HUP0700504A2 - Benzo[1,2,3]thiadiazine-1,1-dioxide derivatives, process for their preparation, pharmaceutical compositions containing the same and their use - Google Patents

Abstract

Benzo[1,2,3]thiadiazine-1,1-dioxide derivatives (I) are new. Benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of formula (I) are new. R 1>, R 2>H or 1-4C alkyl; and R 3>-R 6>H, halo, 1-4C alkyl or alkoxy group containing 1-4C alkyl. Independent claims are included for: (1) the preparation of (I); and (2) a preparation of a medicament comprising mixing (I) with a vehicle or optionally with other excipients and transforming the obtained mixture into a dosage form. [Image] ACTIVITY : CNS-Gen.; Tranquilizer; Nootropic; Anabolic; Eating-Disorders-Gen.; Hypnotic; Neuroleptic; Endocrine-Gen.; Antialcoholic; Antismoking; Antiaddictive; Sedative. MECHANISM OF ACTION : None given.

Description

The invention relates to new benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of general formula (I), pharmaceutical compositions containing such active ingredients, a process for preparing the active ingredients and their therapeutic use.

The subject of our invention is more particularly benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of general formula (I), in which

R ¹ and R ² independently represent a hydrogen atom or a straight or branched alkyl group having 1-4 carbon atoms,

R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a C 1 H straight or branched alkyl group or a C 1-4 alkoxy group.

The first synthesis of the benzo[l,2,3]thiadiazine-1,1-dioxide ring system occurred in 1917 (E. Schrader, J. Prakt. Chem. 1918, 96, 180-185.), when 2-cyanobenzenesulfonic acid chloride was cyclized with hydrazine, yielding a 4-hydrazino-substituted benzo[l,2,3]thiadiazine-1,1-dioxide derivative (Scheme 1).

A similar process is known for the preparation of diuretic 4-hydrazinobenzo[1,2,3]thiadiazine-1,1-dioxide derivatives (P. Schmidt, K. Eichenberger, M. Wilhelm, Helv. Chim. Acta 1962, 45, 996-999.).

The preparation of the unsubstituted benzo[1,2,3]thiadiazine-1,1-dioxide structural unit starting from sodium formylbenzenesulfonate has been carried out by two different methods (J. F. King, A. Hawson, D. M. Deaken, J. Komery, J C. S. Chem. Comm. 1969, 33-34.; J. F. King, A. H. Huston, J. Komery, D. M. Deaken, D. R. K. Harding, Can. J. Chem 1971, 49, 936-942.). The two reaction routes are illustrated in Scheme 2.

According to the first method, sodium o-formylbenzenesulfonate is reacted with thionyl chloride, and the o-formylbenzenesulfonic acid chloride thus prepared is reacted with hydrazine to obtain benzo[1,2,3]thiadiazine-1,1-dioxide.

According to the second method, the sodium salt of o-formylbenzenesulfonic acid is reacted with hydrazine, and then the resulting hydrazide is converted to benzo[1,2,3]thiadiazine-1,1-dioxide with phosphorus pentachloride or phosphorus oxychloride in the presence of hydrazine.

According to the state of the art, the preparation of known 4-phenylbenzo[1,2,3]thiadiazine-1,1-dioxides is carried out starting from the corresponding o-aminobenzophenone, via a diazonium compound, in such a way that the diazonium compound prepared in the known manner is treated with sulfur dioxide in the presence of copper(I) salts to form a sulfonic acid chloride, and the 4-phenylbenzo[1,2,3]thiadiazine-1,1-dioxide product is obtained by using one of the two methods described above. (J. B. Wright, J. Het. Chem. 1968, 5, 453-459.).

United States Patent No. 3,407,197 discloses certain benzo[1,2,3]thiadiazine-1,1-dioxide derivatives containing a phenyl group in the 4-position, which exhibit disinfectant, pesticidal (mothicidal) and herbicidal activity.

U.S. Patent No. 3,407,198 relates to benzo[1,2,3]thiadiazine-1,1-dioxide derivatives alkylated at the 2-position, which, in addition to the above effects, also exert a central nervous system effect, which is not disclosed in detail. The reaction route used for the preparation is illustrated in Scheme 3.

According to the state of the art, 4-phenylbenzo[1,2,3]thiadiazine-1,1-dioxide derivatives with diuretic activity are also known (Ο. B. T. Nielsen, C. K. Nielsen, P. W. Feit, J. Med. Chem. 1973, 16, (10); 1170-1177.). Their preparation is essentially carried out using the Wright method described above. The reaction is shown in Scheme 4.

International patent application WO 99/67240 relates to compounds with antibiotic activity substituted with benzo[1,2,3]thiadiazine-1,1-dioxide derivatives at the 2-position of the carbapenem ring system.

As a result of the significantly accelerated scientific and technological development and the ongoing social transformations of our time, civilized people are exposed to many sources of stress. Stress often results in the development of a disease or condition belonging to the anxiety group.

Anxiety is a characteristic symptom of central nervous system origin, which can develop as a result of stress, psychiatric illness, pathological internal medicine, trauma, surgical condition. The most commonly used drugs for the treatment of various anxiety conditions are the so-called benzodiazepine-type drugs, e.g. diazepam, chlordiazepoxide, alprazolam.

Although many pharmaceutical agents have been developed for the treatment of anxiety disorders and the resulting condition, they have numerous side effects that impair quality of life. It is also known that many central nervous system diseases can be treated with the greatest efficiency by using combination therapy. Therefore, there is a continuous demand for the development of new anxiolytic, i.e. anti-anxiety, pharmaceutical agents that can be used in pharmaceutical preparations.

The aim of our research activity was to develop new active pharmaceutical ingredients that can be used in pharmaceutical preparations for the treatment of anxiety-related disorders, such as generalized anxiety disorder, panic disorder, agoraphobia, social phobia and other phobias, post-traumatic stress disorder, and central nervous system disorders accompanied by anxiety symptoms.

The above object is achieved according to our invention.

Our invention is based on the surprising discovery that compounds of general formula (I), in which formula

1'2 r r

R and R independently represent a hydrogen atom, a straight or branched alkyl group having 1-4 carbon atoms,

R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a C 1-4 straight or branched alkyl group or a C 1-4 alkoxy group, exhibit anxiolytic activity and, due to this activity, are suitable for the prevention and treatment of diseases and conditions belonging to the anxiety symptom group, such as generalized anxiety disorder, panic disorder, agoraphobia, social phobia and other phobias, post-traumatic stress disorder, and nervous system diseases accompanied by anxiety symptoms, such as attention deficit hyperactivity disorder, anorexia, bulimia, obsessive-compulsive disorders, sexual dysfunction. The compounds of general formula (I) are novel.

The anxiolytic effect of the compounds of general formula (I) is particularly surprising, since it cannot be related to the disinfectant, diuretic, insecticidal or herbicidal effects of compounds of similar structure, known in the art, containing the 4-phenylbenzo[l,2,3]thiadiazine-l,l-dioxide structural unit. Although it is known in the art that 4-phenylbenzo[l,2,3]thiadiazine-l,l-dioxide derivatives have central nervous system effects, the central nervous system effects of the known compounds have not been characterized in terms of either the proximal area of action or the potency of the effect.

The subject of our invention is the new benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of general formula (I), where

R and R independently represent a hydrogen atom, a straight or branched alkyl group having 1-4 carbon atoms,

R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a C 1-4 straight or branched alkyl group or a C 1-4 alkoxy group.

In the present patent application, the term "halogen atom" means a fluorine, bromine, chlorine or iodine atom.

The term "C1-4 straight or branched alkyl group" means a saturated hydrocarbon group of 1-4 carbon atoms, such as methyl, ethyl, η-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

"C1-C4 alkoxy" means an alkoxy group in which the alkyl group is a straight or branched chain alkyl group having 1-4 carbon atoms as defined above.

A further subject of our invention is a process for the preparation of compounds of general formula (I).

Compounds of formula (I) in which R ¹ is hydrogen and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as described above can be prepared using methods known in the art.

Compounds of general formula (I), where R ¹ = hydrogen and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ have the above meanings, can be prepared from compounds of general formula (II) (Gy. Lukács, M. PorcsMakkay, Gy. Símig, Tetrahedron Letters 2003, 44, 3211—3214.); where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ mean the above, following the acetylhydrazine reaction by acidic ring closure or by hydrazine ring closure of or/o-acylsulfonic acid derivatives of general formula (III) prepared by analogy with the routes known from the literature (F. Huet, A. Lechevallier, M. Pellet, JM Conia, Synthesis 1978, 6365.) (JB Wright, J. Het. Chem. 1968, 5, 453 459.).

Compounds of general formula (I) where R ¹ and R ⁶ are hydrogen atoms and R ² , R ³ , R ⁴ , R ⁵ have the above meanings can be prepared by reacting a compound of general formula (I) where R ¹ is hydrogen atom, R ⁶ is halogen atom, and R ² , R ³ , R ⁴ , R ⁵ have the above meanings with 1-5 molar equivalents of alkyl lithium, preferably butyl lithium, in an inert organic solvent, preferably tetrahydrofuran or diethyl ether at room temperature or lower, preferably between (-78°C) and (+25°C), and then the resulting organometallic compound is converted into the desired compound of general formula (I) by reaction with water.

The compounds of general formula (I) in which R ¹ is an alkyl group, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above, are prepared by alkylating a compound of general formula (I) in which R ¹ is a hydrogen atom and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above, by analogy with the methods known from the literature (Houben-Weyl: Amine, XI/1, p. 98; JB Wright, J. Het. Chem. 1968, 5, 453 459); with alkyl halide derivatives in an organic solvent in the presence of an acid scavenger. An organic or inorganic base, preferably potassium tert-butylate or sodium hydride, is used as the acid scavenger, and N-dimethylformamide or tetrahydrofuran is preferably used as the organic solvent.

The pharmacological effect of the compounds of general formula (I) according to our invention was examined in the elevated plus maze test in rats.

Our tests were performed according to the method of S. Pellow et al. (J. Neurosci. Methods. 1985, 14, 149-167). For the test, we used a wooden floor cross with arms 100 cm long and 15 cm wide, raised 50 cm above the ground. The two opposite arms of the cross had 40 cm high black Plexiglas walls on both longitudinal sides and at the end (closed arm); they were open only towards the central 15x15 cm part of the cross. The other two opposite arms had no walls (open arm).

Male Sprague-Dawley rats weighing 200-220 g were used for the experiment. After a 60-minute pre-treatment period (oral treatment), the animal was placed in the center of the cross-shaped maze. Four different parameters were measured during a 5-minute measurement period: time spent in the open arm, time spent in the closed arm, number of entries into the open arm, number of entries into the closed arm.

Animals are generally afraid of open and bright areas, so they spend little time there. The anxiolytic effect of the compounds was indicated by the increase in the time spent in the open arm (sec) and/or the number of entries into the open arm. The lowest effective dose (minimum effective dose, MED) was determined for each compound with respect to the time spent in the open arm and the number of entries into the open arm. The known anxiolytic effect of l,3-dihydro-5-phenyl-7-chloro-l-methyl-2Hl,4-benzodiazepin-2-one (international non-proprietary name diazepam) was used as a comparative substance for the study. The doses used were 0.1, 0.3, 1.0 and 3.0 mg/kg for diazepam, and 0.01, 0.1 and 1.0 mg/kg for the compounds of our invention. The treatments were administered orally.

Table 1

Anxiolytic effect in the elevated plus maze test

Compound MED dose (mg/kg p.o.) Diazepam 1.00 Example 3 <0.01 Example 5 <0.01 Example 17 <0.01 Example 20 <0.01

The tested compounds increased the time spent in the open field and the number of entries into the open field in the rat anxiety test (Table 1). This suggests that the molecules shown as examples have significant anxiolytic effects.

As a result of the experiment, we found that the compounds of general formula (I) surprisingly and not obviously have a significant anxiolytic effect in a rodent behavioral model, so they may be suitable for the prevention or treatment of conditions and diseases belonging to the anxiety disorder group, such as generalized anxiety disorder, panic disorder, agoraphobia, social phobia, other phobias, post-traumatic stress disorder and all those nervous system diseases that are accompanied by anxiety symptoms, such as attention deficit hyperactivity disorder, stress-induced adjustment disorder, post-traumatic stress disorder, anorexia nervosa, bulimia nervosa, insomnia, parasomnia, obsessive-compulsive disorders, sexual dysfunctions and pathological conditions resulting from the use or withdrawal of chemical agents, such as alcohol, caffeine, nicotine, narcotics, sleeping pills, tranquilizers, doping agents.

A further subject of our invention are pharmaceutical compositions which contain one or more compounds of general formula (I) and one or more carriers or excipients known per se.

The pharmaceutical composition according to the invention generally contains 0.1-95% by weight, preferably 5-75% by weight, of active ingredient.

The pharmaceutical compositions of the invention can be administered orally (e.g. in the form of powders, tablets, coated tablets, capsules, microcapsules, granules, pellets, dragees, solutions, suspensions or emulsions), parenterally (e.g. in the form of intravenous, intramuscular, subcutaneous or intraperitoneal injection preparations or infusion preparations), rectally (e.g. in the form of suppositories), transdermally (e.g. in the form of patches), as implants or topically (e.g. in the form of creams, ointments or patches). The pharmaceutical compositions of the invention in solid, soft or liquid dosage forms can be prepared using methods known per se in the art.

Orally administrable solid pharmaceutical preparations containing the compounds of general formula (I) as active pharmaceutical ingredients may contain, in addition to the active ingredient, fillers or carriers (e.g. lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binders (e.g. gelatin, sorbitol, polyvinylpyrrolidone), disintegrants (e.g. croscarmellose, Na-carboxymethylcellulose, crospovidone), tabletting aids (e.g. magnesium stearate, talc, polyethylene glycol, silicic acid, silicon dioxide) and surfactants (e.g. sodium lauryl sulfate).

Orally administrable liquid pharmaceutical compositions containing the compounds of formula (I) as active pharmaceutical ingredients may be, for example, solutions, suspensions or emulsions, and may contain suspending agents (e.g. gelatin, carboxymethylcellulose), emulsifying agents (e.g. sorbitan monooleate), solvents (e.g. water, oils, glycerin, propylene glycol, ethanol), pH adjusting agents (e.g. acetate, phosphate, citrate buffers) and stabilizing agents (e.g. methyl 4-hydroxybenzoate).

Parenterally applicable liquid pharmaceutical preparations containing the compounds of general formula (I) as active pharmaceutical ingredients are sterile isotonic solutions which, in addition to solvents, may contain pH-regulating substances and preservatives.

Soft pharmaceutical preparations containing the compounds of general formula (I) as active pharmaceutical ingredients, such as suppositories, contain the active ingredient uniformly distributed in the suppository base (e.g. polyethylene glycol or cocoa butter).

The compositions of the invention comprising the compound of formula (I) as a pharmaceutical active ingredient can also be prepared in the form of a modified, sustained or controlled release composition. In this way, the release of the active ingredient of formula (I) from the pharmaceutical composition in a time-controlled manner can, for example, result in a sustained drug effect or reduce the frequency of administration. The modified, sustained or controlled release pharmaceutical compositions can be prepared using methods known in the art.

A further subject of our invention is a process for the preparation of pharmaceutical compositions containing compounds of general formula (I) by mixing a compound of general formula (I) with pharmaceutically suitable carriers and excipients and converting it into a pharmaceutical composition using known technological processes of pharmaceutical preparation. Carriers and excipients that can be used in pharmaceutical production and the applicable processes are described in the literature (Remington’s Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990).

The pharmaceutical compositions of the invention containing the compound of general formula (I) as an active ingredient contain the active ingredient in a dosage unit formulation.

The subject of our invention is the use of compounds of general formula (I) for the treatment of various forms of anxiety, such as generalized anxiety disorder, panic disorder, agoraphobia, social phobia and simple phobias (e.g. excessive fear of animals, natural environment, blood, life situations), other specific phobias, post-traumatic stress disorder and the following nervous system diseases and conditions accompanied by anxiety symptoms: attention deficit hyperactivity disorder, stress-induced adjustment disorder, post-traumatic stress disorder, anorexia nervosa, bulimia nervosa, insomnia, parasomnia, obsessive-compulsive disorders, sexual dysfunctions and pathological conditions resulting from the use or withdrawal of chemical substances, such as alcohol, caffeine, narcotics, sleeping pills, tranquilizers, doping agents.

Our invention also provides a method for treating various forms of anxiety, such as generalized anxiety disorder, panic disorder, agoraphobia, social phobia and simple phobias (e.g. excessive fear of animals, natural environments, blood, life situations), other specific phobias, post-traumatic stress disorder, attention deficit hyperactivity disorder, stress-induced adjustment disorder, post-traumatic stress disorder, anorexia nervosa, bulimia nervosa, insomnia, parasomnia, obsessive-compulsive disorders, sexual dysfunctions and pathological conditions resulting from the use or withdrawal of chemical substances, such as alcohol, caffeine, nicotine, narcotics, sleeping pills, tranquilizers, doping agents, by administering a compound of general formula (I) to a patient in need of such treatment in a therapeutically effective amount. The dose used in the treatment depends on several factors, such as the type and severity of the disease to be treated, the age, physical condition, body weight of the person to be treated and the quality of other therapy used. It is the responsibility of the doctor to determine the appropriate dose.

: ··: :.:. .· ··· ♦ · · ··

The process according to the invention is illustrated by the following examples, without limiting the scope of the invention.

Example 1

7-Chloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

Hydrazine monohydrate (8.0 ml; 8.25 g; 0.165 mol) was added dropwise to a solution of 2-acetyl-5-chlorobenzosulfonyl chloride (5.70 g; 0.0225 mol) in tetrahydrofuran (50 ml), and the mixture was heated at boiling point for 1 hour. The reaction mixture was then poured into water, and the precipitated crystals were collected.

Product: 2.70 g of white crystals (52%).

Op.: 187-189 °C (2-propanol).

IR(KBr): 3273 (NH); 1311, 1171 (S=O) cm' ¹ .

1 HNMR (CDCl ₃ , 400 MHz): 8.26 (1H, s); 7.97 (1H, d, 7=2.1 Hz); 7.73 (1H, dd, 7=2.2; 8.5 Hz); 7.62 (1H, d, 7=8.5 Hz); 2.52 (3H, s) ppm.

¹³ CNMR (CDCl 3 , 400 MHz): 149.3; 138.2; 135.4; 133.0; 128.0; 126.6; 121.2; 76.7; 20.0 ppm.

Elemental analysis based on the formula C8H7CIN2O2S (230.67):

Calcd: C 41.66%; H 3.06%; Cl 15.37%; N 12.14%; S 13.90%

Found: C 41.72%; H 2.93%; Cl 15.23%; N 12.19%; S 14.10%.

Example 2

4-Ethyl-7-chlorobenzo[1,2,3]thiadiazine-1,1-dioxide

4-Ethyl-7-chlorobenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 5-chloro-2-propionylbenzosulfonyl chloride (13.9 g; 0.052 mol) and hydrazine monohydrate (4.9 ml; 5.0 g; 0.1 mol).

Product: 11.7 g of white crystals (92%).

• · · · ♦ « · ♦ · · · · · · ··· ♦· ··♦·

Op.: 196-198 °C (2-propanol).

IR (KBr): 3132 (NH); 1328, 1181 (S=0) cm' ¹ .

¹ HNMR (DMSO, 400 MHz): 12.3 (1H, s); 8.06 (1H, dd, 7=1.0; 1.6 Hz); 7.97 (1H, dd, 7=9.4; 1.0 Hz); 7.95 (1H, dd, 7=1.6 8.5 Hz); 2.95 (2H, q, 7=7.3 Hz); 1.20 (3H, t, 7=7.4 Hz) ppm.

¹³ CNMR (DMSO, 200 MHz): 152.1; 136.7; 135.1; 133.1; 129.0; 125.8; 120.1; 25.8; 11.4 ppm.

Elemental analysis based on the formula C9H9CIN2O2S (244.70):

Calculated: C 44.18%; H 3.71%; Cl 14.49%; N 11.45%; S 13.10%

Found: C 44.06%; H 3.69%; Cl 14.45%; N 11.47%; S 13.02%.

Example 3

7,8-Dichloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 6-acetyl-2,3-dichlorobenzosulfonyl chloride (5.4 g; 0.019 mol) and hydrazine monohydrate (1.9 ml; 2.0 g; 0.04 mol).

Product: 4.5 g of white crystals (90%).

M.p.: 217-219 °C (ethanol).

IR (KBr): 3155 (NH); 1337, 1162 (S=O) cm' ¹ .

1HNMR (DMSO, 400 MHz): 12.42 (1H, s); 8.15 (1H, d, 7=8.6 Hz); 7.88 (1H, d, 7=8.6 Hz); 2.48 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 148.6; 136.3; 134.1; 133.5; 128.5; 128.0; 125.3; 94.1; 20.3 ppm.

Elemental analysis based on the formula CgH ₆ C12N2O2S (265.12):

Calcd: C 36.24%; H 2.28%; Cl 26.74%; N 10.57%; S 12.09%

Found: C 36.24%; H 2.36%; Cl 27.38%; N 10.59%; S 11.86%.

Example 4

7,8-Dichloro-4-ethylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-4-ethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2,3-dichloro-6-propionylbenzosulfonyl chloride (26.54 g; 0.088 mol) and hydrazine monohydrate (6.3 ml; 6.5 g; 0.13 mol).

Product: 21.5 g of white crystals (88%).

Op.: 238-239 °C (2-propanol).

IR(KBr): 3113 (NH); 1332, 1192 (S=O) cm' ¹ .

1HNMR (DMSO, 400 MHz): 12.43 (1H, s); 8.14 (1H, d, 7=8.8 Hz); 7.93 (1H, d, 7=8.8 Hz);

2.93 (2H, q, 7=7.4 Hz); 1.17 (3H, t, 7=7.4 Hz) ppm.

¹³ CNMR (DMSO, 400 MHz): 152.4; 136.2; 134.1; 133.8; 128.0; 127.5; 125.4; 26.3; 11.4; ppm.

Elemental analysis based on the formula C9H8CI2N2O2S (279.15):

Calcd: C 38.73%; H 2.89%; Cl 25.40%; N 10.04%; S 11.49%

Found: C 38.81%; H 2.86%; Cl 25.27%; N 10.06%; S 11.35%.

Example 5

7,8-Dichloro-4,5-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-4,5-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-acetyl-5,6-dichloro-3-methylbenzosulfonyl chloride (6.03 g; 0.02 mol) and hydrazine monohydrate (6.6 ml; 6.55 g; 0.131 mol).

Product: 2.07 g of white crystals (37%).

M.p.: 222-227 °C (ethanol).

IR (KBr): 3224 (NH); 1356, 1157 (S=0) cm' ¹ .

1HNMR (DMSO, 400 MHz): 12.1 (1H, s); 8.02 (1H, s); 2.62 (3H, s); 2.53 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 152.1; 138.6; 137.1; 135.5; 135.2; 128.1; 123.0; 24.4; 22.7 ppm.

Elemental analysis based on the formula C9H8Cl2N2O2S (279.15): Calculated: C 38.73%; Η 2.89%; Cl 25.40%; N 10.04%; S 11.49%

Found: C 38.68%; H 2.88%; Cl 25.19%; N 10.03%; S 11.39%.

Example 6

8-Chloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

8-Chloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-acetyl-6-chlorobenzosulfonyl chloride (19.0 g; 0.075 mol) and hydrazine monohydrate (7.3 ml; 7.51 g; 0.15 mol).

Product: 14.7 g of white crystals (85%).

Op.: 206-207 °C (2-propanol).

IR (KBr): 3213 (NH); 1319.1167 (S=O) cm' ¹ .

1HNMR (DMSO, 200 MHz): 12.23 (1H, s); 7.98-7.83 (4H, m); 2.48 (3H, s) ppm.

¹³ CNMR (DMSO, 200 MHz): 148.8; 134.3; 133.8; 131.8; 130.1; 126.9; 126.7; 20.4 ppm.

Elemental analysis based on the formula C8H7CIN2O2S (230.67):

Calcd: C 41.66%; H 3.06%; Cl 15.37%; N 12.14%; S 13.90%.

Found: C 41.75%; H 3.09%; Cl 15.18%; N 12.06%; S 13.80%.

.L

Example 7

8-Chloro-4-methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

8-Chloro-4-methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 6-acetyl-2-chloro-3-methoxybenzosulfonyl chloride (2.83 g; 0.01 mol) and hydrazine monohydrate (3.4 ml; 3.5 g; 0.07 mol).

Product: 2.17 g of white crystals (83%).

Op.: 227-229 °C (acetonitrile).

IR (KBr): 3159 (NH); 1338, 1196 (S=O) cm' ¹ .

1HNMR (DMSO, 400 MHz): 11.94 (1H, s); 7.84 (1H, d, 7=9.0 Hz); 7.60 (1H, d, 7=9.0 Hz); 4.02 (3H, s); 2.43 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 157.3; 149.0; 133.5; 128.5; 122.0; 116.2; 114.8; 57.4; 20.3 ppm.

Elemental analysis based on the formula C9H9CIN2O3S (260.70):

Calcd: C 41.47%; H 3.48%; Cl 13.60%; N 10.75%; S 12.30%

Found: C 41.34%; H 3.45%; Cl 13.52%; N 10.68%; S 12.12%.

Example 8

4-Methyl-8-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

4-Methyl-8-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-acetyl-6-methoxybenzosulfonyl chloride (5.00 g; 0.02 mol) and hydrazine monohydrate (6.3 ml; 6.50 g; 0.13 mol).

Product: 3.28 g of white crystals (73%).

M.p.: 194-197 °C (methanol).

IR (KBr): 3205 (NH); 1314, 1169 (S=O) cm' ¹ .

*HNMR (DMSO, 400 MHz): 11.8 (1H, s); 7.79 (1H, t, 7=8.2 Hz); 7.48 (1H, d, 7=8.3 Hz); 7.37 (1H, d, 7=7.5 Hz); 3.96 (3H, s); 2.43 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 154.2; 147.8; 133.9; 129.3; 122.4; 118.6; 115.5; 56.7; 20.2ppm.

Elemental analysis based on the formula C9H10N2O3S (226.26):

Calculated: C 47.78%; H 4.46%; N 12.38%; S 14.17%

Measured: C 47.81%; H 4.44%; N 12.33%; S 13.89%.

Example 9

7,8-Dimethoxy-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dimethoxy-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 6-acetyl-2,3-dimethoxybenzosulfonyl chloride (18.1 g; 0.065 mol) and hydrazine monohydrate (6.3 ml; 6.5 g; 0.13 mol).

Product: 10.2 g of white crystals (61%).

M.p.: 238-240 °C (methanol).

IR (KBr): 3222 (NH); 1326, 1318, 1131 (S=O) cm' ¹ .

¹ HNMR (DMSO, 500 MHz): 11.57 (1H, s); 7.58 (1H, d, 7=8.8 Hz); 7.51 (1H, d, 7=8.9 Hz);

3.97 (3H, s); 3.87 (3H, s); 2.39 (3H, s) ppm.

Elemental analysis based on the formula C10H12N2O4S (256.28):

Calcd: C 46.87%; H 4.72%; N 10.93%; S 12.51%.

Measured: C 46.87%; H 4.53%; N 11.08%; S 12.64%.

•· 4**· 4 ·*

λ. ::· -- .l

Example 10

7,8-Dichloro-4,6-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-4,6-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-acetyl-5,6-dichloro-4-methylbenzosulfonyl chloride (6.03 g; 0.02 mol) and hydrazine monohydrate (9.7 ml; 10.0 g; 0.2 mol).

Product: 4.25 g of white crystals (76%).

M.p.: 224-226 °C (ethanol).

IR (KBr): 3235 (NH); 1328, 1147 (S=O) cm' ¹ .

1HNMR (DMSO, 500 MHz): 12.31 (1H, s); 7.89 (1H, d, 7=0.7 Hz); 2.55 (3H, d, 7=0.6 Hz); 2.47 (3H, s) ppm.

¹³ CNMR (DMSO, 500 MHz): 148.5; 142.9; 136.5; 131.3; 128.5; 127.5; 125.4; 21.4; 20.3 ppm.

Elemental analysis based on the formula C9H8CI2N2O2S (279.15):

Calcd: C 38.73%; H 2.89%; Cl 25.40%; N 10.04%; S 11.49%

Found: C 38.94%; H 3.01%; Cl 25.48%; N 9.81%; S 11.28%.

Example 11

7,8-Dichlorobenzo[1,2,3]thiadiazine-1,1 -dioxide process “a”

To a solution of 2,3-dichloro-6-[1,3]dioxolan-2-yl-benzenesulfonyl chloride (60.34 g; 0.19 mol) in 2-propanol (290 ml) at 10 °C was added acetylhydrazine (28.15 g; 0.38 mol). After stirring for 1 hour, the crystals were colored (66.8 g). The thus obtained A-acetyl-N-(2,3-dichloro-6-[1,3]dioxolan-2-yl-benzenesulfonyl)-hydrazine was boiled with an aqueous hydrochloric acid solution (10 %; 400 ml) for 2.5 hours and then filtered. Product: 41.52 g of white crystals (87 %).

Op.: 183-185 °C (2-propanol).

IR (KBr): 3242 (NH); 1361, 1175 (S=O) cm' ¹ .

♦ * · * » • » * < γ · ς l ^; · ^: · ζ.

HNMR (DMSO, 400 MHz): 8.46 (1Η, bs); 7.94 (1H, s); 7.83 (1H, d, 7=8.4 Hz); 7.45 (1H, d, 7=8.4 Hz) ppm.

Elemental analysis based on the formula C7H4CI2N2O2S (251.09):

Calculated: C 33.48%; H 1.61%; Cl 28.24%; N 11.16%; S 12.77%.

Found: C 33.89%; H 1.64%; Cl 27.98%; N 11.06%; S 12.63%.

Procedure "b"

7,8-Dichlorobenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-formyl-5,6-dichlorobenzosulfonyl chloride (22.12 g; 0.081 mol) and hydrazine monohydrate (7.8 ml; 8.0 g; 0.16 mol).

Product: 14.0 g of white crystals (69%).

M.p.: 183-185 °C (ethanol).

Example 12

6-Methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

6-Methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-formyl-4-methoxybenzosulfonyl chloride (4.69 g; 0.02 mol) and hydrazine monohydrate (9.7 ml; 10.0 g; 0.2 mol).

Product: 2.37 g of white crystals (56%).

M.p.: 163-164 °C (ethanol).

IR (KBr): 3215 (NH); 1311, 1141 (S^jcm ¹ .

¹ HNMR (DMSO, 400 MHz): 12.2 (1H, s); 8.21 (1H, s); 7.89 (1H, d, 7=8.6 Hz); 7.41 (1H, d, 7=2.6 Hz); 7.38 (1H, dd, 7=2.6; 8.7 Hz); 3.90 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 162.3; 141.6; 129.6; 126.0; 122.3; 119.3; 111.6; 56.2 ppm.

Elemental analysis based on the formula C8H8N2O3S (212.23):

Calculated: C 45.28%; H 3.80%; N 13.20%; S 15.11%

Measured: C 45.36%; H 3.84%; N 12.94%; S 14.96%.

Example 13

4-Methylbenzo[1,2,3]thiadiazine-l, 1-dioxide

To a solution of 8-chloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide (2.3 g; 0.01 mol) in tetrahydrofuran (20 ml) at -78 °C was added dropwise butyllithium (1.6 M hexane solution; 16 ml; 0.04 mol). The mixture was stirred at -78 °C for 1 hour, then poured into ice-water (100 g). The mixture was washed with ethyl acetate (60 ml); the aqueous phase was acidified with concentrated hydrochloric acid, extracted with diethyl ether (3 x 50 ml), dried, and evaporated.

Product: 1.8 g of white crystals (92%).

Op.: 183-185 °C (2-propanol).

IR (KBr): 3229 (NH); 1314, 1173 (S=O) cm' ¹ .

1HNMR (DMSO, 400 MHz): 12.06 (1H, s); 7.99-7.85 (4H, m); 2.49 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 148.6; 133.6; 133.1; 132.6; 127.7; 127.1; 120.1; 19.8 ppm.

Elemental analysis based on the formula C8H8N2O2S (196.23):

Calcd: C 48.97%; H 4.11%; N 14.28%; S 16.34%

Measured: C 49.20%; H 4.20%; N 14.25%; S 16.23%.

Example 14

4-Methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

4-Methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 13 using 8-chloro-4-methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide (4.16 g; 0.016 mol) and butyllithium (2.5 M hexane solution; 20 ml; 0.05 mol).

Ί * ♦· *>

4- ·“ /. ·.?

Product: 2.27 g of white crystals (63%).

M.p.: 174-176 °C (methanol).

IR(KBr): 3237 (NH); 1314, 1163 (S=O) cm ¹ .

*HNMR (DMSO, 400 MHz): 11.85 (1H, s); 7.83 (1H, d, 7=8.4 Hz); 7.43-7.38 (2H, m); 3.94 (3H, s); 2.43 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 161.8; 148.6; 135.4; 129.5; 120.9; 119.7; 103.6; 56.4; 19.8 ppm.

Elemental analysis based on the formula C9H10N2O3S (226.26):

Calcd: C 47.78%; H 4.46%; N 12.38%; S 14.17%

Measured: C 48.03%; H 4.51%; N 12.26%; S 14.08%.

Example 15

7-Chlorobenzo[1,2,3]thiadiazine-1,1-dioxide

7-Chlorobenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 13 using 7,8-dichlorobenzo[1,2,3]thiadiazine-1,1-dioxide (4.01 g; 0.016 mol) and butyllithium (2.5 M hexane solution; 20 ml; 0.05 mol).

Product: 1.31 g of white crystals (38%).

M.p.: 221-223 °C (ethanol).

IR (KBr): 3230 (NH); 1331.1170 (S=O) cm' ¹ .

1HNMR (DMSO, 400 MHz): 12.63 (1H, s); 8.35 (1H, d, 7=0.5 Hz); 8.08 (1H, dt, 7=0.5; 2.1 Hz); 7.99 (1H, dd, 7=2.1; 8.4 Hz); 7.91 (1H, d, 7=8.3 Hz) ppm.

¹³ CNMR (DMSO, 400 MHz): 141.7; 136.9; 134.3; 133.4; 130.4; 126.3; 119.9 ppm.

Elemental analysis based on the formula C7H5CIN2O2S (216.65):

Calcd: C 38.81%; H 2.33%; Cl 16.36%; N 12.93%; S 14.80%

Found: C 39.16%; H 2.28%; Cl 16.29%; N 12.69%; S 14.52%.

Example 16

2,4-Dimethyl-7-chlorobenzo[1,2,3]thiadiazine-1,1-dioxide

To a solution of 7-chloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide (4.61 g; 0.02 mol) in ΛζΑ-dimethylformamide (20 ml) at 10°C was added potassium tert-butylate (4.4 g; 0.04 mol). Subsequently, methyl iodide (2.5 ml; 5.6 g; 0.04 mol) was added dropwise to the mixture. The reaction mixture was stirred at 50°C for 1 hour, then poured into ice water, the precipitated crystals were filtered and washed with water.

Yield: 3.57 g of white crystals (75%).

M.p.: 116-117 °C.

IR (KBr): 1590 (C=N); 1328, 1178 (S=O) cm' ¹ .

1HNMR (CDCl 3 , 400 MHz): 7.97 (1H, d, /=2.1 Hz); 7.70 (1H, dd, /=2.1; 8.5 Hz); 7.58 (1H, d, /= 8.5 Hz); 3.53 (3H, s); 2.50 (3H, s) ppm.

Elemental analysis based on the formula C9H9CIN2O2S (244.70):

Calcd: C 44.18%; H 3.71%; Cl 14.49%; N 11.45%; S 13.10%

Found: C 44.02%; H 3.70%; Cl 14.43%; N 11.48%; S 13.02%.

Example 17

7,8-Dichloro-2,4-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-2,4-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 7,8-dichloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide (2.65 g; 0.01 mol); potassium tert-butylate (2.24 g; 0.02 mol) and methyl iodide (1.3 ml; 2.8 g; 0.02 mol).

Product: 2.5 g of white crystals (90%).

Op.: 220-222 °C (2-propanol).

IR (KBr): 1334, 1158 (S=O) cm' ¹ .

1 HNMR (CDCl ₃ , 400 MHz): 7.79 (1H, d, 7=8.6 Hz); 7.49 (1H, d, 7=8.6 Hz); 3.55 (3H, s); 2.49 (3H, s) ppm.

¹³ CNMR (CDCl 3 , 400 MHz): 147.2; 137.6; 136.5; 132.9; 128.9; 127.8; 125.5; 39.2; 20.6 ppm.

Elemental analysis based on the formula C9H8CI2N2O2S (279.15):

Calculated: C 38.73%; H 2.89%; Cl 25.40%; N 10.04%; S 11.49%

Found: C 38.90%; H 3.05%; Cl 25.08%; N 10.02%; S 11.51%.

Example 18

7,8-Dichloro-4-ethyl-2-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-4-ethyl-2-methylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 7,8-dichloro-4-ethylbenzo[1,2,3]thiadiazine-1,1-dioxide (11.2 g; 0.04 mol); potassium tert-butylate (9.0 g; 0.08 mol) and methyl iodide (5.0 ml; 11.4 g; 0.08 mol).

Product: 10.2 g of white crystals (87%).

M.p.: 119-120 °C (methanol).

IR (KBr): 1329, 1158 (S=O) cm ⁴ ′HNMR (CDCl 3 , 500 MHz): 7.79 (1H, d, 7=8.6 Hz); 7.52 (1H, d, 7=8.6 Hz); 3.56 (3H, s); 2.86 (2H, q, 7=7.4 Hz); 1.27 (3H, t, 7=7.4 Hz) ppm.

¹³ CNMR (CDCl 3 , 125.6 MHz): 151.5; 137.7; 133.7; 133.5; 128.6; 128.2; 125.3; 36.5; 27.3; 11.8ppm.

Elemental analysis based on the formula C10H10Cl2N2O2S (293.17):

Calcd.: C 40.97%; H 3.44%; Cl 24.19%; N 9.56%; S 10.94% • · · · · · · · • ···«· · · · · · · · · ·♦ ·

Found: C 41.24%; H 3.47%; Cl 23.84%; N 9.54%; S 10.90%.

Example 19

2,4-Diethyl-7,8-dichlorobenzo[1,2,3]thiadiazine-1,1-dioxide

2,4-Diethyl-7,8-dichlorobenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 7,8-dichloro-4-ethylbenzo[1,2,3]thiadiazine-1,1-dioxide (1.0 g; 0.0036 mol); potassium tert-butylate (0.8 g; 0.0072 mol) and ethyl iodide (0.56 ml; 1.1 g; 0.0072 mol).

Product: 0.75 g of white crystals (68%).

M.p.: 79-82 °C (methanol).

IR (KBr): 1334, 1152 (S=O) cm' ¹ .

1 HNMR (CDCl ₃ , 200 MHz): 7.78 (1H, d, 7-8.6 Hz); 7.52 (1H, d, 7=8.6 Hz); 3.97 (2H, q, 7=7.1 Hz); 2.88 (2H, q, 7=7.3 Hz); 1.43 (3H, t, /=7.1 Hz); 1.28 (3H, t, 7=7.3 Hz) ppm.

Elemental analysis based on the formula C11H12Cl2N2O2S (307.20):

Calculated: C 43.01%; H 3.94%; Cl 23.08%; N 9.12%; S 10.44%

Found: C 43.12%; H 3.97%; Cl 22.97%; N 9.11%; S 10.35%.

Example 20

7,8-Dichloro-2-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

To a suspension of potassium tert-butylate (1.12 g; 0.01 mol) in Λ/TV-dimethylformamide (5 ml) at room temperature was added dropwise a solution of 7,8-dichlorobenzo[1,2,3]thiadiazine-1,1-dioxide (1.26 g; 0.005 mol) in ΛζΑ-dimethylformamide (15 ml). The suspension was stirred for 30 minutes, then methyl iodide (2.13 g; 0.93 ml; 0.015 mol) was added dropwise. The reaction mixture was stirred for 1 hour, then poured into water, and the crystals were filtered off. The resulting crystalline mixture was stirred with diethyl ether (25 ml) for 1 hour, filtered, and the filtrate, which contained 7,8-dichloro-2methylbenzo[1,2,3]thiadiazine-1,1-dioxide, was evaporated. The evaporation residue was filtered from ethanol.

Yield: 0.67 g yellow crystals (50%).

M.p.: 120-121 °C (hexane - ethyl acetate 1:1).

IR (KBr): 1338, 1178 (S=O) cm ¹ .

¹ HNMR (DMSO, 400 MHz): 8.37 (1H, s); 8.20 (1H, d, >8.4 Hz); 7.89 (1H, d, J=8.4 Hz); 3.53 (3H, s) ppm.

¹³ CNMR (DMSO, 400 MHz): 141.3; 136.7; 135.0; 131.4; 129.1; 128.3; 125.4; 36.1 ppm.

Elemental analysis based on the formula C8H6CI2N2O2S (265.12):

Calcd: C 36.24%; H 2.28%; Cl 26.74%; N 10.57%; S 12.09%

Found: C 36.35%; H 2.38%; Cl 27.04%; N 10.65%; S 11.84%.

Example 21

7-Chloro-2-methylbenzo[1,2,3]thiadiazine-1,1-dioxide

To a suspension of sodium hydride (2.63 g; 0.055 mol) in tetrahydrofuran (50 ml) at room temperature was added dropwise a solution of 7-chlorobenzo[1,2,3]thiadiazine-1,1-dioxide (10.83 g; 0.05 mol) in tetrahydrofuran (150 ml). The suspension was stirred for 30 minutes, then methyl iodide (9.3 ml; 21.30 g; 0.150 mol) was added dropwise. The reaction mixture was stirred for 1 hour, then acetone was added and stirred until complete dissolution. The reaction mixture was evaporated, water was added to the residue and filtered. The crude product was stirred with tetrahydrofuran at room temperature, filtered and the filtrate was evaporated to dryness.

Product: 3.9 g yellow crystals (34%).

M.p.: 131-133 °C (hexane - ethyl acetate 1:1).

IR (KBr): 1321, 1172 (S=O) cm ¹ .

1HNMR (DMSO, 200 MHz): 8.41 (1H, s); 8.17 (1H, d, 7=1.5 Hz); 8.03 (1H, dd, 7=1.8; 8.6 Hz); 7.94 (1H, d, 7=8.3 Hz); 3.50 (3H, s) ppm.

Elemental composition based on the formula C8H7CIN2O2S (230.67):

Calcd: C 41.66%; H 3.06%; Cl 15.37%; N 12.14%; S 13.90%

Found: C 41.04%; H 3.09%; Cl 15.01%; N 12.01%; S 13.72%.

Example 22

2-Methyl-6-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

2-Methyl-6-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 6-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide (2.12 g; 0.01 mol), potassium tert-butylate (2.24 g 0.02 mol) and methyl iodide (1.2 ml; 2.8 g; 0.02 mol).

Product: 0.63 g yellow crystals (28%).

M.p.: 99-101 °C (hexane - ethyl acetate 1:1).

IR(KBr): 1313, 1167 (S=O) cm' ¹ .

1HNMR (CDCl 3 , 400 MHz): 7.91 (1H, d, 7=9.1 Hz); 7.89 (1H, s); 7.22 (1H, dd, 7=2.5 8.7 Hz); 6.96 (1H, d, 7=2.5 Hz); 3.98 (3H, s); 3.58 (3H, s) ppm.

¹³ CNMR (CDCl 3 , 400 MHz): 162.8; 140.1; 130.0; 125.1; 123.4; 118.7; 110.5; 55.9; 35.3 ppm.

Elemental analysis based on the formula C9H10N2O3S (226.26):

Calculated: C 47.78%; H 4.46%; N 12.38%; S 14.17%

Measured: C 47.37%; H 4.50%; N 12.03%; S 14.01%.

Example 23

2-Methylbenzo[1,2,3]thiadiazine-1,1-dioxide

2-Methylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using benzo[1,2,3]thiadiazine-1,1-dioxide (1.82 g; 0.01 mol; prepared according to the procedure known from the literature: King, J. F.; Huston, B. L.; Hawson, A., Deaken, D. M., Harding, D. R. K. Can. J. Chem., 1971, 49, 943.), potassium Werz-butylate (2.5 g 0.02 mol) and methyl iodide (1.3 ml; 2.8 g; 0.02 mol) and the product was recovered by pouring the reaction mixture into water, extracting with diethyl ether, evaporating and filtering the residue from hexane.

Product: 0.63 g of white crystals (32%).

M.p.: 79-80 °C (hexane - ethyl acetate 1:1).

IR(KBr): 1332, 1175 (S=O) cm' ¹ .

1 HNMR (CDCl ₃ , 200 MHz): 8.03-7.96 (2H, m); 7.81-7.70 (2H, m); 7.61-7.52 (1H, m); 3.61 (3H, s) ppm.

¹³ CNMR (CDCl 3 , 200 MHz): 140.7; 132.7; 132.4; 132.0; 128.0; 127.0; 121.1; 35.5ppm.

Elemental analysis according to the formula C8H8N2O2S (196.23):

Calcd: C 48.97%; H 4.11%; N 14.28%; S 16.34%

Found: C 48.79%; H 4.14%; N 14.22%; S 16.11%.

Example 24

7,8-Dichloro-2,4,5-trimethylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-2,4,5-trimethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 7,8-dichloro-4,5-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide (2.79 g; 0.01 mol), potassium tert-butylate (2.24 g 0.02 mol) and methyl iodide (1.9 ml; 4.25 g; 0.03 mol).

Product: 5.17 g of white crystals (88%).

M.p.: 166-168 °C (ethanol).

IR (KBr): 1327, 1149 (S=O) cm ¹ .

¹ HNMR (CDCl ₃ , 200 MHz): 7.60 (1H, s); 3.47 (3H, s); 2.58 (3H, s); 2.55 (3H, s) ppm.

Elemental analysis based on the formula C10H10Cl2N2O2S (293.19):

Calcd: C 40.97%; H 3.44%; Cl 24.18%; N 9.56%; S 10.94%

Found: C 41.28%; H 3.46%; Cl 24.26%; N 9.28%; S 10.75%.

Example 25

8-Chloro-7-methoxy-2,4-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide

8-Chloro-7-methoxy-2,4-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 8-chloro-4-methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide (3.91 g; 0.015 mol), potassium tert-butylate (3.37 g; 0.03 mol) and methyl iodide (2.8 ml; 6.4 g; 0.045 mol).

Product: 3.74g white crystals (91%).

M.p.: 151-152 °C (ethanol).

IR (KBr): 1323, 1194 (S=O) cm' ¹ .

HNMR (CDCl 3 , 400 MHz): 7.53 (1H, d, 7=8.9 Hz); 7.21 (1H, d, 7=8.9 Hz); 4.01 (3H, s); 3.51 (3H, s); 2.45 (3H, s) ppm.

Elemental analysis based on the formula C10H11CIN2O3S (274.74):

Calcd: C 43.72%; H 4.04%; Cl 12.90%; N 10.20%; S 11.67%

Found: C 43.60%; H 4.10%; Cl 12.98%; N 10.15%; S 11.58%.

Example 26

7,8-Dichloro-2,4,6-trimethylbenzo[1,2,3]thiadiazine-1,1-dioxide

7,8-Dichloro-2,4,6-trimethylbenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 7,8-dichloro-4,6-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide (2.79 g; 0.01 mol), potassium tert-butylate (2.24 g; 0.02 mol) and methyl iodide (1.9 ml; 4.25 g; 0.03 mol).

Product: 1.75 white crystals (95%).

M.p.: 179-180 °C (ethanol).

IR (KBr): 1355.1183 (S=O) cm' ¹ .

1HNMR (CDCl 3 , 200 MHz): 7.96 (1H, s); 3.42 (3H, s); 2.57 (3H, s); 2.49 (3H, s) ppm.

Elemental analysis based on the formula C10H10Cl2N2O2S (293.19):

Calculated: C 40.97%; H 3.44%; Cl 24.18%; N 9.56%; S 10.94%

Found: C 40.67%; H 3.44%; Cl 24.06%; N 9.32%; S 11.17%.

Example 27

8-Chloro-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

8-Chloro-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 1 using 2-formyl-6-chloro-5-methoxybenzosulfonyl chloride (2.69 g; 0.01 mol) and hydrazine monohydrate (2.4 ml; 2.5 g; 0.05 mol).

Product: 1.66 g of white crystals (67%).

M.p.: 189-191 °C (ethyl acetate).

IR (KBr): 3292 (NH); 1282, 1160 (S=O) cm' ¹ .

1HNMR (DMSO, 400 MHz): 12.29 (1H, s); 8.19 (1H, s); 7.84 (1H, d, J=8.8 Hz); 7.66 (1H, d, J=8.8 Hz); 4.02 (3H, s) ppm.

Elemental analysis based on the formula C8H7CIN2O3S (246.67):

Calcd: C 38.95; H 2.86; Cl 14.37; N 11.36; S 13.00%

Found C 39.23; H 2.80; Cl 14.38; N 10.97; S 13.04%.

i ^: · ^: · .:1. ·.

• · · · · ····

Example 28

8-Chloro-2-methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide

8-Chloro-2-methyl-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide was prepared according to the procedure described in Example 16 using 8-chloro-7-methoxybenzo[1,2,3]thiadiazine-1,1-dioxide (1.23 g; 0.005 mol); potassium tert-butylate (1.12 g; 0.01 mol) and methyl iodide (0.65 ml; 1.4 g; 0.01 mol).

Yield: 0.97g white crystals (74%).

M.p.: 173-175 °C (ethanol).

IR (KBr): 1333, 1174 (S=O) cm' ¹ .

*HNMR (DMSO, 400 MHz): 8.24 (1H, s); 7.86 (1H, d, J=8.8 Hz); 7.70 (1H, d, J~8.8 Hz); 4.02 (3H, s) 3.45 (3H, s) ppm.

Elemental analysis based on the formula C9H9CIN2O3S (260.70):

Calcd: C 41.47; H 3.48; Cl 13.60; N 10.75; S 12.30%

Found C 41.40; H 3.40; Cl 13.45; N 10.65; S 12.34%.

Claims (15)

·· ·♦·· · Patent claims 1. Benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of the general formula (I), in which R ¹ and R ² independently represent a hydrogen atom, a straight or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a straight or branched alkyl group having 1-4 carbon atoms or an alkoxy group having 1-4 carbon atoms. 2. 7,8-Dichloro-4-methylbenzo[1,2,3]thiadiazine-1,1-dioxide 3. 7,8-Dichloro-4,5-dimethylbenzo[1,2,3]thiadiazine-1,1-dioxide 4. 2,4-Dimethyl-7-chlorobenzo[1,2,3]thiadiazine-1,1-dioxide 5. 2,4-Diethyl-7,8-dichlorobenzo[1,2,3]thiadiazine-1,1-dioxide 6. A process for preparing a benzo[1,2,3]thiadiazine-1,1-dioxide derivative of the general formula (I), wherein R ¹ and R ² independently represent a hydrogen atom, a linear or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1-4 carbon atoms or an alkoxy group having 1-4 carbon atoms, in such a way that a) for the preparation of compounds of general formula (I) in which R ¹ represents a hydrogen atom, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the above-mentioned, a 2-acylbenzenesulfonic acid chloride derivative of formula (II) in which R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the above-mentioned, is reacted with a hydrazine compound, preferably acetylhydrazine, followed by a strong acid, preferably hydrochloric acid, or b) for the preparation of compounds of general formula (I) in which R ¹ represents a hydrogen atom, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the above-mentioned, a 2-acylbenzenesulfonic acid chloride derivative of formula (III) in which R ² , R ³ , R ⁴ , R ⁵ and R ⁶ represent the above-mentioned, is reacted with a hydrazine compound, or c) for the preparation of benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of formula (I), in which R ¹ and R ⁶ are hydrogen and R ² , R ³ , R ⁴ , R ⁵ are as defined above, the corresponding benzo[1,2,3]thiadiazine-1,1-dioxide derivative of formula (I), in which R ¹ is hydrogen, R ⁶ is halogen, preferably chlorine, and R ² , R ³ , R ⁴ , R ⁵ are as defined above, is reacted with alkyl lithium and then with water, or d) for the preparation of benzo[1,2,3]thiadiazine-1,1-dioxide derivatives of general formula (I), where R ¹ is a straight or branched alkyl group having 1-4 carbon atoms, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above, the corresponding benzo[1,2,3]thiadiazine-1,1-dioxide derivative of general formula (I), where R ¹ is a hydrogen atom, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, is reacted with an alkyl halide in which the quality of the alkyl group is the same as that of the R ¹ group. 7. Variant d) of the process according to claim 2, characterized in that the alkyl halide used is an alkyl chloride, alkyl bromide or alkyl iodide. 8. Compounds of general formula (I) according to claims 1-5 for pharmaceutical use. 9. Pharmaceutical compositions for the prevention or treatment of anxiety disorders, comprising a compound of general formula (I), wherein R ¹ and R ² independently represent a hydrogen atom, a linear or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1-4 carbon atoms or an alkoxy group having 1-4 carbon atoms, and one or more pharmaceutically acceptable carriers and optionally excipients. 10. Pharmaceutical compositions for the prevention or treatment of generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorders, post-traumatic stress disorder, and post-stress anxiety states, which comprise a compound of general formula (I), in which R ¹ and R independently represent a hydrogen atom, a straight or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a straight or branched alkyl group having 1-4 carbon atoms or a alkoxy group having 1-4 carbon atoms, and one or more pharmaceutically acceptable carriers and, if desired, excipients. 11. Pharmaceutical preparations for the prevention or treatment of attention deficit hyperactivity disorder, stress-induced adjustment disorder, post-traumatic stress disorder, anorexia nervosa, bulimia nervosa, insomnia, parasomnia, obsessive-compulsive disorders, sexual dysfunctions and pathological conditions resulting from the use or withdrawal of chemical agents, such as alcohol, caffeine, nicotine, narcotics, sleeping pills, tranquilizers, doping agents, which contain a compound of general formula (I), in which R ¹ and R ² independently represent a hydrogen atom, a C 1-4 straight or branched alkyl group, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a C 1-4 straight or branched alkyl group or a C 1-4 alkoxy group and one or more pharmaceutically acceptable carriers and, if desired, excipients. 12. A process for the preparation of a pharmaceutical composition according to any one of claims 9-11, characterized in that a compound of general formula (I) according to claim 1 is mixed with one or more pharmaceutically acceptable carriers and, if desired, excipients and converted into a pharmaceutical form. 13. The use of compounds of general formula (I) in which R ¹ and R ² independently represent a hydrogen atom, a linear or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a linear or branched alkyl group having 1-4 carbon atoms or an alkoxy group having 1-4 carbon atoms, for the preparation of a pharmaceutical composition for the prevention and treatment of central nervous system diseases and conditions, in particular anxiety, generalized anxiety disorder, panic disorder, agoraphobia and other phobias, obsessive-compulsive disorders, post-traumatic stress disorder, post-stress anxiety states, attention deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, personality disorders, sexual dysfunction, alcohol, nicotine or drug addiction. 14. Compounds of general formula (I) in which R ¹ and R ² independently represent a hydrogen atom, a straight or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a straight or branched alkyl group having 1-1 carbon atoms or a alkoxy group having 1-4 carbon atoms, are used for the prevention and treatment of central nervous system diseases, in particular anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorders, post-traumatic stress disorder, post-stress anxiety states, attention deficit hyperactivity disorder, stress-induced adjustment disorder, post-traumatic stress disorder, anorexia nervosa, bulimia nervosa, insomnia, parasomnia, obsessive-compulsive disorders, sexual dysfunctions and pathological conditions resulting from the use or withdrawal of chemical agents, such as alcohol, caffeine, nicotine, narcotics, sleeping pills, tranquilizers, doping agents. 15. A method for the prevention and treatment of central nervous system diseases, in particular anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorders, post-traumatic stress disorder, attention deficit hyperactivity disorder, stress-induced adjustment disorder, post-traumatic stress disorder, anorexia nervosa, bulimia nervosa, insomnia, parasomnia, obsessive-compulsive disorders, sexual dysfunctions and pathological conditions resulting from the use or withdrawal of chemical agents, such as alcohol, caffeine, nicotine, narcotics, sleeping pills, tranquilizers, doping agents, by administering to a person in need of such treatment one or more compounds of general formula (I), in which R ¹ and R ² independently represent a hydrogen atom, a straight or branched alkyl group having 1-4 carbon atoms, R ³ , R ⁴ , R ⁵ and R ⁶ independently represent a hydrogen atom, a halogen atom, a straight or branched alkyl group having 1-4 carbon atoms alkyl group or C1-4 alkoxy group, is administered in a therapeutically effective amount. EGISGYÖGYSZFRGYÁR...... rf _Λ ^x . Publicly Operated Joint Stock Company kJ _________________-......-............-................................................ ttila Head of Industrial Property Protection Department Dr. Gyula Simig Research Director R