RU2157808C2 - Substituted 6r-1,3,4-thiadiazine-2-amines and pharmaceutical composition thereof - Google Patents

Abstract

FIELD: medical and pharmaceutical industries. SUBSTANCE: described are new substituted 6R-1,3,4-thiadiazine-2-amines of formula I:

wherein Ar is phenyl or phenyl substituted by one or more chlorine, bromine, C₁-C₄ alkoxy or C₁-C₄ alkyl groups; each of R¹ and R² is independently hydrogen atom or C₁-C₄ alkyl residual; and R³ and R⁴ are independently selected from C₁-C₄ alkyl groups, and pharmaceutically acceptable salts thereof. Said compounds are useful as anesthetizing, cardiovascular and hypometabolic agents. Also described are pharmaceutical compositions which comprise said agents. EFFECT: improved properties of the pharmaceutical composition. 7 cl, 10 ex, 2 tbl

Description

Technical field
The invention relates to new derivatives of 6-R-1,3,4-thiadiazin-2-amines, their use as anesthetics, cardiovascular and hypometabolic agents used in medicine and veterinary medicine, and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION
Anesthesia can generally be described as a condition in which detrimental effects, such as surgical procedures, are invisible to the body; this condition may be accompanied by loss of consciousness (general anesthesia), or it may occur without loss of consciousness (local anesthesia). A complete or general anesthetic administered by inhalation or intravenously causes deep sleep and loss of motor activity (hypnosis), analgesia, muscle relaxation and provides protection against increased blood pressure and heart rate from surgical stress. Anesthetics generally exhibit hypometabolic activity and often act as respiratory or cardiovascular depressants. Some anesthetics can be used to deliberately create a hypotensive effect, which is very valuable for intracranial and other surgical operations. Despite the fact that a large number of chemicals with anesthetic and cardiovascular activity, created and / or brought to the pharmaceutical market, there is a constant need for new drugs with hypometabolic activity that could cause sleep, reduce motor activity, cause hypotension , bradycardic, hypocoagulating, antiplatelet and other hypobiotic effects, such as reduced oxygen consumption and lower body temperature, which would be valuable for Use in complex surgical operations or in the treatment of life-threatening and / or traumatic conditions, such as concussion, myocardial infarction, and which would have high activity, prolonged action and excellent toxicity profiles for the central nervous system and cardiovascular system without side effects such as tremor, convulsions, respiratory failure and palpitations.

 There is a significant amount of data on 6-R-1,3,4-thiadiazin-2-amines (see reviews [1-3]). Also in the patent literature there is evidence of muscle relaxant (4-7], sedative [8, 9], antispasmodic (1-12] and other types of biological activity [3]. A number of 5-aryl-substituted 1,3,4-thiadiazines are specifically described in inventions [14–20], as well as their 6-alkyl and 6-phenyl analogues [13 and 21]. The value of 6-R-1,3,4-thiadiazin-2-amines as hypometabolic anesthetics and cardiovascular agents is still it has not yet been recognized by anyone, Moreover, many of these substances are new and have not previously been described in the literature.

Previous inventions for 6-R-1,3,4-thiadiazin-2-amines include:
1. N. Beyer, Z. Chem., 1969, Bd. 9, S. 361.

 2. S.V. Usoltseva, G.P. Andronnikova, V.S. Mokrushin, Chemistry heterocycle. Conn., 1991, N. 4, p. 435.

 3. A.P. Novikova, N.M. Perova, O.N. Chupakhin, Chemistry heterocycle. Conn., 1991, N. 11, p. 1443.

 4. W.D. Jones and F.P. Miller US-A-4309426 (1982).

 5. W.D. Jones and F.P. Miller BE-A-884991 (1980).

 6. W.D. Jones and F.P. Miller DE-A-3042295 (1982).

 7. FR-A-2493 844 (1982).

 8. US-A-4,272,532 (1981).

 9. F.P. Miller and W.D. Jones. BE-A-884990 (1980).

 10. W.D. Jones and F.P. Miller DE-A-3031703 (1981).

 11. Fisons PLC, Japan Kokai, Tokyo Koho JP-A-6253976.

 12. W.D. Pfeiffer and E. Bulka, DD-A-220311 (1985).

 13. N. Yoshida, K. Tanaka, and Y. Iizuka. Japan Kokai 7488889 (1974).

 14. L. N. Rasina, O. N. Chupakhin, M.V. Siberian, Radiobiology, 30 (2), 162-5 (1990).

 15. A.V. Belik et al. Pharmaceutical Chemistry Journal, 26 (3), 62-64 (1992).

 16. N.M. Perova et al. Chemistry heterocycle. Conn., N 4, 565-6 (1993).

 17. E. Bulka and W.D. Pfeiffer, DD-A-288824.

 18. W.D. Pfeiffer and E. Bulka, Synthesis, N 7, 485-6 (1977).

 19. T. Werner et al, US-A-4940790 (1990).

 20. A.P. Novikova et al. SU-A-172 6478.

 21. E. Bulka et al, DD-A-228248.

где Ar представляет фенил или фенил, замещенный одним или более атомами хлора, брома, C₁-C₄ алкокси или C₁-C₄ алкильными группами; каждый из R¹ и R² представляет, независимо, атом водорода или C₁-C₄ алкильный остаток; и R³ и R⁴ независимо выбраны из C₁-C₄ алкильных групп; и их фармацевтически приемлемых солей.Summary of the invention
According to one aspect of the invention, the use of substituted 6-R-1,3,4-thiadiazin-2-amines of the following general formula as anesthetics or cardiovascular agents is provided:

where Ar represents phenyl or phenyl substituted with one or more chlorine, bromine, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkyl groups; each of R ¹ and R ² independently represents a hydrogen atom or a C ₁ -C ₄ alkyl residue; and R ³ and R ^{4 are} independently selected from C ₁ -C ₄ alkyl groups; and their pharmaceutically acceptable salts.

 According to a further aspect of the invention, novel substituted 6-K-1,3,4-thiadiazin-2-amines of the above general formula are provided. According to another aspect of the invention, pharmaceutical compositions are provided comprising, as an active agent, one or more of the above substituted derivatives of 6-R-1,3,4-thidiazin-2-amines or pharmaceutically acceptable salts thereof.

Description of the invention
1,3,4-Thiadiazines suitable for use in this invention are substituted at the 5th position of the thiadiazine ring with unsubstituted phenyl or phenyl substituted with one or more straight or branched C ₁ -C ₄ alkyl, alkenyl, alkoxy or acyloxy groups, one or several hydroxy groups, or halogen atoms. In preferred compounds of this formula, Ar is either unsubstituted phenyl or phenyl substituted with one or more alkyl or alkoxy groups, chlorine or bromine atoms, substitution is preferred at positions 3 or 4 of the aryl moiety. In addition, the compounds contain a 4-amino-1-phenyl-2,3-dialkylpyrazol-5-one or 4- (N-alkylamino) -1-phenyl-2,3-dialkyl-pyrazol-5 residue at position 2 of the thiadiazine ring -one in which the phenyl moiety is unsubstituted phenyl or phenyl substituted with C ₁ -C ₄ alkyl, alkenyl, alkoxy or acyloxy groups, one or more hydroxy groups or halogen atoms. In addition, the compounds may be substituted at position 6 of the thiadiazine ring (R ¹ ) and / or in the amino group at position 2 of the thiadiazine ring (R ² ) of one of the R ¹ -R ⁴ alkyl groups.

According to the invention, the 1,3,4-thiadiazines described above can be prepared by reacting an α-haloarylalkanone of the formula Ar-CO-CH (R ¹ ) X with a thiosemicarbazide of the formula NH ₂ -NH-CS-NR ² Y, where Ar, R ¹ and R ^{2 are} defined above, X is a halogen, preferably a chlorine or bromine atom, and Y is 1-phenyl-2,3-dialkylpyrazol-5-one-4-yl, in which the alkyl or dialkyl groups are preferably straight or branched alkyl C ₁ -C ₄ chain, and wherein the phenyl moiety is unsubstituted phenyl or phenyl substituted by C ₁ -C ₄ alkyl, alkenyl, al- oxyl or acyloxy groups, or by one or more halogen atoms or hydroxy groups.

1,3,4-Thiadiazines can be isolated and / or used in free form or converted into addition salts with pharmacologically acceptable mineral or organic acids. Suitable for the preparation of acid addition salts are, for example, mineral acids such as hydrobromic acid, hydrochloric, sulfuric or phosphoric acids; organic carboxylic acids such as acetic, lactic, maleic, fumaric, oxalic, tartaric, citric or gluconic acids; or
organic sulfonic acids such as sulfonic acids, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid, trifluoro-methanesulfonic acid and cyclohexylamidosulfonic acid.

 The α-haloarylalkanones used as starting materials for the preparation of the thiadiazines described above are known from the literature or can be obtained from arylalkanones by reaction with suitable halogenating agents according to the method described in the Guben-Weyl guide, vol. E4 (1960), p. 171-189 Suitable compounds are, for example, α-bromoaryl ethanone and α-bromoarylbutanone, in which aryl may be phenyl or substituted phenyl, obtained by halogenation of the correspondingly substituted 1-arylalkanones with elemental bromine or copper (II) bromide according to the method of King and Ostrum, J. Org. Chem. 29, 3459-3461 (1964).

с гидразином. Для того, чтобы избежать осложнений, связанных с побочными реакциями, получение тиосемикарбазидов ведут преимущественно в апротонных растворителях, таких как, например, хлороформ, тетрахлорметан, диэтиловый эфир или диоксан.Substituted thiosemicarbazides, which are used as starting materials, are in most cases known from the literature or can be obtained by the methods described in the Guben-Weyl guide, vol. E4, pp. 506-515 and C. Jensen et al., Acta Chem. Scand. 22, 1-50 (1968). Thus, thiosemicarbazides can be prepared by adding hydrazide to isothiocyanates or by reacting N, N-disubstituted thiocarbamoyl chlorides with hydrazine, respectively, or by reacting ethyl dithiocarbamates of the formula

with hydrazine. In order to avoid complications associated with adverse reactions, the preparation of thiosemicarbazides is carried out mainly in aprotic solvents, such as, for example, chloroform, carbon tetrachloride, diethyl ether or dioxane.

The reaction of α-haloarylalkanones with thiosemicarbazides is expediently carried out using equimolar amounts of both reagents in a solvent or diluent which is inert with respect to these reagents. Suitable alcohols are, in particular, lower alcohols such as methanol, ethanol, n-propanol, isopropanol and various butanols, or ethyl acetate and mixtures of these solvents, but ethanol should be preferred. The reaction is usually carried out at temperatures between 20 ^o C and the boiling point of this reaction medium, but most often between 20 ^o C and 70 ^o C. Depending on the reactivity of the reagents, the nature of the reaction medium and temperature, the reaction time can be in the range of 5 minutes to 2 hours. The final products usually crystallize in analytically pure form while slowly cooling the reaction mixture.

 Depending on the solubility, the substances can be administered either orally or through parenteral injection of a dissolved form. They can be used alone, for example, in the form of microcapsules, in mixtures with each other, or in combination with suitable adjuvants and / or excipients.

 The invention also relates to pharmaceutical compositions which comprise an effective amount of at least one of the above thiadiazine compounds, if necessary, in the form of one of the acid addition salts, and which contain at least one of these active substances in addition to pharmaceutically acceptable excipients, diluents and / or other excipients. Suitable solid or liquid dosage forms include, for example, granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, elixirs, suspensions, emulsions, drops or injection solutions, as well as preparations for the targeted delivery of the active substance, in the manufacture of which excipients are usually used, such as fillers, disintegrants, binders, shelling agents, disintegrants, lubricants, perfumes, sweeteners or solubilizers. Suitable excipients are, for example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk albumin, gelatin, flour, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents such as sterile water and monoatomic and polyhydric alcohols, for example glycerin.

 Pharmaceutical preparations are preferably manufactured and used for treatment in dosage forms, each of which contains, as an active ingredient, a specific dose of at least one thiadiazine compound and / or at least one corresponding acid addition salt. In the case of injectable solutions, thiadiazine is preferably used for treatment in doses of from 10 to about 600, preferably from about 20 to about 500, even more preferably from about 30 to about 400 mg / kg.

Compounds suitable for use are represented by the following examples:
1. 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine;
2. 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine;
3. 2-N- (1-phenyl-2,3-dimethylpiraeol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine;
4. 2-N-Methyl-N- (1-phenyl-2,3-dimethylpiraeol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine;
5. 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine;
6. 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-ethoxyphenyl) -6H-1,3,4-thiadiazine;
7. 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-chlorophenyl) -6H-1,3,4-thiadiazine;
8. 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine;
9. 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine.

Examples
All compounds were obtained in 60-80% yields by condensation of α-haloarylalkanones with the corresponding 4-substituted thiosemicarbazides, proceeding smoothly when heated in ethanol. The structure of the compounds is proved by spectral data (UV, IR, ¹ H NMR); their purity is confirmed by thin layer chromatography and elemental analysis.

 Example 1

 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyraeol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine.

Compound 1 was obtained by heating 2 g (0.01 mol) of α-bromoacetophenone with 2.9 g (0.01 mol) of 4-methyl-4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide in ethanol for 20 minutes. The reaction mixture was cooled and made basic with a dilute ammonia solution to pH 8-9. The colorless precipitate was filtered off, recrystallized from a 30% water-ethanol mixture, and dried. Yield 2.7 g (70%). T. pl. 154-156 ^o C. R _f = 0.6 (eluent: ethanol-chloroform 1: 8). Found,%: C 64.4; H 5.4; N 17.7. C ₂₁ H ₂₁ N ₅ OS. Calculated,%: C 64.4; H 5.4; N 17.9. ¹ H NMR in DMSO-d ₆ , δ ppm: 2.2 (3H, s, CH ₃ ); 3.2 (3H, br.s, NCH ₃ ); 3.35 (3H, br. S, NCH ₃ ); 3.7 (2H, s, CH ₂ S); 7.4-7.9 (10H, m, two C ₆ H ₅ ).

 Example 2

 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine.

Compound 2 was prepared analogously to the synthesis of compound 1 from α-bromo-4-bromoacetophenone and 4-methyl-4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide. Yield 72%. Mp 169-170 ^o C. R _f = 0.5 (eluent: ethanol-chloroform 10: 1). Found,%: C 53.6; H 4.3; N 14.6. C ₂₁ H ₂₀ BrN ₅ OS. Calculated,%: C 53.6; H 4.3; N 14.9. ¹ H NMR in DMSO-d ₆ , δ, ppm: 2.2 (3H, s, CH ₂ ); 3.2 (3H, br.s, NCH ₃ ); 3.35 (3H, br. S, NCH ₃ ); 3.65 (2H, s, CH ₂ S); 7.4-8.0 (9H, m, C ₆ H ₅ and C ₆ H ₄ ).

 Example 3

 2-N- (1-Phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine.

Compound 3 was prepared analogously to the synthesis of compound 1 from α-bromoacetophenone and 4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide. Yield 88%. T. pl. 112-114 ^o C. R _f = 0.58 (eluent: ethanol-chloroform 1: 8). Found,%: C 63.5; H 5.2; N 18.4. C ₂₀ H ₁₉ N ₅ OS. Calculated,%: C 63.6; H 5.1; N 18.5. ¹ H NMR in DMSO-d ₆ , δ, ppm: 2.2 (3H, s, CH ₃ ); 3.1 (3H, s, NCH ₃ ); 3.9 (2H, s, CH ₂ S); 7.3-8.0 (10H, m, two C ₆ H ₅ ).

 Example 4

 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine.

Compound 4 was obtained by heating 0.5 g (0.002 mol) of α-bromobutyrophenone with 0.5 g (0.002 mol) of 4-methyl-4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide in 10 ml of ethanol for 20 minutes. The reaction mixture was cooled, made basic with a 7% ammonia solution to pH 9 and held for 30 minutes. The yellowish precipitate was filtered off, recrystallized from a mixture of water and isopropanol 30:70 and dried. Yield 0.6 g (75%). T. pl. 88-89 ^o C. R _f = 0.35 (eluent; ethanol-chloroform 1:10). Found,%: C 64.4; H 6.0; N 16.7. C ₂₃ H ₂₅ N ₅ OS. Calculated,%: C 64.5; H 6.2; N 16.3. ¹ H NMR in DMSO-d ₆ , d, ppm: 0.9 (3H, t, -CH ₃ ); 2.2 (3H, s, CH ₃ ); 3.05 (2H, q, -CH ₂ -); 3.18 (3H, br. S, NCH ₃ ); 3.30 (3H, br. S, NCH ₃ ); 4.25 (1H, m, = CHS); 7.2-8.1 (10H, m, two C ₆ H ₅ ).

 Example 5

 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine.

Compound 5 was prepared analogously to the synthesis of compound 4 from α-bromobutyrophenone and 4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide. Yield 74%. T. pl. 79-80 ^o C. R _f = 0.32 (eluent: ethanol-chloroform 1:10). Found,%: C 63.3; H 5.7; N 17.6. C ₂₂ H ₂₃ N ₅ OS. 0.5H ₂ O. Calculated,%: C 63.8; H 5.8; N 17.8. ¹ H NMR in DMSO-d ₆ , d, ppm: 1.05 (3H, t, -CH ₃ ); 1.70 (2H, m, CH ₂ ); 2.20 (3H, s, CH ₃ ); 3.10 (3H, br. S, NCH ₃ ); 4.35 (1H, m, = CHS); 7.0-8.1 (10H, m, two C ₆ H ₅ ).

 Example 6

 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-ethoxyphenyl) -6H-1,3,4-thiadiazine.

Compound 6 was obtained by heating 2.4 g (0.01 mol) of 4-ethoxy-α-bromoacetophenone with 2.8 g (0.01 mol) of 4-methyl-4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) -thiosemicarbazide in 100 ml of absolute ethanol for 20 minutes. The reaction mixture was cooled, made basic with 7% ammonia solution to pH 8-9. The yellowish precipitate was filtered off, recrystallized from a mixture of water and ethanol 80:20 and dried. Yield 3.5 g (74%). T. pl. 164-165 ^o C. R _f = 0.25 (eluent: ethanol-chloroform 1: 10). Found,%: C 63.3; H 5.9; N 15.8. C ₂₃ H ₂₅ N ₅ O ₂ S. Calculated,%: C 63.4; H 5.8; N 16.1. ¹ H NMR in DMSO-d ₆ , d, ppm: 1.34 (3H, t, -CH ₃ ); 2.2 (3H, s, CH ₃ ); 3.14 (3H, s, NCH ₃ ); 3.30 (3H, br. S, NCH ₃ ); 3.60 (2H, br. S, CH ₂ S); 4.13 (2H, q, OCH ₂ -); 7.45 (5H, m, C ₆ H ₅ ).

 Example 7

 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino 5- (4-chlorophenyl) -6H-1,3,4-thiadiazine.

Compound 7 was prepared analogously to the synthesis of compound 6 from 4-chloro-α-bromoacetophenone and 4-methyl-4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide. Yield 77%. Mp 178-179 ^o C. R _f = 0.3 (eluent: ethanol-chloroform 1:10). Found,%: C 57.7; H 4.7; N 15.8. C ₂₁ H ₂₀ ClN ₅ OS • 5H ₂ O. Calculated,%; C 58.0; H 4.8; N 16.2. ¹ H NMR in DMSO-d ₆ , δ, ppm: 2.20 (3H, s, CH ₃ ); 3.15 (3H, br. S, NCH ₃ ); 3.30 (3H, br. S, NCH ₃ ); 3.65 (2H, s, CH ₂ S); 7.3-8.0 (9H, m, C ₆ H ₅ and C ₆ H ₄ ).

 Example 8

 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine.

Compound 8 was prepared analogously to the synthesis of compound 6 from 3-bromo-α-bromoacetophenone and 4- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide. Yield 76%. T. pl. 69-70 ^o C. R _f = 0.38 (eluent: ethanol - chloroform 1:10). Found,%: C 50.6; H 4.2; N 14.6. C ₂₀ H ₁₈ BrN ₅ OS • H ₂ O. Calculated,%: C 50.2; H 3.9; N 14.8. ¹ H NMR in DMSO-d ₆ , δ, ppm: 2.20 (3H, s, CH ₃ ); 3.10 (3H, br. S, NCH ₃ ); 3.95 (2H, s, CH ₂ S); 7.1-8.0 (9H, m, C ₆ H ₅ and C ₆ H ₄ ).

 Example 9

 2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino 5- (3-bromophenyl) -6H-1,3,4-thiadiazine.

Compound 9 was prepared analogously to the synthesis of compound 6 from 3-bromo-α-bromoacetophenone and 4-N-methyl- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) thiosemicarbazide. Yield 82%. T. pl. 88-90 ^o C. R _f = 0.48 (eluent: ethanol-chloroform 1: 10). Found,%: C 49.4; H 4.4; N 14.7. C ₂₁ H ₂₀ BrN ₅ OS • 2H ₂ O. Calculated,%: C 49.8; H 4.7; N 14.9. ¹ H NMR in DMSO-d ₆ , δ, ppm: 2.20 (3H, s, CH ₃ ); 3.15 (3H, br. S, NCH ₃ ); 3.25 (3H, br.s, NCH ₃ ); 3.55 (2H, s, CH ₂ S); 7.0-8.2 (9H, m, C ₆ H ₅ and C ₆ H ₄ ).

Experimental biological part
The hypometabolic activity of the compounds used here was demonstrated as follows. In all cases, tests were carried out on mice of the BALB line of 3-4 months of age. In all experiments, non-toxic doses of the test substances were used, which ranged from 60 to 400 mg / kg. In the case of water-soluble substances, aqueous solutions of the test compounds were administered intraperitoneally (ip), while insoluble compounds were administered orally (po).

 To demonstrate the effect of the test substances on body temperature and oxygen consumption, 5-6 mice were used in in vivo experiments for each dose.

Changes in rectal temperature (absolute values - in ^o C) were measured with a TREM-1 medical electrothermometer (Table 1). The oxygen consumption rate was monitored by measuring the oxygen concentration in a closed vessel using an MN 5130 optical-acoustic gas analyzer. Oxygen consumption data are given in percent relative to the initial oxygen concentration taken as 100% (Table 2).

It was found that when used in non-toxic doses, all compounds lower the rectal temperature in the range from 3 to 15 ^o C depending on the structure of the substance, dose and method of administration. It was found that some of the tested substances cause a sharp drop in body temperature (7-8 ^o C for 30 minutes), while others show only a moderate effect (7-10 ^o C for 3 hours), as illustrated in Table. 1.

Compound 1 was administered orally at a dose of 0.16 mg / kg (1/2 LD ₁₆ ), and then rectal temperature was measured. After 1 hour, body temperature was about 5 ^o C lower than the original. Over the next 4 hours, it decreased further, reaching 26.4 ^o C (with a total drop of 12.5 ^o C), while after 24 hours the temperature was restored to 96% from the starting point. The motor activity of mice was also fully restored. In the case of lower doses (1/4 LD ₁₆ or 1/8 LD ₁₆ ), a lower temperature drop was observed.

When administered in a dose of 1/2 LD _16, compound 1 also caused a significant drop in oxygen consumption: 76% from the initial level after 5 minutes with a maximum drop to 58% after 60-90 minutes (Table 2). The period of maximum temperature drop is accompanied by severe akinesia and suppression of reflex functions, but no tremor or convulsions were observed.

 Example 10

Composition for the manufacture of tablets
2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine - 200 mg
Wheat Starch - 30 mg
Lactose - 67 mg
Magnesium Stearate - 3 mg
A portion of the wheat starch is used to prepare a granular starch paste, which, together with the remainder of the wheat starch, is granulated, sieved and mixed with the active ingredient and magnesium stearate. The mixture is compressed into tablets weighing 300 mg each.

In a similar manner, tablets are prepared whose active ingredient is the following compounds of the invention:
2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine;
2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine;
2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine;
2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine;
2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-ethoxyphenyl) -6H-1,3,4-thiadiazine;
2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-chlorophenyl) 6H-1,3,4-thiadiazine;
2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine and
2-N-Methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine.

Claims (6)

1. Substituted 6-R-1,3,4-thiadiazin-2-amines of the general formula

where Ar is phenyl or phenyl substituted with one or more chlorine, bromine, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkyl groups;
each of R ¹ and R ² independently represents a hydrogen atom or a C ₁ -C ₄ alkyl residue;
R ³ and R ^{4 are} independently selected from the range of C ₁ - C ₄ alkyl groups;
and their pharmaceutically acceptable salts.  2. Substituted 6-R-1,3,4-thiadiazin-2-amines according to claim 1, selected from the following series: 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one -4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine; 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine; 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-ethoxyphenyl) -6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-chlorophenyl) -6H-1,3,4-thiadiazine; 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine, and their pharmaceutically acceptable salts.  3. Substituted 6-R-1,3,4-thiadiazin-2-amines, the formula of which is given in paragraph 1, and their pharmaceutically acceptable salts having hypometabolic and cardiovascular activity.  4. The substituted 6-R-1,3,4-thiadiazin-2-amines according to claim 3, selected from the following series: 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one -4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-bromophenyl) -6H-1,3,4-thiadiazine; 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine; 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5-phenyl-6H-6-ethyl-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-ethoxyphenyl) -6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (4-chlorophenyl) -6H-1,3,4-thiadiazine; 2-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine; 2-N-methyl-N- (1-phenyl-2,3-dimethylpyrazol-5-one-4-yl) amino-5- (3-bromophenyl) -6H-1,3,4-thiadiazine, and their pharmaceutically acceptable salts.  5. A pharmaceutical composition having hypometabolic and cardiovascular activity, comprising an effective amount of an active agent and a pharmaceutically acceptable excipient, diluent and / or other excipients, characterized in that it contains as an active agent one of the compounds of general formula I according to claim 1 or a pharmaceutically acceptable salt thereof.  6. The pharmaceutical composition according to claim 5, characterized in that it as an active agent contains one of the compounds listed in claim 4, or a pharmaceutically acceptable salt thereof.

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