PT100518A - 1,4-BENZOTIAZEPINE-3 (2H) ONA DERIVATIVES, ITS USE AND PREPARATION PROCESS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

73 960 ΜΑΤ / ΜΑΚ / Ρ332

The present invention relates to 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one, to pharmaceutical compositions containing the same, to processes for the preparation and use thereof treatment of neurological disorders, such as epilepsy.

In particular, the present invention relates to compounds of formula I

wherein n = 0, 1 or 2; R 1 is independently halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 1 to 4 carbon atoms, optionally alkylated carbamoyl or optionally alkylated sulfamoyl; R2, R3, R4, R5 and R6 independently represent hydrogen or alkyl of 1 to 4 carbon atoms, and m = 0 or an integer between 1 and 4.

Compounds of formula I wherein n = 0, R 2 and / or R 3 are hydrogen or methyl and R 4, R 5 and R 6 are hydrogen and the compounds of formula I in which n = 0, 1 or 2, R 2 represents methoxy, m R2, and / or R3 represent hydrogen or methyl and R4, R5 and R6 represent hydrogen, are known [see Szabo et al. Chem. 119, 2904-2913 (1986)]. The present invention therefore provides novel compounds of formula I, wherein n = 0, 1 or 2; R 1 represents independently halo, C 1 -C 4 -alkyl or alkoxy, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, C 1 -C 4 -alkanoyl, optionally alkylated carbamoyl or optionally alkylated sulfamoyl; R2, R3, R4, R5 and R6 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and 73 960 ΜΑΤ / ΜΑΚ / Ρ332 -3-

wherein R 2 and / or R 3 are H or methyl and R 4, R 5 and R 9 are hydrogen, and are not both 0 and when n = 0, 1 or 2, 2, R 1 is methoxy, R 2 and / or R 3 are H or methyl and R 4, R 5 and R 6 are hydrogen, m is not equal to 2. When m is greater than 1, the substituents R 1 may be the same or different.

In the preferred compounds of formula I, n = 0 or 1, m = 0 or 1, R2 is fluoro, chloro, bromo, iodo, methyl, methoxy, polyhaloalkyl (eg trifluoromethyl), nitro, cyano, carboxy and acetyl , dimethylcarbamoyl or dimethylsulphamoyl and R2, R3, R4, R5 and R6 are independently H or methyl.

In particularly preferred compounds of formula I, n = 0 or 1, m is 0 or 1 and R 1 is fluoro, chloro, bromo, methyl or methoxy and R 2 and R 4 are independently H or methyl and R 3, R 5 and R 6 are H.

Specific compounds of formula I wherein n = 0 are: 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one; 4.5-dihydro-2-methyl-1,4-benzothiazepine-3 (2H) -one, 4,5-dihydro-N-methyl-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro -6-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-9-fluoro -1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-bromo-1,4 benzothiazepine-3 (2H) -one; 4,5-dihydro-6-methoxy-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-methyl-1,4- (2H) -one; 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one.

Specific compounds of formula I wherein n = 1 are: 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-7-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one 1-oxide; -4- 73 960 ΜΑΤ / ΜΑΚ / Ρ332 f, & 4,5-dihydro-6-methyl-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one 1-oxide; and stereoisomers thereof.

Those skilled in the art will appreciate that certain compounds of formula I contain one or more chiral centers. Thus, for example, compounds of formula I wherein n is 1 contain a chiral center on the sulfur atom; compounds of formula I wherein R 2 and R 3 are not identical contain a chiral center at the carbon atom 2 and compounds of formula I wherein R 5 and R 6 are not identical contain a chiral center at the carbon atom 5. When a compound of formula I contains a single chiral center, may exist in two enantiomeric forms. The present invention includes each enantiomer and mixtures of the enantiomers. The enantiomers can be obtained by methods known to those skilled in the art. Such methods typically include resolution by the formation of diastereomeric salts or complexes which may be separated, for example, by crystallization; formation of diastereomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography, followed by release of the desired enantiomer of the separated derivative; selective derivatization of an enantiomer by reaction with a specific reagent for the enantiomer, for example oxidation or enzymatic reduction; or gas-liquid or liquid chromatography on a chiral medium, for example on a chiral support or in the presence of a chiral solvent. Alternatively, it may be possible to synthesize a specific enantiomer by asymmetric synthesis using reagents, substrates, catalysts or optically active solvents, or convert one enantiomer to the other by asymmetric transformation.

When a compound of formula I contains more than one chiral center may exist in diastereoisomeric forms. The diastereomers may be separated by processes known to those skilled in the art, for example, chromatography or crystallization. The present invention includes each diastereoisomer of the compounds of formula I and mixtures thereof. The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I wherein n = 0, 1 or 2; R 1 represents independently halo alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 4 carbon atoms, optionally alkylated carbamoyl and optionally alkylated sulfamoyl; R 2, R 3, R 4, R 5 and R 6 independently represent hydrogen or C 1 -C 4 -alkyl, n = 0 or an integer from 1 to 4 together with a pharmaceutically acceptable diluent or carrier. -convulsants in the treatment of neurological disorders such as epilepsy.

In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus, the therapeutic compositions of the present invention may take the form of any of the pharmaceutical compositions known for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage forms.

Compositions for oral administration are the preferred compositions of the invention and these are the dosage forms known for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. Excipients used in the preparation of these compositions are the excipients known in the art of pharmacology. The tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example corn starch and lubricating agents, for example magnesium stearate and compression of the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art to provide a delayed release of the compounds of the present invention. Such tablets may be, if desired, provided with enteric coatings by known methods, for example, by the use of cellulose acetate phthalate. Likewise, capsules, for example hard or soft gelatin capsules, containing the active compound, with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently contain 1 to 500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium, in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose and oily suspensions containing a compound of the present invention in a suitable vegetable oil , for example arachis oil.

Compositions of the invention suitable for rectal administration are the dosage forms known for such administration, for example suppositories based on cocoa butter or polyethylene glycol.

Compositions of the invention suitable for parenteral administration are the dosage forms known for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.

The compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. Alternatively, the active compounds may be in a pharmaceutically acceptable cream or ointment base.

In some formulations it may be beneficial to use the compounds of the present invention in the form of very small particle size, for example as obtained by milling with fluid energy. ΜΑΤ / ΜΑΚ / Ρ3 3 2

-7-

In the compositions of the present invention, the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat neurological disorders, such as epilepsy, in animals, including humans. For such treatment, the amount of the compound of formula I administered per day, is in the range of 1 to 1000 mg, preferably 5 to 500 mg, administered as a single dose or in divided doses, or less than once per day.

The processes for the preparation of the compounds of formula I will be described below. These processes form a further aspect of the present invention.

Compounds of formula I wherein n = 0 may be prepared by cyclization of compounds of formula II

II wherein R 7 is H or a group derived from an alcohol and Y is a salt-forming anion (for example chloride) by treatment with a base (for example sodium carbonate), optionally by heating.

Compounds of formula I wherein n = 0 may be prepared by the reaction of compounds of formula III

And

III-8- 73 960 ΜΑΤ / ΜΑΚ / Ρ332 / f);

in which Y is a salt-forming anion (for example chloride), with a halosubstituted ester of formula IV

R

In which Z is, for example, chlorine or bromine and R 8 is a group derived from an alcohol, in the presence of a base of the formula: ), optionally by heating, optionally followed by treatment with aqueous sodium carbonate.

The compounds of formula I may be prepared by the cyclisation of compounds of formula V

v

Compounds of formula I wherein n = 0 and R 4 is H may be prepared from compounds of formula VI,

by the Ritter reaction, in the presence of a strong acid such as sulfuric acid, followed by hydrolysis.

Compounds of formula I in which n = 0 and R 2, R 3, R 4, R 5, and R 6 are H may be prepared by the Beckmann rearrangement of from 9 9 960 ΜΑΤ / ΜΆΚ / Ρ 322

stations of formula VII - " θα

VII wherein Rg is H or arylsulfonyl (e.g. p-toluenesulfonyl)

Compounds of formula I wherein n = 1 may be prepared by the oxidation of compounds of formula I wherein n = 0 (for example using sodium periodate).

Compounds of formula I wherein n = 2 may be prepared by the oxidation of compounds of formula I wherein n = 0 or 1 (for example using peracetic acid).

Compounds of formula I wherein R 4 is alkyl may be prepared by the alkylation (for example with dimethyl sulfate) of compounds of formula I wherein R 4 is H.

Compounds of formula II wherein R 7 is H may be prepared by the reaction of compounds of formula III with a halo-substituted acid of formula VIII

Z-C-CO2 H VIII

Wherein Z is, for example, chlorine or bromine, in the presence of a base (for example sodium methoxide). Compounds of formula II in which R 7 is other than H may be prepared by esterification of compounds of formula II wherein R is H. 73 960 ΜΑΤ / ΜΑΚ / 323

The compounds of formula III may be prepared by the benzoylation of compounds of formula IX

for example by hydrolysis, followed by salt formation.

Compounds of formula V may be prepared by reacting compounds of formula X

with a compound of the formula C1COOCH2C1.

The compounds of formula VI may be prepared by the reaction of compounds of formula XI

with a halo-substituted acetonitrile, in the presence of a base (for example sodium carbonate).

Compounds of formula IX may be prepared by the reaction of compounds of formula X with a benzoylating agent (for example benzoyl chloride) in the presence of a base (for 9-11 / 9 -11 73 7360 / (E.g. sodium hydroxide).

Compounds of formula X wherein R 5 and R 6 are H, may be prepared by reduction of compounds of formula XII

or by reduction of compounds of formula XIII

SH (R 1) m

XIII CONH-

or by the reduction of compounds of formula XIV (R 1)

SH

XIV

CN

or by reduction of compounds of formula XV

For example with lithium aluminum hydride.

Compounds of formula XII may be prepared by reacting compounds of formula XVI (following formula XVI) 7360 ΜΑΤ / ΜΑΚ / Ρ 322

or by the reaction of compounds of formula XVII and s-s

XVII CO.O.CO.OEt CO.O.CO.OEt with ammonia.

Compounds of formula XV may be prepared by the reaction of a compound of formula XVIII NO,

(R) m KA

XVIII

CN

with a compound of formula XIX

And a base such as potassium hydroxide in dimethylformamide, as described by Beck and Yahner [J Org Chem, vol 43, p.1604-1606 (1978)].

Compounds of formula XVI may be prepared by xx-13-

ΜΑΤ / ΜΑΚ / Ρ332 reaction of compounds of formula XX ir>

COOH for example with thionyl chloride.

Compounds of formula XVII may be prepared by reacting compounds of formula XX with ethyl chloroformate in the presence of a base such as triethylamine.

Compounds of formula XX may be prepared by the diazotization of compounds of formula XXI

XXI followed by reaction with an alkali metal disulfide for example disodium disulphide. The anticonvulsive activity of the compounds of formula I has been demonstrated by observing the ability of the compounds to antagonize myoclonic attacks induced by administration of bicuculline. In these experiments groups of female mice weighing in the range of 25 to 30 grams had free access to food and water up to one hour prior to administration of the compound of formula I to be tested. The test compound was administered orally in one or more doses in 1% aqueous methylcellulose solution. One hour later, (+) -bicuculin was given at a dose of 0.55 mg / kg intravenously in a tail vein. During the next two minutes the animals were submitted to / 7; And the percentage of animals showing attacks was recorded. A dose value limiting the 50% attacks of the animals (ED50) was then calculated from the linear regression plot of the percentage of animals showing attacks, as a function of the dose of the compound of formula I administered, in cases where there were results for more than one dose. The invention will now be illustrated by the following Examples.

Example 1 .............. ......

A solution of ethyl bromoacetate (7.2 ml) in methanol (90 ml) was added dropwise to a stirred suspension of 2-mercaptobenzylamine hydrochloride (11.4 g) and sodium methoxide (7.44 g) in methanol (360 ml). The mixture was stirred at room temperature for 30 minutes and then the solvent was removed by evaporation under reduced pressure. The residue was stirred at room temperature with a solution of sodium carbonate (12 g) in water (180 ml) for six hours. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol to give 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one (mp 184-186 ° C).

Yield 7.4 g. The ED50 in the test described above was, for this compound, 5.7 mg / kg.

Exemolo 2

A solution of sodium periodate (2.67 g) in water (45 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-1,4-benzothiazepine-3- ( 2H) -one (2.23 g) in dichloromethane (175 ml). Stirring was maintained at room temperature for 1 day. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (98: 2) gave 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 195-197 ° C), which was recrystallized from ethanol. 73 960 ΜΑΤ / ΜΑΚ / Ρ332

ED50 in the test described above was, for this compound, 6.3 mg / kg.

Example 3

A solution of ethyl 2-bromopropionate (2.8 ml) in anhydrous methanol (40 ml) was added dropwise to a stirred suspension of 2-mercaptobenzylamine hydrochloride (4 g) and sodium methoxide (2.37 g g) in anhydrous methanol (120 ml). Stirring was maintained at room temperature for 30 minutes and then under reflux for 1.5 hours. The solvent was removed by evaporation under reduced pressure and stirred at room temperature with a solution of sodium carbonate (4 g) in water (80 ml) overnight. The precipitated product was separated by filtration, washed with water, dried and recrystallized from ethanol to give 4,5-dihydro-2-methyl-1,4-benzothiazepine-3 (2H) -one (mp 214-216 ° W). Yield 2.59 g. The ED50 in the test described above was, for this compound, 18.7 mg / kg.

Example 4

A solution of 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one (0.53 g) in dry dimethylsulfoxide (30 ml) was added dropwise with stirring, to a mixture of a 57% sodium hydride suspension in mineral oil (0.14 g) and dry dimethylsulfoxide (10 ml). Stirring was maintained at room temperature for 30 minutes and then dimethyl sulfate (572 ml) was added. The mixture was stirred at room temperature for 2 hours, at 100 ° C for a further 2 hours and at room temperature overnight. Water was added and the mixture was extracted with ether, washed, dried and evaporated. The crude product was purified by flash chromatography using a mixture of dichloromethane and ethyl acetate (1: 1) as eluent to give 4,5-dihydro-N-methyl-1,4-benzothiazepine-3 (2H) - (mp 86-88 ° C) which was recrystallized from hexane. The above compound was administered to mice in the test described above at a dose of 100 mg / kg. 50% of the animals revealed 73 960 MAT / MAK / P3 32 J /. 6 attacks, indicating that the ED50 value should be close to 100 mg / kg.

Exemolo 5

A mixture of 3-fluoro-2-methylaniline (50 g) and acetic anhydride (400 ml) was stirred at room temperature for 2 hours and then poured onto ice. The resulting solid was collected by filtration, washed with water and dried to give 3-fluoro-2-methylacetanilide (mp 132-134 ° C).

3-Fluoro-2-methyl-isothiocyanate was added with stirring. (20 g) was added to a mixture of magnesium sulfate (18.9 g), potassium permanganate (54.7 g) and water (2300 ml) at 80 ° C. The mixture was heated for 2.5 hours, cooled and filtered. The filtrate was acidified with a 1: 1 mixture of sulfuric acid and water to give N-acetyl-6-fluoroanthranilic acid (mp 201-204 ° C).

A mixture of N-acetyl-6-fluoroanthranilic acid (48 g), sodium hydroxide (150 g) and water (660 ml) was heated under reflux for 3 hours. The mixture was cooled and acidified to pH 4 with hydrochloric acid. 6-Fluoroanthranilic acid (mp 162-164 ° C) was collected by filtration.

A solution of 6-fluoroanthranilic acid (33 g) in a mixture of water (214 ml) and hydrochloric acid (44 ml) was treated with a solution of sodium nitrite (14.4 g) in water ( 60 ml), added dropwise. The solution was stirred for 1 hour at 0 ° C and then added to a sodium disulfide solution [prepared by treating a mixture of sodium sulphide nonahydrate (55 g) and sulfur (7.15 g) in water ( 66 ml) was treated with a solution of sodium hydroxide (88 g) in water (22 ml)]. The mixture was allowed to stand for 3 hours at room temperature and acidified with hydrochloric acid. The resulting precipitate was dissolved in a warm solution of sodium carbonate (7 g) in water (700 ml). The solution was then filtered and acidified with hydrochloric acid. The 2,2'-dithiobis (6-fluorobenzoic acid) (mp 224-230 ° C) precipitated and collected by filtration. ; 0.7 - 73 960 ΜΑΤ / ΜΆΚ / Ρ332 washed with water.

A mixture of 2,2'-dithiobis (6-fluorobenzoic acid) (16 g) and thionyl chloride (125 ml) was stirred and heated under reflux for 3.5 hours. The mixture was evaporated under reduced pressure to give a residue which was triturated with hexane to give 2,2'-dithiobis (6-fluorobenzoyl chloride).

A solution of ammonium hydroxide (40 ml) was added dropwise to a solution of 2,2'-dithiobis (6-fluoro-benzoyl chloride) (14.5 g) in dioxane (200 ml). The mixture was stirred at room temperature for 3 hours and then acidified with 6N hydrochloric acid. 2,2'-dithiobis (6-fluorobenzamide) (mp 203-205 ° C) precipitated and collected by filtration.

A stirred suspension of 2,2'-dithiobis (6-fluorobenzamide) (12 g) in dry ether (200 ml) was treated with lithium aluminum hydride (5.82 g). The mixture was stirred and heated under reflux for 4 hours. After cooling the mixture, ethyl acetate (48 ml) was added and then the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (150 ml), with external cooling. The aqueous phase was separated and basified with aqueous sodium hydroxide solution (prepared from sodium hydroxide (7.5 g) and water (18 ml) and then benzoyl chloride (28 ml) was added dropwise . The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to give S, N -dibenzoyl-6-fluoro-2-mercaptobenzylamine (mp 149-152 ° C), which was recrystallized from ethanol.

A suspension of S, N-dibenzoyl-6-fluoro-2-mercaptobenzylamine (8.5 g), and sodium hydroxide (9.97 g) in water (145 ml) was heated under reflux in an atmosphere of nitrogen for 4.5 hours. After cooling on ice, the mixture was acidified with concentrated hydrochloric acid and a solid collected by filtration, which was treated with absolute boiling ethanol, to give 6-fluoro-2-mercaptobenzylamine hydrochloride. -18- 73 960 ΜΑΤ / ΜΑΚ / Ρ332 * / zm · -

Sodium methoxide (2.4 g) was added to a solution of 6-fluoro-2-mercaptobenzylamine hydrochloride (4 g) in anhydrous methanol (110 ml) and stirred for 10 minutes at room temperature. Ethyl bromoacetate (3.48 g) dissolved in methanol (25 ml) was added dropwise, stirred for half an hour at room temperature and refluxed for 1 hour. The solvent was removed by evaporation under reduced pressure and the residue stirred at room temperature with a solution of sodium carbonate (4.5 g) in water (60 ml) for 4 hours. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol to give 4,5-dihydro-6'-fluoro-4 ', 4-benzothiazepine-3 (2H) - (mp 164-165 ° C). Yield 2.7 g. the ED 50 in the test described above was, for this compound of 1.7 mg / kg.

Exemolo 6

A solution of sodium periodate (1.19 g) in water (15 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-6-fluoro-1,4-benzothiazepine- 3 (2H) -one (1.1 g) in dichloromethane (125 ml). Stirring was maintained at room temperature for 3 days. The mixture was evaporated to dryness, under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (95: 5) afforded 4,5-dihydro-6-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 225-227 ° C ) which was recrystallized from ethanol. Yield 0.7 g. The ED50 in the test described above was, for this compound of 1.5 mg / kg.

Example 7

A solution of 5-fluoroanthranilic acid (13.5 g) in a mixture of water (87 ml) and hydrochloric acid (18 ml) was treated at 0 ° with a solution of sodium nitrite (5.8 g g) in water (25 ml), added dropwise. The solution was stirred for 1 hour at 0 ° C and then added to a solution of disodium disulphide (prepared from sodium sulfide nonahydrate (22.5 g), sodium hydroxide (3.6 g) and sulfur (2.9 g) in 73 960 ΜΑΤ / ΜΑΚ / Ρ 322

C. Water (27 ml)]. The mixture was allowed to stand for 3 hours at room temperature and acidified with hydrochloric acid. 2,2-dithiobis (5-fluorobenzoic acid) (mp 225-235 ° C), precipitated and collected by filtration.

A mixture of 2,2'-dithiobis (5-fluorobenzoic acid) (7.5 g) and thionyl chloride (177 ml) was stirred and heated under reflux for 4 hours. The mixture was evaporated under reduced pressure to give 2,2'-dithiobis (5-fluorobenzoyl chloride (m.p. 117 ° C).

A solution of 2,2'-dithiobis (5-fluorobenzoyl chloride) (7.6 g) in dioxane (250 ml) was saturated with anhydrous ammonia gas. The mixture was stirred at room temperature for 3 hours and then poured into water and acidified with concentrated hydrochloric acid. 2,2'-dithiobis (5-fluorobenzamide) (mp 180-183 ° C) precipitated and collected by filtration.

A stirred suspension of 2,2'-dithiobis (5-fluorobenzamide) (2.3 g) in dry ether (35 ml) was treated with lithium aluminum hydride (1.1 g) for 1.5 hours. The mixture was stirred and heated under reflux for 5 hours. After cooling the mixture, ethyl acetate (9 ml) was added with stirring and then the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (28 ml), with external cooling. The aqueous layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (5.4 ml) was added dropwise. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to afford S, N -dibenzoyl-5-fluoro-2-mercaptobenzylamine (m.p. 153-154 ° C).

A suspension of S, N-dibenzoyl-5-fluoro-2-mercaptobenzylamine (3 g), sodium hydroxide (3.5 g) in water (51 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. hours. After cooling, the mixture was acidified with concentrated hydrochloric acid and filtered to remove benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 5-fluoro-2-mercaptobenzylamine hydrochloride.

A solution of ethyl bromoacetate (1.2 g) in methanol (10 ml) was added dropwise to a stirred suspension of 5-fluoro-2-mercaptobenzylamine hydrochloride (1.37 g) and sodium methoxide (0.8 g) in methanol (40 ml). The mixture was stirred at room temperature for 30 minutes and then heated under reflux for one hour. The solvent was removed by evaporation under reduced pressure at ambient temperature with a solution of sodium carbonate ( 4.5 g) in water (60 ml) overnight. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol to give 4,5-dihydro-7-fluoro-1,4-benzothiazepine-3 (2H) -one (mp 179 DEG- 181 ° C).

A solution of sodium periodate (1.19 g) in water (15 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-7-fluoro-1,4- benzothiazepine-3 (2H) -one (1.1 g) in dichloromethane (100 ml). Stirring was maintained at room temperature for 3 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (95: 5) afforded 4,5-dihydro-7-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 190-192 ° C), which was recrystallized from ethanol. Yield 0.84 g. The above compound was administered to mice in the test described above at a dose of 100 mg / kg. 22% of the animals showed seizures, indicating that the ED50 value would be less than 100 mg / kg.

Example 8

A mixture of 2,2-dithiobis (4-fluorobenzoic acid) (20 g) and thionyl chloride (75 ml) was stirred and heated under reflux for 2 hours. The mixture was evaporated under reduced pressure to give 2,2'-dithiobis (4-fluorobenzoyl chloride) (m.p. 130-135Â ° C). V /. V /. -21- / 73 960 ΜΑΤ / ΜΑΚ / Ρ332

A solution of 2,27-dithiobis (4-fluorobenzoyl chloride) (17 g) in dioxane (400 ml) was saturated with anhydrous ammonia gas. The mixture was stirred at room temperature overnight and then poured into water and acidified with concentrated hydrochloric acid. 2,27-dithiobis (4-fluorobenzamide) (m.p. 245-249 ° C) precipitated and collected by filtration.

A stirred suspension of 2,27-dithiobis (4-fluorobenzamide) (7 g) in dry ether (100 ml) was treated over 1.5 hours with lithium aluminum hydride (3.4 g). The mixture was stirred and heated under reflux for 5 hrs. After the cooling of the mixture, ethyl acetate (28 ml) was added and then the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (88 ml) under external cooling. The aqueous layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (16 ml) was added dropwise. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to afford S, N -dibenzoyl-4-fluoro-2-mercaptobenzylamine (mp 112-114 ° C).

A suspension of S, N-dibenzoyl-4-fluoro-2-mercapto-benzylamine (6.4 g), sodium hydroxide (7.8 g) in water (115 ml) was heated under reflux in an atmosphere of nitrogen for 5 hours. After cooling, the mixture was acidified with concentrated hydrochloric acid and filtered to remove benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 4-fluoro-2-mercaptobenzylamine hydrochloride.

A solution of ethyl bromoacetate (2.7 g) in methanol (25 ml) was added dropwise to a stirred suspension of 4-fluoro-2-mercaptobenzylamine hydrochloride (3.1 g) and sodium methoxide (1, 86 g) in methanol (90 ml). The mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was stirred at 73 960 ΜΑΤ / ΜΑΚ / Ρ 3 3 sec: /

at room temperature with a solution of sodium carbonate (3.5 g) in water (50 ml) overnight. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol to give 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one (mp 202 DEG- 203 ° C). Yield 2.29 g. The ED50 in the test described above was, for this compound, 51.5 mg / kg.

Exemolo 9

A solution of the periodate of β-toluate (<25 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-8-fluoro-1 , 4-benzothiazepine-3 (2H) -one (1.47 g) in dichloromethane (200 ml). Stirring was maintained at room temperature for 2 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (95: 5) afforded 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 207-210ø C) which was recrystallized from ethanol. Yield 1.05 g. The ED50 in the test described above was, for this compound, 41 mg / kg.

Example 10

A solution of 3-fluoroantrilic acid (17.63 g), sodium hydroxide (4.4 g) and sodium nitrite (15.64 g) in water (128 ml) was added dropwise thereto a mixture of concentrated hydrochloric acid (28 ml) and ice (40 g). The solution was stirred for 3 hours at 0 ° C and then added to a disodium disulfide solution (prepared by heating a mixture of sodium sulfide nonahydrate (60 g) and sulfur (8.1 g) in water ( 86 ml) and addition of a solution of sodium hydroxide (10.58 g) in water (27 ml)]. The mixture was allowed to stand for 30 minutes in an ice bath at room temperature overnight and was acidified with hydrochloric acid (90 ml). The resulting solid was collected by filtration and dissolved in a warm aqueous solution of 10% sodium carbonate. Solid precipitated by the addition of hydrochloric acid which was dissolved in ethanol (200 ml) and treated with a 5% solution of iodine in ethanol (70 ml). The mixture was stirred overnight at ambient temperature and the solvent was removed by evaporation. Ethanol (100 ml) and water (100 ml) were added and the product 2,2f-dithiobis (3-fluorobenzoic acid) m.p. 216-222 ° C precipitated and collected by filtration.

A mixture of 2,2'-dithiobis (3-fluorobenzoic acid) (9 g) and thionyl chloride (80 ml) was stirred and heated under reflux for 1 hour. The mixture was evaporated to give a residue which was dissolved in dichloromethane (200 ml).

Ammonium hydroxide (14 ml) was added dropwise at 0-5 ° C and the mixture was stirred for 2 hours, the solvent was removed by evaporation and water (300 ml) was added to the residue. The resulting suspension was stirred at room temperature for 1 hour. The product, 2,2-dithiobis (3-fluorobenzamide) (mp 187-189 ° C) was collected by filtration.

A stirred suspension of 2,2'-dithiobis (3-fluoro-benzamide (8 g) in dry ether (60 ml) was treated with lithium aluminum hydride (4 g). The mixture was stirred and heated under reflux for After cooling the mixture, ethyl acetate (40 ml) was added with stirring and then the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (100 ml) under external cooling. The mixture was stirred at room temperature overnight, and the precipitated solid was collected by filtration, washed with water, and dried (MgSO 4) and evaporated to dryness. recrystallized from ethanol to give S, N -dibenzoyl-3-fluoro-2-mercaptobenzylamine (mp 163-164 ° C).

A suspension of S, N-dibenzoyl-3-fluoro-2-mercaptobenzylamine (7.48 g) and sodium hydroxide (8.95 g) in water was refluxed under nitrogen for 5 hours. (138 ml). 73 960 ΜΑΤ / ΜΑΚ / Ρ332 /// y_____ -24-

After cooling the mixture, it was acidified with concentrated hydrochloric acid and filtered to remove the benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 3-fluoro-2-mercaptobenzylamine hydrochloride (mp 222-226 ° C).

A solution of ethyl bromoacetate (1.92 ml) in methanol (45 ml) was added dropwise to a stirred suspension of 3-fluoro-2-mercaptobenzylamine hydrochloride (3.36 g) and The mixture was stirred at room temperature for 30 minutes and then heated under reflux for one hour. The solvent was removed by evaporation under reduced pressure and the solvent was removed under reduced pressure. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol for 2 hours. The residue was stirred at room temperature with a solution of sodium carbonate (5.64 g) in water (80 ml) for 1.5 hours. to give 4,5-dihydro-9-fluoro-1,4-benzothiazepine-3 (2H) -one (mp 210-212 ° C) Yield 1.81 g The above compound was administered to mice in the test described above at a dose of 100 mg / kg. 20% of the animals showed attacks indicating that the ED 50 value should be less than 100 mg / kg.

Example 11

A stirred suspension of 2,2-dithiobis (6-chloro-benzonitrile) (9 g) in dry ether (270 ml) was treated with lithium aluminum hydride (6 g). The mixture was stirred and heated under reflux for 5 hours. After cooling the mixture, ethyl acetate (45 ml) was added with stirring and the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (300 ml), with external cooling. The aqueous phase was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (23 ml) was added dropwise. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with water to give S, N -dibenzoyl-6-chloro-2-mercaptobenzylamine (mp 73-60 °).

171-173 ° C).

A suspension of S, N-dibenzoyl-6-chloro-2-mercaptobenzylamine (11 g) and sodium hydroxide (17.7 g) in water (170 ml) was heated under reflux under nitrogen for 5 hours. ml). After cooling, the mixture was acidified with concentrated hydrochloric acid and filtered to remove the benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 6-chloro-2-mercaptobenzylamine hydrochloride.

A solution of ethyl bromoacetate (4.17 ml) in methanol (150 ml) was added dropwise to a stirred suspension of 6-chloro-2-mercaptobenzylamine hydrochloride (5.25 g) and sodium methoxide (2.7 g) in methanol (150 ml). The mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was stirred overnight at room temperature with a solution of sodium carbonate (8 g) in water (100 ml). The precipitated product was separated by filtration and washed with water, dried and crystallized from ethanol to give 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one (mp 170-172 ° C ). Yield 4.5 g. The ED50 in the test described above was, for this compound, 0.2 mg / kg.

Example 12

A solution of sodium periodate (0.85 g) in water (10 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-6-chloro-1,4-benzothiazepine -3 (2H) -one (0.85 g) in dichloromethane (60 ml). Stirring was maintained at room temperature for 4 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (95: 5) as the eluent gave 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 231-233 ° C) which was recrystallized from ethanol. Yield 0.6 g. 73 960 ΜΆΤ / ΜΑΚ / Ρ 3 3 2

-26- λ ·

ED50 in the test described above was 1.2 g / kg for this compound.

Exemolo 13

A stirred suspension of 2,2'-dithiobis (6-methylbenzamide) (15 g) in dry ether (270 ml) was treated with lithium aluminum hydride (7.4 g) . The mixture was stirred and heated under reflux for 5 hours. After cooling the mixture, ethyl acetate (65 ml) was added with stirring and then the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (234 ml) with ether. separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (25.3 ml) was added dropwise. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water and crystallized from ethanol to give S, N -dibenzoyl-2-mercapto-6-methylbenzylamine (mp 165-168 ° C).

A suspension of S, N-dibenzoyl-2-mercapto-6-methylbenzylamine (8 g) and sodium hydroxide (11.7 g) in water (under nitrogen) was refluxed under nitrogen for 5 hours. 160 ml). After cooling, the mixture was acidified with concentrated hydrochloric acid and filtered to remove benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 2-mercapto-6-methylbenzylamine hydrochloride.

A solution of ethyl bromoacetate (2.19 g) in methanol (25 ml) was added dropwise to a stirred suspension of 2-mercapto-6-methylbenzylamine hydrochloride (2.4 g) and (1.41 g) in methanol (75 ml). Stirring was continued at room temperature for 30 minutes and then under reflux for 1 hour. The solvent was removed by evaporation under reduced pressure and the residue was stirred at room temperature with a solution of sodium carbonate (4.5 g) in water (80 ml) for 4 hours. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol, to give 4- -1,4-benzothiazepine-3 (2H) -one (mp 186-187 ° C). Yield 1 g. ED 50 in the test described above was, for this compound, 20 mg / kg.

Example 14

A solution of sodium periodate (1.1 g) in water (15 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-6-methyl-1,4- benzothiazepine-2 (2H) -one (1 g) in dichloromethane (125 ml). Stirring was carried out at room temperature for 4 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (95: 5) as the eluent afforded 4,5-dihydro-6-methyl-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 235 DEG- 238 ° C) which was recrystallized from ethanol. Yield 0.86 g. The ED50 in the test described above was, for this compound of 2.8 mg / kg.

Example 15

A solution of 2,2'-dithiobis (6-methoxybenzoic acid) (13 g) and triethylamine (8.08 g) in tetrahydrofuran (25 ml) was cooled in an ice bath and drop was added dropwise, ethyl chloroformate (9.02 g) with vigorous stirring. The mixture was stirred for an additional 30 minutes and then treated with anhydrous ammonia gas. The mixture was stirred at room temperature overnight and then poured into water. The product 2,2'-dithiobis (6-methoxybenzamide) (mp 225-227 ° C) precipitated and collected by filtration.

A stirred suspension of 2,2'-dithiobis (6-methoxybenzamide) (7 g) in dry ether (180 ml) was treated with lithium aluminum hydride (4.6 g) . The mixture was stirred and heated under reflux for 5 hours. After cooling the mixture, ethyl acetate (35 ml) was added with stirring and then the mixture was treated with a 2: 1 mixture of hydrochloric acid and water (90 ml) with external cooling. The aqueous phase was separated and basified with aqueous solution of 5N sodium hydroxide and then benzoyl chloride (18 ml) was added dropwise. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water and dried, to give S, N -dibenzoyl-2-mercapto-6-methoxybenzylamine (mp 145-150 ° C).

A suspension of S, N-dibenzoyl-2-mercapto-6-methoxybenzylamine (4.6 g) and sodium hydroxide (7.4 g) in water was refluxed under nitrogen for 5 hours (70 ml). After cooling, the mixture was acidified with concentrated hydrochloric acid and filtered to remove benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 2-mercapto-6-methoxybenzylamine hydrochloride.

A solution of ethyl bromoacetate (1.82 g) in methanol (17 ml) was added dropwise to a stirred suspension of 2-mercapto-6-methoxybenzylamine hydrochloride (2.25 g) and sodium (1.18 g) in methanol (60 ml). The mixture was stirred at room temperature for 30 minutes and then heated under reflux for 1 hour. the solvent was removed by evaporation under reduced pressure. The residue was stirred at room temperature with a solution of sodium carbonate (3 g) in water (50 ml) overnight. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol to give 4,5-dihydro-6-methoxy-1,4-benzothiazepine-3 (2H) -one (mp 166-168 ° C). Yield 1.5 g. The ED50 in the test described above was, for this compound, 63.4 mg / kg.

Example 16

A solution of 4-methoxyanthranilic acid (26.25 g) in a mixture of water (90 ml) and hydrochloric acid (33 ml) was treated with a solution of sodium nitrite (11.35 g ) in water (40 ml), added dropwise. The solution was stirred for 1 hr at -78 ° C. Was added at 0 ° C and then added to a solution of disodium disulphide [prepared from nonahydrated sodium sulfide (39.5 g), sodium hydroxide (7 g) and sulfur (5.2 g ) in water (55 ml)]. The mixture was allowed to stand for 3 hours at room temperature and acidified with hydrochloric acid. The product 2,2'-dithiobis (4-methoxybenzoic acid) (mp 292-295 ° C) precipitated and collected by filtration.

A mixture of 2,2'-dithiobis (4-methoxybenzoic acid) (12 g) and thionyl chloride (110 ml) was stirred and heated under reflux for 1.5 hours. The mixture was evaporated under reduced pressure to give 2,2'-dithiobis (4-methoxybenzoyl chloride).

A solution of 2,2'-dithiobis (4-methoxybenzoyl chloride (12.1 g) in dioxane (150 ml) was saturated with anhydrous ammonia gas. The mixture was stirred at room temperature overnight and then poured into water and acidified with concentrated hydrochloric acid.The product 2,2'-dithiobis (4-methoxybenzamide) (mp 230-233 ° C) precipitated and collected by filtration.

A stirred suspension of 2,2'-dithiobis (4-methoxybenzamide) (8.7 g) in dry ether (250 ml) was treated with lithium aluminum hydride (5.6 g ). The mixture was stirred and heated under reflux for 5 hours. After cooling the mixture, ethyl acetate (43 ml) was added with stirring, and the mixture was then treated with a 2: 1 mixture of hydrochloric acid and water (150 ml), with external cooling. The aqueous phase was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (23 ml) was added dropwise. The mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to afford S, N -dibenzoyl-2-mercapto-4-methoxybenzylamine (mp 125-130 ° C).

A suspension of S, N-dibenzoyl-2-mercapto-4-methoxybenzylamine (2.5 g) and sodium hydroxide (4.2 g) in water was refluxed under nitrogen under nitrogen for 5 hours (45 ml). After cooling, the mixture was acidified with chloroacetyl chloride,

concentrated and filtered to remove benzoic acid. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in boiling absolute ethanol. Evaporation of the solvent gave 2-mercapto-4-methoxybenzylamine hydrochloride.

A solution of ethyl bromoacetate (1.45 ml) in methanol (50 ml) was added dropwise to a stirred suspension of 2-mercapto-4-methoxybenzylamine hydrochloride (1.8 g) and sodium (0.94 g) in methanol (15 ml). The mixture was stirred at room temperature for 30 minutes then heated under reflux for 1 hour. The solvent was removed by evaporation under reduced pressure and the residue was stirred at room temperature with a solution of sodium carbonate (2 g) in water (30 ml) for 2 hours. The precipitated product was separated by filtration, washed with water, dried and crystallized from ethanol to give 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one (mp 182-184 ° C). Yield 1.16 g. The above compound was administered to mice in the test described above at a dose of 100 mg / kg. 50% of the animals showed seizures, indicating that the ED 50 value should be about 100 mg / kg.

Exemolo 17

A solution of sodium periodate (0.53 g) in water (10 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-8-methoxy-1,4 3 (2H) -one (0.52 g) in dichloromethane (60 ml). Stirring was maintained at room temperature for 5 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane: ethanol (95: 5) as the eluent afforded 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one 1-oxide (mp 198-200 ° C) which was recrystallized from ethanol. Yield 0.42 g. The ED 50 in the test described above was, for this compound, 66.7 mg / kg.

Claims (15)

E. A compound according to claim 1 having the formula I wherein n = 0, 1 or 2; R re represents from ind pen d d d d H H H H H H & &. alkyl of 1 to 4 carbon atoms or alkoxy, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 1 to 4 carbon atoms, optionally alkylated carbamoyl or optionally alkylated sulfamoyl; R 2, R 3, R 4, R 5 and R 8 independently represent hydrogen or alkyl having 1 to 4 carbon atoms; wherein R 2 and / or R 3 are H or methyl and R 4, R 5 and R 6 are hydrogen, and are not both 0 and when n = 0, 1 or 1, 2, R 1 is methoxy, R 2 and / or R 3 are H or methyl and R 4, R 5 and R 6 are hydrogen, m is not 2. Compounds of the formula I according to claim 1, characterized in that n = 0 or 1, m = 0 or 1, R 1 is fluoro, chloro, bromo, iodo, methyl, methoxy, polyhaloalkyl, nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulfamoyl and R2, R3, R4, R5 and R6 are independently H or methyl. Compounds of formula I according to claim 1 wherein n = 0 or 1, m is 0 or 1, R 1 is fluoro, chloro, bromo, methyl or methoxy and R 2 and R 4 are independently H or methyl and R 3, R 5 and R 6 are H. A compound of formula I as claimed in claim 1, characterized in that: 4,5-dihydro-2-methyl-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-N-methyl-1,4-benzothiazepine-3 (2H) -one; 73 960 ΜΑΤ / ΜΑΚ / Ρ 322 γ 4,5-dihydro-6-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-9-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-bromo-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-methyl-1H-4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-methoxy-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one. A compound of formula I as claimed in claim 1, characterized in that: 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-7-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-methyl-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one 1-oxide; and stereoisomers thereof. Pharmaceutical compositions characterized in that they comprise a therapeutically effective amount of a compound of formula I in which n = 0, 1 or 2; represents independently halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 1 to 4 carbon atoms, optionally alkylated carbamoyl and sulfamoyl optionally alkylated; R 2, R 3, R 4, R 5 and R 6 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4, together with a pharmaceutically acceptable diluent or carrier. Pharmaceutical compositions according to claim 6, characterized in that they comprise a therapeutically effective amount of a compound of formula I, wherein n = 0 or 1, m = 0 or 1, is fluoro, chloro, bromo, iodo, methyl, methoxy, polyhaloalkyl, nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulfamoyl and R2, R3, R4, R5 and R6 are independently H or methyl. Pharmaceutical compositions according to claim 6, characterized in that they comprise a therapeutically effective amount of a compound of formula I, wherein n = 0 or 1, m is 0 or 1 and K 1 is fluoro, chloro, bromo, methyl or methoxy and R 2 and R 4 are independently H or methyl and R 3, R 5 and R 6 are H. Pharmaceutical compositions according to claim 6, characterized in that they comprise a therapeutically effective amount of a compound selected from the group consisting of 4,5-dihydro-1,4-benzothiazepine-3 (2H) ) -one; 4,5-dihydro-2-methyl-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-N-methyl-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-9-fluoro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-bromo-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-methyl-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-6-methoxy-1,4-benzothiazepine-3 (2H) -one; 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one. Pharmaceutical compositions according to claim 6, characterized in that they comprise a therapeutically effective amount of a compound of formula I selected from: 4,5-dihydro-1,4-benzothiazepine-3 (2H) -one 1 -oxide; 4,5-dihydro-6-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-7-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-8-fluoro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-chloro-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-6-methyl-1,4-benzothiazepine-3 (2H) -one 1-oxide; 4,5-dihydro-8-methoxy-1,4-benzothiazepine-3 (2H) -one 1-oxide; and stereoisomers thereof. A compound of formula I, wherein n = 0, 1 or 2; R 1 is independently halo, alkyl of 1 to 4 MAT / MAK / P332 Carbon, C1 -C4 alkoxy, C1 -C4 haloalkyl, nitro, cyano, carboxy, C1 -C4 alkanoyl, optionally alkylated carbamoyl and optionally alkylated sulfamoyl; R 2, R 3, R 4, R 5 and R 8 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4 for use in the treatment of neurological disorders. A compound of formula I, wherein n = 0, 1 or 2; Rx is independently halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 1 to 4 carbon atoms, carbamoyl optionally alkylated and optionally alkylated sulfamoyl; R 2, R 3, R 4, R 5 and R 8 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4, for use in the treatment of epilepsy. Use of a compound of formula I, wherein n = 0, 1 or 2; R 4 is independently halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 1 to 4 carbon atoms, carbamoyl optionally alkylated and optionally alkylated sulfamoyl; R 2, R 3, R 4, R 5 and R 8 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4, in the preparation of a medicament for the treatment of neurological disorders. Use of a compound of formula I, wherein n = 0, 1 or 2; RL is independently halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, nitro, cyano, carboxy, alkanoyl of 1 to 4 carbon atoms, optionally alkylated carbamoyl and optionally alkylated sulfamoyl; R 2, R 3, R 4, R 5 and R 8 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4, in the preparation of a medicament for the treatment of epilepsy. -35- 73 960 ΜΑΤ / ΜΑΚ / Ρ332 A process for the preparation of compounds of formula I according to claim 1, characterized in that it comprises the step of: A) cyclisation of compounds of the formula II (R 2 R 3 a) -C (O) R 2 - wherein R 7 is H or a group derived from an alcohol and Y is a salt-forming anion by treatment with a base, optionally by heating, B) reacting compounds of formula III III wherein Y is a salt-forming anion with a halo-substituted ester of formula IV wherein Z is, for example, chlorine or bromine and Rg is a group derived from an alcohol, in the presence of a base, optionally by heating, followed optionally by treatment with aqueous sodium carbonate; C) cyclisation of compounds of formula V (See Formula V) V -36-73 960 ΜΑΤ / ΜΑΚ / Ρ32 SH c-nh.co.ch2ci D) from compounds of formula VI VI by the Ritter reaction, in the presence of a strong acid, followed by hydrolysis? E) Beckmann rearrangement of compounds of formula VII VII wherein R6 is H or arylsulfonyl; F) oxidation of compounds of formula I wherein n = 0, to give compounds of formula I wherein n = 1; G) oxidizing compounds of formula I wherein n = 0 or 1, to yield compounds of formula I wherein n = 2; H) alkylation of compounds of formula I wherein R 4 is H, to give compounds of formula I wherein R 4 is alkyl. Lisbon, 2 &amp; MÀi 1992 By THE BOOTS COMPANY PLC = 0 0FICIAL AGENT =