WO1992021668A1

WO1992021668A1 - Benzothiazepinones and their use as anticonvulsants

Info

Publication number: WO1992021668A1
Application number: PCT/EP1992/001221
Authority: WO
Inventors: William Roger Buckett; Paul John Harris; John Rosindale Housley; James Edward Jeffery; Kenneth John Nichol; Enriqueta Fernandez Navarro
Original assignee: The Boots Company Plc
Priority date: 1991-05-25
Filing date: 1992-05-25
Publication date: 1992-12-10
Also published as: CN1087338A; IE921589A1; PT100518A; IL101972A0; AU1880792A; GB9111376D0; MX9202432A

Abstract

Compounds of formula (I) in which n = 0, 1 or 2; R1 independently represents halo, 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 sulphamoyl; R2, R3, R4, R5 and R6 independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4 have utility as anticonvulsants in the treatment of neurological disorders such as epilepsy.

Description

Benzothiazeplnones and their use as antlconvulsants

^• This invention relates to 4 , 5-dihydro-l, 4-benzo- thiazepin-3 (2H)ones, to pharmaceutical compositions containing them, to processes for their preparation and to their use in the treatment of neurological disorders such as epilepsy.

In particular the present invention relates to compounds of formula I

in which n = 0, 1 or 2; R-^ independently represents 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 sulphamoyl; R₂, R3, R4, Re and Re independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4.

Compounds of formula I in which n and m = 0, R₂ and/or R3 represent hydrogen or methyl and R4, R5 and Rg represent hydrogen and compounds of formula I in which n = 0, 1 or 2, R^ represents methoxy, m = 2, R₂ and/or R3 represent hydrogen or methyl and R4, R5 and Rg represent hydrogen are known [see Szabo et al Chem Ber 119, 2904-2913 (1986)] . The present invention therefore provides novel compounds of formula I in which n = 0, 1 or 2; R-_j_ independently represents halo, 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 sulphamoyl; R₂, R3, R₄, R₅ and Rg independ¬ ently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4 with the provisos that when R and/or R3 represent H or methyl and R₄, R-- and Rg represent hydrogen, n and m are not both 0 and that when n = 0, 1 or 2, R-_j_ is methoxy, R₂ and/or R represent H or methyl and R4, R5 and Rg represent hydrogen, m does not equal 2. When m is greater than 1, the substituents represented by R-_ may. be the same or different.

In preferred compounds of formula I, n = 0 or 1, m = 0 or 1, R_]_ is fluoro, chloro, bromo, iodo, methyl, methoxy, polyhaloalkyl (eg trifluoromethyl) , nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethyl- sulphamoyl and R , R3, R₄, R5 and Rg are independently H or methyl.

In particularly preferred compounds of formula I, n = 0 or 1, m is 0 or 1 and R-_j_ is fluoro, chloro, bromo, methyl or methoxy and R₂, and R4, are independently H or methyl, and R3, R5 and Rg are H.

Specific compounds of formula I in which n = 0 are:-

4,5-dihydro-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-2-methyl-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-N-methyl-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-6-fluoro-l,4-benzothiazepin-3 (2H)one; 4,5-dihydro-8-fluoro-1,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-9-fluoro-1,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-6-chloro-l,4-benzothiazepin-3 (2H) -one; 4,5-dihydro-β-bromo-l,4-benzothiazepin-3 (2H) -one; 4,5-dihydro-6-methyl-l,4-benzothiazepin-3 (2H) -one; 4,5-dihydro-6-methoxy-l,4-benzothiazepin-3 (2H) -one; 4, 5-dihydro-8-methoxy-l,4-benzothiazepin-3 (2H) -one;

Specific compounds of formula I in which n - 1 are:-

4,5-dihydro-l,4-benzothiazepin-3 (2H) -one 1-oxide; 4,5-dihydro-6-fluoro-1,4-benzothiazepin-3 (2H)-one 1-oxide;

4, 5-dihydro-7-fluoro-1, 4-benzothiazepin-3 (2H) -one

1-oxide; 4,5-dihydro-8-fluoro-1,4-benzothiazepin-3 (2H)-one 1-oxide; 4, 5-dihydro-6-chloro-l, 4-benzothiazepin-3 (2H) -one 1-oxide; 4,5-dihydro-6-methyl-l,4-benzothiazepin-3 (2H)-one

1-oxide; 4, 5-dihydro-8-methoxy-l,4-benzothiazepin-3 (2H) -one 1-oxide; and their stereoisomers.

It will be appreciated by those skilled in the art that certain compounds of formula I contain one or more chiral centres. Thus, for example compounds of formula I in which n is 1 contain a chiral centre at the sulphur atom; compounds of formula I in which R₂ and R are not identical contain a chiral centre at the 2-carbon atom and compounds of formula I in which R5 and Rg are not identical contain a chiral centre at the 5-carbon atom. When a compound of formula I contains a single chiral centre it may exist in two enantiomeric forms. The present invention includes each enantiomer and mixtures of the enantiomers. The enantiomers may be obtained by methods known to those skilled in the art. Such methods typically include resolution via formation of diastereo- isomeric salts or complexes which may be separated, for example, by crystallisation; formation of dia- stereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography followed by the liberation of the desired enantiomer from the separated derivative; selective derivatisation of one enantiomer by reaction with an enantiomer-specific reagent, for example enzymatic oxidation or reduction; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support or in the presence of a chiral solvent. Alternatively, it may be possible to synthesi^'se a specific enantiomer by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or to convert one enantiomer into the other by asymmetric transformation.

When a compound of formula I contains more than one chiral centre it may exist in diastereoisomeric forms. The diastereoisomers may be separated by methods known to those skilled in the art, for example chromatography or crystallisation. The present invention includes each diastereoisomer of 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 in which n = 0, 1 or

2; R-L independently represents 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 sulphamoyl; R , R3, R4, R5 and

Rg 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. Such pharmaceutical formulations may be used as anticonvulsants 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 known pharmaceutical compositions 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 form.

Compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oil suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art. 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 maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, 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 each

SUBSTITUTESHEET 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 carboxymethyl- cellulose, 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 known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.

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

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 dispersed 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 particles of very small size, for example as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. The 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 human beings. In such treatment the amount of the compound of formula I administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in a single or in divided doses at one or more times during the day.

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

Compounds of formula I in which n = 0 may be prepared by the cyclisation of compounds of formula II

wherein R₇ 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 in which n = 0 may be prepared by the reaction of compounds of formula III

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

in which Z is, for example, chloro or bromo and Rg is a group derived from an alcohol, in the presence of a base (for example sodium methoxide) optionally by heating optionally followed by treatment with aqueous sodium carbonate.

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

Compounds of formula I in which n = 0 and R₄ is H may be prepared from compounds of formula VI

by the Ritter reaction in the presence of a strong acid such as sulphuric acid followed by hydrolysis. Compounds of formula I in which n = 0 and R₂, R , R₄, R₅ and Rg are H may be prepared by the Beckirtann rearrangement of compounds of formula VII

in which Rg is H or arylsulphonyl (for example p_- toluenesulphonyl) .

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

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

Compounds of formula I in which R₄ is alkyl may be prepared by the alkylation (for example with dimethyl- sulphate) of compounds of formula I in which R₄ is H.

Compounds of formula II in which Ry is H may be prepared by the reaction of compounds of formula III with a halo-substituted acid of formula VIII

2-C-COoH VIII in which Z is, for example, chloro or bromo in the presence of a base (for example sodium methoxide) . Compounds of formula II in which Rη is other than H may be prepared by esterification of compounds of formula II in which R is H.

Compounds of formula III may be prepared by the debenzoylation of compounds of formula IX

for example by hydrolysis followed by salt formation.

Compounds of formula V may be prepared by the reaction of compounds of formula X

with a compound of formula C1C0CH C1.

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 reaction of compounds of formula X with a benzoylating agent (for example benzoyl chloride) in the presence of a base (for example sodium hydroxide) .

Compounds of formula X in which R^ and Rg are H may be prepared by reduction of compounds of formula XII

or the reduction of compounds of formula XIII

or the reduction of compounds of formula XIV

or the reduction of compounds of formula XV

for example with lithium aluminium hydride.

Compounds of formula XII may be prepared by the reaction of compounds of formula XVI

(R I.

or by the reaction of compounds of formula XVII

with ammonia.

Compounds of formula XV may be prepared by the reaction of a compound of formula XVIII

XVIII

with a compound of formula XIX

HS-CH₂-CH₂—CN XIX

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

Compounds of formula XVI may be prepared by the reaction of compounds of formula XX

for example, with thionyl chloride.

Compounds of formula XVII may be prepared by the reaction of compounds of formula XX with ethyl chloro- formate in the presence of a base such as triethylamine.

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

followed by reaction with an alkali metal disulphide for example disodiu disulphide. The anticonvulsant activity of the compounds of formula I was demonstrated by observing the ability of the compound to antagonise the myoclonic seizures induced by the administration of bicuculline. In these experiments groups of female mice in the weight range 25 to 30 gram had free access to food and water until one hour before administration of the compound of formula I to be tested. The compound to be tested was orally administered at one or more doses in 1% aqueous methylcellulose solution. One hour later (+)- bicuculline at a dose of 0.55 mg/kg was administered intravenously into a tail vein. During the following two minutes the animals were observed and the percentage of animals showing seizures was recorded. A value for the dose limiting the seizures to 50% of the animals

(EDC_Q) was then calculated from the regression straight line plot of the percentage of animals having seizures against the dose of the compound of formula I administered when results at more than one dose were available.

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 ambient temperature for 30 minutes and then the solvent was removed by evaporation at reduced pressure. The residue was stirred at ambient 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 crystallised from ethanol to give 4,5-dihydro-l,4-benzothiazepin-3 (2H) -one (m.p. 184-186°C) . Yield 7.4 g.

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

Example 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-l,4-benzothiazepin-3 (2H) -one (2.23 g) in dichloromethane (175 ml). The stirring was continued at ambient temperature for 1 day. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloro¬ methane:ethanol (98:2) gave 4, 5-dihydro-l, 4- benzothiazepin-3 (2H) -one 1-oxide (m.p. 195-197°C) which was recrystallised from ethanol.

The ED₅₀ iⁿ the test described above for this compound was 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) in anhydrous methanol (120 ml) . The stirring was continued at ambient temperature for 30 minutes, then at reflux for 1.5 hours. The solvent was removed by evaporation at reduced pressure, and the residue stirred at ambient 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 recrystallised from ethanol to give 4,5-dihydro-2- methyl-1,4-benzothiazepin-3 (2H)-one (m.p. 214-216°C) . Yield 2.59 g.

The ED5_Q in the test described above for this compound was 18.7 mg/kg.

Example 4

A solution of 4,5-dihydro-l,4-benzothiazepin-3 (2H)- one (0.53 g) in dry dimethyl sulphoxide (30 ml) was added dropwise with stirring to a mixture of a 57% suspension of sodium hydride in mineral oil (0.14 g) and dry dimethyl sulphoxide (10 ml) . Stirring was continued at ambient temperature for 30 minutes and then dimethyl sulphate (572 ml) was added. The mixture was stirred at ambient temperature for 2 hours, at 100°C for another 2 hours, and at ambient temperature overnight. Water was added and the mixture extracted with ether, washed, dried and evaporated. The crude product is purified by flash chromatography using a mixture of dichloromethane ethyl acetate (1:1) as eluent to give 4,5-dihydro-N- methyl-l,4-benzothiazepin-3 (2H)-one (m.p. 86-88°C) which was recrystallised from hexane.

The above compound was administered to mice in the test described above at 100 mg/kg. 50% of the animals showed seizures indicating that the EDCJ_Q value would be around 100 mg/kg.

Example 5

A mixture of 3-fluoro-2-methylaniline (50 g) and acetic anhydride (400 ml) was shaken at ambient 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 (m.p. 132-134°C) .

BSTITUTE SHEET 3-Fluoro-2-methylacetanilide (20 g) was added with stirring to a mixture of magnesium sulphate (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 sulphuric acid and water to give N-acetyl-6- fluoroanthranilic acid (m.p. 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-Fluoro- anthranilic acid (m.p. 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 at 0°C 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 solution of disodium disulphide [prepared by treating a mixture of sodium sulphide nonahydrate (55 g) and sulphur (7.15 g) in water (66 ml) with a solution of sodium hydroxide (88 g) in water (22 ml)]. The mixture was allowed to stand for 3 hours at ambient temperature and acidified with hydrochloric acid. The resulting precipitate was dissolved in a hot solution of sodium carbonate (7 g) in water (700 ml) . The solution was then filtered and acidified with hydrochloric acid. 2,2'-Dithiobis(6-fluorobenzoic acid) (m.p. 224-230°C) precipitated and was collected by filtration and 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-fluorobenzoylchloride) .

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

A stirred suspension of 2,2'-dithiobis(6-fluoro¬ benzamide) (12 g) in dry ether (200 ml) was treated with lithium aluminium hydride (5.82 g) . The mixture was stirred and heated under reflux for 4 hours. After the mixture had been cooled, 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 layer 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 ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to give S,N-dibenzoyl-6-fluoro-2-mercaptobenzylamine (m.p. 149-152°C) which was recrystallised from ethanol.

A suspension of S,N-dibenzoyl-6-fluoro-2-mercapto- benzylamine (8.5 g) , sodium hydroxide (9.97 g) in water (145 ml) was heated under reflux in a nitrogen atmosphere for 4.5 hours. After cooling in ice, the mixture was acidified with concentrated hydrochloric acid and a solid collected by filtration and treated with boiling absolute ethanol to give 6-fluoro-2- mercaptobenzylamine hydrochloride. 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 ambient temperature. Ethyl bromoacetate (3.48 g) dissolved in methanol (25 ml) was added dropwise, shaken for half an hour at ambient temperature and refluxed for 1 hour. The solvent was removed by evaporation at reduced pressure, and the residue shaken at ambient 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 crystallised from ethanol to give 4,5-dihydro-6- fluoro-l,4-benzothiazepin-3 (2H)one (m.p. 164-165°C) . Yield 2.7 g.

The DCJ_Q in the test described above for this compound was 1.7 mg/kg.

Example 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-l,4-benzothiazepin- 3(2H)one (1.1 g) in dichloromethane (125 ml). The stirring was continued at ambient temperature for 3 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane:ethanol (95:5) gave 4,5-dihydro-6- fluoro-1,4-benzothiazepin-3 (2H) -one 1-oxide (m.p. 225- 227°C) which was recrystallised from ethanol. Yield 0.7 g.

The EDCJ_Q in the test described above for this compound was 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°C with a solution of sodium nitrite (5.8 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 sulphide nonahydrate (22.5 g) , sodium hydroxide (3.6 g) and sulphur (2.9 g) in water (27 ml)]. The mixture, was allowed to stand for 3 hours at ambient temperature and acidified with hydrochloric acid. 2,2'-Dithiobis(5- fluorobenzoic acid) (m.p. 225-235°C) precipitated and was 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-fluorobenzoylchloride) (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 ambient temperature for 3 hours and then poured into water and acidified with concentrated hydrochloric acid. 2,2'-Dithiobis(5-fluorobenzamide) (m.p. 180- 183°C) precipitated and was collected by filtration.

A stirred suspension of 2,2'-dithiobis (5-fluoro¬ benzamide) (2.3 g) in dry ether (35 ml) was treated over 1.5 hours with lithium aluminium hydride (1.1 g) . The mixture was stirred and heated under reflux for 5 hours. After the mixture had been cooled, 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 ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to give S,N-dibenzoyl-5-fluoro-2-mercaptobenzylamine (m.p. 153-154°C) .

A suspension of S,N-dibenzoyl-5-fluoro-2-mercapto- benzylamine (3 g) , sodium hydroxide (3.5 g) in water

(51 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. 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 dissolved in boiling absolute ethanol. Evaporation of 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 ambient temperature for 30 minutes and then heated under reflux for one hour. The solvent was removed by evaporation at reduced pressure. The residue was stirred 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 crystallised from ethanol to give 4,5-dihydro-7- fluoro-l,4-benzothiazepin-3 (2H) -one (m.p. 179-181°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-l,4-benzothiazepin- 3(2H)-one (1.1 g) in dichloromethane (100 ml). The stirring was continued at ambient temperature for 3 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane:ethanol (95:5) gave 4,5-dihydro-7- fluoro-l,4-benzothiazepin-3 (2H)-one 1-oxide (m.p. 190- 192°C) which was recrystallised from ethanol. Yield 0.84 g.

The above compound was administered to mice in the test described above at 100 mg/kg. 22% of the animals showed seizures indicating that the ED-- - 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-fluorobenzoylchloride) (m.p. 130-135°C) .

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

A stirred suspension of 2,2'-dithiobis(4-fluoro- benzamide) (7 g) in dry ether (100 ml) was treated over 1.5 hours with lithium aluminium hydride (3.4 g) . The mixture was stirred and heated under reflux for 5 hours. After the mixture had been cooled, ethyl acetate (28 ml) was added and then the mixture was treated with a 2:1 mixture of hydrochloric acid and water (88 ml) with 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 ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to give S,N-dibenzoyl-4- fluoro-2-mercaptobenzylamine (m.p. 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 a nitrogen atmosphere for 5 hours. 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 solvent gave 4-fluoro-2-mercapto- benzylamine 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 ambient temperature for 30 minutes and then heated under reflux for 1 hour. The solvent was removed by evaporation at reduced pressure. The residue was stirred at ambient 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 crystallised from ethanol to give 4,5-dihydro-8- fluoro-l,4-benzothiazepin-3 (2H)-one (m.p. 202-203°C) . Yield 2.29 g.

The ED₅o in the test described above for this compound was 51.5 mg/kg.

SHEET Example 9

A solution of sodium periodate (1.6 g) in water

(25 ml) was added dropwise with cooling to a stirred solution of 4,5-dihydro-8-fluoro-l,4-benzothiazepin- 3(2H)-one (1.47 g) in dichloromethane (200 ml). The stirring was continued at ambient temperature for 2 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane:ethanol (95:5) gave 4,5-dihydro-8- fluoro-l,4-benzothiazepin-3 (2H)-one 1-oxide (m.p.

207-210°C) which was recrystallised from ethanol. Yield 1.05 g) .

The EDc_jg in the test described above for this compound was 41 mg/kg.

Example 10

A solution of 3-fluoroanthranilic acid (17.63 g) , sodium hydroxide (4.4 g) and sodium nitrite (15.64 g) in water (128 ml) was added dropwise to 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 solution of disodium disulphide [prepared by heating a mixture of sodium sulphide nonahydrate (60 g) and sulphur (8.1 g) in water (86 ml) and adding 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 and at ambient temperature overnight and was then acidified with hydrochloric acid (90 ml) . The resulting solid was collected by filtration and dissolved in a warm 10% aqueous solution of sodium carbonate. A solid was 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 removed by evaporation. Ethanol (100 ml) and water (100 ml) were added and 2,2'-dithiobis(3-fluorobenzoic acid) (m.p. 216-222°C) precipitated and was 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 under reduced pressure 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 stirred for 2 hours. The solvent was removed by evaporation and water (300 ml) added to the residue. The resulting suspension was stirred at ambient temperature for 1 hour. 2,2'-Dithiobis(3- fluorobenzamide) (m.p. 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 aluminium hydride (4 g) . The mixture was stirred and heated under reflux for 5 hours. After the mixture had been cooled, 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) with external cooling. The aqueous layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (8 ml) was added dropwise. The mixture was stirred at ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and recrystallised from ethanol to give S,N-dibenzoyl-3-fluoro-2-mercaptobenzylamine (m.p. 163-164°C) . A suspension of S,N-dibenzoyl-3-fluoro-2-mercapto- benzylamine (7.48 g) , sodium hydroxide (8.95 g) in water

(138 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. After the mixture had been cooled, 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 solvent gave 3-fluoro-2-mercaptobenzylamine hydrochloride (m.p. 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 sodium methoxide (1.32 g) in methanol (120 ml) . The mixture was stirred at ambient temperature for 30 minutes and then heated under reflux for one hour. The solvent was removed by evaporation at reduced pressure and the residue was stirred at ambient temperature with a solution of sodium carbonate (5.64 g) in water (80 ml) for 1.5 hours. The precipitated product was separated by filtration, washed with water, dried and crystallised from ethanol to give 4,5-dihydro- 9-fluoro-l,4-benzothiazepin-3(2H)-one (m.p. 210-212°C) . Yield 1.81 g.

The above compound was administered to mice in the test described above at 100 mg/kg. 20% of the animals showed seizures indicating that the ED^_Q value would be below 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 aluminium hydride (6 g) . The mixture was stirred and heated under reflux for 5 hours. After the mixture had been cooled, ethyl acetate (45 ml) was added with stirring and the mixture treated with a 2:1 mixture of hydrochloric acid and water (300 ml) with external cooling. The aqueous layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (23 ml) was added dropwise. The mixture was stirred at ambient temperature overnight. The precipitated solid was collected by filtration, and washed with water to give S,N-dibenzoyl-6-chloro-2- mercaptobenzylamine (m.p. 171-173°C) .

A suspension of S,N-dibenzoyl-6-chloro-2-mercapto- benzylamine (11 g) , sodium hydroxide (17.7 g) in water (170 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. 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 solvent gave 6-chloro-2-mercapto- benzylamine 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 ambient temperature for 30 minutes and then heated under reflux for 1 hour. The solvent was removed by evaporation at reduced pressure.. The residue was stirred overnight at ambient 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 crystallised from ethanol to give 4, 5-dihydro-6-chloro- l,4-benzothiazepin-3 (2H)-one (m.p. 170-172°C) . Yield 4.5 g. The ED50 iⁿ the test described above for this compound was 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-l,4-benzothiazepin- 3{2H)-one (0.85 g) in dichloromethane (60 ml). The stirring was continued at ambient temperature for 4 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane:ethanol (95:5) as^' eluant gave 4,5-^' dihydro-6-chloro-l,4-benzothiazepin-3 (2H) -one 1-oxide (m.p. 231-233°C) which was recrystallised from ethanol. Yield 0.6 g.

The EDCJ_Q in the test described above for this compound was 1.2 mg/kg.

Example 13

A stirred suspension of 2,2'-dithiobis(6-methyl- benzamide) (15 g) in dry ether (270 ml) was treated over 1.5 hours with lithium aluminium hydride (7.4 g) . The mixture was stirred and heated under reflux for 5 hours. After the mixture had been cooled, ethyl acetate (65 ml) was added with stirring and then the mixture treated with a 2:1 mixture of hydrochloric acid and water (234 ml) with external cooling. The aqueous layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (25.3 ml) was added dropwise. The mixture was stirred at ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and crystallised from ethanol to give S,N-dibenzoyl-2- mercapto-6-methylbenzylamine (m.p. 165-168°C) . A suspension of S,N-dibenzoyl-2-mercapto-6-methyl- benzylamine (8 g) , sodium hydroxide (11.7 g) in water

(160 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. 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 solvent gave 2-mercapto-6-methylbenzyl- amine 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 hydro¬ chloride (2.4 g) and sodium methoxide (1.41 g) in methanol (75 ml) . ■ The stirring was continued at ambient temperature for 30 minutes, then at reflux for 1 hour. The solvent was removed by evaporation at reduced pressure, and the residue stirred at ambient 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 crystallised from ethanol to give 4, 5-dihydro-6-methyl- l,4-benzothiazepin-3 (2H)-one (m.p. 186-187°C) . Yield 1 g.

The ED_5Q in the test described above for this compound was 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-l,4-benzothiazepin- 3(2H)-one (1 g) in dichloromethane (125 ml). The stirring was continued at ambient temperature for 4 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane:ethanol (95:5) as eluant gave 4,5- dihydro-6-methyl-l,4-benzothiazepin-3 (2H) -one 1-oxide (m.p. 235-238°C) which was recrystallised from ethanol. Yield 0.86 g) .

The ED₅₀ in the test described above for this compound was 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 ethyl chloro- • formate (9.02 g) added dropwise with vigorous stirring. The mixture was stirred for a further 30 minutes and then treated with anhydrous ammonia gas. The mixture was stirred at ambient temperature overnight and then poured into water. 2,2'-Dithiobis(6-methoxybenzamide) (m.p. 225-227°C) precipitated and was collected by filtration.

A stirred suspension of 2,2'-dithiobis(6-methoxy- benzamide) (7 g) in dry ether (180 ml) was treated over 1.5 hours with lithium aluminium hydride (4.6 g) . The mixture was stirred and heated under reflux for 5 hours. After the mixture has been cooled, 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 layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (18 ml) was added dropwise. The mixture was stirred at ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to give S,N-dibenzoyl-2-mercapto-6-methoxybenzylamine (m.p. 145-150°C) . A suspension of S,N-dibenzoyl-2-mercapt0-6-methoxy- benzylamine (4.6 g) , sodium hydroxide (7.4 g) in water

(70 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. 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 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-meth.oxybenzylam.ine hydrochloride (2.25 g) and sodium methoxide (1.18 g) in methanol (60 ml) . The mixture was stirred at ambient temperature for 30 minutes and then heated under reflux for 1 hour. The solvent was removed by evaporation at reduced pressure. The residue was stirred at ambient 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 crystallised from ethanol to give 4,5-dihydro-6-methoxy- l,4-benzothiazepin-3 (2H)-one (m.p. 166-168°C) . Yield 1.5 g.

The ED50 in the test described above for this compound was 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 at 0°C with a solution of sodium nitrite (11.35 g) in water (40 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 sulphide nonahydrate (39.5 g) , sodium hydroxide (7 g) and sulphur (5.2 g) in water (55 ml)]. The mixture was allowed to stand for 3 hours at ambient temperature and acidified with hydrochloric acid. 2,2'-Dithiobis(4- methoxybenzoic acid) (m.p. 292-295°C) precipitated and was 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-methoxybenzoylchloride) .

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 ambient temperature overnight and then poured into water and acidified with concentrated hydrochloric acid. 2,2'-Dithiobis(4-methoxybenzamide) (m.p. 230-233°C) precipitated and was collected by filtration.

A stirred suspension of 2,2'-dithiobis(4-methoxy- benzamide) (8.7 g) in dry ether (250 ml) was treated over 1.5 hours with lithium aluminium hydride (5.6 g) . The mixture was stirred and heated under reflux for 5 hours. Af er the mixture had been cooled, ethyl acetate (43 ml) was added with stirring and then the mixture was treated with a 2:1 mixture of hydrochloric acid and water (150 ml) with external cooling. The aqueous layer was separated and basified with 5N aqueous sodium hydroxide solution and then benzoyl chloride (23 ml) was added dropwise. The mixture was stirred at ambient temperature overnight. The precipitated solid was collected by filtration, washed with water and dried to give S,N-dibenzoyl-2-mercapto-4-methoxybenzylamine (m.p. 125-130°C) . A suspension of S,N-dibenzoyl-2-mercapto-4-methoxy- benzylamine (2.5 g) and sodium hydroxide (4.2 g) in water (45 ml) was heated under reflux in a nitrogen atmosphere for 5 hours. 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 solvent gave 2-mercapto-4-methoxybenzyl- amine 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 methoxide (0.94 g) in methanol (15 ml) . The mixture was stirred at ambient temperature for 30 minutes and then heated under reflux for 1 hour. The solvent was removed by evaporation at reduced pressure and the residue was stirred at ambient 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 crystallised from ethanol to give 4,5-dihydro-8-methoxy- l,4-benzothiazepin-3 (2H)-one (m.p. 182-184°C) . Yield 1.16 g.

The above compound was administered to mice in the test described above at 100 mg/kg. 50% of the animals showed seizures indicating tht the ED^_Q value would be around 100 mg/kg.

Example 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-l,4-benzothiazepin- 3(2H)one (0.52 g) in dichloromethane (60 ml). The stirring was continued at ambient temperature for 5 days. The mixture was evaporated to dryness under reduced pressure. Purification by flash chromatography using dichloromethane:ethanol (95:5) as eluant gave 4,5- dihydro-8-methoxy-l,4-benzothiazepin-3 (2H)-one 1-oxide (m.p. 198-200°C) which was^' recrystallised from ethanol. Yield 0.42 g) .

The ED50 in the test described above for this compound was 66.7 mg/kg.

Example 18

A sample of 4,5-dihydro-l,4-benzothiazepin-3 (2H)- one 1-oxide (130 mg - prepared as in Example 2) was separated into its two enantiomers by high pressure chromatography on a Chiralcel type OD column of internal dimension 25 cm x 2 cm (Daicel Chemical Industries) eluted with solvents ranging from pure ethanol to a 2:1 mixture of hexane and ethanol. The first eluted fraction was shown by high pressure liquid chromatography on a column of the above type (internal dimension 25 cm x 4.6 mm) to have an optical purity of at least 95% This sample had a specific optical rotation [α]^ of -110.6° (c = 7.1, ethanol) and was therefore (-)-4,5-dihydro-l,4-benzothiazepin-3 (2H)-one 1-oxide.

The second eluted fraction had an optical purity of 93.5% [contaminated with 6.5% of the (-)-isomer], and a specific optical rotation [ajg^** of +105.2° (c = 8.9, ethanol). The major component was therefore (+)-4,5- dihydro-1,4-benzo-thiazepin-3 (2H) -one 1-oxide.

Claims

Compounds of formula I

in which n = 0, 1 or 2; R-^ independently represents halo, 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 sulphamoyl; R₂ R3/ R₄/ R5 and Rg independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4 with the provisos that when R₂ and/or R3 represent H or methyl and R₄, R5 and Rg represent hydrogen, n and m are not both 0 and that when n = 0, 1 or 2, R-_j_ is methoxy, R₂ and/or R3 represent H or methyl and R , R-- and Rg represent hydrogen, m does not equal 2.

2. Compounds of formula I as claimed in claim 1 in which n = 0 or 1, m = 0 or 1, . R-_ is fluoro, chloro, bromo, iodo, methyl, methoxy, polyhaloalkyl, nitro, cyano, carboxy, acetyl, dimethyl-carbamoyl or dimethyl- sulphamoyl and R , R3, R , R5 and Rg are independently H or methyl.

3. Compounds of formula I as claimed in claim 1 in which n = 0 or 1, m is 0 or 1 and R-_j_ is fluoro, chloro, bromo, methyl or methoxy and R₂, and are independently H or methyl, and R3, R5 and Rg are H. 4. A compound of formula I as claimed in claim 1 selected from:

4,5-dihydro-2-methyl-l,4-benzothiazepin-3(2H)-one; 4,5-dihydro-N-methyl-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-6-fluoro-l,4-benzothiazepin-3 (2H)one; 4,5-dihydro-8-fluoro-1,4-benzothiazepin-3(2H)-one; 4,5-dihydro-9-fluoro-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-6-chloro-l,4-benzothiazepin-3(2H)-one; 4,5-dihydro-6-bromo-l,4-benzothiazepin-3(2H)-one. 4,5-dihydro-6-methyl-l,4-benzothiazepin-3 (2H)-one^'; 4,5-dihydro-6-methoxy-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-8-methoxy-l,4-benzothiazepin-3 (2H) -one;

5. A compound of formula I as claimed in claim 1 selected from:

4,5-dihydro-l,4-benzothiazepin-3 (2H) -one 1-oxide; 4,5-dihydro-6-fluoro-1,4-benzothiazepin-3 (2H)-one

1-oxide; 4,5-dihydro-7-fluoro-1, 4-benzothiazepin-3 (2H) -one 1-oxide; 4,5-dihydro-8-fluoro-l,4-benzothiazepin-3 (2H)-one 1-oxide; 4,5-dihydro-6-chloro-l, 4-benzothiazepin-3 (2H)-one

1-oxide; 4,5-dihydro-6-methyl-l,4-benzothiazepin-3(2H)-one 1-oxide;

4,5-dihydro-8-methoxy-l,4-benzothiazepin-3 (2H) -one 1-oxide;

and their stereoisomers.

6. Pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I in which n = 0, 1 or 2; R-_j_ independently represents 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 sulphamoyl; R , R3, R₄, R5 and Rg 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.

7. Pharmaceutical compositions as claimed in claim 6 comprising a therapeutically effective amount of a compound of formula I in which n = 0 or l, m = 0 or 1, R~_ is fluoro, chloro, bromo, iodo, methyl, methoxy, polyhaloalkyl, nitro, cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl and R₂, R3, R₄, R₅ and Rg are independently H or methyl.

8. Pharmaceutical compositions as claimed in claim 6 comprising a therapeutically effective amount of a compound of formula I in which n = 0 or 1, m is 0 or 1 and R-_|_ is fluoro, chloro, bromo, methyl or methoxy and R₂, and R₄, are independently H or methyl, and R3, R and Rg are H.

9. Pharmaceutical compositions as claimed in claim 6 comprising a therapeutically effective amount of a compound of formula I selected from:

4,5-dihydro-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-2-methyl-l,4-benzothiazepin-3 (2H) -one;

4,5-dihydro-N-methyl-l,4-benzothiazepin-3 (2H)-one;

4,5-dihydro-6-fluoro-l,4-benzothiazepin-3 (2H)one;

4,5-dihydro-8-fluoro-l,4-benzothiazepin-3 (2H) -one;

4,5-dihydro-9-fluoro-l,4-benzothiazepin-3 (2H)-one; 4,5-dihydro-6-chloro-l,4-benzothiazepin-3 (2H) -one;

4,5-dihydro-6-bromo-l,4-benzothiazepin-3(2H)-one;

4,5-dihydro-6-methyl-l,4-benzothiazepin-3 (2H)-one;

4,5-dihydro-6-methoxy-l,4-benzothiazepin-3 (2H) -one; 4,5-dihydro-8-methoxy-l,4-benzothiazepin-3(2H)-one.

10. Pharmaceutical compositions as claimed in claim 6 comprising a therapeutically effective amount of a compound of formula I selected from:

4,5-dihydro-l,4-benzothiazepin-3 (2H)-one 1-oxide; 4,5-dihydro-6-fluoro-l,4-benzothiazepin-3 (2H) -one

1-oxide; 4, 5-dihydro-7-fluoro-l,4-benzothiazepin-3 (2H) -one 1-oxide; 4,5-dihydro-8-fluoro-l,4-benzothiazepin-3(2H)-one 1-oxide; 4, 5-dihydro-6-chloro-l, 4-benzothiazepin-3 (2H)-one

1-oxide; 4,5-dihydro-6-methyl-l,4-benzothiazepin-3(2H)-one 1-oxide;

4,5-dihydro-8-methoxy-l,4-benzothiazepin-3 (2H)-one 1-oxide;

and their stereoisomers.

11. A method of treating neurological disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I in which n = 0, 1 or 2; Rι_ independently represents 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 sulphamoyl; R₂, R3 R₄/ R5 and Rg independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4.

12. A method of treating epilepsy comprising the administering to a patient in need thereof a therapeutically effective amount of a compound of formula I in which n = 0, 1 or 2; R^ independently represents 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 sulphamoyl; R₂/ R3 R₄/ R5 and Rg independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and = 0 or an integer from 1 to 4.

13. The use of a compound of formula I in which n = 0, 1 or 2; R-L independently represents 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 sulphamoyl; R₂, R3, R₄, R₅ and Rg independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4 in the treatment of neurological disorders.

14. The use of a compound of formula I in which n = 0, 1 or 2; R-L independently represents 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 sulphamoyl; R₂, R3, R₄, R5 and Rg independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and m = 0 or an integer from 1 to 4 in the treatment of in the treatment of epilepsy.

15. The use of a compound of formula I in which n = 0, 1 or 2; R-L independently represents 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 sulphamoyl; R₂, R3, R₄, R5 and Rg 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 .

16. The use of a compound of formula I in which n = 0,

1 or 2; R-L independently represents 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 sulphamoyl; R₂, R3, R , R5 and

Rg independently represent hydrogen or alkyl of 1 to 4 carbon atoms; and = 0 or an integer from 1 to 4 in the preparation of a medicament for the treatment of epilepsy.

17. A process for the preparation of compounds of formula I as claimed in claim 1, comprising the step of

A) cyclisation of compounds of formula II

wherein R₇ 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) reaction of compounds of formula III

in which Y is a salt-forming anion with a halo- substituted ester of formula IV

Z—C—C0₂R3 - ^R3

in which Z is chloro or bromo and Rg is a group derived from an alcohol, in the presence of a base optionally by heating optionally followed by treatment with aqueous sodium carbonate;

C) cyclisation of compounds of formula V

D) from compounds of formula VI

by the Ritter reaction in the presence of a strong acid followed by hydrolysis;

E) the Beckmann rearrangement of compounds of formula VII

T

in which Rg is H or arylsulphonyl;

F) oxidation of compounds of formula I in which n = 0 to give compounds of formula I in which n = 1;

G) oxidation of compounds of formula I in which n = 0 or 1 to give compounds of formula I in which n = 2; or

H) the alkylation of compounds of formula I in which R₄ is H to give compounds of formula I in which R is alkyl.