RU2152943C1 - Pharmaceutically acceptable salts of substituted 6h-1,3,4- -thiadiazine-2-amines and their pharmaceutical compositions - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes the novel substituted 6H-1,3,4-thiadiazine-2-amines of the general formula (I)

where

Description

 The invention relates to new derivatives of 6H-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 can be accompanied by loss of consciousness (general anesthesia), or occurs 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 have been 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 the inventions [14-20], as well as their 6-alkyl and 6-phenyl analogues [13 and 21]. The importance of 6H-1,3,4-thiadiazin-2-amines as hypometabolic anesthetics and cardiovascular agents has not yet been claimed. 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. H. 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-2493844 (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. Chibiryak, Radiobiology, 30 (2), 162-5 (1990).

 15. A.V. Belik et al., Chemical and Pharmaceutical 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-4,940,790 (1990).

 20. A.P. Novikova et al. SU-A-1726478.

 21. E. Bulka et al, DD-A-228248.

где

представляет морфолиновый, тиоморфолиновый, пиперидиновый, пирролидиновый или гексаметилениминовый фрагменты; или фармацевтически приемлемые соли этих соединений.BACKGROUND OF THE INVENTION
According to one aspect of the invention, there is provided the use of substituted 6H-1,3,4-thiadiazin-2-amines of the following general formula as anesthetics or cardiovascular agents:

Where

represents morpholine, thiomorpholine, piperidine, pyrrolidine or hexamethyleneimine fragments; or pharmaceutically acceptable salts of these compounds.

 In accordance with a further aspect of the invention, novel substituted 6H-1,3,4-thiadiazin-2-amines of the above formula are provided.

 According to another aspect of the invention, there is provided a pharmaceutical composition comprising one or more of the above derivatives of 6H-1,3,4-thiadiazin-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 5-position of the thiadiazine ring with an ethoxalylmethoxyme residue and are free compounds or their pharmaceutically acceptable salts. In addition, the compounds are substituted at position 2 of the thiadiazine ring by a cycloalkylimine residue, mainly consisting of morpholine, thiomorpholine, piperidine, pyrrolidine and hexamethyleneimine fragments.

где

имеет значения, определенные выше.The invention further relates to a method for producing the 1,3,4-thiadiazines described above, according to which an ester (mainly ethyl) of γ-halo-α-methoxyiminoacetoacetic acid is reacted with a thiosemicarbazide of the formula

Where

has the meanings defined above.

 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, paratoluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and cyclohexylamidosulfonic acid.

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 interaction of γ-halo-α-methoxyiminoketoesters with thiosemicarbazides is expediently carried out using equimolar amounts of both reagents in a solvent or diluent that 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 5 ^° C. and 30 ^° C., preferably between 18 ^° C. and 20 ^° C. Depending on the reactivity of the reactants, the nature of the reaction medium and the temperature, the reaction time can be from 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 by 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 or preparations 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 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.

 The pharmaceutical preparations are preferably produced and used in the treatment in dosage forms, each of which contains as a 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. Ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide;
2. Ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate, mesylate;
3. Ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide;
4. Ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate, mesylate;
5. Ethyl 1-methoxyimino-1- (2-piperidino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide;
6. Ethyl 1-methoxyimino-1- (2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide;
7. Ethyl-1-methoxyimino-1- (2-hexamethyleneimino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide.

EXAMPLES
All compounds were obtained with yields of 60-80% condensation of ethyl γ-bromo-α-methoxyiminoacetoacetates 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

 Ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide.

A cooled solution of 5 g (0.02 mol) of ethyl γ-bromo-α-methoxyiminoacetoacetate in 15 ml of absolute ethanol was added dropwise to a suspension of 3.2 g (0.02 mol) of thiocarbazinic acid morpholide in 30 ml of absolute ethanol at 5-7 ^o C. The mixture was stirred first at the above temperature for 2 hours, and then at 18-20 ^o C for 5 hours. The colorless precipitate was filtered off and recrystallized twice from absolute ethanol. Yield 6.5 g (82%). T. pl. 213- 214 ^o C. R _f = 0.6 (eluent: butanol - acetic acid - water 4: 1: 5). Found,%: C 36.7; H 4.8; N, 14.3. C ₁₂ H ₁₉ BrN ₄ O ₄ S. Calculated,%: C 36.5; H 4.8; N, 14.2. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.30 (3H, t, -CH ₃ , COOC ₂ H ₅ ); 3.85 (8H, m, morpholino); 4.06 (2H, s, CH ₂ S); 4.10 (3H, s, OCH ₃ ); 4.30 (2H, q, OCH ₂ -, COOC ₂ H ₅ ).

 Example 2

 Ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate, mesylate.

Methanesulfonic acid, 0.7 g (0.007 mol), was added dropwise with stirring to a solution of 2 g (0.006 mol) of compound 1 in dry benzene. The colorless precipitate obtained after 15-20 minutes of stirring was filtered off and recrystallized from absolute ethanol. Yield 2.5 g (95%). T. pl. 181-182 ^o C. R _f = 0.45 (eluent: butanol - acetic acid - water 4: 1: 5). Found,%: C 38.2; H 5.5; N, 13.6. C ₁₃ H ₂₂ N ₄ O ₇ S ₂ . Calculated,%: C 38.1; H 5.4; N 13.7. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.28 (3H, t, -CH ₃ , COOC ₂ H ₅ ); 2.35 (3H, s, SCH ₃ ); 3.74 (8H, m, morpholino); 3.88 (2H, s, CH ₂ S); 4.02 (3H, s, OCH ₃ ); 4.29 (2H, q, OCH ₂ -, COOC ₂ H ₅ ).

 Example 3

 Ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide.

Compound 3 was prepared analogously to the synthesis of compound 1 by the reaction of ethyl γ-bromo-α-methoxyiminoacetoacetate with thiocarbazinic acid thiomorphide at 18-20 ^° C for 6 hours. Yield 73%. T. pl. 202-203 ^o C. R _f = 0.7 (eluent: butanol - acetic acid - water 4: 1: 5). Found,%: C 35.6; H 4.8; N 13.7. C ₁₂ H ₁₉ BrN ₄ O ₃ S ₂ . Calculated,%: C 35.0; H 4.6; N, 13.6. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.27 (3H, t, -CH ₃ , COOC ₂ H ₅ ); 2.84 (4H, m, N (CH ₂ ) ₂ thiomorpholino); 4.06 (3H, s, OCH ₃ ); 4.10 (4H, m, S (CH ₂ ) ₂ thiomorpholino); 4.17 (2H, s, CH ₂ S); 4.30 (2H, q, OCH ₂ -, COOC ₂ H ₅ ).

 Example 4

 Ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate, mesylate.

Compound 4 was prepared analogously to the synthesis of compound 2 from 2-thiomorpholino-5-ethoxalyl-6H-1,3,4-thiadiazine and methanesulfonic acid. Yield 90%. T. pl. 171-172 ^o C. R _f = 0.59 (eluent: butanol - acetic acid - water 4: 1: 5). Found,%: C 36.4; H 5.4; N 13.2. C ₁₃ H ₂₂ N ₄ O ₆ S ₃ . Calculated,%: C 36.6; H 5.2; N 13.1. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.34 (3H, s, -CH ₃ ); 2.33 (3H, s, SCH ₃ ); 2.9 [4H, m, N (CH ₂ ) ₂ thiomorpholino]; 3.90 (3H, s, OCH ₃ ); 4.10 [4H, m, S (CH ₂ ) ₂ thiomorpholino]; 4.18 (2H, s, CH ₂ S); 4.32 (2H, q, OCH ₂ -, COOC ₂ H ₅ ).

 Example 5

 Ethyl 1-methoxyimino-1- (2-piperidino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide.

Compound 5 was prepared analogously to the synthesis of compound 1 by the reaction of ethyl γ-bromo-α-methoxyiminoacetoacetate with 4,4-pentamethylenetiosemicarbazide. Yield 67%. T. pl. 201-202 ^o C. R _f = 0.35 (eluent: butanol - acetic acid - water 4: 1: 5). Found,%: C 39.5; H 5.7; N, 14.3. C ₁₃ H ₂₁ BrN ₄ O ₃ S. Calculated,%: C 39.7; H 5.3; N, 14.3. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.32 (3H, t, -CH ₃ , COOC ₂ H ₅ ); 1.72 (6H, t, piperidino); 3.88 (4H, m, piperidino); 4.08 (2H, s, CH ₂ S); 4.10 (3H, s, OCH ₃ ); 4.32 (2H, q, OCH ₂ -, COOC ₂ H ₅ ).

 Example 6

 Ethyl 1-methoxyimino-1- (2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide.

Compound 6 was prepared analogously to the synthesis of compound 1 by reacting ethyl γ-bromo-α-methoxyiminoacetoacetate with 4,4-tetramethylenetiosemicarbazide. Yield 59%. T. pl. 208-209 ^o C. R _f = 0.29 (eluent: butanol-acetic acid-water 4: 1: 5). Found,%: C 38.0; H 5.1; N, 15.0. C ₁₂ H ₁₉ BrN ₄ O ₃ S. Calculated,%: C 38.0; H 5.0; N, 14.8. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.31 (3H, t, -CH ₃ , COOC ₂ H ₅ ); 1.90-2.03 (4H, m, pyrrolidino); 3.50-3.95 (4H, m, pyrrolidino); 4.06 (2H, s, CH ₂ S); 4.17 (3H, s, OCH ₃ ); 4.32 (2H, q, OCH ₂ -, COOC ₂ H ₂ ).

 Example 7

 Ethyl-1-methoxyimino-1- (2-hexamethyleneimino-6H-1,3,4-thiadiazin-5-yl) acetate, hydrobromide.

Compound 7 was prepared analogously to the synthesis of compound 1 by the reaction of ethyl γ-bromo-α-methoxyiminoacetoacetate with 4,4-hexamethylenetiosemicarbazide. Yield 60%. T. pl. 186-187 ^o C. R _f = 0.3 (eluent: butanol - acetic acid - water 4: 1: 5). Found,%: C 41.8; H 5.2; N 13.5. C ₁₄ H ₂₃ BrN ₄ O ₃ S. Calculated,%: C 41.3; H 5.7; N 13.5. ¹ H NMR in DMSO-d ₆ , δ, ppm: 1.30 (3H, t, -CH ₃ , COOC ₂ H ₅ ); 1.5-2.1 (8H, m, hexamethyleneimino); 3.75-4.0 (4H, m, hexamethyleneimino); 4.05 (2H, s, CH ₂ S); 4.18 (3H, s, OCH ₃ ); 4.35 (2H, q, OCH ₂ -, COOC ₂ H ₅ ).

EXPERIMENTAL BIOLOGICAL PART
The hypometabolic activity of the compounds of the invention was demonstrated as follows. In all cases, tests were performed 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. The 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 dissolved in a 1: 9 twin-water mixture (the concentration of the saturated solution was 40 mg / ml) and was administered intraperitoneally at a rate of 0.2 ml per 20 gram mouse. Values of LD ₁₆ , LD ₅₀ , LD _{84 are} defined as 788.4; 830.5 and 881.5 mg / kg. The introduction of compound 1 caused a drop in body temperature, akinesia, suppression of reflexes to external influences, and the inhibited state of mice.

 Data on oxygen consumption for a period of 10-300 minutes with a 30-minute interval are presented in table. 2. It was found that compound 1 reduces oxygen consumption by 7–10 times during the first hour, by 3–4 times during the next 2 hours, and by 2 times during the fourth hour relative to the initial value (Table 2).

The rectal temperature of mice and rats fell 10 minutes after drug administration by about 3-4 ^° C, and after 30 minutes, 7-8 ^° C for mice and about 5 ^° C for rats. The maximum temperature drop (12-13 ^o C) was achieved after 90-120 minutes for mice, and after 5 hours the temperature difference was 2 ^o C. A complete restoration of oxygen consumption was not observed (table 2).

 Example 8

 Composition for the manufacture of tablets.

Ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate hydrobromide - 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:
mesylatethyl-1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate hydrobromide,
ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate mesylate,
ethyl 1-methoxyimino-1- (2-piperidin-6H-1,3,4-thiadiazin-5-yl) acetate hydrobromide,
ethyl 1-methoxyimino-1- (2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl) acetate hydrobromide, and
hydrobromidethyl-1-methoxyimino-1- (2-hexamethyleneimino-6H-1,3,4-thiadiazin-5-yl) acetate.

Claims (6)

1. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines of the general formula

Where

represents a morpholine, thiomorpholine, piperidine, pyrrolidine or hexamethyleneimine fragment. 2. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines according to claim 1, selected from the following series:
ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-piperidino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-hexamethyleneimino-6H-1,3,4-thiadiazin-5-yl) acetate.  3. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines, the formula of which is given in claim 1, having hypometabolic and cardiovascular activity. 4. Pharmaceutically acceptable salts of substituted 6H-1,3,4-thiadiazin-2-amines according to claim 3, selected from the following series:
ethyl 1-methoxyimino-1- (2-morpholino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-thiomorpholino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-piperidino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-pyrrolidino-6H-1,3,4-thiadiazin-5-yl) acetate,
ethyl 1-methoxyimino-1- (2-hexamethyleneimino-6H-1,3,4-thiadiazin-5-yl) acetate.  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.  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.

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