2,3,4-BENZOTHIADIAZEPINE-2,2-DIOXIDE DERIVATIVES

Field of the invention

The invention relates to 2,3,4-benzothiadiazepine-2,2-dioxide derivatives and enantiomers of general Formula (I), process for their preparation, medicaments containing said compounds and the use thereof. 2,3,4- Benzothiadiazepine-2,2-dioxide derivatives of general Formula (I) are effective in the treatment of disorders of the central nervous system. Further objects of the present invention are the use of the compounds of the general Formula (I) in the manufacture of a medicament containing the same as active ingredient.

Technical background of the invention

The compounds of the general Formula (I) of the present invention are new. The most closely related compound known from the prior art is 1,3-dihydro- 2,3,4-benzothiadiazepine-2,2-dioxide of Formula (B) (J. F. King, A. Hawson, B. L. Huston, L. J. Danks, J. Komery, Can. J. Chem., 1971, 49, 943).

Substituted derivatives of the Formula (B) have never been described.

Summary of the invention

The aim of the present invention is to provide new 2,3,4- benzothiadiazepine derivatives effective in the treatment of disorders of the central nervous system. The above mentioned aim can be achieved by the new compounds of the general Formula (I),

wherein,

'a' represents a single or double bond,

R and R represent, independently, a hydrogen atom, halogen atom, cyano group, Ci-6 alkyl group, C _1-6 alkoxy group trifluoromethyl group or other C _1-6 alkyl group substituted by one or more halogen atom or if

'a' represents a single bond,

R ¹ and R ² together form a group of the formula =N-S-N= attached to the atoms of the bond 'a' according to the partial Formula (A)

R ³ and R ⁴ represent, independently, a hydrogen atom, Ci _-6 alkyl group, Ci _-6 alkenyl group, C _3-6 cycloalkyl group, aryl group or aralkyl group,

R ⁵ and R ⁶ represent, independently, a hydrogen atom, halogen atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group or other Cj-6 alkyl group substituted by one or more halogen atom and/or enantiomers and/or pharmaceutically suitable acid addition salts thereof.

A further object of the present invention is to provide a process for the preparation of the compounds of the general Formula (I).

An other object of the invention are pharmaceutical compositions comprising as active ingredient one or more compounds of the general Formula (I) as defined in claim 1 and/or enantiomers and/or pharmaceutically acceptable acid addition salts thereof in a therapeutically effective dose together with one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

The present invention further relates to the compounds of the general Formula (I) for the use as a medicament.

The present invention further relates to the use of the compounds of the general Formula (I) in the treatment and/or prevention of the disorder of the central nervous system. Furthermore our invention relates to a method of treatment, which comprises administering a patient suffering from a central nervous system disorder, a therapeutically effective dose of one or more compounds of general Formula (I) as defined in claim 1 and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof.

Detailed description of the invention

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

wherein

'a' represents a single or double bond,

R ¹ and R ² represent, independently, a hydrogen atom, halogen atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group, or other C _1-6 alkyl group substituted by one or more halogen atom or if

represents a single bond,

R ¹ and R ² together form a group of the formula =N-S-N= attached to the atoms of the bond 'a' accordin to the partial Formula

R ³ and R ⁴ represent, independently, a hydrogen atom, C _1-6 alkyl group, C _1-6 alkenyl group, C _3- 6 cycloalkyl group, aryl group or aralkyl group, R ⁵ and R ⁶ represent, independently, a hydrogen atom, halogen atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, trifluoromethyl group or other C _1- alkyl group substituted by one or more halogen atom and/or enantiomers and/or pharmaceutically suitable acid addition salts thereof.

The definitions of the substituents referred to in the present specification are the following.

The expression "alkyl group" represents a straight or branched saturated hydrocarbon chain having 1-6 carbon atoms, preferably 1-4 carbon atoms, e.g. methyl, ethyl, w-propyl, /-propyl, w-butyl, /-butyl, s-butyl, t-butyl group.

"Alkoxy group" represents a hydroxy group substituted with an above defined alkyl group.

"Alkenyl group" represents a straight or branched-chain hydrocarbon group containing one double bond and having 1-6 carbon atoms, preferably 1-4 carbon atoms.

"Aralkyl group" represents an alkyl group substituted at any position by an aromatic substituent, e.g. an optionally substituted phenyl group. Preferably the aralkyl group is an optionally substituted benzyl group.

"Halogen atom" is a fluorine, chlorine, bromine or iodine atom, preferably chlorine or fluorine.

"Pharmaceutically acceptable" acid addition salts are salts formed with a non-toxic inorganic acid, e.g. hydrochloric acid, sulfuric acid, phosphoric acid, or with a non-toxic organic acid, e.g. acetic acid, fumaric acid, maleic acid, lactic acid, maleic acid, tartaric acid.

Preferable representatives of the compounds of the general Formula (I) are:

8- cyano-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiazepi ne-2,2-dioxide; 7-cUoro-5-(3-fluoro-phenyl)-l,3-dihyclro-2,3,4-benzothiadiaz epine-2,2-dioxide,

9- (4-memyl-phenyl)-5H,7H-[l,2,5]tluadiazolo[3,4-/z]-2,3,4-benz othiadiazepine- 6,6-dioxide;

9-(4-memoxy-phenyl)-5H,7H-[l,2,5]thiadiazolo[3,4-/2][2,3,4]b enzothiadiazepine- 6,6-dioxide; 9-(3,4-dimethoxy-phenyl)-5H,7H-[l,2,5]thiadiazolo[3,4- h] [2,3 ,4]benzothiadiazepine-6,6-dioxide;

9-(4-fluoro-phenyl)-5H,7H-[l,2,5]tWadiazolo[3,4-¾][2,3,4]be nzothiadiazepine- 6,6-dioxide;

7-cUoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiaze pien-2,2-dioxide; 7-fluoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzotbiadiaz epine-2,2-dioxide; 7,8-dicMoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiad iazepine-2,2- dioxide;

7-c oro-5-(4-fluoro-phenyl)-3-methyl-l,3-dihydro-2,3,4-berizotWa diazepine-2 dioxide;

7-c oro-3-ethyl-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiad iazepine-2,2- dioxide;

7-chloro-5-(4-fluoro-phenyl)-3 -propyl- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepine-2,2- dioxide;

7-chloro-5-(4-fluoro-phenyl)-3-(prop-2-inyl)-l,3-dihydro-2,3 ,4- benzothiadiazepine-2,2-dioxide;

7-c oro-5-(4-fluoro-phenyl)-3-isopropyl-l,3-dihydro-2,3,4-benzot Wadiazepine- 2,2-dioxide;

7-chloro-5-(4-fluoro-phenyl)-3 -(3 -methyl-but-2-enyl)- 1 ,3 -dihydro-2,3 ,4- benzothiadiazepine-2,2-dioxide;

7-chloro-5-(4-fluoro-phenyl)-3-(3-methyl-butyl)-l,3-dihydro- 2,3,4- benzothiadiazepine-2,2-dioxide;

3-benzyl-7-chloro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benz othiadiazepine-2,2- dioxide;

7-fluoro-5-(4-fluoro-phenyl)-3-methyl-l,3-dihydro-2,3,4-benz otWadiazepine-2,2- dioxide;

7-fluoro-3-ethyl-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzo 1hiadiazepine-2,2- dioxide;

3-butyl-7-fluoro-5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepine-2,2- dioxide;

7-fluoro-5-(4-fluoro-phenyl)-3 -(3-methyl-but-2-enyl)- 1 ,3 -dihydro-2,3 ,4- benzothiadiazepine-2,2-dioxide; 7-fluoro-5-(4-fluoro-phenyI)-3-(3-methyl-butyl)-l,3-dihydro- 2,3,4- benzothiadiazepine-2,2-dioxide;

7-fluoro-5-(4-fluoro-phenyl)-3-hexyl-l,3-dihydro-2,3,4-benzo thiadiazepine-2,2- dioxide;

3-benzyl-7-fluoro-5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepine-2,2- dioxide;

7- fluoro-5 -(4-fluoro-phenyl)-3 -(3 -phenyl-propyl)- 1 ,3 -dihydro-2,3 ,4- benzothiadiazepine-2,2-dioxide;

5-(3-fluoro-phenyl)-7-chloro-3-methyl- 1 ,3-dihydro-2,3 ,4-benzothiadiazepine-2,2- dioxide;

8- cyano-5 -(4-fluoro-phenyl)-3 -methyl- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepine-2,2- dioxide;

8- fluoro-5-(4-fluoro-phenyl)-3-methyl-l,3-dihydro-2,3,4-benzot iadiazepine-2,2- dioxide;

5-(4-fluoro-phenyl)-8-cUoro-3-methyl-l,3-dihydro-2,3,4-benzo thiadiazepine-2,2- dioxide;

5-(4-fluoro-phenyl)-3-methyl-8-trifluorrnethyl-l,3-dihydro-2 ,3,4- benzothiadiazepine-2,2-dioxide;

7,8-dicWoro-5-(4-fluoro-phenyl)-3-memyl-l,3-dihydro-2,3,4-be nzothiadiazepine- 2,2-dioxide;

9- (4-fluoro-phenyI)-7-methyl-5H,7H-[l,2,5]thiadiazolo[3,4- ^][2,3,4]benzothiadiazepine-6,6-dioxide;

7,8-dichloro-3-ethyl-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-b enzothiadiazepine- 2,2-dioxide;

7-chIoro-5-(4-fluoro-phenyl)- 1 ,3 -dimethyl- 1 ,3-dihydro-2,3 ,4-benzothiadiazepine- 2,2-dioxide;

7-chloro- 1 -ethyl-5-(4-fluoro-phenyl)-3 -methyl- 1 ,3 -dihydro-2,3 ,4- benzothiadiazepine-2,2-dioxide

and/or enantiomers and/or pharmaceutically suitable acid addition salts thereof.

The invention further relates to enantiomers of the compounds of the general Formula (I) and the mixtures thereof. A further object of the present invention is to provide a process for the preparation of the compounds of the general Formula (I), which consist of simple reaction steps providing high yield.

The reaction method used in the preparation of the compounds of the present invention is demonstrated in Reaction Scheme 1 (Figure 1).

Figure 1 The compounds of the general Formula (I) of the present invention, wherein R ³ and R ⁴ are hydrogen atoms and R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 (I, R ³ =R ⁴ =H) and pharmaceutically suitable acid addition salts thereof are prepared by reacting the compound of the Formula (II), wherein R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 and M represents monovalent or multivalent metals, preferably alkali metals, more preferably a sodium atom, with tionyl chloride, and subsequently the obtained compound of the general Formula (III), wherein R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1, is reacted with hydrazine.

The compounds of the general Formula (I) of the present invention, wherein R ⁴ is hydrogen and R ¹ , R ² , R ⁵ , R ⁶ and R ³ are defined in claim 1 provided that R ³ is different from hydrogen (I, R ³ ≠H, R ⁴ =H) and pharmaceutically suitable acid addition salts thereof are prepared by reacting the 2,3,4-benzothiadiazepine- dioxide derivatives of the general Formula (I), wherein R ³ and R ⁴ are hydrogen, R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 (I, R ³ =R ⁴ =H), with agents suitable for introducing an alkyl group, alkenyl group or aralkyl group, in the presence of a base.

Furthermore, the compounds of the general Formula (I) of the present invention, wherein R ⁴ is hydrogen and R ¹ , R ² , R ⁵ , R ⁶ and R ³ are defined in claim 1 provided that R ³ is different from hydrogen (I, R ³ ≠H, R ⁴ =H) and pharmaceutically suitable acid addition salts thereof can be prepared by reacting compounds of the general formula (III), wherein R , R , R and R are defined in claim 1, with a substituted hydrazine of general formula (VT), wherein R is defined in claim 1.

R3-NH-NH ₂ (VI)

The compounds of the general Formula (I) of the present invention, wherein R ³ and R ⁴ are defined in claim 1 provided that R ³ and R ⁴ are identical and different from hydrogen and R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 (I, R ³ =R≠H) and pharmaceutically suitable acid addition salts thereof are prepared by reacting the 2,3,4-benzothiadiazepine-dioxide derivatives of the general Formula (I), wherein R ³ and R ⁴ are hydrogen, R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 (I, R ³ =R ⁴ =H), with agents suitable for introducing an alkyl group, alkenyl group or aralkyl group, in the presence of a base.

Furthermore, the compounds of the general Formula (I) of the present invention, wherein R ³ and R ⁴ are defined in claim 1 provided that R ³ and R ⁴ are different from hydrogen and R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 (I, R ³ ≠H, R ⁴ ≠H) and pharmaceutically suitable acid addition salts thereof can be prepared by reacting the 2,3, 4-benzothiadiazepine-di oxide derivatives of the general Formula (I), wherein R ⁴ is hydrogen, R ¹ , R ² , R ⁵ , R ⁶ and R ³ are defined in claim 1 provided that R ³ is different from hydrogen (I, R ³ ≠H, R ^4=: H), with agents suitable for introducing an alkyl group, alkenyl group or aralkyl group, in the presence of a base.

Further objects of the present invention are the compounds of the general Formula (ΙΠ),

and the compounds of the general Formula (Π),

wherein M represents monovalent or multivalent metals, preferably alkali metals more preferably a sodium atom.

Preferred representatives of the compounds of the general Formula (II) are:

sodium [4-chloro-2-(4-fluoro-benzoyl)-phenyl]-methanesulfonate;

sodium [6-[(3,4-dimethoxy-phenyl)-carbonyl]-2, 1 ,3-benzothiadiazole-5-yl]- methanesulfonate;

sodium [6-[(4-fluoro-phenyl)-carbonyl]-2, 1 ,3-benzothiadiazole-5-yl]- methanesulfonate;

sodium [6-[(4-methoxy-phenyl)-carbonyl]-2, 1 ,3-benzothiadiazole-5-yl]- methanesulfonate.

Further object of the present invention is the for the preparation of the compounds of general Formula (ΠΙ), which comprises reacting the compound of general Formula (II), wherein R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1 with thionyl chloride. Another object of the present invention the process for the preparation of the derivatives of general Formula (II), wherein R ¹ , R ² , R ⁵ and R ⁶ are defined in claim 1, which comprises reacting the compound of general Formula (IV), wherein R , R , R and R are defined in claim 1 with ammonium sulfite or alkali sulfite in the present of water or water-immiscible solvent, preferably in acetone, dioxane or in an aliphatic alcohol comprising 1 to 4 carbon atoms or in the mixture thereof.

Compounds of the Formula (IV)

were prepared by a method known from the art for the synthesis of compounds with a similar structure (J Org. Chem., 1988, 53, 3621; J Org. Chem., 2003, 68, 4123). The [substituted 2-(substituted arylcarbonyl)-phenyl]methanesulfonate salts of the Formula (II)

are prepared by the replacement of the halogen atom to sulfonic acid moiety in water, a water-miscible solvent (acetone, dioxane, alcohols) or in a mixture of water and a water-miscible solvent, by reacting the halogen compound with ammonium or alkali sulfites.

The compounds of Formula (II) are new and have not been described in the literature before. The metal salts of the general Formula (II) are formed by monovalent or multivalent metals, preferably alkali metals more preferably sodium atom. The sulfonyl chlorides of the Formula (III) are prepared from the new benzylsulfonyl derivatives of the Formula (II) with tionyl chloride. The 2,3,4- benzothiadiazepine-2,2-dioxide derivatives of the general Formula (I), wherein R ³ and R ⁴ represent hydrogen atom, are obtained from sulfonyl chlorides of the Formula (ΙΠ) by closing the ring with hydrazine. Preferably the compounds of Formula (ΠΙ) are not purified, but the crude product was reacted with hydrazine immediately.

An alternative one-pot method involves ring closure of sulfonyl chlorides of Formula (ΠΙ) by reacting with compound of Formula (VI),

R ³ -NH-NH ₂ (VI) wherein R ³ represents alkyl, alkenyl or aralkyl group. This one-pot method yields 2,3,4-benzothiadiazepine-2,2-dioxide derivatives of the Formula (I), wherein R ³ is an alkyl, alkenyl or aralkyl group and R ⁴ represents hydrogen.

Optionally the 2,3,4-benzothiadiazepine-2,2-dioxide derivatives of the Formula (I), wherein R ³ and R ⁴ represent hydrogen, can be converted to compounds of the Formula (I), wherein R represents alkyl group, alkenyl group or aralkyl group and R ⁴ represents hydrogen atom, by reacting with an agent suitable for introducing an alkyl, alkenyl group or aralkyl group, in the presence of a base. In the reaction the agent suitable for introducing an alkyl group, alkenyl group or aralkyl group is the alkylating agent of the Formula (V)

RX (V) wherein R represents R ³ substituent of the end-product as defined in claim 1, X represents a leaving group, e.g. halogen atom, methanesulfonyloxy group or p- toluenesulfonyloxy group, preferably halogen atom, more preferably chlorine, bromine, or iodine atom. The base used is an organic or inorganic base, e.g. alkali metal carbonate, alkali metal hydrogencarbonate, aliphatic or alicyclic secondary or tertiary amines, preferably l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). If desired, the 2,3,4-benzothiadiazepine-2,2-dioxide derivatives of Formula (I), wherein R ³ represents alkyl group, alkenyl group or aralkyl group and R ⁴ represents hydrogen, can be converted to compounds of Formula (I), wherein R ³ and R ⁴ represents alkyl group, alkenyl group or aralkyl group, by reacting with an alkylating agent of the Formula (V), wherein R represents R ⁴ substituent of the end-product as defined in claim 1, in the presence of a strong base. The strong base is an organic or inorganic base, e.g. alkali metal alkoxide, alkali metal hydride, alkaline earth metal hydride or alkyllithium compound, preferably alkyl lithium compound, more preferably butyllithium.

There is a one-pot method, wherein the 2,3,4-benzothiadiazepine-2,2- dioxide derivatives of Formula (I), wherein R ³ and R ⁴ represents hydrogen can be converted directly to compounds of Formula (I) wherein R ³ and R ⁴ represent the same alkyl group, alkenyl group or aralkyl group by reacting with alkylating agent of the Formula (V) in the presence of a strong base.

In this case the alkylating agent of the Formula (V) as defined above is used in 2 molar equivalent amount relative to the molar amount of the starting compound. The strong base in the alkylation reaction is organic or inorganic base in 2 molar equivalent amount, e.g. alkali metal alkoxide, alkali metal hydride, alkaline earth metal hydride or alkyl lithium compound, preferably alkyllithium compound, more preferably butyllithium.

Further objects of the present invention are pharmaceutical compositions comprising as active ingredient one or more compounds of the general Formula (I) as defined in claim 1 and/or enantiomers and/or pharmaceutically acceptable acid-addition salts thereof in a therapeutically effective dose together with one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

Pharmaceutical compositions of the present invention contain in general 0.1 to 95.0 per cent by weight, preferably 1.0 to 50.0 per cent by mass, more preferably 5.0 to 30.0 per cent by mass of active ingredient.

The pharmaceutical compositions of the present invention are suitable for oral (e.g. powders, tablets, film-coated tablets, capsules, microcapsules, drops/pills, solutions, suspensions or emulsions), parenteral (e.g. in form of intravenous, intramuscular, subcutaneous or intraperitoneal injections or infusion compositions), rectal (e.g. in form of suppositories), transdermal (e.g. patches) administration, or can be used in the form of implants or for local treatment (e.g. ointment, gels or patches).

The solid, semisolid or liquid pharmaceutical dosage forms of the present invention are known per se, the methods of manufacturing the compositions are known in the state of the art.

The solid pharmaceutical compositions suitable for oral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and optionally comprise binding agents such as gelatine, sorbitol, polyvinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, polyethylene glycol, silica etc.; wetting agents such as sodium laurylsulfate etc.

The liquid pharmaceutical compositions suitable for oral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethyl cellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methy p-hydroxybenzoate etc. and a the carrier.

Typical parenteral compositions consisting of a solution or suspension of the compound of Formula (I) and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrohdone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to adiriinistration.

Compositions of the present invention for nasal administration containing a compound of Formula (I) and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof may conveniently be formulated as aerosols, drops, gels and powders.

Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of Formula (I) and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon. The adniinistration of aerosol dosages can also take the form of a pump-atomiser.

Compositions of the present invention containing a compound of Formula (I) and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof are suitable for buccal or sublingual administration including tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerol, etc.

Compositions of the present invention containing a compound of Formula (I) and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter, polyethylene glycol or other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

Compositions of the present invention containing a compound of Formula (I) and/or pharmaceutically suitable acid additional salts thereof for transdermal administration include ointments, gels and patches.

Dosage forms listed above as well as other dosage forms are known per se, see e. g. Remington's Pharmaceutical Sciences, 18 ^th Edition, Mack Publishing Co., Easton, USA (1990).

The compositions containing the compounds of the general Formula (I) of the present inventions contain the active ingredient in form of dose units.

The typical dosage for adult patients is 0,1-1000 mg of a compound of Formula (I) or an enantiomer or a pharmaceutically acceptable acid additional salt thereof, which can be administered once or in portions. The actual dose depends on many factors and its determination of is a medical task.

A further subject of the invention is the medical use of the compounds defined in claims 1 and the use of the compounds of general Formula (I) and or enantiomers and/or pharmaceutically suitable acid additional salts thereof as a medicament in the treatment of diseases of the central nervous system. Furthermore our invention relates to a method of treatment, which comprises administering a patient suffering from a central nervous system disorder a therapeutically effective dose of one or more compounds of general Formula (I) as defined in claim 1 and/or enantiomers and/or pharmaceutically suitable acid additional salts thereof.

In the investigations of biological efficiency of the compounds of general Formula (I) as defined in claim 1, it has been found that the compounds are effectively modulating central nervous system functions, thus, it is expected that the compounds of the invention are well suited for the prevention and/or treatment of several diseases of the central nervous system.

The in vivo biological effectiveness of the compounds of the present invention on the central nervous system was examined by the following experimental model.

Changes in amino acid neurotransmitter levels in the cortical area of male rats

Male SPDR rats weighing 200-250 g, were used in the experiments. Changes in the concentration of amino acid neurotransmitters were measured from cortical areas by high-performance liquid chromatography (HPLC) and electrochemical detection. The investigations were carried out with two experimental groups wherein each group contained 8 animals. One group was administered intraperitoneally by vehicle only (control group). The other group was administered intraperitoneally by the compound of the Example 15, suspended in vehicle. The dose of administration was in the form of 0.4 % aqueous methylcellulose suspension.

The animals were decapitated 30 minutes after the administration, brains have been removed and required brain regions were dissected. The tissues were stored at -70 °C.

The tissues were homogenised in ice-cold 0.1 M perchlorate in 500 volume excess. The homogenates were intensively mixed, centrifuged at 4 °C at 20,000 rpm for 20 minutes, the supematants were removed and an aliquot thereof was immediately injected after derivatisation without further sample purification.

The automatic derivatisation was carried out at 25 °C using o- phtaldialdehyde/Na ₂ S0 ₃ reagent; the reaction time was 10 minutes.

The assay was performed using an Agilent 1100 HPLC, separation was carried out by gradient elution on an Agilent Zorbax SB-C18 (250 ^χ 4,6 mm, 5 μπι) column, utilising 0,1 M NaH ₂ P0 ₄ , pH=4,5/ methanol eluent.

For electrochemical detection, ESA Coulochem III detector was used (analytical cell: ESA 5011 A), the potential of working electrode was +650 mV.

The tissue concentrations of the amino acids were measured by standard solutions containing amino acids with known concentration.

It has been found that concentrations of the amino acid taurine were significantly increased in the frontal cortex of the animals administered with the compound of Example 16 of the present invention, compared to frontal cortex obtained from animals of the control group. Figure 2 demonstrates the results. Taurine levels in rat frontal cortex

(MeaniSEM, N=8)

1000

900

800

700

600

· _* »-· 500

1 400

300

200

Control Example 16

Treatment group

*: p<0,05 vs. control

Figure 2

It is known from the literature that taurine, which is non-proteinaceous arnino acid, occurs in high quantities in the central nervous system (Oja and Saransaari, Proc. West. Pharmacol. Soc, 50i 8-15, 2007.). Taurine plays important role in several neurophysiologic processes. It is also known that taurine possesses antioxidant properties and regulates the intracellular calcium level, thus modulates neuronal receptor function (Szymansk and Winiarska, Postepy. Hig. Med. Dosw., 62_ 75-86, 2008.). The extent of long-term potentiation (LTP) in striatum decreased in taurine transporter knock-out mice and there were pathological changes in neuroreceptor expression (Warskulat is mtsai, Methods Enzymol, 428: 439-58, 2007.). These results support the important modulator role of taurine in the central nervous system.

It has been surprisingly found that compounds of the present invention induce a statistically significant increase in the amount of taurine in the examined brain regions, resulting in the effective modulation of neuronal functions by the taurine pathway. Therefore, it is expected that the compounds of the present invention are well suited for the prevention and/or treatment of several diseases of the central nervous system. Due to this surprising effect, it has been recognized that the compounds of the present invention are able to modulate the active function of central nervous system, normalize the pathological features, thus are expected to be effective in the treatment of disorders of the central nervous system.

The invention is further elucidated by means of following Examples without restricting the scope of the present invention to the Examples.

Examples:

Halogen - sulfite exchange (Process "A")

To the solution of 540 ml dioxane and 800 ml water, 0.27 mol of (substituted 2- chloromethyl-phenyl)-(substituted aryl)-methanone and 0.36 mol of sodium sulfite are added and boiled for ca. two hours. After cooling ca. 800 ml solvent is evaporated from the reaction mixture.

Process A/1 : the residual aqueous phase is extracted with ethyl acetate or tert-butyl methyl ether and the organic phase is extracted with 2x80 ml 1M NaOH solution. The combined alkaline and aqueous phase is decoloured with activated carbon and evaporated to ca. 250 ml. Thus an oily product is obtained. 52 ml of concentrated hydrochloric acid is added to the mixture under cooling and stirring and the reaction mixture is stirred for half an hour. The precipitated substance is filtered, washed and dried (sodium salt).

Process A 2: If the evaporation of the aqueous phase results in sulfonic acid crystals, the crystals are filtered, washed and dried.

Example 1

Sodium [4-chloro-2-(4-fluoro-benzoyl)-phenyl]-methanesulfonate

The title product is prepared according to the process A/1 starting from (5-chloro- 2-chloromethyl-phenyl)-(4-fluorophenyl)-methanone.

Yield: 60 %

Melting point: 254-256 °C (water)

IR (KBr): 3448, 1667, 1598, 1412 cm ^"1 HNMR (DMSO-t¾, 500 MHz): 7.80 (dd, J=8.8, 5.7 Hz, 2H), 7.55 (m, 2H), 7.35 (t, J=8.8 Hz, 2H), 7.23 (m, 1H), 3.98 (s, 2H) ppm.

CNMR (DMSO-i/ ₆ , 125 MHz): 194.9, 165.1 (d, J = 251.5 Hz), 141.0, 134.6, 134.0 (d, J=2.9 Hz), 133.6, 133.4 (d, J=9.3 Hz), 130.8, 129.9, 127.9, 115.5 (d, J=22.0 Hz), 53.0 ppm.

Elemental analysis [calculated on the basis of the Formula C)4H ₉ ClF0 ₄ SNa (350.73)]

Calculated: C 47.94, H 2.59, CI 10.11, S 9.14 %

Measured: C 47.56, H 2.77, CI 10.00, S 9.06 %

Gravimetric Na content: 6.22% (calculated: 6.55%)

Example 2

Sodium [4,5-dichloro-2-(4-fluoro-benzoyl)-phenyl]-methanesuIfonate

The title product is prepared according to the process A/1 starting from (4,5- dichloro-2-chloromethyl-phenyl)-(4-fluorophenyl)-methanone.

Yield: 70 %

Melting point: 216-230 °C (water)

IR (KBr): 3456, 1758, 1667, 1598, 1506, 1285, 1225, 1149, 1044 cm ^"1 .

HNMR (DMSO-<¾, 500 MHz): 7.79 (dd, J=8.8, 5.6 Hz, 2H), 7.75 (s, 1H), 7.46 (s,

1H), 7.35 (t, J=8.9 Hz, 2H), 3.96 (s, 2H) ppm.

Example 3

Sodium [6-[(3,4-dimethoxyphenyI)-carbonyI]-2,l ₅ 3-benzothiadiazoI-5-yl]- methanesulfonate The title product is prepared according to the process A/2 starting from [6- (chloromethyl)-2,l,3-benzothiadiazol-5-yl](3,4-dimethoxyphen yl)-methanone.

Yield: 86 %

Melting point: 282-283 °C (water)

HNMR (DMSO-ti ₆ , 500 MHz): 8.15 (d, J = 0.6 Hz, 1H), 7.91 (d, J = 0.5 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 4.13 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3 H) ppm.

Example 4

Sodium [6-[(4-fluorophenyl)-carbonyI]-2,l,3-benzothiadiazol-5-yI]- methanesulfonate

The title product is prepared according to the process A/2 starting from [6- (chloromethyl)-2, 1 ,3 -benzothiadiazol-5-yl] (4-methoxyphenyl)-methanone.

Yield: 90 %

Melting point: 320-323 °C (water), with decomposition IR (KBr): 3527, 1657, 1600, 1207, 1044 cm ^-1 .

HNMR (DMSO-<¼, 500 MHz): 8.09 (d, J = 0.6 Hz, 1H), 7.91 (d, J = 0.6 Hz, 1H), 7.90 (dd, J = 8.8, 5.5 Hz, 2H), 7.36 (t, J = 8.9 Hz, 2H), 4.21 (s, 2H) ppm.

CNMR (DMSO-i ₆ , 125 MHz): 194.89, 165.10 (d, J = 251.5 Hz), 154.62, 152.35, 141.24, 136.54, 134.03 (d, J = 2.9 Hz), 133.76 (d, J = 9.3 Hz), 124.14, 121.50, 115.32 (d, J = 22.0 Hz), 53.74 ppm.

Elemental analysis [calculated on the basis of the Formula Ci4HgFN20 S ₂ Na (374.35)]

Calculated: C 44.92, H 2.15, N 7.48 %

Measured: C 44.59, H 2.16, N 7.23 % Example 5

Sodium [6-[(4-methoxyphenyl)-carbonyl]-2,l,3-benzothiadiazol-5-yl]- methanesulfonate

The title product is prepared according to the process A/2 starting from [6- (chloromehyl)-2, 1 ,3-benzothiadiazol-5-yl](4-methoxyphenyl)methanone

Yield: 79 %

Melting point: 287-288 °C (water), with decomposition IR (KBr): 3527, 1647, 1598, 1300 cm ^"1 .

HNMR (DMSO-i4, 125 MHz): 8.13 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=9.2 Hz, 2H), 7.06 (d, J=9.2 Hz, 2H), 4.16 (s, 2H), 3.87 (s, 3H) ppm.

Ring closing reaction (process "B")

78 mmol of sodium [2-(substituated-benzoyl)-substituted phenyl]- methanesulfonate and 100 ml thionyl chloride are boiled for 4 hours. The reaction mixture is evaporated. The residue is dissolved in 250 ml of dichloromethane and the solution is added dropwise to the solution of 750 ml dichloromethane and 75 ml hydrazine under cooling and vigorous stirring. The mixture is stirred for 1.5 hours without cooling. The solution is acidified under ice-cooling with 160 ml cc. hydrochloric acid (to pH=l). The phases are separated and the aqueous phase is extracted with 2><100 ml dichloromethane. The combined aqueous layer is dried over MgSC ^< 4 and evaporated. Process B/l: the crystalline residue is triturated with mixture of 40 ml ethanol and 30 ml hexane, filtered, washed with 2x20 ml cold ethanol, and dried.

Process B/2: the residue is subjected to flash chromatographic purification with the appropriate solvent and the product is obtained by evaporation.

Example 6

8-Cyano-5-(4-fluoro-phenyl)-l,3-dihydro-2,3 ₅ 4-benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process B/l starting from sodium [5- cyano-2-(4-fluoro-benzoyl)-phenyl]-methanesulfonate.

Yield: 35 %

Melting point: 218-219 °C (ethanol) IR (KBr): 3215, 1601, 1510, 1325, 1150 cm- ¹ .

HNMR (DMSO-< , 200 MHz): 10.52 (bs, IH), 8.16 (d, J=1.5 Hz, IH), 7.96 (dd, J=8.2, 1.8 Hz, IH), 7.67 (dd, J=9.2, 5.8 Hz, 2H), 7.44 (d, J=7.9 Hz, IH), 7.34 (t, J=8.9 Hz, 2H), 4.83 (s, 2H) ppm.

Elemental analysis [calculated on the basis of the Formula [C ₁₅ H ₁₀ FN3O ₂ S

(315.33)]

Calculated: C 57.14, H 3.20, N 13.30 %

Measured: C 57.89, H 3.39, N 13.29 %

Example 7

7-Chloro-5-(3-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiaz epin-2,2- dioxide The title product is prepared according to the process B/1 starting from sodium [4- chloro-2-(3 -fluoro-benzoyl)-phenyl] -methanesulfonate.

Yield: 42 %

Melting point: 195-198 °C (ethanol) IR (KBr): 3200, 1320, 1159 cm ^-1 .

HNMR (CDCI3, 200 MHz): 7.58 (dd, J=8.1, 2.2 Hz, IH), 7.46 (d, J=8.4 Hz, IH), 7.19-7.50 (m, 5H), 7.14 (bs, IH), 4.40 (s, 2H) ppm.

Elemental analysis [calculated on the basis of the Formula C ₁ 4H ₁₀ ClFN ₂ O2S

(324.76)]

Calculated: C 51.78, H 3.10, CI 10.92, N 8.63 %

Measured: C 52.13, H 3.09, CI 10.85, N 8.44 %

Example 8

9-(4-Methylphenyl)-5 - ^r ,7jfiT-[l,2,5]thiadiazolo[3,4-^]-2^,4-benzothiadiazepi n-

6,6-dioxide

The title product is prepared according to the process B/1 starting from sodium [6- [(4-methoxyphenyl)-carbonyl] -2, 1 ,3 -benzothiadiazol-5-yl] -methanesulfonate.

Yield: 70 %

Melting point: 212-215 °C (ethyl acetate) IR (KBr): 3095, 1325, 1150 cm- ¹ .

HNMR (CDCI ₃ , 125 MHz): 10.26 (s, IH), 8.38 (d, J=0.6 Hz, IH), 7.95 (s, IH), 7.62 (d, J=8.2, 2H), 7.32 (d, J=8.1 Hz, 2H), 4.92 (s, 2H), 2.39 (s, 3H) ppm. Elemental analysis [calculated on the basis of the Formula Ci5Hi ₂ N ₄ 0 ₂ S ₂

(344.42)]

Calculated: C 52.31 , H 3.51 , N 16.27 %

Measured: C 51.98, H 3.45, N 16.32 %

Example 9

9-(4-Methoxyphenyl)-5H,7H-[l,2,5]thiadiazoIo[3,4- A][2,3,4]benzothiadiazepin-6,6-dioxide

The title product is prepared according to the process B/1 starting from sodium - [6-(4-memoxy-berizoyl)-benzo[l,2,5]thiadiazol-5-il]-methanes ulfonate.

Yield: 68 %

Melting point: 225-227 °C (ethyl acetate) IR (KBr): 3101, 1601, 1321, 1148 cm ^"1 .

HNMR (CDC1 ₃ , 200 MHz): 10.19 (bs, 1H), 8.37 (s, lH), 7.98 (s, 1H), 7.70 (d, J= 8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.92 (s, 2H), 3.84 (s, 3H) ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₅ Hi ₂ N ₄ 0 ₃ S ₂

(360.42)]

Calculated: C 49.99, H 3.36, N 15.55 %

Measured: C 49.11, H 3.45, N 15.29 %

Example 10

9-(3,4-Dimethoxypheiiyl)-5H,7H- [1 ,2,5] thiadiazolo [3,4- h] [2,3,4] benzothiadiazepin-6,6-dioxide The title product is prepared according to the process B/1 starting from sodium [6- (3,4-dimethoxy-benzoyl)-benzo[ 1 ,2,5]thiadiazoI-5-yl]-methanesulfonate.

Yield: 70 %

Melting point: 228-230 °C (ethyl acetate) IR (KBr): 3096, 1517, 1322 cm ^'1 .

HNMR (CDC1 ₃ , 125 MHz): 10.16 (s, IH), 8.37 (s, IH), 7.93 (s, IK), 7.52 (s, IK), 7.04 (m, 2H), 4.89 (s, 2H), 3.83 (s, 3H), 3.81 (bs, 6H)ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₆ H ₁₄ N ₄ 0 ₄ S2

(390.44)]

Calculated: C 49.22, H 3.61, N 14.35 %

Measured: C 49.00, H 3.72, N 14.12 %

Example 11

9-(4-FIuorophenyl)-5H ^r ,7^-[l,2,5]tihadiazolo[3,4-A] [2,3,4]beiLzothiadiazepin-

6,6-dioxide

The title product is prepared according to the process B/1 starting from sodium [6- [(4-fluorophenyl)-carbonyl]-2,l,3-benzothiadiazol-5-yl]-meth anesulfonate.

Yield: 68 %

Melting point: 222-225 °C (ethanol-DMF) IR (KBr): 3137, 1597, 1569, 1508, 1326 cm ^"1 .

HNMR (DMSO-ii ₆ , 500 MHz): 10.34 (s, IH), 8.38 (s, IH), 8.02 (s, IH), 7.80 (dd, J = 8.7, 5.5 Hz, 2H), 7.36 (t, J = 8.9 Hz, 2H), 4.96 (s, 2H) ppm. C MR (DMSO-</ ₆ , 125 MHz): 172.04, 164.33 (d, J = 250.0 Hz), 154.43, 152.96, 136.26, 133.11, 132.42 (d, J = 2.9 Hz), 132.19 (d, J = 8.7 Hz), 122.60, 121.47, 115.81 (d, J = 22.0 Hz), 55.10 ppm.

Elemental analysis [calculated on the basis of the Formula Ci ₄ H ₉ FN ₄ 0 ₄ S ₂

(348.38)]

Calculated: C 48.27, H 2.60, N 16.08, S 18.41 %

Measured: C 48.30, H 2.55, N 16.17, S 18.43 %

Example 12

7-Chloro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiaz epin-2,2- dioxide

The title product is prepared according to the process B/1 starting from sodium [4- chloro-2-(4-fluoro-benzoyl)-phenyl]-methanesulfonate.

Yield: 68 %

Melting point: 195-198 °C (methanol)

IR (KBr): 3222, 1602, 1508, 1329, 1157 cm ^"1 .

HNMR (CDCI3, 500 MHz): 7.70 (dd, J=5.3 Hz, 2H), 7.57 (dd, J=8.2, 2.1 Hz, IH), 7.46 (d, J=8.2 Hz, IH), 7.25 (d, J=2.2 Hz, IH), 7.15 (t, J=8.6 Hz, 2H), 7.08 (bs, IH), 4.39 (s, 2H) ppm.

CNMR (CDCI3, 125 MHz): 171.2, 165.1 (d, J=254.4 Hz), 135.3, 135.0, 131.7 (d, J=8.8 Hz), 131.7, 131.0 (d, J=2.9 Hz), 130.7, 129.5, 129.2, 116.0 (d, J=22.0 Hz), 55.7 ppm.

Elemental analysis [calculated on the basis of the Formula Ci4H ₁₀ ClFN2O2S (324.76)]

Calculated: C 51.78, H 3.10, N 8.63 % Measured: C 51.61, H 3.16, N 8.71 %

Example 13

7-Fluoro-5-(4-fluoro-phenyI)-l,3-dihydro-2,3 _» 4-benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process B/l starting from, sodium [4-fluoro-2-(4-fluoro-benzoyl)-phenyl]-methanesulfonate.

Yield: 62 %

Melting point: 196-200 °C (ethanol-hexane) IR (KBr): 3201, 1602, 1507, 1318, 1163 cm ^'1 .

HNMR (DMSO-fife, 500 MHz): 10.33 (s, 1H), 7.68 (m, 3H), 7.49 (td, J=8.5, 2.7 Hz, lH), 7.34 (t, J=8.8 Hz, 2H), 7.10 (dd, J=9.2, 2.7 Hz, 1H), 4.71 (s, 2H) ppm. CNMR (DMSO-<&, 125 MHz): 170.4 (d, J=1.5 Hz), 164.1 (d, J=249.5 Hz), 161.2 (d, J=246.6 Hz), 136.1 (d, J=7.8 Hz), 132.2 (d, J=2.9 Hz), 131.9 (d, J=8.8 Hz), 131.8 (d, J=8.8 Hz), 128.9 (d, J=3.4 Hz), 118.2 (d, J=22.0 Hz), 115.9 (d, J=23.4 Hz), 115.8 (d, J=22.0 Hz), 54.6 ppm.

Elemental analysis [calculated on the basis of the Formula Ci ₄ H ₁₀ F ₂ N ₂ O ₂ S (308.31)]

Calculated: C 54.54, H 3.27, S 10.40, N 9.09 %.

Measured: C 54.89, H 3.23, S 10.28, N 9.16 %.

Example 14

7,8-Dichloro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothia diazepin-2,2- dioxide The title product is prepared according to the process B/1 starting from sodium [4,5-dichloro-2-(4-fluoro-benzoyl)-phenyl]-methanesulfonate.

Yield: 72 %

Melting point: 196-200 °C (acetonitrile)

IR (KBr): 3443, 3200, 1599, 1508, 1327, 1166 cm ^'1 .

HNMR (DMSO-fife, 500 MHz): 10.45 (s, 1H), 8.00 (s, 1H), 7.69 (dd, J=9.0, 5.5

Hz, 2H), 7.51 (s, 1H), 7.35 (t, J=8.8 Hz, 2H), 4.77 (s, 2H) ppm.

CNMR (DMSO-</ ₆ , 125 MHz): 169.9, 164.2 (d, J=250 Hz), 134.5, 133.8, 133.0,

132.0 (d, J=8.8 Hz), 131.9 (d, J=2.9 Hz), 131.2, 131.1, 130.8 (d, J=22.0 Hz), 54.4 ppm.

Elemental analysis [calculated on the basis of the Formula Ci4H9Cl ₂ FN ₂ 0 ₂ S

(359.21)]

Calculated: C 46.81, H 2.53, S 8.93, CI 19.74, N 7.80 %

Measured: C 46.55, H 2.63, S 8.78, CI 19.51, N 7.71 %

Example 15

6-{[(4-Fluorophenyl)-carbonyl]-2,1 -benzothiadiazol-5-yl}-methanesulfonic acid chloride

5.34 mmol sodium [6-[(4-fluorophenyl)-carbonyl]-2,l,3-benzothiadiazol-5-yl]- methanesulfonate is added to 5 ml thionyl chloride and are boiled for 2.5 hours. After cooling the reaction mixture is evaporated. The residue is dissolved in 10 ml chloroform and is clarified by carbon, after filtering the mixture is evaporated. The residue is triturated with hexane, filtered and dried.

Yield: 85 %

Melting point: 148-151 °C (hexane) IR (KBr): 2993, 1665, 1595, 1230, 850 cm ^"1 .

HNMR (CDC1 ₃ , 500 MHz): 8.33 (s, 1H), 8.17 (s, lH), 7.95 (dd, J = 5.4, 3.5 Hz, 2H), 7.21 (t, J = 8.5 Hz, 2H), 5.60 (s, 2H) ppm.

CNMR (CDCI3, 125 MHz): 194.6, 166.10 (d, J = 256.8 Hz), 154.4, 153.6, 138.3, 133.5, 133.4, 132,7 (d, J = 3.0 Hz), 128.1, 127.0, 125.0, 115.9, 77.0 (t, J = 31.7 Hz), 66.7 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₄ H ₈ C1FN ₂ 0 ₃ S ₂

(370.81)]

Calculated: C 45.35, H 2.17, N 7.55 %

Measured: C 45.59, H 2.16, N 7.23 %

N(3)-alkyIating reaction (Process "C")

119 mmol of l,3-dihydro-2,3,4-berizothiadiazepin-2,2-dioxide, appropriately substituted on the benzene ring and containing an appropriately substituted phenyl group in position 5, is added to 1000 ml acetonitrile. 21.45 ml (144 mmol) of DBU and 146 mmol alkylating agent of the Formula (V) are added to the solution at room temperature. The reaction mixture is stirred at 20-60 °C until the starting material is used up. The amount of starting material is monitored by TLC.

The reaction mixture is evaporated and dissolved in 300 ml dichloromethane and 250 ml water. After separating, the aqueous layer is extracted with 100 ml dichloromethane. The combined organic phase is washed with 2x200 ml water, dried over MgS0 ₄ and evaporated.

Process C/l: the crystalline residue is triturated with 50 ml methanol and after stirring for 30 min, it is filtered and dried. An analytical sample is obtained by recrystallization from the solvent indicated.

Process C/2: If the residue is oily and not crystallized from methanol, the residue is subjected to flash chromatography on silica gel (20-fold amount) with hexane;ethyl acetate=l:l eluent and it is crystallised. The solvent used for recrystallization is indicated right after the melting point of each compound.

Process C/3: if the residue is crystalline but soluble in methanol the residue is crystallized. The solvent used for recrystallization is indicated right after the melting point of each compound.

Example 16

7-Chloro-5-(4-fluoro-phenyl)-3-methyI-l,3-dihydro-2^,4-benzo thiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/l starting from, 7-chloro- 5-(4-fluoro-phenyl)-l,3-dmydro-2,3,4-benzothiadiazepin-2,2-d ioxide and methyl iodide.

Yield: 92 %

Melting point: 219-221 °C (acetonitrile)

IR (KBr): 2966, 2944, 1601, 1509, 1323, 1135 cm ^"1 .

HNMR (CDCI3, 500 MHz): 7.71 (dd, J=9.0, 5.4 Hz, 2H), 7.55 (dd, J=8.3, 2.2 Hz, IH), 7.45 (d, J=8.2 Hz, IH), 7.24 (d, J=2.2 Hz, IH), 7.14 (t, J=8.6 Hz, 2H), 4.35 (s, 2H), 3.49 (s, 3H) ppm.

CNMR (CDCI3, 125 MHz): 169.9, 165.1 (d, J-253.9 Hz), 135.7, 134.9, 131.7 (d, J=8.8 Hz), 131.6, 130.9 (d, J=3.4 Hz), 130.4, 128.9, 128.7, 116.0 (d, J=22.0 Hz), 55.3, 35.3 ppm.

Elemental analysis [calculated on the basis of the Formula CjsHnClFNiOiS (338.79)

Calculated: C 53.18, H 3.57, N 8.27, S 9.46, CI 10.46 %

Measured: C 52.96, H 3.56, N 8.23, S 9.55, CI 10.53 % Example 17

7-Chloro-3-ethyl-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzo thiadiazepin- 2,2-dioxide

The title product is prepared according to the process C/l starting from 7-chloro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and ethyl iodide.

Yield: 90 %

Melting point: 171-172 °C (diisopropyl ether— ethanol) IR (KBr): 2976, 1603, 1508, 1326, 1137 cm ^'1 .

HNMR (DMSO-<4, 500 MHz): 7.72 (dd, J=8.3, 2.2 Hz, IH), 7.71 (dd, J=8.9, 5.4 Hz, 2H), 7.70 (d, J=8.4 Hz, IH), 7.36 (t, J=8.8 Hz, 2H), 7.31 (d, J=2.0 Hz, IH), 4.84 (s, 2H), 3.45 (q, 2H), 1.05 (t, 3H) ppm.

CNMR (DMSO-</ ₆ , 125 MHz): 170.5, 164.3 (d, J=250.0 Hz), 136.1, 133.1, 132.1 (d, J=8.8 Hz), 131.8 (d, J=2.9 Hz), 131.4, 131.4, 130.6, 128.1, 115.9 (d, J=22.0 Hz), 54.3, 42.4, 13.1 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₆ H ₁₄ C1FN ₂ 0 ₂ S (352.82)]

Calculated: C 54.47, H 4.00, CI 10.05, S 9.09, N 7.94 %

Measured: C 54.32, H 3.92, CI 9.87, S 9.29, N 7.93 %

Example 18

7-Chloro-5-(4-fluoro-phenyl)-3-propyl-l,3-dihydro-2,3,4-benz othiadiazepm-

2,2-dioxide The title product is prepared according to the process C/2 starting from 7-chloro- 5-(4-fluoro-phenyl)-l ,3-dihydro-2,3,4-benzothiadiazepin-2,2 -dioxide and propyl iodide.

Yield: 85 %

Melting point: 122-122.5 °C (diisopropyl ether— hexane) IR (KBr): 2938, 1601, 1509, 1335, 1135 cm- ¹ .

HNMR (CDC1 ₃ , 500 MHz): 7.72 (dd, J=8.9, 5.4 Hz, 2H), 7.55 (dd, J=8.2, 2.2 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.14 (t, J=8.7 Hz, 2H), 4.34 (s, 2H), 3.53 (t, J=7.1 Hz, 2H), 1.49 (m, 2H), 0.72 (t, J-7.4 Hz, 3H) ppm.

CNMR (CDCI3, 125 MHz): 170.9, 165.0 (d, J=254.4 Hz), 135.9, 134.6, 131.6 (d, J=9.3 Hz), 131.4, 131.0 (d, J=2.9 Hz), 130.4, 129.3, 128.2, 115.9 (d, J=22.0 Hz), 55.5, 49.2, 21.1, 10.8 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₇ H ₁₆ C1FN ₂ 0 ₂ S (366.84)]

Calculated: C 55.66, H 4.40, CI 9.66, S 8.74, N 7.64 %

Measured: C 55.68, H 4.41, CI 9.62, S 8.82, N 7.57 %

Example 19

7-ChIoro-5-(4-fluoro-phenyl)-3-(prop-2-inyI)-l,3-dihydro-2,3 _» 4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/2 starting from 7-chloro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and 3 - bromo-propine.

Yield: 91 % Melting point: 139-140 °C (diisopropyl ether)

IR (KBr): 3305, 1605, 1508, 1329, 1131, 1065, 844 cm ¹ .

HNMR (DMSO-<¼, 500 MHz): 7.76 (dd, J=8.3, 2.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.9, 5.5 Hz, 2H), 7.39 (t, J=8.8 Hz, 2H), 7.32 (d, J=2.1 Hz, 1H), 4.95 (s, 2H), 4.21 (d, J=2.5 Hz, 2H), 3.25 (t, J=2.5 Hz, 1H ppm).

CNMR (DMSO-i/e, 125 MHz): 170.7, 164.5 (d, J=250.5 Hz), 135.9, 133.4, 132.3 (d, J=9.3 Hz), 131.7, 131.5, 131.5 (d, J=2.9 Hz), 130.4, 128.3, 116.0 (d, J-22.0 Hz), 78.3, 76.1, 54.3, 38.2 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₇ Hi ₂ ClFN ₂ 0 ₂ S (362.81)]

Calculated: C 56.28, H 3.33, CI 9.77, S 8.84, N 7.72 %

Measured: C 56.39, H 3.34, CI 9.62, S 8.99, N 7.72 %

Example 20

7-Chloro-5-(4-fluoro-phenyl)-3-isopropyl-l,3-dihydro-2,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/l starting from 7-chloro- 5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiazepin-2,2- dioxide and isopropyl iodide.

Yield: 82 %

Melting point: 147-151 °C (diisopropyl ether)

IR (KBr): 3080, 1601, 1544, 1508, 1323, 1158, 1139, 852 cm ^"1 .

HNMR (CDCI ₃ , 500 MHz): 7.74 (dd, J=8.8, 5.4 Hz, 2H), 7.53 (dd, J=8.3, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.16 (t, J=8.5 Hz, 2H), 4.31 (s, 2H), 4.29 (m, 1H), 1.28 (d, J=6.6 Hz, 6H) ppm. CNMR (CDCI3, 125 MHz): 172.4, 165.0 (d, J=253.9 Hz), 135.8, 134.5, 131.6 (d, J=8.8 Hz), 131.4, 131.4 (d, J=3.4 Hz), 130.3, 129.8, 128.2, 115.9 (d, J=22.0 Hz), 56.4, 50.3, 20.7 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₇ Hi6ClFN ₂ 0 ₂ S (366.84)]

Calculated: C 55.66, H 4.40, CI 9.66, S 8.74, N 7.64 %

Measured: C 55.33, H 4.41, CI 9.55, S 8.60, N 7.54 %

Example 21

7-Chloro-5-(4-fluoro-phenyl)-3-(3-methyI-but-2-enyI)-l,3-dih ydro-2,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/3 starting from 7-chloro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and 1 - bromo-3 -methyl-but-2-ene.

Yield: 93 %

Melting point: 168-169 °C (diisopropyl ether) IR (KBr): 2925, 1598, 1505, 1327, 1155, 1133 cm ^-1 .

HNMR (CDCI3, 500 MHz): 7.66 (dd, J=9.0, 5.4 Hz, 2H), 7.54 (dd, J=8.2, 2.1 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.13 (t, J=8.4 Hz, 2H), 5.04 (t, J=1.3 Hz, 1H), 4.33 (s, 2H), 4.16 (d, J=6.9 Hz, 2H), 1.70 (d, J=l.l Hz, 6H) ppm.

CNMR (CDCI3, 125 MHz): 170.7, 164.9 (d, J = 253.9 Hz), 137.7, 135.9, 134.7, 131.6 (d, J = 8.8 Hz), 131.4, 131.2 (d, J = 3.4 Hz), 130.4, 129.2, 128.5, 117.9, 115.9 (d, J = 22.0 Hz), 55.7, 45.88, 25.8, 18.1 ppm. Elemental analysis [calculated on the basis of the Formula C ₁ 9H ₁₈ C1FN ₂ 0 ₂ S (392.88)]

Calculated: C 58.09, H 4.62, CI 9.02, S 8.16, N 7.13 %

Measured: C 58.01, H 4.68, CI 8.96, S 8.15, N 7.07 %

Example 22

7-Chloro-5-(4-fluoro-phenyl)-3-(3-methyl-butyl)-l,3-dihydro- 2,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/l starting from 7-chloro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and 1 - bromo-3-methyl-but-2-ene.

Yield: 90 %

Melting point: 123-124 °C (diisopropyl ether-hexane) IR (KBr): 2960, 1603, 1556, 1510, 1326, 1134, 847 cm ^'1 .

HNMR (CDCI3, 500 MHz): 7.72 (dd, 2H, J=8.9, 5.4 Hz), 7.54 (dd, IH, J=8.2, 2.2 Hz), 7.44 (d, IH, J=8.3 Hz), 7.23 (d, IH, J=2.2 Hz), 7.15 (t, 2H, J=8.6 Hz), 4.33 (s, 2H), 3.59 (t, J=7.0 Hz, 2H), 1.39 (m, IH), 1.34 (m, 2H), 0.74 (d, J=6.3 Hz, 6H) ppm.

CNMR (CDCI3, 125 MHz): 170.9, 165.0 (d, J=254.4 Hz), 135.9, 134.6, 131.6 (d, J=8.8 Hz), 131.4, 131.0 (d, J=2.9 Hz), 130.4, 129.3, 128.2, 116.0 (d, J=22.0 Hz), 55.5, 46.2, 36.6, 25.7, 22.3 ppm.

Elemental analysis [calculated on the basis of the Formula C19H20CIFN2O2S

(394.90)]

Calculated: C 57.79, H 5.10, CI 8.98, S 8.12, N 7.09 %

Measured: C 57.56, H 5.18, CI 8.93, S 8.39, N 7.08 % Example 23

3-BenzyI-7-chloro-5-(4-fluoro-phenyl)-l,3-dihydro-2^,4-benzo thiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/2 starting from 7-chloro- 5-(4-fluoro-phenyl)-l ,3-dmydro-2,3,4-benzothiadiazepin-2,2-dioxide and benzyl bromide.

Yield: 89 %

Melting point: 153 °C (diisopropyl ether) IR (KBr): 1600, 1506, 1333, 1153, 842 cm ^"1 .

HNMR (CDCI3, 500 MHz): 7.56 (dd, J=8.2, 2.2 Hz, IH), 7.49 (dd, J=8.9, 5.4 Hz, 2H), 7.20 (m, 3H), 7.05 (t, J-8.6 Hz, 2H), 7.02 (d, J=2.0 Hz, IH), 7.00 (d, J=2.0 Hz, 2H), 4.73 (s, 2H), 4.40 (s, 2H) ppm.

CNMR (CDCI3, 125 MHz): 171.7, 165.0 (d, J=253.9 Hz), 136.0, 135.5, 134.7, 131.6 (d, J=9.3 Hz), 131.5, 130.8 (d, J=2.9 Hz), 130.4, 129.3, 128.5, 128.3, 128.2, 127.5, 115.8 (d, J=22.0 Hz), 55.7, 51.3 ppm.

Elemental analysis [calculated on the basis of the Formula C ₂ iH ₁₆ ClFN202S (414.89)]

Calculated: C 60.80, H 3.89, CI 8.55, S 7.73, N 6.75%

Measured: C 60.73, H 3.75, CI 8.42, S 7.88, N 6.75%

Example 24

7-FIuoro-5-(4-fluoro-phenyl)-3-methyl-l,3-dihydro-2,3,4-benz othiadiazepin-

2,2-dioxide The title product is prepared according to the process C/l starting from 7-fluoro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and methyl iodide.

Yield: 90 %

Melting point: 169-171 °C (ethanol)

IR (KBr): 2992, 2947, 1601, 1555, 1493, 1326, 1263, 1231 cm ^"1 .

HNMR (CDC1 ₃ , 500 MHz): 7.72 (dd, J=8.4, 5.4 Hz, 2H), 7.50 (dd, J=8.4, 5.1 Hz, IH), 7.28 (td, J=8.3, 2.3 Hz, IH), 7.14 (t, J=8.3 Hz, 2H), 6.97 (dd, J=8.4, 2.4 Hz, IH), 4.36 (s, 2H), 3.15 (s, 3H) ppm.

CNMR (CDCI3, 125 MHz): 169.9, 165.0 (d, J=253.9 Hz), 162.0 (d, J=251.0 Hz), 136.1 (d, J=7.8 Hz), 131.7 (d, J=8.8 Hz), 131.1 (d, JM8.8 Hz), 130.9 (d, 1=2.9 Hz), 126.5 (d, J=3.4 Hz), 118.6 (d, J=22.0 Hz), 115.9 (d, J=23.4 Hz), 115.9 (d, J=22.0 Hz), 55.1, 35.3 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₅ H ₁₂ F ₂ N ₂ 0 ₂ S

(322.34)]

Calculated: C 55.89, H 3.75, S 9.95, N 8.69 %

Measured: C 56.31, H 3.73, S 10.18, N 8.81 %

Example 25

7-Fluoro-3-ethyI-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzo thiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/l starting from 7-fluoro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and ethyl iodide.

Yield: 94 %

Melting point: 148-151 °C (diisopropyl-ether)

IR (KBr): 2977, 2935, 1602, 1553, 1507, 1330, 1233, 1144 cm ^"1 . HNMR (DMSO-i¾, 500 MHz): 7.72 (m, 3H), 7.51 (td, J=8.6, 2.7 Hz, IH), 7.36 (t, J=8.8 Hz, 2H), 7.14 (dd, J=9.0, 2.7 Hz, IH), 4.80 (s, 2H), 3.44 (q, J=7.0 Hz, 2H), 1.04 (t, J=7.2 Hz, 3H) ppm.

CNMR (DMSO- ₆ , 125 MHz): 170.6 (d, J=2.0 Hz), 164.3 (d, J=250.0 Hz), 161.4 (d, J=246.6 Hz), 136.2 (d, J=7.8 Hz), 132.1 (d, J=8.8 Hz), 131.8 (d, J=8.8 Hz), 131.8 (d, J=2.9 Hz), 128.0 (d, J=2.9 Hz), 118.5 (d, J=21.5 Hz), 115.9 (d, J=22.0 Hz), 115.5 (d, J=23.4 Hz), 54.1, 42.32, 13.1 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₆ H ₁₄ F ₂ N ₂ 0 ₂ S

(336.36)]

Calculated: C 57.13, H 4.20, S 9.53, N 8.33 %

Measured: C 56.86, H 4.25, S 9.59, N 8.33 %

Example 26

3-Butyl-7-fluoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzo thiadiazepin-

2,2- dioxide

The title product is prepared according to the process C/l starting from 7-fluoro- 5-(4-fluoro-phenyl)- 1 ,3-dihydro-2,3,4-benzothiadiazepin-2,2-dioxide and butyl iodide.

Yield: 88 %

Melting point: 99-103 °C (ethanol)

IR (KBr): 3072, 2971, 2938, 2909, 2861, 1602, 1549, 1497, 1331, 1233, 1156, 1131, 1080 cm- ¹ .

HNMR (DMSO-i¾, 500 MHz): 7.72 (m, 3H), 7.51 (td, J=8.7, 2.7 Hz, IH), 7.36 (t, J=8.9 Hz, 2H), 7.24 (dd, J=9.0, 2.7 Hz, IH), 4.81 (s, 2H), 3.41 (t, J=7.0 Hz, 2H), 1.40 (m, 2H), 1.05 (m, J=7.0 Hz, 2H), 0.74 (t, 3H) ppm. CNMR (DMSO-i ₆ , 125 MHz): 170.8 (d, J=1.5 Hz), 164.3 (d, J=250.5 Hz), 161.3 (d, J=246.6 Hz), 136.3 (d, J=8.3 Hz), 132.0 (d, J=8.8 Hz), 131.7 (d, J=8.8 Hz), 131.7 (d, J=2.9 Hz), 128.2 (d, J=2.9 Hz), 118.5 (d, J=21.5 Hz), 115.9 (d, J=22.0 Hz), 115.3 (d, J=23.4 Hz), 54.1, 46.5, 29.4, 19.1, 13.5 ppm.

Elemental analysis [calculated on the basis of the Formula C] ₈ H ₁₈ F ₂ N ₂ 0 ₂ S

(364.42)]

Calculated: C 59.33, H 4.98, S 8.80, N 7.69 %

Measured: C 59.06, H 5.04, S 8.99, N 7.61 %

Example 27

7-Fluoro-5-(4-fluoro-phenyl)-3-(3-methyI-but-2-enyl)-l,3-dih ydro-2,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/l starting from 7-fluoro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and 1 - bromo-3-methyl-but-2-ene.

Yield: 91 %

Melting point: 154-157 °C (ethanol)

IR (KBr): 2977, 2918, 1599, 1555, 1494, 1322, 1260, 1231, 1156, 1132 cm ^" '. HNMR (CDC1 ₃ , 500 MHz): 7.67 (dd, J=8.8, 5.5 Hz, 2H), 7.48 (dd, J=8.5, 5.1 Hz, 1H), 7.27 (td, J=8.4, 2.6 Hz, 1H), 7.12 (t, J=8.8 Hz, 2H), 6.95 (dd, J=8.5, 2.7 Hz, 1H), 5.03 (t, J=7.1 Hz, lH), 4.33 (s, 2H), 4.16 (d, J=7.1 Hz, 2H), 1.69 (s, 6H) ppm.

CNMR (CDCI ₃ , 125 MHz): 170.8 (d, J=1.5 Hz), 164.9 (d, J=253.9 Hz), 162.0 (d, J=250.5 Hz), 137.6, 136.2 (d, J=7.8 Hz), 131.6 (d, J=8.8 Hz), 131.2 (d, J=3.4 Hz), 131.0 (d, J=7.8 Hz), 126.8 (d, J=3.4 Hz), 118.5 (d, J=21.5 Hz), 117.9, 115.8 (d, J=22.0 Hz), 115.7 (d, J=23.0 Hz), 55.5, 45.8, 25.8, 18.1 ppm. Elemental analysis [calculated on the basis of the Formula C19H18F2N2O2S

(376.43) ]

Calculated: C 60.63, H 4.82, S 8.52, N 7.44 %

Measured: C 60.48, H 4.93, S 8.42, N 7.40 %

Example 28

7-Fluoro-5-(4-fluoro-phenyl)-3-(3-methyl-butyl)-l,3-dihydro- 2,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/l starting from 7-fluoro- 5-(4-fluoro-phenyl)- 1 ,3-dihydro-2,3,4-benzothiadiazepin-2,2-dioxide and 1 - bromo-3-methyl-but-2-ene.

Yield: 90 %

Melting point: 130-133 °C (ethanol)

IR (KBr): 2956, 2923, 2869, 1602, 1555, 1495, 1325, 1263, 1232, 1158, 1133, 1079 cm ^"1 .

HNMR (CDC1 ₃ , 500 MHz): 7.73 (dd, J=8.9, 5.4 Hz, 2H), 7.49 (dd, J=8.5, 5.1 Hz, 1H), 7.28 (td, J=8.3, 2.7 Hz, 1H), 7.14 (t, J=8.7 Hz, 2H), 6.96 (dd, J=8.4, 2.7 Hz, 1H), 4.33 (s, 2H), 3.59 (t, J=7.2 Hz, 2H), 1.39 (m, 1H), 1.34 (q, J=6.8 Hz, 2H), 0.81 (d, J=6.4 Hz, 6H) ppm.

CNMR (CDCI3, 125 MHz): 170.9 (d, J=1.5 Hz), 165.0 (d, J=254.4 Hz), 162.0 (d, J=251.0 Hz), 136.3 (d, J=7.3 Hz), 131.6 (d, J=8.8 Hz), 131.0 (d, J=8.3 Hz), 131.0 (d, J=3.9 Hz), 126.9 (d, J=2.3 Hz), 118.5 (d, J=22.0 Hz), 115.9 (d, J=22.0 Hz), 115.5 (d, J=23.4 Hz), 55.4, 46.1, 36.6, 25.7, 22.3 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁ 9H ₂₀ F ₂ N2O ₂ S

(378.44) ] Calculated: C 60.30, H 5.33, S 8.47, N 7.40 %

Measured: C 60.10, H 5.44, S 8.50, N 7.37 %

Example 29

7-Fluoro-5-(4-fluoro-phenyl)-3-hexyl-l,3-dihydro-2,3,4-benzo thiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/2 starting from 7-fluoro- 5-(4-fluoro-phenyl)-l ,3-dihydro-2,3,4-benzothiadiazepin-2,2-dioxide and hexyl bromide.

Yield: 82 %

Melting point: 93-96 °C (IP A)

IR (KBr): 2930, 2858, 1600, 1554, 1495, 1326, 1263, 1231, 1158, 1076 cm ^-1 . HNMR (DMSO-fl? ₆ , 500 MHz): 7.73 (m, 3H), 7.51 (td, J=8.6, 2.7 Hz, 1H), 7.36 (t, J=8.8 Hz, 2H), 7.11 (dd, J=8.9, 2.7 Hz, 1H), 4.81 (s, 2H), 3.41 (t, J=6.4 Hz, 2H), 1.42 (m, 2H), 1.10 (m, 4H), 0.98 (m, 2H), 0.73 (t, J=7.0 Hz, 3H) ppm.

CNMR (DMSO-i/ ₆ , 125 MHz): 171.0 (d, J=1.5 Hz), 164.4 (d, J=250.5 Hz), 161.3 (d, J=247.1 Hz), 136.3 (d, J=7.8 Hz), 132.0 (d, J = 8.8 Hz), 131.7 (d, J=8.3 Hz), 131.6 (d, J=2.9 Hz), 128.2 (d, J 2.9 Hz), 118.4 (d, J=22.0 Hz), 115.9 (d, J=22.0 Hz), 115.3 (d, J=23.4 Hz), 54.2, 46.7, 30.7, 27.1, 25.4, 22.1, 13.8 ppm.

Elemental analysis [calculated on the basis of the Formula C ₂ o¾ ₂ F ₂ N ₂ 0 ₂ S (392.47)]

Calculated: C 61.21, H 5.65, S 8.17, N 7.14 %

Measured: C 61.15, H 5.83, S 8.13, N 7.10 %

Example 30 3-Benzyl-7-fluoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benz othiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/3 starting from 7-fluoro- 5-(4-fluoro-phenyl)- 1 ,3 -dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and benzyl bromide.

Yield: 90 %

Melting point: 184-187 °C (ethanol)

IR (KBr): 3430, 2995, 2949, 2926, 1598, 1547, 1494, 1320, 1232, 1 153, 1129, 1074 cm ^"1 .

HNMR (DMSO-i/ ₆ , 500 MHz): 7.77 (dd, J=8.6, 5.4 Hz, 1H), 7.55 (td, J=8.7, 2.7 Hz, IK), 7.53 (dd, J=9.0, 5.5 Hz, 2H), 7.30 (t, J=8.8 Hz, 2H), 7.24 (t, J=1.8 Hz, 2H), 7.21 (t, J=1.5 Hz, IK), 7.00 (d, J=2.5 Hz, 2H), 6.99 (dd, J = 9.0, 2.7 Hz, 1H), 4.92 (s, 2H), 4.64 (s, 2H) ppm.

CNMR (DMSO-_i ₆ , 125 MHz): 171.1 (d, J= 1.5 Hz), 164.3 (d, J=250.0 Hz), 161.4 (d, J=247.6 Hz), 136.3 (d, J=7.8 Hz), 136.2, 132.0 (d, J=9.3 Hz), 131.9 (d, J=8.8 Hz), 131.4 (d, J-2.9 Hz), 128.4, 128.2 (d, J=2.0 Hz), 128.1, 127.4, 1 18.6 (d, J=22.0 Hz), 1 15.9 (d, J=22.0 Hz), 1 15.2 (d, J=23.4 Hz), 54.1 , 50.8 ppm.

Elemental analysis [calculated on the basis of the Formula C ₂₁ H ₁ F ₂ N ₂ 0 ₂ S

(398.44)]

Calculated: C 63.31, H 4.05, S 8.05, N 7.03 %

Measured: C 63.03, H 4.03, S 7.91, N 6.98 %

Example 31

7-Fluoro-5-(4-fluoro-phenyI)-3-(3-phenyl-propyl)-l,3-dihydro -2,3,4- benzothiadiazepin-2,2-dioxide The title product is prepared according to the process C/l starting f om 7-fluoro- 5-(4-fluoro-phenyl)-l ,3-dihydro-2,3,4-benzothiadiazepin-2,2-dioxide and 3- phenyl-propyl bromide.

Yield: 80 %

Melting point 163-167 °C (ethanol)

IR (KBr): 2992, 2939, 2867, 1601, 1557, 1495, 1451, 1424, 1329, 1262, 1230, 1158, 1059 cm- ¹ .

HNMR (DMSO-da, 500 MHz): 7.74 (m, 3H), 7.53 (td, J=8.7, 2.7 Hz, 1H), 7.37 (t, J=8.8 Hz, 2H), 7.22 (t, J=7.4 Hz, 2H), 7.20 (dd, J=8.9, 2.7 Hz, 1H), 7.14 (t, J=7.3 Hz, 1H), 7.02 (d, J=7.1 Hz, 2H), 4.84 (s, 2H), 3.43 (t, J=6.8 Hz, 2H), 2.31 (t, J=7.7 Hz, 2H), 1.72 (qn, J=7.8 Hz, 2H) ppm.

CNMR DMSO-de, 125 MHz): 171.2 (d, J=1.5 Hz), 164.4 (d, J=250.0 Hz), 161.4 (d, J=247.1 Hz), 141.3, 136.3 (d, J=7.8 Hz), 132.1 (d, J=9.3 Hz), 131.8 (d, J=8.8 Hz), 131.6 (d, J=2.9 Hz), 128.4, 128.4, 128.2 (d, J=2.9 Hz), 125.9, 118.5 (d, J=21.5 Hz), 115.9 (d, J=22.0 Hz), 115.4 (d, J-23.9 Hz), 54.2, 46.2, 31.9, 29.4 ppm.

Elemental analysis [calculated on the basis of the Formula C ₂₃ H ₂₀ F ₂ N ₂ O ₂ S

(426.49)]

Calculated: C 64.77, H 4.73, S 7.52, N 6.57 %

Measured: C 64.70, H 4.89, S 7.58, N 6.56 %

Example 32

5-(3-Fluoro-phenyl)-7-chloro-3-methyl-l,3-dihydro-2,3,4-benz othiadiazepin-

2,2-dioxide The title product is prepared according to the process C/1 starting from 7-chloro- 5-(3-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiazepin-2,2- dioxide and methyl iodide.

Yield: 85 %

Melting point 172-173 °C (ethanol)

IR (KBr): 2992, 2939, 2867, 1601, 1557, 1495, 1451, 1424, 1329, 1262, 1230, 1158, 1059 cm ^'1 .

HNMR (CDC1 ₃ , 500 MHz): 7.56 (dd, J=8.2, 2.2 Hz, 1H), 7.49 (m, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.41 (m, 2H), 7.25 (m, 2H), 4.36 (s, 2H), 3.16 (s, 3H) ppm.

CNMR (CDCI3, 125 MHz): 169.7 (d, J=2.9 Hz), 162.8 (d, J=248.0 Hz), 136.8 (d, J=7.3 Hz), 135.4, 134.9, 131.7, 130.5, 130.3 (d, J=7.8 Hz), 128.9, 128.6, 125.5 (d, J=2.9 Hz), 118.9 (d, J=21.5 Hz), 116.0 (d, J=23.4 Hz), 55.3, 35.4.

Elemental analysis [calculated on the basis of the Formula C ₁₅ H ₁₂ C1FN ₂ 0 ₂ S (338.79)]

Calculated: C 53.18, H 3.57, CI 10.46, S 9.46, N 8.27 %

Measured: C 53.00, H 3.60, CI 10.37, S 9.53, N 8.17 %

Example 33

8-Cyano-5-(4-fluoro-phenyl)-3-methyl-l,3-dihydro-2,3j4-benzo thiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/1 starting from 7-chloro- 5-(3-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiazepin-2,2- dioxide and methyl iodide.

Yield: 80 % Melting point 284-285 °C (methanol)

HNMR (CDC1 ₃ , 500 MHz): 7.81 (d, J=1.0 Hz, IH), 7.78 (dd, J=8.1, 1.6 Hz, IH), 7.69 (dd, J=8.9, 5.3 Hz, IH), 7.15 (t, J=8.6 Hz, 2H), 4.41 (s, 2H), 3.15 (s, 3H) ppm.

CNMR (CDCI3, 125 MHz): 169.7, 165.2 (d, J=254.9 Hz), 138.3, 132.4, 132.2, 131.8, 131.6 (d, J=9.3 Hz), 130.4 (d, J=2.9 Hz), 129.6, 117.1, 116.1 (d, J=22.0 Hz), 115.4, 55.2, 35.3 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₆ H ₁₂ FN ₃ 02S (329.36)]

Calculated: C 58.35, H 3.67, S 9.74, N 12.76 %

Measured: C 57.96, H 3.69, S 9.87, N 12.62 %

Example 34

8-FIuoro-5-(4-fluoro-phenyI)-3-methyl-l,3-dihydro-2,3 _? 4-benzothiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/l starting from 8-fluoro- 5-(4-fluoro-phenyl)- 1 ,3-dihydro-2,3,4-benzothiadiazepin-2,2-dioxide and methyl iodide.

Yield: 92 %

Melting point 205-206 °C (methanol)

HNMR (CDCI3, 500 MHz): 7.70 (dd, J=8.4, 5.4 Hz, 2H), 7.25 (m, 2H), 7.18 (dt, J=8.3, 2.4 Hz, IH), 7.12 (t, J=8.4 Hz, 2H), 4.35 (s, 2H), 3.14 (d, J=0.6 Hz, 3H) ppm.

CNMR (CDC1 ₃ , 125 MHz): 170.3, 165.0 (d, J=253.4 Hz), 163.9 (d, J=253.9 Hz), 132.9 (d, J=8.8 Hz), 131.7 (d, J=8.8 Hz), 131.3 (d, J-3.4 Hz), 131.1 (d, J=9.3 Hz), 130.4 (d, J=3.4 Hz), 116.5 (d, J=22.9 Hz), 115.9 (d, J=22.0 Hz), 115.8 (d, J=22.0 Hz), 55.5 (d, J=2.0 Hz), 35.3 ppm.

Elemental analysis [calculated on the basis of the Formula C]5Hi ₂ F ₂ N ₂ 0 ₂ S (322.34)]

Calculated: C 55.89, H 3.75, S 9.95, N 8.69 %

Measured: C 55.40, H 3.67, S 9.95, N 8.57 %

Example 35

5-(4-Fluoro-phenyl)-8-chloro-3-methyl-l,3-dihydro-2,3,4-benz othiadiazepin-

2,2-dioxide

The title product is prepared according to the process C/l starting from 8-chloro- 5-(4-fluoro-phenyl)-l,3-dmydro-2,3,4-benzothiadiazepin-2,2-d ioxide and methyl iodide.

Yield: 90 %

Melting point 250-251 °C (methanol)

HNMR (CDC1 ₃ , 500 MHz): 7.70 (dd, J=8.9, 5.4 Hz, 2H), 7.52 (d, J=2.0 Hz, 1H), 7.46 (dd, J=8.3, 2.0 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.13 (t, J-8.5 Hz, 2H) ppm. CNMR (CDCI3, 125 MHz): 170.3, 165.0 (d, J=253.9 Hz), 137.7, 132.5, 132.1, 131.7 (d, J=9.3 Hz), 131.1 (d, J=3.4 Hz), 130.1, 129.3, 128.9, 115.9 (d, J=21.7 Hz), 55.4, 35.3 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₅ H ₁₂ C1FN ₂ 0 ₂ S (338.79)]

Calculated: C 53.18, H 3.57, CI 10.46, S 9.46, N 8.27 %

Measured: C 52.79, H 3.62, CI 10.90, S 9.90, N 8.16 % Example 36

5-(4-Fluoro-phenyl)-3-methyl-8-trifluoromethyl-l,3-dihydro-2 ,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/1 starting from 5-(4- fluoro-phenyl)-8-(trifluoromethyl)-l,3-dihydro-2,3,4-berizot hiadiazepin-2,2- dioxide and methyl iodide.

Yield: 88 %

Melting point 160-162 °C (methanol)

HNMR (CDC1 ₃ , 500 MHz): 7.78 (s, IH), 7.75 (d, J=8.7 Hz, IH), 7.71 (dd, J=8.7, 5.4, 2H), 7.41 (d, J=7.9 Hz, IH), 7.14 (t, J=8.5 Hz, 2H), 4.44 (s, 2H), 3.16 (s, 3H) ppm.

CNMR (CDC1 ₃ , 125 MHz): 170.0, 165.1 (d, J=254.4 Hz), 137.5, 133.4 (q, J=33.2 Hz), 131.7 (d, J=9.3 Hz), 131.4, 130.8 (d, J=3.4 Hz), 129.4, 126.0 (d, J=3.7 Hz), 125.6 (q, J=3.6 Hz), 123.2 (q, J=272.9 Hz), 116.0 (d, J=22.0 Hz), 55.6, 35.3 ppm.

Elemental analysis [calculated on the basis of the Formula Ci6H ₁₂ F N ₂ 0 ₂ S

(372.34)]

Calculated: C 51.61, H 3.25, S 8.61, N 7.52 %

Measured: C 51.52, H 3.32, S 8.54, N 7.46 %

Example 37

7,8-Dichloro-5-(4-fluoro-phenyI)-3-methyl-l,3-dihydro-2,3,4- benzothiadiazepin-2,2-dioxide The title product is prepared according to the process C/l starting from 8- dicMoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiaze pin-2,2-dioxide and methyl iodide.

Yield: 92 %

Melting point 236-239 °C (EPA-DMF)

IR (KBr): 2970, 2921, 1601, 1546, 1509, 1475, 1328, 1229, 1159, 1 136, 1071. HNMR (DMSO-i ₆ , 500 MHz): 8.03 (s, 1H), 7.72 (dd, J=8.9, 5.5 Hz, 2H), 7.54 (s, 1H), 7.36 (t, J=8.9 Hz, 2H), 4.90 (s, 2H), 3.01 (s, 3H) ppm.

CNMR (DMSO-i ₆ , 125 MHz): 169.1, 164.4 (d, J=250.5 Hz), 134.4, 134.1, 132.3 (d, J=8.8 Hz), 132.0, 131.4, 131.3 (d, J-2.9 Hz), 131.2, 130.49, 115.9 (d, J=22.0 Hz), 53.5, 34.9 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₆ H ₁₂ F ₄ N ₂ 0 ₂ S (372.34)]

Calculated: C 48.27, H 2.97, CI 19.00, S 8.59, N 7.51 %

Measured: C 48.31 , H 2.99, CI 18.96, S 8.60, N 7.53 %

Example 38

9-(4-fluorophenyl)-7-methyl-5H,7H-[l,2,5]thiadiazolo[3,4- h] [2,3,4] benzothiadiazepin-6,6-dioxide

The title product is prepared according to the process C/l starting from 9-(4- fluorophenyl)-5H,7H-[l,2,5]thiadiazolo[3,4-/z][2,3,4]benzoth iadiazepin-6,6- dioxide and methyl iodide.

Yield: 95 %

Melting point 272-275 °C (ethanol-DMF) IR (KBr): 3137, 1597, 1569, 1508, 1326 cm- ¹ .

HNMR (DMSO-i/e, 500 MHz): 10.34 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.80 (dd, J = 8.7, 5.5 Hz, 2H), 7.36 (t, J = 8.9 Hz, 2H), 4.96 (s, 2H) ppm.

CNMR (DMSO-£¾, 125 MHz): 172.0, 164.3 (d, J = 250.0 Hz), 154.4, 153.0, 136.3, 133.1, 132.4 (d, J = 2.9 Hz), 132.2 (d, J = 8.7 Hz), 122.6, 121.5, 115.8 (d, J = 22.0 Hz), 55.1 ppm.

Elemental analysis [calculated on the basis of the Formula Ci ₅ HnFN ₄ 0 ₂ S2

(362.41)]

Calculated: C 49.71, H 3.06, N 15.46, S 17.70 %

Measured: C 50.04, H 3.06, N 15.82, S 17.50 %

Example 39

7,8-Dichloro-3-ethyl-5-(4-fluoro-phenyl)-l,3-dihydro-2^,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process C/3 starting from 7,8- dicUoro-5-(4-fluoro-phenyl)-l,3-dihydro-2,3,4-benzothiadiaze pin-2,2-dioxide and ethyl iodide.

Yield: 76 %

Melting point 218-221 °C (acetonitryle) IR (KBr): 2986, 1601, 1326, 1138 cm ^"1 .

HNMR (DMSO-< , 500 MHz): 8.03 (s, 1H), 7.74 (dd, J=9.0, 5.5 Hz, 2H), 7.55 (s, 1H), 7.36 (t, J=8.8 Hz, 2H), 4.86 (s, 2H), 3.46 (q, 2H), 1.05 (t, 3H) ppm.

CNMR (DMSO- e, 125 MHz): 170.07, 164.43 (d, J = 250.5 Hz), 134.60, 134.10, 132.22 (d, J = 9.3 Hz), 132.21, 131.57 (d, J = 2.9 Hz), 131.44, 131.17, 130.29, 115.92 (d, J = 22.0 Hz), 53.81, 42.46, 13.08 ppm. Elemental analysis [calculated on the basis of the Formula C ₁ 6H ₁₃ Cl2FN ₂ 0 ₂ S (387.26)]

Calculated: C 49.62, H 3.38, S 8.28, CI 18.31, N 7.23 %

Measured: C 49.60, H 3.45, S 8.19, CI 18.03, N 7.26 %

C(l)-alkylating reaction (Process "D")

15 mmol of l,3-dmydro-2,3,4-benzothiadiazepine-2,2-dioxide, alkylated (aralkylated) in position 3, appropriately substituted on the aromatic carbocycle and containing an appropriately substituted phenyl group in position 5 is added to 100 ml tetrahydrofurane. To the solution is added 7 ml (17.5 mmol) 2.5 M BuLi in hexane under stirring in an acetone-dry ice bath at -78 °C.

After stirring for one hour at this temperature, 16.5 mmol alkyl iodide is added to the red solution in 8 ml tetrahyclrofurane. After warming to room temperature, the reaction mixture is added to 150 ml ice and stirred half an hour. After extracting the aqueous mixture with 180 ml ethyl acetate, the organic layer is extracted with brine, dried over MgS0 ₄ and evaporated. The product is crystallized. The solvent used by crystallization is indicated at the melting points of each compound.

Example 40

7-Chloro-5-(4-fluoro-phenyl)-l,3-dimethyl-l,3-dihydro-2,3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process D starting from 7-chloro-5- (4-fluoro-phenyl)-3-methyl- 1 ,3-dihydro-2,3 ,4-benzothiadiazepin-2,2-dioxide and methyl iodide.

Yield: 87 % Melting point: 139-143 °C (2-propanol)

IR (KBr): 2937, 1602, 1550, 1508, 1317, 1236, 1143, 1041 cm ^'1 .

HNMR (CDC1 ₃ , 500 MHz): 7.73 (dd, J=9.0, 5.4 Hz, 2H), 7.58 (dd, J=8.4, 2.2 Hz,

IH), 7.45 (d, J=8.4 Hz, IH), 7.20 (d, J=2.2 Hz, IH), 7.14 (t, J=9.0 Hz, 2H), 4.36

(q, J=7.1 Hz, IH), 3.16 (s, 3H), 1.88 (d, J=7.1 Hz, 3H) ppm.

CNMR (CDC1 ₃ , 125 MHz): 169.6, 165.0 (d, J=253.9 Hz), 136.1, 134.4, 133.4,

131.7 (d, J=8.8 Hz), 131.3, 130.9 (d, J=3.4 Hz), 128.4, 127.1, 115.9 (d, J=22.0

Hz), 57.4, 35.9, 10.4 ppm.

Elemental analysis [calculated on the basis of the Formula C ₁₆ H ₁₄ C1FN ₂ 0 ₂ S (352.82)]

Calculated: C 54.47, H 4.00, CI 10.05, S 9.09, N 7.94 %

Measured: C 54.56, H 4.09, CI 9.90, S 9.00, N 7.93 %

Example 41

7-Chloro-l-ethyl-5-(4-fluoro-phenyl)-3-methyl-l,3-dihydro-2, 3,4- benzothiadiazepin-2,2-dioxide

The title product is prepared according to the process D starting from 7-chloro-5- (4-fluoro-phenyl)-3 -methyl- 1 ,3-dihydro-2,3,4-benzothiadiazepin-2,2-dioxide and ethyl iodide.

Yield: 92 %

Melting point: 175-177 °C (ΓΡΑ)

IR (KBr): 2970, 2935, 1603, 1509, 1316, 1146, 841 crn ¹ .

HNMR (CDCI3, 500 MHz): 7.80-7.70 (m, 2H), 7.6-7.4 (m, 2H), 7.21 (d, J=2.2 Hz, IH), 7.14 (t, J=8.4 Hz, 2H), 4.16 (q, J=4.5 Hz, IH), 3.14 (bs, 3H), 2.52-2.35 (m, IH), 2.34-2.10 (m, IH). 1.06 (t, J=7.3 Hz, 3H) ppm. CNMR (CDCI3, 125 MHz): 169.4 (d, J=102.5 Hz), 162.3, 136.0, 134.1, 132.4, 131.4 (d, J=9.1 Hz), 131.0 (d, J=12.5 Hz), 128.5, 128.2, 115.8 (d, J=21.9 Hz), 77.0 (t, J=32.0 Hz), 65.0, 35.6, 11.8 ppm.

Elemental analysis [calculated on the basis of the Formula C] ₇ H ₁₆ C1FN ₂ 0 ₂ S (366.84)]

Calculated: C 55.66, H 4.40, CI 9.66, S 8.74, N 7.64 %

Measured: C 55.40, H 4.39, CI 9.50, S 8.66, N 7.63 %