents a radical -CH; - CH (Rio) - S- CH; - for which Rio represents a radical COOalq.

This reaction is generally carried out in an inert solvent such as an alcohol (ethanol for example), at a neighboring temperature of 20 ° C.

The derivatives of formula (II) for which -R-R4-RE- R, - represents a radical -CH-CH (Rio) -S-CH-- for which R represents a radical -COOalq can be obtained. by reduction of a derivative of formula: ^ g ^^ In which R-, has the same meanings as in the formula (I).

This reaction is preferably carried out in the magnesium medium, in an inert solvent such as an aliphatic alcohol (1-6C) (methanol for example), at a temperature of 40 ° C.

The derivatives of formula (IX) can be obtained according to the following reaction scheme. twenty in these formulas R-, has the same meanings as in the formula (I), alq represents an aalkyl radical, BOC represents a tert-butoxycarbonyl radical.

It is implicit for the person skilled in the art that, for the application of the processes according to the invention described above, it may be necessary to introduce protective groups of the amino functions in order to avoid secondary reactions. In particular, the procedure is carried out according to the methods described by T. Greene, Protective Groups in Organic Synthesis, A. Wiley Interscience Publication (1981), or by Me Omie, Protective Groups in Organic Chemistry, Plenum _ ^ ^ m ^ Press (1973). The amino functions can, for example, be protected by methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichloretyl, trichloroacetyl, trifluoroacetyl, chloracetyl, triflyl, benzylhydryl, benzyl, allyl, formyl, acetyl, benzyloxycarbonyl or their substituted derivatives. or in the form of tert-butyl or methyl carbamates then regenerated in the medium of trifluoroacetic acid or hydrochloric acid in the tetrahydrofuran or benzyl carbamates then regenerated by hydrogenation after having applied the process according to the invention.

The reaction mixtures obtained by the various methods described above are treated following classic physical methods (evaporation, extraction, distillation, chromatography, crystallization for example) or chemical (formation of salts for example).

The enantiomers of the compounds of formula (I) containing at least one asymmetric site can be obtained by synthesis from the chemical precursors or by splitting the racemates for example by chromatography on chiral stationary phase type (S, S) WHELCK -01k, Chiralcel OJR or chiral column according to WH PIRKLE ^^^^^^^^^^^^^ ^^^^^^^ A ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ gg ^ l ^^^^^^^^^^^ gg ^ gfgg ^^^^ g ^ and contributors, Asymmetric Synthesis, vol. 1, Academic Press (1983).

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

As examples of pharmaceutically acceptable salts, the addition salts with the mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isothioate, theoophilinacetate, salicylate, methylene-bis-β- can be cited. oxmaftoato, hydrochloride, sulfate, nitrate and phosphate.

The compounds of formula (I) have interesting pharmacological properties. These compounds are anticonvulsants and interfere with glutamate-allergenic transmission and are therefore useful to treat or prevent all ischemia (such as focal or global ischemia) resulting in cerebral vascular accidents such as thromboembolic and hemorrhagic shock, a cardiac arrest, arterial hypotension , a surgical intervention ^^ «fa * ^ ..... .- ^ .., MÉÍÍttÍIÉ F? '- lí? < - "**" - - - - - - * - - Cardiac, vascular or pulmonary anea or severe hypoglycemia.They are also useful in the treatment of the effects due to anoxia, either perinatal or subsequent to a drowning, a high pressure or cerebrospinal lesions These compounds can also be used to treat or prevent the evolution of neurodegenerative diseases, chorea of HUNTINGTON, ALZHEIMER's disease and other dementias of amyotrophic lateral sclerosis or other diseases of motor neurons , of the olivópontocerebellar atrophy and of the PARKINSON disease These compounds can also be used against epileptogenic (epilepsy) and / or convulsive manifestations, for the treatment of cerebral or spinal traumatisms, of traumatisms related to the degeneration of the inner ear (R PUJOL et al., Neuroreport, 3, 299-302 (1992) or of the retina (JL MONSINGER et al., Exp. Neurol, 113, 10 - 17 (1991), of tinnitus, of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991)), of depression (TRULLAS et al., Eur. J. Pharmacol., 1185, 1 (1990)), of schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), of the TOURETE syndrome, of hepatic encephalopathies, of sleep disorders, of attention deficit disorders, of disorders of the hormonal conditions (excess secretion of HG or HL, secretion of corticosterone), as analgesics (DICKENSON and collaborators, Neeurosc. Letters, 121, 263 (1991)), anti-inflammatories (SLUTA et al., Neeurosci. Letters, 149, 99-102 (1993)) anti-anorexic (SORRELS et al., Brain Res., 572, 265 (1992)), anti-jaqueca, anti-emetics and to treat poisonings by neurotoxins or by other NMDA or AMPA receptor agonist substances, as well as neurological disorders associated with viral diseases such as viral meningitis and encephalitis, AIDS (LIPTON et al., Neuron, 7, 111 (1991 )), rabies, rubella and tetanus (BAGETA et al., Br. JJ Pharmacol., 101, 776 (1990)). These compounds are also useful for the prevention, tolerance and dependence of the withdrawal symptoms to drugs, alcohol and the inhibition of the habit and the dependence to the apláceos, barbiturates, amphetamines and benzodiasepinas, can ngualmente be used in the treatment of deficits related to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RTT syndrome, homocysteinemia, hyperprolmemia, hydroxybutyric acid-aminoaciduria, saturnin encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The activity of these products as anticonvulsants has been determined in the mouse according to the maximum electric shock method. White CD1 mice are treated intravenously with the compounds to be tested in saline medium, 10 minutes before being subjected to an electric shock (75 mA; 0.04 seconds) by means of the ocular electrodes. Normally this shock produces a tonic seizure in the untreated mouse, characterized by an extension of the limbs. If the tonic seizure does not ensue, the animal is considered protected. In this test, the compounds of formula (I) have an ED 50 equal to or less than 4 mg / kg.

The activity of these products as antiglutamate has been determined on the seizures induced by glutamate according to a technique inspired by that of I. P. LAPIN, J. Neural. Transmission, 54, 229-238 (1982); Intracerebroventricular injection of glutamate is carried out according to a technique inspired by that of R. CHERMAT and P. SIMÓN, J. Pharmacol. (Paris), 6, 489-492 (1975). Its ED50 is less than 10 mg / kg.

The compounds of formula (I) have a mild toxicity. Its LD50 is higher than 15 mg / kg IV in the mouse.

For medicinal use, the compounds of formula (I) can be used as such or in the state of pharmaceutically acceptable salts, that is to say non-toxic in the doses of use.

Particularly useful are the compounds of formula (I) for which R represents a trifluoromethoxy or trifluoromethyl radical.

Preferred compounds of formula (I) are those by which Ri represents a sulfur atom, R; represents a hydrogen atom, -R3- R- R5- Re- represents a chain of the formula -CH- CH- CH- CH-, -CH- CH- CH- CO-, -CH- CH- CH- CH ( RS) -, -CH-- CH- CH2- Se-, -CH- CH- Se- CH-, -CH- CH-- CH- S-, -CH-- CH-- CH- SO-, -CH - CH- CH- SO-, -CH- CH-- CH-- N (Rc,) -, -CH-- CH- CO- CH-, -CH- CH-- CH (Re) - CH-, - CH-- CH-- S- CH--, -CH-- CH- SO- CH-, -CH- CH-- SO- CH-, -CH - C (alk) (alq ') - S- CH- , -CH- CH (RU,)) - S- CH-, -CH- CH- O- CH-, -CH- CH- N (Rq) - CH- or -CH- CO- N (Ro) - CH -, R- represents a trifluoromethyl or tpfluoromethoxy radical, Rc represents a hydroxy radical, R represents a hydrogen atom or a radical alkyl or benzyl, Ri0 represents an alkyl radical and alk represents an alkyl radical, its isomers, racemic, enantiomers and its salts.

More particularly interesting are the following compounds of formula (I): ü¿a úm * i¿ * ** m-? ^ g ^ g ^^^ y »^ - ^^^^^ S¡¡« you ?? . 2-imino-9-trifluoromethoxy-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3-jk] [l] benzazepin-7-ol, . 2-imino-9-trifluoromethoxy-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3- j k] • 1] benzazepine, . 2-imino-9-trifluoromethyl-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3- jk] [l] benzazepine, . 7,7- 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine dioxide, 7- 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [l, 5] benzothiazepine oxide, . 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine, 6- benzyl-2-imino-9-trifluoromethoxy-6,7-dihydro-4H-thiazolo [3, 4, 5-kj] [1,4] benzodiazepma-5-ketone,. 6- benzyl-2-imino-9-trifluoromethoxy-4, 5, 6, 7-tetrahydro-2H-thiazolo [3, 4, 5-kj] [1,4] benzodiazepine, . 2-imino-9-trifluoromethoxy-4, 5-dihydro-2H, 7H-5 thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine, . 2-imino-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine, 6,6- 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine dioxide, 7, 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine oxide, 15. 6,6- 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine dioxide, . 2- imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-20 thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine, . 2-imino-9-trifluoromethyl-4, 5, 6, 7-tetrahydro-2H-thiazolo- [5, 4, 3-jk] [l] benzazepin-7-ol, «S? 3S _, - ¿^^^^ B¡ sfe ^^ ^ ^ ^ j ^ s * jgtó¡jgßg ^^^^^^^ 6, 6 - 2-imino-9-trifluoromethoxy-4 dioxide , 5- dihydro-2H, 7H-thiazolol [3, 4, 5- of] [4, 1] benzothiazepine, 6- 2-imino-9-trifluoromethoxy-4,5- 5 dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine oxide, . 6- benzyl-2-imino-9-trifluoromethyl-6,7-dihydro-4H, -thiazolo- [3, 4, 5-kj] [1,4] benzodiazepine, 5-ketone, 6- benzyl-2-imino-9-trifluoromethyl-4, 5, 6, 7-tetrahydro-2H, -thiazolo- [3, 4, 5-kj] [1,4] benzodiazepine, 5-ketone, . 2-immo-55-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine, - carbamoyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, twenty . 5,5-dimethyl-2-imino-9-trifluoromethyl-2H, 4H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, . 5- hydroxymethyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, their isomers, racemic, enantiomers and their salts, The following compounds are still more particularly preferred: . (R, S) -6- 2-imino-9-tpfluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepma, (+) - 6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine oxide, (+) - 6- 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine oxide, . (R, S) -2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, (+) - 2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, twenty . (+) - 2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, and its salts. -áÉ-saS 1 »> ... "^ ...." - ".-.-- _w- ^ ^ ... ^^ .. ^. ^^^ JM The following examples illustrate the invention without limiting it.

EXAMPLE 1 Add 10 drop of bromine, diluted in 10 ml of acetic acid, to a solution of 1.7 g of potassium thiocyanate and 1.9 g of (R), in 10 minutes at a neighboring temperature of 20 ° C. S) -7-trifluoromethoxy-2,3,4,5-tetrahydro-10 1 H- [1] benzazepine-5-ol in 30 ml of acetic acid. The reaction mixture is stirred for 20 hours at the same temperature, poured onto the ice, alkalized with a 20% ammonia solution and extracted three times with 100 ml of ethyl acetate. The organic phases are gathered and concentrated to dryness under reduced pressure (2kPa) at 40 ° C. The residue (0.4 g) is chromatographed on silica gel eluting with ethyl acetate. The isolated product is taken up again in a mixture of 4 ml of isopropyl ether and petroleum ether (50-50 by volume) and thus 0.15 g of (r, S) -2-imino-9-trifluoromethoxy-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3- jk] [l] benzazepin-7-ol in the form of a solid cream melting at 167 ° C [analysis C12HF11F3N202S,% calculated C: 47.37, H: 3.64, F: 18.73, N: 9.21, O: 110.52, S: 10.54,% found C: 447.6, H: 33.5, F: 18.4, N: 9.1, S: 10.6].

Mi - Iii-ii-ki gg ^ ^ ggu ^ y ^ jj ^^ The (R, S) - 7-trifluoromethoxy-2, 3, 4, 5-tetrahydro-1H- [1] benzazepine - 5- ol can be prepared as follows: 1.08 g of magnesium coils is added to a neighboring temperature of 20 ° C to a solution of 3.6 g of (R, S) -1- (toluene-4-sulfonyl) 7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-5-ol in 30 ml of tetrahydrofuran and 40 ml of methanol. The reaction mixture is stirred for 24 hours at the same temperature poured into distilled water and the gelatinous mass formed, taken up again by the ethyl ether, is filtered and then washed three times with 40 ml of ethyl ether. The pale yellow filtrate thus obtained is dried over magnesium sulfate, then evaporated under reduced pressure at 50 ° C. 1.9 g of (R, S) -7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-5-ol is thus obtained in the form of a cream solid which melts at 110 ° C.

The (R, S) -1- (toluene-4-sulfonyl) -7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-5-ol can be prepared as follows: a a solution of 3.7 g of 1- (toluene-4-sulfonyl) -7-trifluoromethoxy-2, 3-dihydro-1H, 4H- [1] benzazepine-5-ketone in 40 ml of ethanol is added in small portions 0.7 g of sodium borohydride and left under stirring for 2 hours at a neighboring temperature of 20 ° C. After usual work-up, 3 g of (R, S) -1- (toluene-4-sulfonyl) -7- trifluoromethoxy-2,3,4,5-tetrahydro-1H [1] benzazepma-5-ol are obtained shape of a beige solid that melts at 160 ° C. 1- (Toluene-4-sulphonyl) -7-trifluoro-methoxy-2-, 3-dihydro-1H, 4H- [1] benzazepma-5-ketone can be prepared in the following manner: to a solution of 2.2 g of 5- Oxo-1- (toluene-4-sulfonyl) -7- trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-4-carboxylic acid ethyl ester in 20 ml of acetic acid is added 5 ml of acid hydrochloric. The formation of a white precipitate is observed and the reaction mixture is kept at reflux for 4 hours. Concentrates to dryness or reudicda pressure, take the yellow oil obtained with 300 ml. of ethyl ether and washed with a saturated solution of sodium bicarbonate. After decanting, washing twice with 50 ml of distilled water and with a saturated solution of sodium chloride, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.2 kPa) at 60 ° C. . This gives 1.58 g of 1- (toluene-4-sulfonyl) -7-trifluoromethoxy-2-, 3-dihydro-1H, 4H- [1] benzazepine-5-ketone or the form of a beige solid that melts at 96 ° C. ° C.

The 1- (toluene-4-sulfonyl) -7-trifluoromethoxy-2,3-dihydro-1H, 4H- [1] benzazepine-5-ketone can be prepared in the following manner: to a solution of 2.2 g of 5- Oxo-1- (toluene-4-sulfonyl) -7- trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-4-carboxylic acid ethyl ester in 20 ml of acetic acid is added 5 ml of acid hydrochloride. The formation of a white precipitate is observed and the reaction mixture is kept at reflux for 4 hours. It is concentrated to dryness under reduced pressure, the yellow oil obtained is taken up again with 300 ml of ethyl ether and washed with a saturated solution of sodium bicarbonate. After decanting, washing twice with 50 ml of distilled water and with a saturated solution of sodium chloride, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.2 kPa) at 60 ° C. . This gives 1.58 g of 1- (toluene-4-sulfonyl) -7-trifluoromethoxy-2-, 3-dihydro-1H, 4H- [1] benzazepine-5-ketone in the form of a beige solid that melts at 96 °. C.

The 5- oxo-1- (toluene-4-sulfonyl) -7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-4-carboxylic acid ethyl ester can be prepared in the following manner: 275 ml of anhydrous toluene under reflux is added, under an argon atmosphere, 9.97 g of potassium tert-butylate, then a solution of 23 g. - - .---- > - • --.- • - - - * - - - - - - * «-? - ifi * -g. of ethyl 2- [(3-ethoxycarbonylpropyl) - (toluene-4-sulfonyl) amino] -5,5-trifluoromethoxybenzoate in 300 ml of anhydrous toluene. When the addition is complete, the heating is continued for one hour. After cooling, 90 ml of an IN-hydrochloric acid IN solution is added, it is taken up again in distilled water and after decantation the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filter and concentrate to dryness under reduced pressure (2.2 kPa) at 60 ° C. The residue obtained is dissolved in 100 ml of boiling cyclohexane after cooling. The precipitate that appeared is separated by filtration and dried at 40 ° C under reduced pressure (70 Pa). 10.75 g of 5- oxo-1- is thus obtained. (toluene-4-sulfonyl) -7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-4-carboxylic acid ethyl ester in the form of a beige powder which melts at 97 ° C.

The ethyl 2- [(3-ethoxycarbonyl-propyl) -toluene-4-sulphonylamino] -5-t-trifluoromethoxybenzoate can be prepared in the following manner: a mixture of 5.5 g of 2- (heated at 80 ° C for 17 hours. ethyl toluene-4-sulfonyl) amino-5-trifluoromethoxybenzoate, 5.6 g of potassium carbonate, 3.18 g of ethyl 4-bromobutyrate in 30 ml of dimethylformamide. Concentrate to dryness under reduced pressure (2.2 kPa) at 60 ° C. The brown oil The obtained MM-11-i-il-1 is dissolved in ethyl acetate and the solution is washed with distilled water then with a saturated solution of sodium chloride, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.2 kPa) at 50 ° C. This gives 55.7 g of ethyl 2- [(3-ethoxycarbonylpropyl) - (toluene-4-sulfonyl) amino] -5-trifluoromethoxybenzoate in the form of a yellow oil [NMR Spectrum? E in DMSO-d6, T = 300 K d in ppm (300 Mhz): 1.10 (3H, T, J = 6Hz, CH3), 1.30 (3H, t, J = 6 Hz, CH3), 1.65 (2H, m, CH;), 2.40 (5H, m, COCH2 and PhCH3) , 3.45 and 3.70 (1H each, m, NCH2), 4.00 (2H, q, J = 6 Hz, OCH;), 4.25 (2H, q, J = 6Hz, OCH;), 7.05 (1H, d, J = 8Hz, CH arom.), 7.40 (4H, s, 4 CH, tosyl), 7.65 (1H, dd, J = 8 and 2 Hz, CH arom.), 7. 70 (1H, d, J = 2Hz, CH arom.)].

The ethyl 2- (toluene-4-sulfonyl) amino-5-trifluoromethoxybenzoate can be prepared in the following manner: to a solution of 17.5 g of ethyl 2-amino-5-trifluoromethoxybenzoate in 70 ml of pyridine is added under stirring at a neighboring temperature of 20 ° C, 16.1 g of toluene-4-sulfonic acid chloride. After 24 hours of agitation, it is concentrated to dryness under reduced pressure (2.2 kPa) at 60 ° C. The brown oil obtained is dissolved in ethyl acetate and the solution is washed successively with a solution of hydrochloric acid (2N), with distilled water and with a saturated solution of sodium chloride, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.2 kPa) at 50 ° C. The orange oil obtained taken up again with the petroleum ether leads to 27.8 g. of ethyl 2- (toluene-4-sulfonyl) amino-5-trifluoromethoxybenzoate in the form of a white powder melting at 76 ° C.

Ethyl 2-amino-5-trifluoroooxymethoxybenzoate can be prepared in the following manner: To 21 g of ethyl 2- tert.-butoxycarbonylaminoo-5-trifluoromethoxybenzoate in 150 ml of dichloromethane are added 55 ml of trifluoroacetic acid. After 4 hours at a neighboring temperature of 20 ° C the black solution obtained is concentrated to dryness. The residue is treated with a dilute solution of sodium bicarbonate and extracted with petroleum ether. The organic phase is washed with distilled water until neutral pH, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.2 kPa) at 50 ° C. This gives 14 g of ethyl 2-amino-5-trifluoro-methoxy-benzoate in the form of a brown oil [NMR-spectrum? E in DMSO-d6, T = 300 K, d in ppmm (300 MHz): 1.30 ( 3HH, t, J = 6Hz, CH3), 4.30 (2H, q, J = 6Hz, OCH;), 6.85 (2H, s, NH2), 6.87 (1H, d, J = 8 Hz, CH arom.) 7.30 (1H, dd, J = 8 and 2Hz, CH arom.), 7.55 (1H, d, 5 J = 2Hz, CH arom.)].

Ethyl 2- tert-butoxycarbonylamino-5-trifluoromethoxybenzoate can be prepared in the following manner: on a solution of 34.5 g of tert-butyl 4-trifluoromethoxyphenylcarbamate in 430 ml of anhydrous tetrahydrofuran, kept under argon at -78 ° C, 200 ml of a 1.5 M solution of tert-butyl lithium in pentane is poured in 1 hour. The temperature is allowed to rise to the vicinity of -20 ° C and left under stirring 2.5 hours. Again the reaction medium is cooled to -78 ° C and 75 ml of diethyl carbonate is poured once. After 16 hours at a neighboring temperature of 20 ° C, 100 ml of a saturated aqueous solution of ammonium chloride and 250 ml of ethyl ether are added. After decanting, the aqueous phase c is again extracted twice 200 ml of ethyl ether. The organic extracts are combined, washed with distilled water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The red oil obtained is dissolved in petroleum ether and the solution is filtered on silica gel washed with petroleum ether. The concentrated filtrate to dryness releases a red oil that critalizes. After recrystallization in 50 ml of hexane, 21.5 g of ethyl 2-tert.-butoxycarbonylamino-5-trifluoromethoxybenzoate are obtained in the form of a cream solid melting at 82 ° C. .-. n * ~ &P:!? e '?. *.

The 4- tert-butyl trifluoromethoxyphenylcarbamate can be prepared in the following manner: a solution of 47 g of di-tert-butyldicarbonate in 100 ml of anhydrous tetrahydrofuran is poured into a solution of 32.75 g in 10 minutes at 0 ° C. of 4-trifluoromethoxyaniline in 150 ml of anhydrous tetrahydrofuran. The reaction medium is stirred at 80 ° C for 3 hours, then concentrated to dryness. A white crystallized product is obtained which is redissolved in 300 ml. of ethyl acetate. The solution is washed three times with distilled water, dried over magnesium sulfate and concentrated to dryness. By trituration in petroleum ether, filtration and drying under reduced pressure (70 Pa) at 20 ° C, 35.5 g of tert-butyl 4-trifluoromethoxyphenylcarbamate is obtained in the form of a white solid which melts at 110 ° C.

EXAMPLE 2 The procedure is as in Example 1 but from 0.7 g of bromine in 5 ml of acetic acid, 1 g of 7-t-fluoro-methoxy-2, 3, 4, 5-tetrahydro-1H- [1] benzazepine and 1.46 g. of potassium thiocyanate in 15 ml of acetic acid. The isolated orange thick oil is chromatographed on silica gel eluting with a mixture »^ J ^ A ^ Sg * i ^^^^^^^^^^^ ethyl acetate and petroleum ether (70-30 by volume). A yellow oil is obtained which is dissolved in isopropyl ether to which 0.45 ml of a hydrochloric isopropanol solution (approximately 5N) is added. The white precipitate formed is then filtered and dried under vacuum (70 Pa) at a temperature of 40 ° C. Thus 0.52 g of 2-immo-9-trifluoromethoxy-4,5,5,6,7-tetrahydro-2H-thiazoloo [5, 4, 3-jk] [l] benzazepine hydrochloride is obtained in the form of a white solid which melts at 270 ° C (with decomposition) [analysis C12H12 CIF3NN20S,% calculated C: 44.38, H: 3.72, Cl: 110.92, F: 17.55, N: 8.63, O: 4.93, S: 9.87,% found C: 44.3, H : 3.5, Cl: 10.9, F: 17.7, N: 9.1].

The 7-trifluoromethoxy-2,3,4,5-tetrahydroo-1H- [1] benzazepine can be prepared in the following manner: on a solution of 2.3 g of 7-trifluoromethoxy-2, 3, 4, 5-tetrahydro- 1H- [1] benzazepine-1-tert-butyl carboxylate in 25 ml of dichloromethane is added with 5 ml of trifluoroacetic acid. After 1 hour at a neighboring temperature of 20 ° C the red solution obtained is concentrated to dryness under reduced pressure. The residue is treated with a dilute solution of sodium bicarbonate and extracted with ethyl ether. The organic phase is washed with distilled water then with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure. (2.2 kPa) at 50 ° C. 1.3 g of brown oil is thus obtained which is chromatographed on silica gel eluting with a mixture of petroleum ether and dichloromethane (70-30 by volume). After evaporation under reduced pressure, 1.14 g of 7- tpfluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine is isolated in the form of a pasty solid used as such in the next step [NMR Spectrum JH in DMSO-d6, T = 300 K, d in ppm (300 MHz): between 1.50 and 1.70 (4H, m, 2CH2), 2.60 (2H, m, PhCH;), 2.90 (2H, m, NCH;), 5.40 (1H, 10 s, NH), between 6.80 and 7.00 (3H, m, 3 CH arom.)].

The 7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-1-tert-butyl carboxylate can be prepared as follows: a solution, maintained g or argon atmosphere at -78 ° C, 5.54 g of 4-trifluoromethoxyphenylcarbamate of tert-butyl in 60 ml of anhydrous tetrahydrofuran, or add in one hour 32 ml of a 1.5 M solution of tert-butyllithium in pentane. The reaction mixture is then stirred for 2.5 hours at a neighboring temperature of -20 ° C. It is again cooled to -78 ° C and poured, drop by drop in 15 minutes, 2.65 ml of 1- chloro-4-iodobutane. The reaction mixture is taken and maintained at boiling for 5 hours. After cooling, 50 ml of a saturated aqueous solution is added of ammonium chloride and extracted three times with 200 ml in total ethyl ether. The organic extracts are combined, washed with distilled water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, then concentrated to dryness under reduced pressure. The oil obtained (6.65 g) is chromatographed on silica gel eluting with a mixture of petroleum ether and dichloromethane (50-50 by volume). Thus, 22.3 g is obtained. of 7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1] benzazepine-1-tert-butyl carboxylate in the form of a yellow oil [NMR Spectrum? E in DMSO-d6, T = 393K , d in ppmm (200 MHz): between 1.65 and 1.90 (4H, m, 2CH-), 2.70 (2H, m, PhCH :), 3.50 (2H, t, J = 6Hz, NCH;), between 7.05 and 7.35 (3H, m, 3 CH arom.)].

EXAMPLE 3 The procedure is as in Example 1, but from 2.38 g of bromine in 5 ml of acetic acid, 3.2 g of 7-trifluoroethyl-2, 3, 4, 5-tetrahydro-1H- [1] benzazepine and g of 5 g of potassium thiocyanate in 35 ml of acetic acid. The brownish yellow oil isolated is chromatographed on silica gel eluting with ethyl acetate. A yellow oil is obtained, which is dissolved in 15 ml of isopropyl ether to which 1 ml of a 1.94 N solution of acid is added. methanesulfonic acid in isopropanol. The white precipitate formed it is then filtered and dried under vacuum (70 Pa) at 50 ° C. This gives 0.7 g of 2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazolo [5, 4, 3- jk] [l] benzazepine mentansulfonate in the form of a white solid which melts to 226 ° C [analisys C13H15F3N2003SS,% calculated C: 42.38, H: 4.1, F: 15.2, N: 7.5, O: 13.3, S: 17.41,% found C: 42.4, H: 3.9, F: 15.2, N: 7.5, S: 17.4]. 7- trifluoromethyl- 2, 3, 4, 5-tetrahydro- 1H- [1] Benzazepine can be prepared as in example 2, but from 5 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H [1] benzazepine-1-tert-butyl carboxylate in 50 ml of dichloromethane and 5 ml of trifluoroacetic acid. 3.3 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H-15 [1] benzazepine is thus obtained in the form of a red oil used as such in the next step [NMR spectrum? E in DMSOO-d6, T = 300 K, d in ppm (300 MHz): between 1.60 and 1.90 (4H, m, 2 CH;), 2.75 (2H, t, J = 6 Hz, PhCH, 3.00 (2H, t, J = 6 Hz, NCH;), 5.90 (1H, broad s, NH), 6.90 (1H, d, J = 8Hz, CH arom.), 7.28 (1H, dd, J = 2 and 8 Hz, CH arom.), 7.33 (1H, d, J = 2 Hz, CH arom.)].

The 7-trifluoromethyl-2, 3, 4, 5-tetrahydro-1H- [1] benzazepine-1-tert-butyl carboxylate can be prepared as in example 2, but from 26.1 g of 4-25 trifluoromethylphenylcarbamate tert-butyl in 300 ml of ^^^^^^^^^^^ _ ^^^^^^^^ fc ^^^ I ^^^^ Ii ^^^^^^^^ g | anhydrous tetrahydro-furan, 160 ml of a 1.5 M solution of tert-butyllithium and 24 g of 1- chloro-4-iodobutane. 36 g of a brown oil is obtained which is chromatographed on silica gel eluting with a mixture of petroleum ether and dichloromethane (70-30 by volume). Thus, 16.2 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-1-tert-butyl carboxylate are obtained in the form of a greenish oil which is used as such in the next step . 10 EXAMPLE 4 To a solution of 1 g of 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo [3, 4, 5-ef] [1, 5] benzothiazepine in 20 ml of dichloromethane is added, dropwise, in 15 minutes and at a neighboring temperature of 20 ° C, a solution of 1.55 g of 3-chloroperbenzoic acid (purity 80%) in 10 ml of dichloromethane, and the mixture it is then stirred for 24 hours at the same temperature. It is added to Then, 100 ml of a 1 M aqueous solution of sodium bicarbonate are added and the mixture is stirred at the same temperature for 1 hour. After separation of the two phases, the aqueous phase is extracted twice with 50 ml of dichloromethane and the combined organic extracts are dried over sulphate mg and concentrates to dryness under reduced pressure (2 kPa). The product obtained (1.4 g) is chromatographed under nitrogen pressure (150 kPa) on 30 g. of silica gel 20-45 μm contained in a 2 cm diameter column, eluting with ethyl acetate. The product obtained (300 mg) 5 is dissolved in 35 ml of absolute ethanol, to which 69 μl of methanesulfonic acid is added. After stirring for 1 hour at a neighboring temperature of 20 ° C, the solution is concentrated to dryness under reduced pressure (2kPa). The product obtained is suspended in isopropanol, separated by filtration, washed with isopropanol and isopropyl ether and dried under reduced pressure. Thus, 0.21 g of methanesulfonate of 7,7-di-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3,4,5-ef] [1,5] benzothiazepine is obtained. in the form of a solid blancco melting at a temperature above 260 ° C [Analysis C12H13F3N2006S3,% calculated C: 33.17, H: 3.02, F: 13.12, N: 6.45, O: 22.10, S: 22.14,% found C: 33.20, H: 2.71 , F: 12.7, N: 6.3330, S: 22.1].

EXAMPLE 5 To a solution of 1 g of 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo [3, 4, 5-ef] [1,5] benzothiazepine in 30 ml of dichloromethane is added, drop to drop, in 15 minutes and at a neighboring temperature of 0 ° C, a -. «A» -j? -i-M-- £ Sit- > MI- > »- - g¡¡ * £ ¿m ^ j ailt & ij && amp; solution of 770 mg of 3-chloroperbenzoic acid (purity 80%) in 5 ml of dichloromethane and the mixture is then stirred for 1 hour at the same temperature. 35 ml of a 1 m aqueous solution of sodium bicarbonate are then added and the mixture is stirred at 20 ° C. for 1 hour. After separation of the two phases, the aqueous phase is extracted with 15 ml of dichloromethane and the combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in 20 ml of isopropyl ether, separated by filtration, washed with isopropyl ether and dried under reduced pressure. The product obtained (716 mg) is dissolved in 70 ml of absolutto ethanol and the solution is filtered, then added with 160 μl of methanesulfonic acid. After stirring for 1 hour at a neighboring temperature of 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in isopropanol, separated by filtration, washed with isopropanol and isopropyl ether and dried under reduced pressure. Thus 0.70 g of methanesulfonate of 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine is obtained in the form of a solid cream melting at a temperature higher than 260 ° C [Analisys C12H13F3N205S3,% calculated C: 34.45, H: 3.13, F: 13.62, N: 6.69, O: 19.12, S: 22.99,% found C: 34.44, H: 2.86, F: 13.37, N: 6.68, S: 22.8].

EXAMPLE 6 5 The procedure is as in Example 1, but from 0.4 ml of bromine in 5 ml of acetic acid, 2 g of 8-trifluoromethoxy-2,3,4,5-tetrahydro [1,5] benzothiazepine and 1.71 g of thiocyanate of potassium in 24 ml of acetic acid. The product The crude obtained is chromatographed under nitrogen pressure (150 kPa) on 40 g of silica gel 20-45 μm contained in a 2.5 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane (50-50 in. volume). Dissolve 0.5 g of the product obtained (about 1.5 g obtained in total) in 80 ml of ethanol to which 0.117 ml of methanesulfonic acid is added. After 16 hours of stirring at 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in 20 ml of isopropyl ether, separated by filtration, washing with isopropyl ether and drying under reduced pressure (2 kPa) at 20 ° C. Thus 0.56 g of 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo [3,4,5-ef] [1,5] benzothiazepine methanesulfonate is obtained in the form of a beige solid that melts at a temperature higher than 260 ° C [Analysis C12H13F3N204S3, calculated% C: ^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ ^^ 35.82, H: 3.26, F: 14.16, N: 6.96, O: 15.9, S: 23.9,% found C: 35.8, H: 3.0, F: 14.3, N: 7.00, S: 23.8].

The 8-trifluoromethoxy-2,3,4,5-tetrahydroo- [1,5] benzothiazepine can be prepared in the following manner: to 21.4 ml of a solution approximately 0.5 M lithium tetrahydroaluminate in tetrahydrofuran, maintained under argon a 5 ° C, a solution of 2.5 g of 8-trifluoromethoxy-2,3-dihydro-5H- [1,5] benzothiazepine-4-ketone in 25 ml of tetrahydrofuran is added dropwise in 15 minutes. The reaction mixture is then stirred for 2 hours at 20 ° C and 500 ml of distilled water, 100 ml of ethyl acetate and 100 ml of a saturated solution of sodium chloride are successively added. After decanting, the aqueous phase is extracted three times with 50 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2kPa). This gives 2 g of 8-trifluoromethoxy-2,3,4,5-tetrahydro- [1,5] benzothiazepine in the form of a yellow oil [Spectrum? E in DMSO-d6, T = 300K, d in ppm ( 300 Mhz): 1.95 (2H, m, CH-); 3.00 (2H, m SCH;); 3.30 (2H, m, NCH-); 5.90 (1H, m, NH); 6.85 (1H, d, J = 8 Hz, CH arom.); 7.00 (1H, d, J = 8 Hz, CH arom.); 7.12 (1H, s, CH arom.)].

The 8-trifluoromethoxy-2, 3-dihydro-5H- [1, 5] benzothiazepine-4-ketone can be prepared in the following manner: to a suspension of 11.5 g of 2-amino-6-trifluoromethoxybenzothiazole in 115 ml of distilled water, 70 g of potash in tablets is added in portions of approximately 10 g. The mixture is then stirred for 16 hours under reflux. After cooling to 20 ° C, 16.4 g of ethyl 3-bromopropionate is added followed by 30 ml of distilled water and the medium is stirred for 16 hours at the same temperature. The mixture is then acidified with concentrated hydrochloric acid at a neighboring temperature of 5 ° C, extracted three times with 50 ml of ethyl acetate. The organic extracts are collected, washed 3 times with distilled water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2 kPa). The obtained crude product is chromatographed under nitrogen pressure (150 kPa) on 250 g of silica gel 20-45 μm contained in a column of 4 cm in diameter, eeluting with a mixture of ethyl acetate and cyclohexane (75-25). in volume). HE thus obtains about 2.5 g of a white solid which is put back into suspension in isopropyl ether and dried under reduced pressure (2 kPa). 1.6 g of 8-trifluoromethoxy-2-, 3-dihydro-5H- [1, 5] benzothiazepine-4-ketone is thus obtained in the form of a white solid which melts at 188 ° C.

The 2-amino-6-trifluoromethoxybenzothiazole can be obtained by the method described by L. M. YAGUPOL'SKII et al., Zh. Obshch. Khim., 33 (7), 2301 (1963).

EXAMPLE 7 The procedure is as in Example 1 but from 1.2 g of bromine in 2 ml of acetic acid, 2.5 g of 4-benzyl-7- tpfluoromethoxy-4,5-dihydro-1H, 2H- [1,4] benzodiazepine- 3- Ketone and 1.6 g of potassium thiocyanate in 25 ml of acetic acid. The obtained product is chromatographed under nitrogen pressure (150 kPa) on 75 g of silica gel 20-45 μm contained in a 2.5 cm diameter column, eluting with ethyl acetate. Dissolve 0.6 g of the product obtained (about 2.25 g obtained in total) in 45 ml of ethanol, to which 0.1 ml of methanesulfonic acid is added. After 3 hours of stirring at 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in ethyl ether, separated by filtration, washed with ethyl ether and dried under reduced pressure (2 kPa) at 20 ° C. This gives 0.74 g of 6-benzyl-2-imino-9-trifluoro-methoxy-6,7-dihydro-4H-thiazolo-methanesulfonate [3, 4, 5-kj] [1,4] benzodiazepine-5-ketone under the form of a solid cream that melts at a temperature above 260 ° C [Analysis C19H18F3N305S2,% calculated C: 46.62, H: 3.71, F: 11.64, N: 8.58, 0: 16.34, S: 13.10,% found C: 46.5, H: 3.4, F: 11.3, N: 8.5, S: 12.6].

EXAMPLE 8 The procedure is as in Example 1 but using 4.15 g of bromine in 5 ml of acetic acid, 8.3 g of 4-benzyl-7-trifluoromethoxy-2, 3, 4, 5-tetrahydro-1H- [11, 4] benzodiazepine in 120 ml of acetic acid and 10 g of potassium thiocyanate. 2.7 g of a brown oil is obtained which is successively chromatographed on silica gel, then on neutral alumina deactivated with 10% water, eluting in both cases with a mixture of ethyl acetate. and of cyclohexane (50-50 by volume). The product obtained (0.68 g) is dissolved in 45 ml of ethanol, to which 0.23 ml of methanesulfonic acid is added. After 2 hours of stirring at 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is put in suspension in ethanol, separated by filtration, washed with ethanol then with ethyl ether and dried under reduced pressure. (2 kPa) at 20 ° C. 0.32 g of 6- benzyl-2-imino-9-trifluoromethoxy-4,5,6,7-tetrahydro-2H-thiazolo [3, 4, 5-kj] [1,4] benzodiazepine dimethanesulfonate is obtained in the form of a beige solid that melts at a temperature above 260 ° C ^^^^^^^^ j ^^^^^^^^^^^^^^^ ifis ^^^ BBB [analysis C20H24F3N3O7S3,% calculated C: 42.02, H: 4.23, F: 9.97, N: 7.35 , O: 19.59, S: 16.83,% found C: 41.2, H: 4.2, F: 9.3, N: 7.2, S: 16.5].

The 4-benzyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1H- [1,4] benzodiazepine can be prepared as in Example 6, but using 95 ml of solution (approximately 0.35 M) of tatrahydroaluminate of lithium in tetrahydrofuran and 6 g of 4-benzyl-7-trifluoromethoxy-4,5-dihydro-1H, 3H- [1,4] benzodiazepine-2-ketone in 40 ml of anhydrous tetrahydrofuran. 4.8 g of 4-benzyl-7-trifluoromethoxy-2, 3, 4, 5-tetrahydro-1H-1, 4-benzodiazepine is obtained in the form of a colorless oil [NMR spectrum? in DMSO-dβ, T = 300 K, d in ppm (300 Mhz): 2.75 (2H, m, NCH;); 3.00 (2H, m, NCH;); 3.58 (2H, s, CH_); 3.63 (2H, s, CH-); 5.65 (1H, t, J = 2Hz, NH); 6.80 (1H, d, J = 2Hz, CH); 6.90 (1H, d, J = 8 Hz, CH); 7.00 (1H, dd, J = 8 and 2 Hz, CH); 7.30 (5H, m, 5 CH aryl)]. 4-Benzyl-7-trifluoromethoxy-4,5-dihydro-1H, 3H- [1,4] benzodiazepine-2-ketone and 4-benzyl-7-trifluoromethoxy-4,5-dihydro-1H, 2H- [ 1, 4] benzodiazepine-3-ketone, can be prepared in the following manner: to a solution, maintained at a temperature of 20 ° C, of 15.1 g of 2-benzylaminomethyl-4-trifluoro-methoxyaniline in 350 ml of ethyl ether, add 16.5 g of chloracetyl chloride then 350 ml of saturated aqueous sodium bicarbonate solution. The reaction mixture is stirred for 1 hour at the same temperature. The insolubles are then removed by filtration and the organic phase is dried over magnesium sulfate., filtered and concentrated to dryness under vacuum (2 kPa). The evaporation residue is placed in solution in 300 ml of a tetrahydrofuran / isopropyl alcohol mixture (50/50 by volume) to which 17.6 g of potassium tert-butoxide is added and stirred for 1 hour at a neighboring temperature of 20 °. C. After acidification with 12 ml of acetic acid and dilution with 350 ml of distilled water, it is extracted twice with 100 ml of ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2kPa). The oil obtained is taken up again with 50 ml of a cyclohexane mixture and ethyl acetate (75/25 by volume) or a crystallized solid. This is separated by filtration, washed with 10 ml of this same mixture and provides 6.04 g of 4-benzyl-7-trifluoromethoxy-4,5-dihydro-1H, 3H- [11,4] benzodiazepine-2-ketone in the form of a white solid that melts at 178 ° C. The filtrate is concentrated to dryness under vacuum (2 kPa) and the residue is chromatographed on 160 g of silica 20-45 μm contained in a 3.5 cm diameter column, eluting with an ethyl acetate / cyclohexane mixture (50/50 in. volume). Thus, 5.72 g of 4-benzyl-7-trifluoromethoxy-4,5-dihydro-1H, 2H- [1,4] benzodiazepine-3-ketone are obtained in the form of a white solid which melts at 124 ° C.

The 2-benzylaminomethyl-4-triffluoromethoxyaniline can be prepared in the following manner: to 97 ml of a 1 M solution of lithium tetrahydroaluminate in tetrahydrofuran, kept under argon at 20 ° C, is added 100 ml of 1,4-dioxane anhydrous, then dropwise a solution of 15 g of N-benzyl-2-ammo-5-trifluoromethoxybenzamide in 70 ml of anhydrous 1,4-dioxane and the mixture is stirred for 24 hours at reflux. After hydrolysis, at 5 ° C, by slow addition of 20 ml of distilled water, the insoluble matter that appears is separated by filtration, washed with distilled water, then with ethyl acetate and removed. The filtrate is decanted and the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is chromatographed under nitrogen pressure (150 kPa) on 150 g of silica gel 20-45 μm contained in a 3.5 cm diameter column, eluting with a mixture of cyclohexane and ethyl acetate (75-25 in. volume). This gives 7.39 g of 2-benzylaminomethyl-4-trifluoromethoxyaniline, in the form of a colorless oil [1 H-NMR spectrum in DMSO-d6, T = 200 K, d in ppm (300 Mhz): 2.65 £ ^^ jg * ^ j (1H, s, NH), 3.65 (2H, s, NCH2), 3.72 (2H, s, NCH2), 55.40 (2H, s, NH2), 6.70 (1H, d, J = 8Hz, CH arom.), 6.98 (1H, d, J = 8Hz, CH arom.) 7.04 (1H, s, CH arom.), Between 7.20 and 7.50 (5H, m, 5CH aromatics)]. The N-benzyl-2-amino-5-trifluoromethoxybenzamide can be prepared in the following manner: a solution of 5 g of N-benzyl-2-tert-butoxycarbonylamino-5-trifluoromethoxybenzamide in 25 ml of trifluoroacetic acid is stored for 15 hours at a neighboring temperature of 20 ° C, then concentrated to dryness under reduced pressure (2kPa). The product obtained is dissolved in ethyl acetate and the solution is washed successively with twice 15 ml of distilled water and 15 ml of saturated aqueous solution of Sodium bicarbonate, then concentrated to dryness under reduced pressure (2kPa). The product obtained is suspended in pentane, separated by filtration and dried under reduced pressure (2 kPa). 3.55 g of N-benzyl-2-amino is thus obtained. 5- trifluoromethoxybenzamide in the form of a solid cream that melts at 143 ° C.

The N-benzyl-2-tert-butoxycarbonylamino-5-trifluoromethoxybenzamide can be prepared in the following manner: to a solution, maintained under an argon atmosphere at -10 ° C, 20 g of 2- tert-butoxycarbonylamino- 5- acid trifluoromethoxybenzoic acid, 16.9 g of 1-hydroxybenzotriazole and 6.8 g of benzylamine in 400 ml of anhydrous tatrahydrofuran, 12.9 g of N-N'-dicyclohexylcarbodimide are added. The mixture is stirred for 2 hours at the same temperature then for 16 hours at a neighboring temperature of 20 ° C. After cooling to 0 ° C, the insoluble matter is separated by filtration, washed with ethyl acetate and the filtrate is concentrated to dryness under reduced pressure (2 kPa). The product obtained is dissolved in 60 ml of ethyl acetate and the solution is washed twice with 25 ml of a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2 kPa). The product obtained is resuspended in a mixture of petroleum ether and pentane (50-50 by volume), separated by filtration, washed with the mixture of petroleum ether and pentane and dried under reduced pressure (2 kPa). ). 21.7 g of N-benzyl-2-tert-butoxycarbonylamino-5-trifluoromethoxybenzamide is thus obtained in the form of a cream solid melting at 144 ° C.

The 2- tert-butoxycarbonylamino-5-trifluoromethoxybenzoic acid can be prepared in the following manner: to a solution, maintained at -70 ° C under an argon atmosphere, of 29 g of tert-butyl 4- trifluoromethoxy phenylcarbamate in 300 ml of anhydrous tetrahydrofuran, is added, dropwise in 1 hour, 168 ml of a 1.5M solution of tert-butyllithium in pentane, The mixture is stirred for 3 hours 30 minutes at -20 ° C, cooled again to - 70 ° C and an excess of solid carbon dioxide dried over anhydrous tetrahydrofuran is added by small amounts. The mixture is stirred for 16 hours at a neighboring temperature of 20 ° C then 500 ml of a saturated aqueous solution in ammonium chloride and 200 ml of ethyl acetate are added. The aqueous phase is extracted twice by 200 ml of ethyl acetate and the organic extracts are combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2kPa). The product is suspended in a mixture of petroleum ether and pentane (50-50 by volume), separated by filtration, washed with pentane and dried under reduced pressure (2 kPa). Thus, 31.7 g of 2-tert-butoxycarbonylamino-5-trifluoromethoxybenzoic acid are obtained in the form of a cream solid melting between 204 and 208 ° C.

EXAMPLE 9 The procedure is as in Example 1 but from 1.5 g of bromine in 5 ml of acetic acid, 2.34 g of 7-trifluoromethoxy-1, 2, 3, 5-tetrahydro- [4,1] benzothiazepine, 2.5 g. of potassium thiocyanate and 20 ml of acetic acid. The product obtained (3.42 g) is chromatographed under nitrogen pressure (150 kPa) on 80 g of silica gel 20-45 μm contained in a 2.5 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane ( 50-50 in volume). The product obtained is concentrated by titration in 5 ml of petroleum ether, separated by filtration and dried under reduced pressure (2 kPa). The product obtained (0.66 g) is dissolved in 30 ml of ethanol, to which 0.15 ml of methanesulfonic acid is added. After 16 hours of stirring at 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is recrystallized in 10 ml of a mixture of ethanol and isopropyl ether (75-25 by volume). Thus, 0.28 g of 2-imino-9-trifluoromethoxy-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] benzothiazepma methanesulfonate is obtained in the form of a yellow solid that melts at a higher temperature at 260 ° C [Analysis C12H13F3N204S3, calculated C: 35.82, H: 3.26, F: 14.16, N: 6.96, 0: 15.9, S: 23.9, and found C: 35.6, H: 3.0, F: 14.1, N: 6.9 , S: 23.7].

The 7-trifluoromethoxy-1, 2, 3, 5-tetrahydro- [4,1] benzothiazepine can be prepared in the following manner: the procedure is as in Example 6, but from 3.4 g of 7-trifluoro-methoxy-1, 5- dihydro-3H [4,1] benzothiazepine-2-ketone in 25 ml of anhydrous tetrahydrofuran of 15.5 ml of i = fa-t. ...- ~ *? t¿3 &a 1M solution of lithium tetrahydroaluminate in tetrahydrofuran and 15 ml of 1, 4-anhydrous dioxane. This gives 2.34 g of 7-trifluoromethoxy-1, 2, 3, 5-tetrahydro [4,1] benzothiazepine in the form of a yellowish oil (XH NMR spectrum in DMS0-d6, T = 300 K, d in ppm ( 300 Mhz): 2.80 (2H,, SCH2), 3.25 (2H, m, NCH2), 3.75 (2H, s, SCH-aryl), 5.60 (1H, t, J = 5Hz, NH), 7.05 (2H, m , 2 CH arom.), 7.20 (1H, s, CH arom.)].

The 7-trifluoro-methoxy-1, 5-dihydro-3H- [4,1] benzothiazepine-2-ketone can be prepared in the following manner: to a solution, maintained at -70 ° C under an argon atmosphere, of 10.3 g of 2- tert-butyl methyltrifluoromethoxyphenylcarbamate in 150 ml of anhydrous terahydrofuran, 47 ml of a 1.5 M solution of tert-butyllithium in pentane is added dropwise in 1 hour. The mixture is stirred for 2 hours at -20 ° C, cooled to -70 ° C, added with 1.1 g of sulfur, then stirred for 1 hour at -20 ° C. The mixture is cooled to -70 ° C, added with 5.4 g of methyl bromoacetate, then stirred for 16 hours at a neighboring temperature of 20 ° C. After hydrolysis by 50 ml of distilled water, 50 ml of ethyl acetate are extracted three times. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2kPa). The product obtained is dissolved in 50 ml of dichloromethane, then 15 ml of trifluoroacetic acid are added. After 2 hours of stirring at a neighboring temperature of 20 ° C, the mixture is concentrated to dryness under reduced pressure (2 kPa). The product obtained is dissolved in 40 ml of ethyl acetate and the solution is washed with 40 ml of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in isopropyl ether, separated by filtration, washed with the same solvent and dried under reduced pressure (2 kPa). 3.45 g of 7-trifluoromethoxy-1,5-dihydro-3H- [4,1] benzothiazepine-2-ketone is thus obtained in the form of a cream solid which melts at 190 ° C.

The tert-butyl 2- methyl-4-trifluoromethoxyphenylcarbamate can be prepared in the following manner: to a solution, maintained at -70 ° C under an argon atmosphere. From 20 g of tert-butyl 4- t-fluoro-methoxyphenylcarbamate in 250 ml of anhydrous tatrahydrofuran, 106 ml of a 1.5 M solution of tert-butyllithium in pentane is added dropwise in 1 hour. The mixture is stirred for 4 hours at -20 ° C, cooled to -70 ° C, added with 10.3 g of iodomethane, then stirred for 16 hours at a neighboring temperature of 20 ° C. After hydrolysis per 100 ml of distilled water, 60 ml of ethyl acetate are extracted three times. The ,,, ... je ».. e-4jaaís, itt. - ».. '. . «J-usf» -. «** • - * -« ... «-... M ^ mm mmm mm * _ •• ** - -". - .. 11 umm r - -, - > _ ^ a ^ > < *? a rfJ - i -a¿w_i ___.

The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in petroleum ether, separated by filtration, washed with the same solvent and dried under reduced pressure (2 kPa). 15.1 g of tert-butyl 2-methyl-4-trifluoromethoxyphenylcarbamate are thus obtained in the form of a light orange solid which melts at 98 ° C.

EXAMPLE 10 The procedure is as in Example 1 but from 1.6 g of bromine in 5 ml of acetic acid, 2.3 g of 7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine, 2.1 g of potassium thiocyanate and 30 ml of acetic acid. After recrystallization from absolute ethanol, 1.15 g of 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine methanesulfonate is obtained under the form of a white solid that melts at a temperature higher than 260 ° C [Analysis C12H13F3N203S3, calculated% C: 37.3, H: 3.39, F: 14.75, N: 7.25, O: 12.42, S: 24.89, O found C: 37.2, H: 3.2, F: 14.4, N: 7.2, S: 24.6].

^^^^^^^ L ^^^^^^^^^^^^^^ j ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -. *. .. Xl £ ÍMl'¿ ¡- «i .. ~ > The 7- trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine can be prepared in the following manner: the procedure is as in Example 6, but from 3.6 g of 7- trifluoromethyl-1, 5-dihydro-3H- [4,1] benzothiazepine-2-ketone in 50 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous 1,4-dioxane and 17.5 ml of a 1 M solution of lithium tetrahydroaluminate in tetrahydrofuran. 2.4 g of 7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine is thus obtained in the form of a beige solid which melts at 94 ° C.

The 7-trifluoromethyl-1, 5-dihydro-3H- [4,1] benzothiazepine-2-ketone can be prepared in the following manner: it is stirred for 3 hours 30 minutes, at a neighboring temperature of 20 ° C, a mixture of 14.3 g of methyl (2- tert.-butoxycarbonylamino-5-trifluoromethyl-benzyl-sulphonyl) acetate in 50 ml of dichloromethane and of 15 ml of trifluoroacetic acid. The mixture is concentrated to dryness under reduced pressure (2 kPa) and the obtained product is dissolved in 40 ml of N, N-dimethylformamide and brought to reflux for 3 hours. The mixture is concentrated to dryness under reduced pressure (2kPa). The product obtained is dissolved in 50 ml of ethyl acetate and the solution is washed twice with 100 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under pressure.

, ~. «¿Ifcá«; ..- .- - reduced (2 kPa). The product obtained is suspended in isopropyl ether, separated by filtration, washed with a mixture of ethyl acetate and cyclohexane (50-50 by volume) and dried under reduced pressure (2 kPa). 3.7 g of 7- trifluoromethyl-1,5-dihydro-3H- [4,1] benzothiazepine-2-ketone are obtained in the form of a beige solid which melts at 239 ° C.

The methyl (2-tert-butoxycarbonylammo-5-trifluoromethyl-benzylsulfonyl) acetate can be prepared in the following manner: to a solution, maintained at -70 ° C under an argon atmosphere, of 13.7 g of 2- methyl- 4- tert-butyl trifluoromethyl-phenylcarbamate in 180 ml of anhydrous tetrahydrofuran, 67 ml of a 1.5 M solution of tert-butyl lithium in pentane is added dropwise in 1 hour 15 minutes. The mixture is stirred for 3 hours at 1-20 ° C, cooled to -70 ° C, added with 1.6 g of sulfur, then stirred for 1 hour at -20 ° C. The mixture is cooled to -40 ° C, added with 7.6 g of methyl bromoacetate, then stirred for 16 hours at a neighboring temperature of 20 ° C. After hydrolysis by 300 ml of distilled water, it is extracted twice by 160 ml of ethyl acetate in total. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is dissolved in petroleum ether and the The solution is then filtered, concentrated to dryness under reduced pressure (2 kPa). 14.3 g of methyl (2- tert -butoxycarbonylamino-5-trifluoromethylbenzylsulfanyl) acetate are obtained in the form of a yellow solid which melts at 54 ° C [NMR spectrum: H in DMS0-d6, T = 300 K, d in ppm (300 Mhz): 1.45 (9H, s, (CH3) 3), 3.25 (2H, s, SCH2CO), 3.60 (3H, s, O CH3), 4.00 (2H, s, SCH2-aryl), 7.60 (2H, m, 2 CH arom.), 7.85 (1H, d, J = 7 Hz, CH arom.), 8.85 (1H, s, NH)].

The methyl (2- tert -butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) acetate can also be prepared by the following method: on a suspension of 5.2 g of sodium hydride (80% dispersion in petrolatum oil) in 59 ml of dimethylformamide, cooled to 0 ° C and kept under a nitrogen atmosphere, poured 14 g of methyl triglycolate and then stirred for 1 hour 30 minutes at a neighboring temperature of 20 ° C. A solution of 37.8 g of tert-butyl 2-bromomethyl-4-trifluoromethyl phenylcarbamate in 30 ml of dimethylformamide is then added and the mixture is stirred for 16 hours. The reaction medium is concentrated to dryness under vacuum (2 kPa) and the obtained paste is taken up again with 200 ml of distilled water and extracted three times with 50 ml of linden acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2).

-HitiiW ** - '- kPa). The oil (32.6 g) is chromatographed on 360 g of silica 20-45 μm contained in a 4 cm diameter column, eluting with a cyclohexane / ethyl acetate mixture (90/10 by volume). This gives 15.2 g of methyl (2-tert-butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) acetate, in the form of a yellow solid which melts at 54 ° C.

The tert-butyl 2- methyl-4-trifluoromethylphenylcarbamate is prepared in the following manner: to a solution, maintained at -70 ° C under an argon atmosphere, of 30 g of tert-butyl 4-trifluoromethylphenylcarbamate in 390 ml of tetrahydrofuran. Anhydrous, 154 ml of a 1.5 M solution of tert-butyllithium in pentane is added dropwise in 1 hour. The mixture is stirred for 4 hours at -20 ° C, cooled to -70 ° C, added with 16.4 g of iodomethane, then stirred for 16 hours at a neighboring temperature of 20 ° C. After hydrolysis by 300 ml of distilled water, 160 ml of ethyl acetate are extracted twice. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in petroleum ether, separated by filtration, washed with the same solvent and dried under reduced pressure (2 kPa). This gives 20.5 g of 2- methyl-4- trifluoromethylphenylcarbamate . ---- ~ nt? *? * mmiu. '~. . - > -. < .J «^. '« - JJc »a.aa. * - -ri.-jw.-i .-. • J .------- B - WMP-H -» -. -t- j- * -: - -M-M-fc - * -.'- »» - «- m -butyl in the form of a beige solid that melts at 101 ° C.

The tert-butyl 2- bromomethyl-4-trifluoromethyl phenylcarbamate can be prepared in the following manner: a mixture of 40 g of tert-butyl 2-methyl-4-trifluoromethyl phenylcarbamate, 26 g of N-bromosuccinimide is boiled. and 1.5 g of benzoyl peroxide in 290 ml of carbon tetrachloride and illuminated with a Mazdasol lamp of 100 for 4 hours. The formed succmimide is removed by filtration and the filtrate is successively washed with 500 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2 kPa). The oil is taken up again with the petroleum ether and the obtained crystals are separated by filtration. 37.9 g of tert-butyl 2-bromomethyl-4-t-fluoroethyl phenylcarbamate are thus obtained in the form of a white solid which melts at 98 ° C.

EXAMPLE 11 The procedure is as in Example 4 but from 6.35 g of 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine and of 15.1 g of 3-chloroperbenzoic acid (purity 80%) in 130 ml of -.j ^ s-, dichloromethane. Thus, 4.12 g of 6,6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H methanesulfonate are obtained. Tiazolo [3, 4, 5- of] [4, 1] benzothiazepine in the form of a white powder melting at a temperature above 260 ° C [Analysis C12H13F3N205S3, calculated% C: 34.45, H: 3.13, F : 13.62, N: 6.69, S: 22.99,% found C: 34.46, H: 2.94, F: 13.17, N: 6.71, S: 23.11].

EXAMPLE 12 The procedure is as in Example 5 but from 230 mg of 2-imino-9-t-fluoro-methyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine and of 198 mg of 3-chloroperbenzoic acid (purity of 80) in 8 ml of dichloromethane. Thus, 210 mg of (R, S) 6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo methanesulfonate [3, 4, 5-de] [4, 1] is obtained. benzothiazepine in the form of a white powder melting at a temperature above 260 ° C [Analysis C12H13F3N204S3, l calculated C: 35.82, H: 3.26, F: 14.16, N: 6.96, S: 23.9, found C: 36.2, H : 2.9, F: 13.9, N: 7.0, S: 23.5].

EXAMPLE 13 400 mg of (R, S) 6-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5- of] [] is dissolved. 4, 1] benzothiazepine in 160 ml dichloromethane and injected over 700 g of chiral stationary phase type (S, S) WELCK-01® contained in a column of 60 mm in diameter and 400 mm in length, eluting with a dichloromethane-heptane / methanol mixture (50/50/2 by volume) at an expense of 70 ml / min. 200 mg of (+) - 6-oxido-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5- of] is obtained [4, 1] benzothiazepine ([a] D 0 = + 27.7 ° ± 1 ° c = 0.2% methanol) and 200 mg of (-) 2- 2-imino-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4,1] benzothiazepine oxide ([a] D C = + 28.2 ° ± 1 ° c = 0.2% methanol). 200 mg of (+) - 6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [33, 4, 5- of] [4, 1] benzothiazepine oxide is dissolved in 30 ml of ethanol with 70 mg of methanesulfonic acid and stirred 16 hours at a neighboring temperature of 20 ° C. The medium is then concentrated to dryness under vacuum (2 kPa) and the colorless lacquer is taken again with 10 ml of acetone. The solid is separated by filtration, washed with 2 times 2 ml of acetone. 240 mg of (+) - 6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo methanesulfonate [3, 4, 5- of] is obtained [4, 1] benzothiazepine in the form of a white solid that melts at 230 ° C (adhesive melt) [analysis C12H13F3N204S3% calculated C: 35.82, H: 3.26, F: 14.16, N: 6.96, S: 23.9,% found C: 35.51, H: 2.78, F: 14.26, N: 6.75, S: 23.95; ([a] L- ° = + 73.1 ° ± 1.1 ° c = 0.5% methanol]. 200 mg of (-) - 6-oxido-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine is dissolved in 30 ml of Ethanol with 70 mg of methanesulfonic acid and stirred 16 hours at a neighboring temperature of 20 ° C. The medium is then concentrated to dryness under vacuum (2 kPa) and the colorless lacquer is taken up again with 10 ml of acetone. The solid is separated by filtration, washed with 2 times 2 ml of acetone, and 230 mg of (-) 6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo methanesulfonate is obtained. [3, 4, 5- of] [4, 1] benzothiazepine in the form of a white solid melting at 235 ° C (sticky melt) [Analysis C12H13F3N204S3% calculated C: 35.82, H: 3.26, F: 14.16, N : 6.96, S: 23.9,% found C: 35.70, H: 3.14, F: 13.30, N: 6.91, S: 24.23; [a] 2"L = + 74.2 ° + 1.2 ° c = 0.5% methanol].

EXAMPLE 14 To a solution, under argon and cooled to 0 ° C, of 1.2 g of 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo [3, 4, 5-ef] [1, 5] benzothiazepine in 20 ml of dichloromethane, 0.92 g of 3-chloroperbenzoic acid is added (purity of 80%). The mixture is stirred for 1 hour 30 minutes at the same temperature. After chromatography eluting with ethyl acetate and treatment with methanesulfonic acid, 0.88 g of methanesulfonate of 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo-7-oxide is obtained [3, 4, 5 - ef] [1, 5] benzothiazepine in the form of a white solid that melts at a temperature above 260 ° C [analysis C12H13F3N204S3,% calculated C: 35.82, H: 3.26, F: 14. 16, N: 6.96, O: 15.9, S: 23.9,% found C: 35.7, H: 3. 3, F: 13.8, N: 6.9, S: 24.0], EXAMPLE 15 The procedure is as in Example 4 but from 1 g of 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo [3, 4, 5-ef] benzothiazepine and 2.2 g of acid 3-Chloroperbenzoic acid (purity 80%) in 20 ml of dichloromethane. Thus, 789 mg of methanesulfonate of 6,6-dimido-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo [3, 4,5-ef] [1,5] benzothiazepine is obtained under the form of a white powder that melts at a temperature above 260 ° C. [Analysis C12H13F3N205S3,% calculated C: 34.45, H: 3.13, F: 13.62, N: 66.69, S: 22.99,% found C: 34.16, H: 3.17, F: 13.56, N: 6.75, S: 23.23].

EXAMPLE 16 The procedure is as in Example 1 but using 6.3 g of bromine in 20 ml of acetic acid, 9 g of trifluoroacetate of 8-trifluoromethyl- 2, 3, 4, 5-tetrahydro- [11, 5] benzothiazepma, 8.3 g of thiocyanate of potassium and 90 ml of acetic acid. The product obtained (6.96 g) is chromatographed under nitrogen pressure (150 kPa) on 90 g of silica gel 20-45 μm contained in a 3 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane ( 50-50 in volume). 4.4 g of the obtained product (about 55.7 obtained in total) is dissolved in 80 ml of ethanol, to which 1.5 ml of methanesulfonic acid is added. Thus, 5 g of 2-immo-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo [3,4,5-ef] [1,5] benzothiazepine methanesulphonate are obtained in the form of a white solid which melts at a temperature above 260 ° C [Analysis C12H13F3N203S3,% calculated C: 37.3, H: 3.39, F: 14.75, N: 7.25, O: 12.42, S: 24.89,% found C: 37.4, H: 3.0, F : 14.7, N: 7.3, S: 25.3]. *? . ~. 8 ~ * k¡ -? I -it * i. - * t ~ - .......-, -J. -. te -. "," J¡mtWmm% & The trifluoroacetate of 8-trifluoromethyl-2,3,4,4,5-tetrahydro- [1,5] benzothiazepine can be prepared in the following manner: to a solution of 13 g of 8 -trifluoromethyl-2, 3, 4, 5-tetrahydro- [1,5] benzothiazepine-5-tert-butyl carboxylate in 30 ml of dichloromethane is added a solution of 15 ml of trifluoroacetic acid. The mixture is stirred for 1 hour at a neighboring temperature of 20 ° C, then concentrated to dryness under reduced pressure (2 kPa). The product obtained is dissolved in 60 ml of ethyl acetate and the solution is washed with 100 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained (16.6 g) is chromatographed under nitrogen pressure (150 kPa) on 160 g of silica gel 20-45 μm contained in a 4 cm diameter column, eluting with a mixture of cyclohexane and ethyl acetate ( 75-25 in volume). The product obtained is suspended in petroleum ether and separated by filtration. 9 g of trifluoroacetate of 8-trifluoromethyl-2,3,4,5-tetrahydro- [1,5] benzothiazepine is obtained in the form of an orange solid which melts at 60 ° C.

The 8-trifluoromethyl-2,3,4,5-tetrahydro- [1,5] benzothiazepine-5-tert-butyl carboxylate can be prepared in the following manner: to a solution maintained at -70 ° C under argon, of 20 g of 4-trifluoromethyl- *. "-. . 'a-g »-a? á £ -é-« ~ y - ** »f" ..iá-M -dM-S &S-SfcJfe lW-tÉfcé ^ phenylcarbamate tert -butyl in 250 ml of tetrahydrofuran Anhydrous, 102 ml of a 1.5 M solution of tert-butyllithium in pentane is added dropwise in one hour The mixture is stirred for 4 hours at -20 ° C, cooled to -60 ° C, 5 added of 2.5 g of sulfur, then stirred for 45 minutes at -20 ° C. The mixture is cooled to -60 ° C., added with 15.6 g of 1- chloro-3-iodopropane, then stirred for 16 hours at a temperature close to 20 ° C, heated for 7 hours at reflux, then at a neighboring temperature of 20 ° C for 48 hours. The mixture is hydrolysed with 200 ml of distilled water and extracted twice with 180 ml of ethyl acetate in total. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa) on 450 g of silica gel 20-45 μm contained in a 6 cm diameter column, eluting with a mixture of cilccohexane and ethyl acetate (90-10 volume). This gives 13 g of 8-trifluoromethyl- [1, 5] benzothiazepine-5-tert-butyl carboxylate in the form of a pale yellow oil (2 H NMR spectrum in DMSO-d6, T = 300 K, d in ppm (300 MHz): 1.50 (9H, s, (CH3) 3), 1-95 (2H, m, CH;), 3.05 (2H , t, J = 6 Hz, SCH;), 3.70 (2H, t, J = 6Hz, CH-C1), 7.60 (1H, dd, J = 8 and 2 Hz, CH arom.), 7.75 (1H, d , J = 2Hz, CH arom.), 7.85 (1H, d, J = 8Hz, CH arom.), 8.60 (1H, s, NHCO)]. "- .u ^ fe ^ - ^^^ a- ^ Afe .- ^.

EXAMPLE 17 The procedure is as in Example 1, but from 0.660 g of bromine in 5 ml of acetic acid, 1 g of (R, S) -3-methyl-5-7- trifluoromethyl- 1, 2, 3, 5-tetrahydro- [4, 1] benzothiazepine, 0.864 g of potassium thiocyanate and 15 ml of acetic acid. Before alkalizing with ammonia, the insoluble material is removed by filtration, rinsed with ethyl acetate. The product obtained is chromatographed under nitrogen pressure (150 kPa) on 40 g of silica gel 20-45 μm contained in a 1.5 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane (50-50 by volume). Dissolve the obtained product (730 mg) in 10 ml of ethanol, to which is added 0.277 g of methanesulfonic acid. After 16 hours of stirring at a neighboring temperature of 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is triturated in acetone, filtered, rinsed with acetone then isopropyl ether and dried. hours in the air under a ventilated caampana. This gives 0.834 g of (R, S) -2-imino-5-methyl-9-t-fluoro-methyl-4,5-dihydro-2H, 7H-thiazolo [33, 4, 5] benzothiazepine methanesulfonate in the form of a white solid that melts at a temperature higher than 260 ° C [Analysis C13H15F3N203S3,% calculated C: 38.99, H: 3.78, F: 14.23, N: 7.00, O: 11.99, S: 24. 02,% found C: 39.05, H: 33.45, F: 13.94, N: 7.03, S: 24.37]. 425 g of (R, S) -2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo-methanesulfonate [3, 4, 5-de] [4, 1] is dissolved. ] benzothiazepine in a mixture of 25 ml of ethanol, 0.5 ml of triethylamine, and 200 ml of n-heptane and injected over 700 g of CHIRALCEL OJ stationary phase (20 μm) contained in a 60 mm diameter and 400 mm column mm in length, eluting with a mixture of n-heptane / isopropanol / triethylamine (90/10 / 0.1 by volume) at an expense of 90 ml / min. 150 mg of (+) - 2-imino-5-methyl-9-t-fluoro-methyl-4,5-dihydro-2H, 7H-thiazolo [33, 4, 5-de] [4, 1] benzothiazepine is obtained in the form of a beige solid that melts at 102 ° C [([a] rr = + 105.8 ° ± 1.7 ° c = 0.5% methanol); Analysis C12H11F3N2S2,% calculated C: 47.36, H: 3.64, F.118.73, N: 9.20, S: 21.07,% found C: 47.59, H: 3.24, F: 18.44, N: 8.99, S: 20.92] and 150 mg of (-) - 2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine in the form of a beige solid melting at 102 ° C [([a] DL = -103.1 ° ± 1.6 ° c = 0.5% methanol); Analysis C12H11F3N2S2,% calculated C: 47.36, H: 3.64, F: 118.73, N: 9.20, S: 21.07,% found C: 47.64, H: 3.24, F: 18.37, N: 8.97, S: 20.93]. Í ^ & The% (R, S) -3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine can be prepared in the following manner: 4.5 g of (R, S) -3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepin-2-ketone in 120 ml of toluene is added dropwise to 16.5 ml of a 2 M solution of the borane-dimethylsulfide complex in toluene and the total is brought to reflux for 1 hour 30 minutes. After returning to 20 ° C, the medium is taken again and stirred for 15 minutes with a saturated solution of sodium bicarbonate then extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The product is chromatographed under nitrogen pressure (150 kPa) on 55 g of 20-45 μm silica gel contained in a 2.5 cm diameter column, eluting with a mixture of cilcohexane and ethyl acetate (80-20 by volume) . This gives 2.36 g of (R, S) -3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine in the form of a colorless oil which crystallizes in the form of crystals whites that melt at 62 ° C.

The (R, S) -3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepin-2-ketone can be prepared in the following manner: a solution of 13.6 g of ( R, S) -2- (2-amino-5-trifluoromethyl-benzylsulfanyl) methyl propionate, 2 g of toluenesulfonic acid-4 and 200 ml of toluene are heated for 48 hours under reflux. After returning to a neighboring temperature of 20 ° C, a saturated aqueous solution of sodium bicarbonate is added and extracted twice by ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2kPa). The product obtained is chromatographed under nitrogen pressure (150 kPa) on 150 g of silica gel 20-45 μm contained in a column of 3.5 cm in diameter, eluting with a mixture of cyclohexane and ethyl acetate (50-50 cm). volume) then pure ethyl acetate. This gives 4.5 g of (R, S) -3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepm-2-ketone in the form of a beige solid which melts 220 ° C.

Methyl (R, S) -2- (2-amino-5-trifluoromethyl-benzylsulfanyl) propionate can be prepared in the following manner: to a solution of 17.3 g of (R, S) -2- (2-ter) methyl-butoxycarbonylammo-5-trifluoromethyl-benzylsulfanyl) propionate and 200 ml of dilutechloromethane, 20 g of trifluoroacetic acid are added in one portion and the totaal is stirred for 16 hours at a neighboring temperature of 20 ° C. After concentration to dryness under reduced pressure (2 kPa) The evaporation residue is taken up again with ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The alkaline phase is extracted once with ethyl acetate and the combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). 13.6 g of methyl (R, S) -2- (2-amino-5-trifluoromethyl-benzylsulfanyl) propionate is thus obtained in the form of a brown oil which is used as such.

The methyl (R, S) -2- (2-tert-butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) propionate can be prepared as in Example 10 but from 15 g of 2-methyl-4-trifluoromethyl-phenylcarbamate of tert-butyl in 210 ml of anhydrous tetrahydrofuran, 91 ml of 1.5 M ter-butillitium solution in pentane, 1.75 g of sulfur and 11 g of (R, S) -2-methyl bromo propionate. You get 17.3 g of (R, S) -2- (2- tert -butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) methyl propionate in the form of a limpid yellow oil which is used as such.

EXAMPLE 18 The procedure is as in Example 1 but from 0.76 g of bromine in 6 ml of acetic acid, 1.3 g of (R, S) -3 - ^. ^ J, • -. lamn * J-M »itt * ,. ? . > .36m etm ... ** -. ^ T ^? M > .

Carbamoyl-7-trifluoromethyl-1, 2, 3, 5-tetrahydro- [4,1] benzothiazepine, 0.912 g of potassium thiocyanate and 11 ml of acetic acid. Before alkalinization with ammonia, the insoluble material is removed by filtration, rinsed with ethyl acetate. The product obtained is chromatographed under nitrogen pressure (150 kPa) on 30 g of silica gel 20-45 μm contained in a column of 2.5 cm in diameter, eluting with a mixture of ethyl acetate and cyclohexane (90-10 in. volume). The product obtained (560 10 mg) is recrystallized in 5 ml of acetonitrile and thus 390 mg of (R, S) -5-carbamoyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H- is isolated thiazolo [3, 4, 5- of] [4, 1] benzothiazepine in the form of a white solid that melts at 114 ° C [Analysis C12H10F3N3OS2,% calculated C: 43.43, H: 15 3.02, F: 17.1, N: 12.61, O: 4.80, S: 19.24,% found C: 42.83, H: 2.79, F: 16.68, N: 12.3, S: 19.01].

The (R, S) -3-carbamoyl-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine can be prepared in the following manner: 3 g of (R, S) is dissolved - methyl trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine-3-carboxylate in 20 ml of a solution of approximately 5.6 M ammonia in methanol and stir at a neighboring temperature of 20 ° C for 16 hours. The medium is concentrated to dryness under reduced pressure and the extract igjggg '* rigSí? ^ ^ - &- ^^^ - ^ ks ~ dry is chromatographed under nitrogen pressure (150 kPa) on 35 g of silica gel 20-45 μm contained in a 2 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane (50-50 by volume) then with pure ethyl acetate. This gives 1.3 g (R, S) -3,3-carbamoyl-7-trifluoromethyl-1,2,3,5-tetrahydro-4 [4,1] benzothiazepine in the form of an orange oil [1H-NMR spectrum in DMSO- d6, T = 300 K, d in ppm (250 MHz): 3.5 and 3.9 (1H each), m, NCH2), 3.6 and 4.6 (1H each, d, J = 16 Hz, SC), 3.6 (1H , dd, J = 4 and 12 Hz, SCH), 6.4 (1H, m, NH), 6.8 (1H, d, J = 7 Hz, CH arom.), 7.1 and 7.5 (1H each, s, CON) , 7.28 (1H, d, J = 7Hz, CH arom.), 7.32 (1H, s, CH arom)].

The (R, S) -7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine-3-carboxylic acid methyl ester can be prepared in the following manner: a temperature of about 40 ° C is mixture of 4.7 g of 7- tpfluromethyl-1,5-dihydro- [4,1] benzothiazepine-3-methyl carboxylate, of 15.55 g of magnesium in spirals and 150 ml of methanol. When the reaction starts, the bath is removed and the reaction maintains the reflux by itself. After the end of the reflux the medium is brought to a neighboring temperature of 0 ° C and 270 ml of 4 M hydrochloric acid is added. The insoluble material is removed by filtration, rinsed with dichloromethane and the filtrate is decanted. The organic extract is dried over The magnesium sulfate was filtered and concentrated to dryness under reduced pressure (2 kPa). This gives 3.07 g of methyl (R, S) -7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzothiazepine-3-carboxylate in the form of a brown cap [NMR spectrum in DMSO] - d6, T = 300 K, d in ppm (250 MHz): between 3.6 and 4.1 (7H, NCH; + SCH + 1/2 SCH; + OCH3), 4.4 (1H, d, J = 16 Hz, SCH; ), 6.5 (1H, m, NH), 6.8 (1H, d, J = 7Hz, CH arom.), 7.28 (1H, d, J = 7Hz, CH arom.), 7.32 (1H, s, CH arom. )].

The methyl 7- trifluoromethyl-1,5-dihydro- [4,1] benzothiazepine-3-carboxylate can be prepared in the following manner: to a solution of 7.05 g of 3- dimethylamino- 2- (2- ter- methyl and 75 ml butoxycarbonylamino-5-trifluoromethylbenzylsulfanyl) acrylate Dichloromethane is slowly added 9.25 g of trifluoroacetic acid and the whole is stirred 24 hours at a neighboring temperature of 20 ° C. The medium is concentrated to dryness under reduced pressure (2 kPa) and the residue is taken up again by 100 ml of a saturated aqueous solution of Sodium bicarbonate and 200 ml of ethyl acetate are extracted once. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2kPa). This gives 6.1 g of 7- trifluoromethyl-1,5-dihydro- [4,1] benzothiazepine-3- Methyl carboxylate in the form of an orange solid that melts at 260 ° C.

The methyl 3-dimethylamino-2- (2-tert-butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) acrylate can be prepared in the following manner: to a solution of 11.3 g of (2-tert-buttoxycarbonylamino-5-trifluoromethyl) - benzyl sulfanyl) methyl acetate and 230 ml of dimethoxy-1, 2-anhydrous ethane, poured 15.6 g of tert-butyloxy-bis- (dimethylamino) methane. The medium is brought to reflux for 2 hours, then stirred for 48 hours at a neighboring temperature of 20 ° C. The medium is then hydrolyzed with 150 ml of a saturated aqueous solution of sodium bicarbonate and extracted with 200 ml of ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue (12.1 g) is chromatographed under nitrogen pressure (150 kPa) on 400 g of silica gel 20-45 μm contained in a 4.5 cm diameter column, eluting with a mixture of cyclohexane and ethyl acetate (80 - 20 in volume). Thus, 7.05 g of methyl 3-dimethylamino- 2- (2-tert-butoxycarbonylamino-5-t-fluoro-methyl-benzylsulfanyl) acrylate is obtained in the form of a cream-XH NMR spectrum in DMSO-d6, T = 300 K, d in ppm (250 MHz): 1.50 (9H, s, (CH3) 3, 2.95 (6H, s, N (CH3);), 3.6 (3H, s, OCH3) 3.80 (2H, s, SCH2), 7.30 ( 1H, d, J = 2Hz, CH arom.), 7.50 (lH, * dd, J * 2 and 7 Hz, CH arom.), 7.65 (1H, s, ethylene CH), 7.90 (1H, d, J = 7Hz, CH arom.) 8.90 (1H, s, NH)].

EXAMPLE 19 The procedure is as in Example 1 but from 0.34 g of bromine in 3 ml of acetic acid, 0.55 g of 3,3-dimethyl-7-trifluoromethyl-1,2-dihydro-5H- [4,1] benzothiazepine, 0.45 g of potassium thiocyanate and 10 ml of acetic acid. The obtained product is chromatographed under nitrogen pressure (150 kPa) on 40 g of silica gel 20-45 μm contained in a 2.5 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane (50-50 in volume). The product obtained (610 mg) is dissolved in 10 ml of ethanol, to which 0.22 g of methanesulfonic acid is added. After 16 hours of stirring at a neighboring temperature of 20 ° C, the solution is concentrated to dryness under reduced pressure (2 kPa). The product obtained is crushed in a mixture of acetone and isopropyl ether (65-35 in volume), filtered, rinsed with acetone then isopropyl ether and dried 16 hours in the air under a ventilated hood. Thus, 0.595 g of 5,5-dimethyl-2-imino-9-trifluoromethyl-2H, 4H, 7H-thiazolo [3, 4, 5] [4, 1-benzothiazepine] methansulfonate is obtained in the form of a »&White solid that melts at a temperature above 260 ° C [analysis C14H17F3N203S3,% calculated C: 40.57, H: 4.13, F: 13.75, N: 6.76, O: 11.58, S: 23.21,% found C : 40.23, H: 3.63, F: 13.46, N: 6.65, S: 23.6]. 3, 3-Dimethyl-7-trifluoroomethyl-1,2-dihydro-5H- [4,1] benzothiazepine can be prepared in the following manner: to a solution of 1.6 g of 3,3-dimethyl-7-trifluoromethyl- 1, 5-dihydro- [4,1] benzothiazepin-2-ketone in 80 ml of anhydrous toluene is added dropwise 7.3 ml of a 2 M solution of borane-dimethylsulfide complex in toluene and the total taken 1 hour at reflux . After returning to 20 ° C, the medium is taken up again and stirred 30 min with a saturated solution of sodium bicarbonate then extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The product is chromatographed under nitrogen pressure (150 kPa) on 100 g of 20-45 μm silica gel contained in a 2.5 cm diameter column, aliquoting with a mixture of cyclohexane and ethyl acetate (80-20 by volume) . 0.55 g of 3, 3-dimethyl-7-trifluoromethyl-1, 2-dihydro-5H- [4,1] benzothiazepine is thus obtained in the form of white crystals which melt at 142 ° C. 3, 3-Dimethyl-7-trifluoromethyl-1,5-dihydro- [4,1] benzothiazepin-2-ketone can be prepared in the following manner: A solution of 3.9 g of acid is refluxed for 72 hours. - (2-amino-5-trifluoromethyl-benzylsulfanyl) -2-methyl propionic acid and 40 ml of xylene. The medium is then concentrated to dryness under reduced pressure (2 kPa) and the residue is chromatographed under nitrogen pressure (150 kPa) on 55 g of 20-45 μm silica gel contained in a 2.5 cm diameter column, eluting with a mixture of cyclohexane and ethyl acetate (75-25 by volume). The product obtained is taken up again and concreted with isopropyl ether and separated by filtration then rinsing with isopropyl ether, drying under reduced pressure. This gives 1.47 g of 3,3-dimethyl-7-trifluoromethyl-1,5-dihydro-4, 1-benzothiazepin-2-ketone in the form of a cream solid melting at 210 ° C. 2- (2-Amino-5-trifluoromethyl-benzyl-sulfanyl) -2-methyl-propionic acid can be prepared as follows: a solution of 2.55 g of 2 is stirred at a temperature of 20 ° C for 5 days. - (2- amino-5-trifluoromethyl-benzylsulfanyl) -2-methyl propionate d-methyl, 0.59 g of potassium hydroxide in pellets (purity of 85%) and 30 ml of absolute ethanol. The medium is then acidified by 18 ml of an approximately 5 M hydrochloric isopropanol solution and the medium is concentrated to dryness under reduced pressure (2 kPa). The residue is taken up again by ethyl acetate and the insoluble material is removed by filtration, rinsed with ethyl acetate. The filtrate is concentrated to dryness under reduced pressure (2 kPa) and the obtained residue is chromatographed under nitrogen pressure (150 kPa) on 50 g of silica gel 20-45 μm contained in a column of 2 ccm in diameter, eluting with a mixture of ethyl acetate and methanol (95- 5 by volume). A product is isolated, which is taken up again with petroleum ether and the product is separated by filtration, rinsed with petroleum ether and dried. This gives 2.2 g of 2- (2-amino-5-trifluoromethyl-benzylsulfanyl) -2-methyl propionic acid under the form of a solid cream that melts at 113 ° C.

The methyl 2- (2-amino-5-trifluoromethyl-benzylsulfanyl) -2-methylpropionate can be prepared as follows: it is stirred at a neighboring temperature of 20 ° C For 72 hours, a solution of 9.2 g of methyl 2- (2-tert-butoxycarbonylamino-5-trifluoromethylbenzylsulfanyl) -2-methylpropionate, 10.3 g of trifluoroacetic acid and 100 ml of dichloromethane. The medium is concentrated to dryness under reduced pressure (2 kPa) and the residue is taken again by 250 ml of a saturated aqueous solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) to provide an oil which is chromatographed under nitrogen pressure (150 kPa) on 80 g of silica gel 20-45 μm contained in a 3 cm diameter column, eluting with a mixture of cyclohexane and ethyl acetate (75-25 by volume) 9. This gives 5 g of 2- (2-amino-5-trifluoromethyl-benzylsulfanyl) -2- Methyl methyl propionate in the form of a yellow oil • NMR spectrum "H in DMSO-d6, T = 300 K, d in ppm (300 MHz): 1.49 (6H, s, 2CH-), 3.6 (3H, s, OCH3), 3.8 (2H, s, SCH;), 5.6 (2H, s, NH;), 6.75 (1H, d, J = 7Hz, CH arom.), 7.25 (1H, d, J = 7 Hz, CH arom.), 7.35 (1H, s, CH arom.)].

The methyl 2- (2- tert -butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) -2-methylpropionate can be prepared as in Example 10 but from 15 g of 2-methyl-4- trifluoromethyl-phenylcarbamate and of ter - butyl in 210 ml of anhydrous tetrahydrofuran, 91 ml of 1.5 M terbutylitium solution in pentane, 1.75 g of sulfur and 11.9 g of methyl 2-bromo-2-methyl propionate. This gives 9.2 g of methyl 2- (2-tert-butoxycarbonylamino-5-trifluoromethyl-benzylsulfanyl) -2-methylpropionate in the form of a colorless oil [NMR Spectrum? E in DMSO-d6, T = 300 K, d in ppm (250 MHz): 1.56 (6H, s, 2 CH3), 1.57 (9H, s, (CH3) 3, 3.6 (3H, s, OCH3), 4.0 (2H, s, SCH2), 7.65 (1H , d, J = 7Hz, CH arom.), 7.75 (2H, m, 2CH arom.), 8.9 (1H, s, NH)].

EXAMPLE 20 Prepare (R, S) -5-hydroxymethyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine in the manner next: to a solution of 2.5 g of (R, S) -2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5- of] [4, 1] benzothiazepine-5-carboxylate of methyl in 25 ml of absolute ethanol, maintained under argon, 300 mg of sodium tetrahydruroborate is added and the whole is brought to reflux for 5 hours. He The medium is then stirred 16 hours at a neighboring temperature of 20 ° C, then hydrolysed with 50 ml of distilled water and extracted with 50 ml of ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure ( 2kPa). The oil obtained is chromatographed under nitrogen pressure (150 kPa) on 30 g of silica gel 20-45 μm contained in a 2.5 cm diameter column, eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume ). The solid obtained is taken again with ether isopropyl, separated by filtration, dried under pressure reduced (2 kPa)). This gives 40 mg of (R,, S)) - 5-hydroxymethyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5- of] [4,1 ] benzothiazepine, in the form of a crude solid melting at 167 ° C [Analysis C12H11F3N20S2,% calculated C: 44.99, H: 3.46, F: 17.79, N: 8.74, O: 4.99, S: 20.02,% found C: 44.41, H: 3.01, F: 16..84, N: 8.51, S: 20.4].

EXAMPLE 21 The procedure is as in Example 1 but from 1.66 g of bromine in 5 ml of acetic acid, 3 g (R, S) -7-trifluoromethyl-1, 2, 3, 5-tetrahydro- [4,1] benzothiazepine-3-methyl carboxylate, 2.2 g of potassium thiocyanate and 30 ml of acetic acid. The obtained product is chromatographed under nitrogen pressure (150 kPa) on 80 g of silica gel 20-45 μm contained in a 3.5 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane (50-50 in volume). This gives 2.5 g of (R, S) -2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5- of] [4, 1] benzothiazepine-5-carboxylate of methyl in the form of an oil.

EXAMPLE 22 The procedure is as in Example 1 but from 1.47 g of bromine in 5 ml of acetic acid, 2 g of 7- trifluoroomethyl-1,2,3,5-tetrahydro- [4,1] benzoxazepine, 3 g of potassium thiocyanate and 50 ml of acetic acid. After chromatography on silica gel eluting with a mixture of ethyl acetate and ciciohexano (50- 50 vol) and treated with methanesulfonic acid, 1.79 g of 9- iinino- give 2- trifluoromethyl- 4 it is obtained 5- dihydro-2H, 7H-thiazolo [3, 4, 5- to] [4, 1] benzoxazepma the form of whitish solid melting at 258 ° C [Analysis C12H13F3N204S2, ^ calculated C: 38.92, H: 3.54, F : 15.39, N: 7.56, O: 17.28, S: 17.31,% found C: 38.67, H: 3.31, F: 15.02, N: 7.69, S: 17.47]. 7- tpfluorometil- 1, 2, 3, 5- tetrahydro- [4,1] benzoxazepma can be prepared as follows: to a suspension of 2.22 g of 7- tpfluorometil- 1, 5- dihydro-3H- [4 , 1] benzoxazepm- 2- ketone in 100 ml toluene dropwise under argon and a neighbor temepratura 20 ° C, 15 ml of a 2N solution is added methylsulfide borane tetrahydrofurane complex. The reaction medium is then brought to and maintained at boiling for 1 hour 45 minutes. After cooling to 20 ° C, it is hydrolysed with 100 ml of a saturated solution of sodium bicarbonate, ----- .. ^ .. ^ y ^ y - y ^^^ -'---. then it is extracted by 2 times * 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, then concentrated in the rotary evaporator. After trituration of the residue in petroleum ether, 2 g of 5-7-trifluoromethyl-1,2,3,5-tetrahydro- [4,1] benzoxazepine is obtained in the form of a yellowish solid which melts at 85 ° C. 7- Trifluoromethyl-1,5-dihydro-3H- [4,1] benzoxazepin-2-ketone can be prepared in the same way as Next: to a solution of 2.95 g of 2-chloro-N- (2-hydroxymethyl-4-trifluoromethylphenyl) acetamide in 330 ml of tetrahydrofuran, 2.9 g of t is added under argon at a neighboring temperature of 5 ° C. - potassium butylate. After 1 hour of stirring at this temperature, the reaction medium is hydrolyzed by 30 ml of a saturated solution of ammonium chloride, then extracted by 150 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, then concentrated in the rotary evaporator. After trituration of the residue in a mixture of ethyl ether and petroleum ether , 2.2 g of 7-trifluoromethyl-1,5-dihydro-3H- [4,1] benzoxazepin-2-ketone is obtained in the form of a blaco solid melting at 183 ° C.

The 2-chloro-N- (2-hydroxymethyl-4-trifluoromethylphenyl) acetamide can be prepared from the ^ K £ jÍ8f ^^ & 4 g ^^^ u i | j £ ^ tt follows:? To a solution of 5.54 g of 2- amino- 5-trifluorometilfenilmetanol in 100 ml of dichloromethane and 6 ml of triethylamine , it is added, under argon and at a neighboring temperature of 5 ° C, 2.1 ml of chloracetyl chloride in solution in 20 ml of dichloromethane. The reaction medium is stirred for 3 hours at 5 ° C, then for 18 hours at room temperature, then poured into 100 ml of a saturated solution of sodium bicarbonate, then extracted with 200 ml of ethyl ether. The organic phase is dried over magnesium sulfate, then concentrated in the rotary evaporator. After chromatography on silica gel eluting with a mixture of cilcohexane and ethyl acetate (65-35 by volume) and trituration of the residue in a mixture of ethyl ether and petroleum ether, 4 g of 2-chloro-N are obtained. - (2-hydroxymethyl-4-trifluoromethylphenyl) acetamide in the form of a white solid which melts at 92 ° C. 2- amino- 5- trifluorometilfenilmetanol can be prepared as follows: to a solution of 7.3 g of 2- amino- 5- trifluoromethylbenzoic in 250 ml of tetrahydrofuran is added under argon and a neighbor temperature of 5 ° C , 7.3 g of sodium hydruroborate, then 24 ml of chlorotrimethylsilane. After 44 hours of stirring at room temperature, the reaction medium is cooled to 5 ° C, then hydrolyzed by 100 ml of distilled water and * .- - i- extracted 2 times by ethyl ether (400 then 150 ml). The combined organic phases are washed with 100 ml of a 1N sodium hydroxide solution, then dried over magnesium sulfate and concentrated in a rotary evaporator. 7.9 g of 2-amino-5-trifluoromethylphenylmethanol is thus obtained in the form of a white solid which melts at 70 ° C.

The 2-amino-5-trifluoromethylbenzoic acid can be prepared according to the method described by M. L. Car elmo et al., Eur. J. Med. Chem. Chim. Ther., 29 (10), 743 (1994).

The medicaments according to the invention are constituted by 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 pharmaceutically compatible product, 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, sachets) or granules can be used. In these compositions, the active principle according to the invention is mixed to one or . SM-jjjfefcSL, -various inert diluents, such as starch, cellulose, sucrose, lactose or silica, under argon stream. 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, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil can be used. These compositions may comprise substances in addition to the diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents can be employed. These compositions may also contain adjuvants, in particular wetting agents, isotonicants, emulsifiers, dispersants and stabilizers. The 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.

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 aereosols.

In human therapeutics, the compounds according to the invention are particularly useful for the treatment and / or prevention of seizures and diseases related to glutamatergenic transmission. They are particularly useful for treating and / or preventing all ischemias (such as focalis or global ischemia) following cerebral vascular accidents such as thromboembolic and / or orogenic shock, cardiac arrest, arterial hypotension, cardiac, vascular or surgical intervention. pulmonary or severe hypoglycemia, in the treatment of the effects due to anoxia, either perinatal or subsequent to drowning, high pressure or cerebro-spinal lesions, to treat or prevent the evolution of neurodegenerative diseases, of HUNTINGTON chorea, ALZHEIMER's disease and other dementias, amyotrophic lateral sclerosis or other motoneuron diseases, olivo-poncecerebellar atrophy and PRKINSON's disease, as well as epileptogenic manifestations (epilepsy ) and / or convulsive, for the treatment of cerebral or spinal traumatisms, trauma related to the degeneration of the inner ear or retina, tinnitus, anxiety, depression, schizophrenia, TOURETE syndrome, Hepatic encephalopathies, sleep problems, disorders of attention deficit, problems of hormonal conditions (excess secretion of HG or HL, secretion of corticosterone), as analgesics, anti-inflammatory, anti-anorexic, anti-headache, antiemetics and to treat poisonings by neurotoxins as well as neurological problems associated with viral diseases such as viral meningitis and encephalitis, AIDS, rabies, rubella and tetanus. These compounds are also useful for the prevention, tolerance and dependence of the symptoms of drug abstinence, alcohol and the inhibition of habit and dependence on opiates, barbiturates, amphetamines and benzodiazepines, 5 can also be used in the treatment of deficits related to mitochondrial abnormalities such as mitochondrial myopathy, LEBER syndrome, WERBICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, aminoacidduria- hydroxybutyric acid, saturnine encephalopathy (chronic lead poisoning) and deficiency in sulfite oxidase.

The doses depend on the effect sought, the duration of the treatment and the route of administration used; are generally comprised between 10 mg and 100 mg per day orall 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 according to age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention: EXAMPLE A Capsules dosed to 50 mg of active product which have the following composition are prepared according to the usual technique: . Compound of formula (I) 50 mg. Cellulose 18 mg. Lactose 55 mg. Colloidal silica 1 mg. Sodium carboxymethyl starch 10 mg. . Talc 10 mg. Magnesium stearate 1 mg EXAMPLE B It is prepared according to the usual technique of tablets dosed to 50 mg of active compound having the following composition: . Compound of formula (I) 50 mg. Lactose 104 mg. Cellulose 40 mg. Polividone 10 mg. Carboxymethylstarch sodium 22 mg -lU-t? *. s. ' sjákaam. . . ^ ¡^^^. Talc 10 mg. Magnesium stearate 2 mg. Colloidal silica 2 mg. Mixture of hydroxymethyl cellulose, glycepine, titanium oxide (72- 3.5- 24.5) c.b.p. 1 finished film tablet of 245 mg.

EXAMPLE C An injectable solution containing 10 mg of active compound 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 c.b.p. 4 ml It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description.

Having described the invention as above, it is claimed as property in the following:

Claims (12)

1 . Compounds of formula: Characterized because Ri represents a sulfur or selenium atom, R represents a hydrogen atom or an alkyl radical, -R 3 -R-RD-RD- / represents a chain of the formula -CH 2 -CH-CH-CH--, -CH-CH-CH-CO-, -CH - CH- CH-- CH (R3) ~, - CH-- CH - CH-- Se-, -CH-- CH- Se- CH_-, -CH; - CH- CH2- S-, - CH-- CH-- CH-- SO-, -CH-- CH-- CH- SO--, -CH; - CH- CH- O-, - CH-- CH-- CH-- N (R9) -, - CH-- CH- CO- CH--, -CH- CH; - CH (R ^) - CH--, -CH- CH- S- CH-, -CH-- CH-- SO- CH--, -CH-- CH2- , t ^ v + vv ^ Jt titm SO- CH; -, -CH- C (alq) (alq ') - S- CH;, -CH- C (alq) (alq') - SO- CH; _, CH- C (alk) (alq ') - S02- CH2, -CH; - CH (R10) - S- CH--, CH- CH (R? - SO- CH2-, -CH- CH (R10) - SO- CH-, -CH- CH- 0 -CH-, -CH-- CH- N (R9) - CH- or -CH; - CO- N (Rq) - CH: -, R7 represents a radicaal polyfluoroalkyl or polyfluoroalkoxy, R represents a hydroxy radical, Rq represents a hydrogen atom or an alkyl or benzyl radical, Riu, represents an alkyl radical, -CH-OH, -COOalq, - COOH or -CONH-, Alk represents an alkyl radical, Alk 'represents an alkyl radical, in these definitions, the radicals and alkyl portions contain 1 to 6 carbon atoms in right or branched chain, and when they contain one or several asymmetric centers, their isomers, racemic and enantiomers and their salts with a mmeraal or organic acid.

2. Compounds of formula (I) according to claim 1 for which R- represents a trifluoromethoxy or trifluoromethyl radical, and when they contain one or more asymmetric centers, their isomers, racemates, enantiomers and their salts with a mineral or organic acid.

3. Compounds of formula (I) according to claim 1 for which R-, represents a sulfur atom, R 2, represents a hydrogen atom, -R 3 -R ,, -R- -Rβ ~, represents a chain of formula -CH - CH- CH- CH--, -CH- CH-- CH- CO-, -CH- CH- CH- CH (R,) -, -CH- CH- CH- Se-, -CH- CH2- Se- CH-, -CH- CH- CH- S-, -CH- CH-- CH- SO-, -CH- CH- CH- SO--, -CH2- CH2- CH- O-, -CH - CH- CH - N (R 9) -, - CH - CH - CO - CH; -, - CH - CH - CH (Rq) - CH - -, - CH - CH - S - CH 2 -, - CH-- CH2- SO- CH-, -CH; - CH- S02- CH; -, -CH- C (alk) (alq ') ~ S- CH2, -CH; - C (alk) (alq') ) - SO- CH; -, CH- C (alq) (alq ') - M SO- CH-, -CH; - CH (R? O) - S- CH2-, CH2- CH (R? O) - SO- CH; -, -CH- CH (R? O) - SO- - CH-, -CH2- CH2- O- CH-, -CH- CH- N (R9) - CH- or -CH2- CO- N (R9) - CH2-, R-, represents a trifluoromethyl or trifluoromethoxy radical, R8 represents a hydroxy radical, Rq, represents a hydrogen atom or an alkyl or benzyl radical, R1 represents an alkyl radical, -CH, OH, -COOalk, -COOH or -CONH;, an alkyl radical and Alk 'represents an alkyl radical, and when it contains one or more asymmetric centers, its isomers, racemic, enantiomeric and its salts with a mineral or organic acid. "7

4. compounds of formula (I) according to claim 1 selected from the following compounds: lH-2¡ . 2-imino-9-trifluoromethoxy-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3- j k] [l] benzazepin-7-ol, . 2-imino-9-trifluoromethoxy-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3- j k] • 1] benzazepine, . 2-imino-9-trifluoromethyl-4, 5, 6, 7-tetrahydro-2H-thiazolo [5, 4, 3- jk] [l] benzazepine, . 7,7- 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1,5] benzothiazepine dioxide, 7. - 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [l, 5] benzothiazepine oxide, . 2-imino-9-trifluoromethoxy-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1, 5] benzothiazepma, . 6- benzyl-2-imino-9-trifluoromethoxy-6,7-dihydro-4H-thiazolo [3, 4, 5-kj] [1,4] benzodiazepine-5-ketone, . 6- benzyl-2-immo-9-trifluoromethoxy-4,5,6,7-tetrahydro-2H-thiazolo [3, 4, 5-kj] [1,4] benzodiazepine, wft,. »- & ---. * .- »» .. . 2-imino-9-trifluoroamphoxy-4, 5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepma, . 2-imino-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine, . 6,6- 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine dioxide, 7, 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [l, 5] benzothiazepma oxide, 6,6- 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [l, 5] benzothiazepma dioxide, . 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazolo- [3, 4, 5-ef] [1, 5] benzothiazepma, . 2-imino-9-trifluoromethyl-4, 5, 6, 7-tetrahydro-2H-thiazolo- [5, 4, 3- jk] [l] benzazepin-7-ol, 6,6-2- imino-9-trifluoromethoxy-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepma, 6-imino-2-oxide - trifluoromethoxy-4, 5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine, . 6- benzyl-2-imino-9-trifluoromethyl-6,7-dihydro-4H, -thiazolo- [3, 4, 5-kj] [1,4] benzodiazepine, 5-ketone, . 6- benzyl-2-imino-9-trifluoromethyl-4, 5, 6, 7-tetrahydro-2H, -thiazolo- [3, 4, 5-kj] [1,4] benzodiazepine, 10 2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo- [3, 4, 5-de] [4, 1] benzothiazepine, 5- carbamoyl-2-imino-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, 15. 5,5-dimethyl-2-imino-9-trifluoromethyl-2H, 4H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, 5- hydroxymethyl-2-imino-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, and when they contain one or several asymmetric centers, their isomers, racemates, enantiomers and their salts with a mineral or organic acid. 25 ^^^^^^^ g ^^ s ^^^^ gg ^? lw ^^^^^! ^^^^^^^^^^^^^ 5. Compounds of formula (I) according to claim 1 selected from the following compounds:

5 . (R, S) - 6-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepma oxide, (+) - 6-imino-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine oxide, 10 (-) - 6- 2-imino-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine oxide, (R, S) -2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, (+) - 2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, twenty . (-) - 2-imino-5-methyl-9-trifluoromethyl-4, 5-dihydro-2H, 7H-thiazolo [3, 4, 5-de] [4, 1] benzothiazepine, and its salts with a mineral or organic acid.

The process for preparing the compounds of formula (I) according to claim 1 for which Ri represents a sulfur or selenium atom, R;, represents a hydrogen atom, - R3- R4- R- e-, represents a chain of formula -CH- CH- CH- CH; -, -CH- CH- CH- CO-, -CH- CH- CH- CH (Rs) -, -CH - CH2- CH- Se-, -CH- CH- Se- CH-, -CH- CH: - CH- S-, -CH2- CH- CH; - O-, -CH- CH- CH-- N (RQ) -, -CH- CH- CO- CH-, -CH- CH- CH (R8) - CH-, -CH- CH- S-CH-, -CH- C (alk) (alq ') - S- CH2, -CH- CH (R1C1) - S- CH-, -CH- CH; - O- CH-, -CH- CH- N (R9) - CH- or -CH- CO- N (R9) -CH-, R, < represents a hydroxy radical, RQ, represents a hydrogen atom or an alkyl or benzyl radical, Rio represents an alkyl radical, -COOalk or -CONH;, alk represents an alkyl radical, alk, represents an alkyl radical, characterized in that it reacts an alkali metal thiocyanate or an alkali metal selenocyanate on a derivative of the formula: (1) in which R 7 has the same meanings as in claim 1 and -R 3 -R 4 -R 3 -R-, represents a chain of the formula -CH-CH- CH- CH; -, -CH; - CH- CH- CO-, -CH- CH- CH-- CH (R ") -, -CH- CH- CH- Se-, -CH- CH- Se- CH-, -CH- CH- CH- S-, -CH- CH- CH- O-, -CH- CH- CH- N (Rq) -, -CH-- CH- CO- CH-, -CH- CH- CH (R8) - CH-, -CH; - CH- S-CH-, -CH- C (alk) (alq ') - S- CH2, -CH- CH (R? L,) - S- CH--, -CH- CH- O- CH; -, -CH- CH- N (R9) - CH- or -CH- CO- N (R9) -CH--, R3, represents a hydroxy radical, R9, represents a hydrogen atom or an alkyl or benzyl radical, Rio represents an alkyl radical, -COOalk or -CONH;, alkyl represents an alkyl radical, represents an alkyl radical, isolates the product and eventually transforms it into salt.

7. Preparation process for the compounds of formula (I) according to claim 1 for which R2 represents an alkyl radical which is characterized in that it alkylates a corresponding compound of formula (I) for which R2 represents a hydrogen atom, isolates the product and eventually transforms it into salt.

8. Process for the preparation of the compounds of formula (I) according to claim 1 for which R2 represents a hydrogen atom or an alkyl radical, -R3-R4-R5-Re represents a chain of formula -CH; -CH- CH (Rv) -CH- or -CH; -CH- CH (R8) ~ and Re represents a hydroxy radical which is characterized in that a corresponding compound of formula (I) is reduced for which R;, represents an hydrogen or an alkyl radical and R-RR-Rβ represents a chain of the formula -CH; -CH; -CO-CH- or -CH- -CH-CH2-CO-, isolates the product and transforms it eventually into salt.

9. Process for preparing the compounds of formula (I) according to claim 1 for which R; represents a hydrogen atom or an alkyl radical and -R3-R4- R5- R6-, represents a chain of formula -CH; - CH-- CH- SO-, -CH- CH- CH2- SO-, -CH- CH- SO- CH-, -CH- CH- SO- CH--, -CH-- C (alk) (alq ') - SO- CH2_, CH- C (alk) (alq') - SO- CH;, CH-- CH (R) - SO - CH -, - CH - CH (Rm) - S02 - CH; -, which is characterized in that a corresponding compound of formula (I) is oxidized for which the R3 - chain -R4-R5-RG-represents a chain of formula -CH-CH-CH-S-. CH-CH-S-CH-, -CH-C (alk) (alq ') -S-CH- or -CH-CH (R? O) - S- CH2-, isolates the product and transforms it eventually into Salt.

10. Preparation process for the compounds of formula (I) according to claim 1 for which R 2 represents a hydrogen atom or an alkyl radical, -R 3 -R 4- «-. j.a «?« rt? »a ^ > -? - «« ^ faa? "- - R" -R6- represents a chain of formula -CH-CH (Rio)) -S-CH, in which Ri represents a radical -COOH that is characterized in that a corresponding compound of formula (I) is hydrolyzed for which R, represents a hydrogen atom or an alkyl radical, -R 3 -R-R £ -Rs- represents a chain of formula -CH-CH (Rio) -S-CH, in which Ri represents a radical -COOalq, isolates the product and eventually transforms it into salt.

11. Medicaments containing as active ingredient at least one compound according to any of claims 1 to 5 or a pharmaceutically acceptable salt of such a compound with a mineral or organic acid. 15

12. Derivatives of formula: Characterized by -Rj- R- R5- Rs-, represents a chain of formula -CH- CH- CH- CH-, -CH- CH2- CH- CO-, -CH2- CH2- _M-i.a - tfai. -to - ..** *.. -...-.. . v .. - IH-T1- * - - ^ - • ^ A «aa * ti- ^ < - "^ M ^ CH- CH (RH) -, -CH- CH- CH- Se-, -CH- CH- Se- CH-, -CH- CH- CH- S-, -CH- CH- CH; - O-, -CH- CH- CH; - N (R9) -, - CH- CH- CO- CH-, -CH- CH- CH (R- CH-, -CH- CH- S- CH-- , -CH-- C (alk) (alq ') - S- CH2, -CH; - CH (R? O) - S- CH--, - CH2- CH: - O- CH-, -CH- CH - N (R9) - CH- or -CH- CO- N (R,) - CH-, R- represents a hydrogen atom or an alkyl or benzyl radical, Ri represents an alkyl radical, -COOalk or - CONH2, alkyl represents an alkyl radical and alk represents an alkyl radical, in these definitions, the radicals and 10 alkyl portions contain 1 to 6 carbon atoms in right or branched chain. fifteen twenty 25 SUMMARY OF THE INVENTION The present invention concerns compounds of formula In which Ri represents a sulfur or selenium atom, R- represents a hydrogen atom or an alkyl radical, -R-R-R "- Ru-, represents a chain of formula - CH - CH - CH - CH -, -CH-- CH - CH-- CO-, -CH-- CH-- CH- CH (Ry -, -CH-- CH-- CH-- Se-, -CH-- CH-- Se- CH--, -CH- CH- CH- S-, -CH-- CH.- CH - SO-, -CH-- CH- CH-- SO-, -CH-- CH-- CH- 0-, -CH-- CH-- CH- N (Rq) -, -CH2- CH- CO- CH; -, -CH- CH- CH (R -) - CH -, --CH-- CH-- S- CH--, -CH- CH-- SO- CH-, -CH- CH-- SO-- CH-, -CH-- C (alk) (alq ') - S- CH2, -CH- C (alq) (alq ') - SO- CH; _, CH-- C (alq) (alq') - SO- CH-, -CH2- CH (R? O) -S- CH--, CH-- CH (R? L,) - SO- CH--, -CH- CH (R10) - SO- CH--, -CH2 -CH_- O- CH--, -CH- CH--N (Rq) -CH- or -CH_- CO- N (R) -CH2-, R7 represents a polyfluoroalkyl or polyfluoroalkoxy radical, Rs represents a hydroxy radical, R represents a hydrogen atom or an alkyl or benzyl radical and Ri represents an alkyl radical, -CH-OH, -COOalq, -COOH or -CONH-, its isomers, enantiomers, its salts, its preparation processes and the drugs that contain them ? * s ^^ ...._ * -_.-. -a »,» 'iafe ^