RU2353614C1 - Antihypotension medication - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: claimed invention relates to application of compounds of general formula I

where R₁=H, CH₃CO, C₂H₅CO, CH₂=CHCO, CH₂=C(CH₃)CO, C₆H₅CO, m-FC₆H₄CO, m-ClC₆H₄CO, BrC₁₁H₂₂CO. R₂=CH₃, C₂H₅, n-C₃H₇, i-C₃H₇, C₄H₉, C₄H₈F, C₂H₄F, C₂H₄OH, CH₂=CH-CH₂-, CH₂-CH-CH₂ X=Cl, Br, I, dialkylphosphate, methane sulfonate, as hypotensive medication. In duration of hypertensive action proposed substances exceed mesatone and other medications, applied in medical practice for hypotensive condition treatment. Also described is pharmacological composition, based on formula I compounds.

EFFECT: obtaining of medication, which in duration of action exceeds mesatone and other medications, applied in medical practice for hypotensive condition treatment.

3 cl, 4 tbl, 6 ex

Description

The invention relates to new medicines that can be used in medical practice in the treatment of chronic and acute antihypertensive conditions (bleeding, trauma, shock, poisoning), especially in emergency and emergency medical care, as it can be used to produce new antihypertensive drugs .

Antihypertensive agents containing isothiourea derivatives and their salts as active substances are claimed.

The invention extends the range of antihypertensive agents. The compound refers to new drugs that may find application in medical practice, as a new chemical compound that affects blood pressure. This substance can be used to treat chronic and acute hypotension.

The invention is directed to the field of satisfying human vital needs - the creation of new drugs that can find application in the chemical-pharmaceutical and medical industries.

At present, hypertensive drugs are known in medical practice that act either directly on the smooth muscles of the vascular wall or through stimulation of alpha-adrenergic receptors. Adrenomimetics (adrenaline, norepinephrine, mesatone, ephedrine, etc.) and polypeptide preparations (glucagon, octapressin, antioteninamide, etc.) are usually used.

The main disadvantage of drugs with a polypeptide structure and most adrenomimetics is their short duration of action. To prolong the action, drugs are administered in the form of perfusion. [I.M. Autkunson, S.I. Dusting, V.I. Rand, Aust. J. Exp. Biol. Med., V.50, p. 847-859 (1972), "Acidosis induced by catecholamines in acidosis"].

By pharmacological properties, the closest prototype of the proposed compounds is the well-known drug mesatone.

Mesatone is 1- (m-hydroxyphenyl) -2-methylaminoethanol hydrochloride. It selectively stimulates α ₁ -adrenoreceptors, causing narrowing of arterioles, increases systolic and diastolic pressure. The antihypertensive effect of mesatone lasts about 20 minutes after intravenous administration (0.1-0.5 ml of a 1% solution) (MD Mashkovsky. Medicines, 14th ed., Moscow: Novaya wave, 2000, part 1, p.233; O.M. Avakyan, Pharmacological regulation of the function of adrenergic receptors, M., Medicine, 1988, C.8).

Adrenomimetics, including mesatone, have some common disadvantages. They act for a short time - only within 20 minutes, increase oxygen consumption by tissues, cause metabolic acidosis, arrhythmias, and excitation of the central nervous system. (O.M. Avakyan. Pharmacological regulation of adrenoreceptor function. M., Medicine, 1988, p. 8; V.G. Kulinsky, A.N. Kovalevsky, Bull. Exper. Biol. Med., 1984, p. 9 " Dualistic control by catecholamines of oxygen consumption by the body of mice "). They are characterized by the occurrence of secondary hypotension. In addition, adrenergic agonists do not correct arterial hypotension caused by adrenergic blocking agents and under conditions of metabolic acidosis have only a weak antihypertensive effect (C. Kortanje, VIMathy, R. Chartdorp, Haunyn Gohinedeleg is Arh. Pharmakol., V. 330, No. 3, p. 187, 1985, "Influence respiratory acidosis or alkalosis on response imediated by and alfa-adrenoreseptor in pithed normotensive rats", IMAutkunson, SI Dusting, VIRand, Aust. J. Expiol. Med., V. 50, p. 847, 1972, 'Acidjsis induced by catecholamines in acidosis').

Studies of the effect of various chemical compounds on blood pressure previously carried out by the inventors have shown that some derivatives of isothiourea, thiazoline and thiazine have the ability to increase the normal and low blood pressure, which changes as a result of endotoxic shock, to one degree or another. However, it should be noted that they do not have a prolonged hypertensive effect and are very toxic.

(S.Ya. Proskuryakov, N.G. Kucherenko, A.I. Trishkina et al., Bull. Exp. Biol and Med., 2002, V.134, No. 10, S.393-396. “NO-inhibiting and vasotropic activity of some compounds containing a thioamidine group. ", S. Ya Proskuryakov, MV Filimonova, Yu. G. Verkhovsky and others, Bull. Exp. Biol. and Med., 2004, V.138, No. 10, C.446-449, “Effect of NO synthase inhibitor 2-AADT on endotoxin-induced changes in rat hemodynamics and respiration”)

As a result of our studies in this direction, it was found that derivatives of isothiourea have a pronounced antihypotensive effect.

The aim of the invention is to increase the duration of the action of antihypertensive drugs and reduce its toxicity compared with drugs used in medical practice for the treatment of antihypertensive conditions.

The goal is achieved by the present invention, namely the use of derivatives of isothioureas and their salts of the structural formula

where R ₁ = H, CH ₃ CO, C ₂ H ₅ CO, CH ₂ = CHCO, CH ₂ = C (CH ₃ ) CO, C ₆ H ₅ CO, m-FC ₆ H ₄ CO, m-ClC ₆ N ₄ CO, BrC ₁₁ H ₂₂ CO; R ₂ = CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , i-C ₃ H ₇ , C ₄ H ₉ , C ₄ H ₄ F, C ₂ H ₄ F, C ₂ H ₄ OH, CH ₂ = CH — CH ₂ -, CH ₂ —CH — CH ₂ ; X = Cl, Br, I, dialkyl phosphate, methanesulfonate as antihypertensive agent.

The goal is also achieved by another invention, namely a pharmacological composition for the treatment of antihypertensive conditions.

A pharmacological composition for the treatment of antihypertensive conditions, containing the active substance and a pharmacologically acceptable carrier, is characterized in that it contains a pharmacologically acceptable isothiourea salt as the active substance.

In particular, bromide can be used as a pharmacologically acceptable salt.

A pharmacological composition, in particular, can be proposed for the treatment of a hypotensive condition caused by blood loss, trauma or shock.

The compounds found are less toxic than mesatone (LD ₅₀ 191 mg / kg). The introduction of these substances to animals does not cause any visible changes in the heart rate of respiration during the entire observation period. By the duration of the hypertensive effect, the proposed substances are superior to mesatone and other drugs used in medical practice for the treatment of hypotensive conditions.

The revealed effects show that the proposed compounds differ from the known agents that are used to increase blood pressure.

Their use in medical practice creates new opportunities in the treatment of acute and possibly chronic arterial hypotension, as well as in cases of emergency and emergency care.

In the available literature, these compounds are not described, which indicates that we obtained them for the first time.

Synthesis of Isothiourea Derivatives

Derivatives of isothiourea having an antihypotensive effect, having the general formula

where R ₁ = H, CH ₃ CO, C ₂ H ₅ CO, CH ₂ = CHCO, CH ₂ = C (CH ₃ ) CO, C ₆ H ₅ CO, m-FC ₆ H ₄ CO, m-ClC ₆ N ₄ CO, BrC ₁ H ₂₂ CO.

R ₂ = CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , i-C ₃ H ₇ , C ₄ H ₉ , C ₄ H ₈ F, C ₂ H ₄ F, C ₂ H ₄ OH, CH ₂ = CH-CH ₂ -, CH ₂ -CH-CH ₂

X = Cl, Br, I, dialkyl phosphate, methanesulfonate.

Example 1. (T-982) 1-Acetyl-2-ethylisothiourea hydrobromide. A mixture of 2.0 g (15.9 mmol) of acetylthiourea and 3.68 g (33.8 mmol) of ethyl bromide in 7 ml of acetonitrile is heated in a sealed ampoule in a boiling water bath for 40 hours. The solvent is drained and the residue is boiled with acetonitrile until dissolved . The crystals that separated out after cooling were filtered off and recrystallized from acetonitrile. Yield 2.0 g (51.9%). T _pl. 120-121 ° C.

¹ H NMR (500 MHz, DMSO-d6) δ 2.2 (s, 3H; CH ₃ CO), 1.3 (t, 3H), 3.3 (q, 2H), 11.2 (w, 2H ; NH ₂₊ ).

C ₅ H ₁₁ BrN ₂ OS

Calculated: C 26.44 H 4.88 N 12.33

Found: C 26.77 H 5.12 N 12.08

Example 2. (T-975) 1-Acetyl-2-isopropylisothiourea hydrobromide. A mixture of 2.0 g (15.9 mmol) of acetylthiourea, 3.3 g (26.5 mmol) of isopropyl bromide and 2.8 g (16.9 mmol) of potassium iodide in 7.5 ml of freshly distilled acetonitrile is heated in a sealed ampoule on 40 hours in a boiling water bath. The KI precipitate was filtered off and the solvent was evaporated. The residue was recrystallized from 4-methyl-pentanone-2. Yield 1.5 g (37.5%). T _pl. 138-140 ° C.

¹ H PMR (500 MHz, DMSO-d6) δ 2.2 (s, 3H; CH ₃ CO), 1.3 (s, 6H), 4.1 (m, 1H), 11.0 (w, 2H ; NH ₂ ⁺ ).

C ₆ H ₁₃ BrN ₂ OS

Calculated: C 29.88 N 5.43 N 11.62

Found: C 29.25 H 5.51 N 11.56

Example 3. (T-977) 2-isopropylisothiourea diisopropyl phosphate. A mixture of 2.0 g (26.3 mmol) of thiourea and 5.9 g (26.4 mmol) of triisopropyl phosphate is heated for 7 hours at 132-135 ° C with stirring. After cooling, 10 ml of 4-methylpentanone-2 was added to the mixture, and the precipitate formed was filtered off and recrystallized from acetone-ethanol (2: 1). Yield 2.5 g (80.6%). T _pl. 197-198 ° C.

¹ H NMR (500 MHz, DMSO-d6) δ 1.3 (d, 6H), 1.2 (d, 6H), 3.8 (m, 1H SCH) 4.2 (m, 1H OCH ₃ ); 9-11 (br, 2H; NH ₂₊ ).

C ₁₀ H ₂₄ N ₂ O ₄ PS

Calculated: C 39.99 H 8.39 N 9.33

Found: C 39.81 H 8.77 N 9.66

Biological study of the properties of isothiourea

The experiments were performed on 40 rats - Wistar males weighing 300-400 g (7-11 animals per group). Each rat was anesthetized with sodium thiopental (60 mg / kg ip) and the parameters of the respiratory rate (HR), heart rate (HR), blood pressure in the left carotid artery, systolic and diastolic (ADS and ADD), as well as indicators were recorded electrocardiograms in three standard leads (ECG).

To create hypovolemic shock from the jugular vein, blood sampling was performed in a volume of 1.4-1.9% by weight of the experimental animal. After stabilization of the indicators, the registration of the indicated parameters was repeated. Then, one of the studied compounds of isothiourea derivatives was injected intraperitoneally to the animal: T-975, T-977, T-982 at a dose of 5 or 10 mg / kg and continued observation until the end of the visible manifestation of the effect. Observation of control animals with blood loss was continued for 90 minutes.

For monitor control and processing of the studied physiological parameters, the Polygraph RM-6000 instrument (Nihon Kohden, Japan) and a cardiograph (Nihon Kohden, Japan) were used. Statistical processing of the research results was carried out using parametric criteria: t - Student's test and Fisher's criterion and nonparametric Mann - Whitney U-test (application package Statistica 5.5).

Experiment Results

Example 1. It is known that severe (severe hemorrhage) is considered blood loss of 20-25 ml / kg or 1.5% of the weight of the animal, moderate (moderate hemorrhage) - 15 mg / kg or 0.7% [Sarkisov, P.I. Remezov. Reproduction of human diseases in an experiment. / Ed. A.A. Vishnevsky // M. - 1960 .-- 780 p. Feuerstein G., Mohamed A.V., Stull R., Goldstein D.S., Zerbe R. L., Ramwell P.W., Faden A.I. Effects of Nafazatrom on cardiovascular, sympathetic, and endocrine responses to hemorrhagic shock in conscious rats.// Circulatory Shock 17: 223-232 (1985).

Tiniakov R., Osei-Owusu P., Scrogin K.E. The 5-HT1A receptor agonist? 8-OH-DPAT, increases cardiac output and renal perfusion in rats subject to hypovolemic shock / // J Pharmacol Exp Ther November 2006: 1124-1135]. In this work, blood loss amounted to 1.4-1.9% of the weight of the experimental animal, which is very severe and involves the death of some animals due to hypovolemic shock.

The depth drop in mean arterial pressure (SBP) in our model of blood loss was 125 mmHg and reached 36% of the original, which even exceeds the literature data (3). 10-15 minutes after the end of the blood sampling, the blood pressure indices of the experimental rats began to gradually increase and by 90 minutes of observation amounted to 66-68% of the initial values (Table 1). The pulse rate in rats decreased due to blood loss, in some animals it was expressed (less than 300 beats per minute). Respiratory rate did not change significantly during the studies. In some rats, breathing became shallow.

The drug T-975 at a dose of 5 mg / kg ip did not cause changes in hemodynamic parameters in rats with blood loss.

Intraperitoneal administration of T-975 at a dose of 10 mg / kg to rats (n = 8) in a state of hypovolemic shock caused a pronounced and steady increase in blood pressure and blood pressure (Table 2). The effect developed already from 4-5 minutes after the injection, without visible changes in the state of the animal, and by 15 minutes it reached 90% of the initial values. After 45 minutes, the antihypovolemic effect of the T-975 preparation gradually decreased. Throughout the entire observation period, the effect remained significant in comparison with the indicators of blood loss in this group and in comparison with the corresponding time of the model of blood loss.

Heart rates increased less pronounced, differences with baseline values remained significant until the end of the observation period. The respiratory rate in experimental rats remained virtually unchanged.

Example 2. The antihypertensive effect of the drug T-977 (5 mg / kg ip, n = 7) developed in rats in a state of hemorrhagic shock also 1-2 minutes after injection (Table 3) without any external signs of the manifestation of the effect . As early as 5 minutes of T-977 action, the blood pressure and blood pressure indicators of the experimental animals were significantly higher than the blood loss and the corresponding time of the blood loss model. The pronounced antihypovolemic effect of T-977 at a dose of 5 mg / kg lasted more than 90 minutes. Blood pressure indices in the studied period of time fully correspond to physiological norms for rats, although in our study they significantly differ from high values of the initial blood pressure and blood pressure.

The pulse rate, significantly reduced as a result of blood loss, already from 10 minutes of the action of T-977 gradually increased, without reaching, however, the initial indicators.

The respiratory rate under the action of T-977, as in other groups, did not change.

Example 3. The introduction of the drug T-982 at a dose of 5 mg / kg in / b rats in a state of hemorrhagic shock (n = 7) caused a pronounced, but relatively short-term antihypovolemic effect (table 4). An increase in blood pressure was observed within 1-2 minutes after the injection and reached a maximum by 7-10 minutes, about 80% of the initial values. However, after 12-15 minutes, the effect of the drug weakened, and by 20-25 minutes after the administration of T-982, the blood pressure values in the majority of experimental rats did not differ from those of the corresponding model of blood loss.

The pulse rate for such a short time of manifestation of the effect did not have time to change significantly.

The respiratory rate in this group of rats increased slightly both after blood loss and under the influence of T-982.

Studies of a number of derivatives of isothiourea revealed compounds with pronounced antihypovolemic activity in a model of hemorrhagic shock in rats. The effect developed from the first minutes after intraperitoneal administration (T-977, T-982, T-975), reached 80-90% of the initial blood pressure by 7-10 minutes (T-982), or by 15-20 minutes (T -975, T-977) and lasted 20-25 minutes (T-982), more than 45 minutes (T-975) and more than 90 minutes (T-977).

The heart rate, reduced in a state of hemorrhagic shock, in most animals under the influence of these compounds had a steady tendency to increase.

Visual reactions in anesthetized animals to the administration of the studied compounds were not observed, the respiratory rate did not change

As can be seen from the above data, the antihypertensive effect of the compounds T-975, T-977 and T-982 at doses of 5 and 10 mg / kg lasts from 25 to 90 minutes, which significantly exceeds the duration of action of mesatone and preparations with a polypeptide structure.

Thus, it was found that the compounds T-975, T-977 and T-982 have a pronounced antihypertensive effect and are able to effectively and sufficiently long-term level the critical decrease in blood pressure caused by severe blood loss without secondary hypotension, which is typical for adrenomimetics, including and for mesatone. It should be noted that these compounds are less toxic than mesatone.

Studies have reliably indicated that the compounds T-975, T-977 and T-982 can be used to treat acute and chronic hypotensive conditions.

Table 1.
Hemodynamic and respiratory rates of anesthetized rats after severe blood loss (n = 11). Groups, time after administration Heart rate ADs ADD NPV (bpm) (mmHg.) (mmHg.) (per minute) Originally 413.1 ± 10.43 186.3 + 3.51 132.9 + 2.31 72.4 ± 3.87 After blood loss 2 minutes - 69.7 ± 6.85 * 48.1 ± 9.04 * - 5 minutes - 75.2 ± 6.94 * 47.0 ± 6.68 * - 10 minutes 359.5 ± 12.86 * 77.4 ± 4.93 * 51.1 ± 5.04 * 83.4 ± 7.72 * 20 minutes 358.7 ± 13.30 * 86.4 ± 8.03 * 62.9 ± 8.30 * 78.6 ± 6.69 30 minutes 372.2 ± 17.11 98.4 ± 9.89 * 73.5 ± 9.44 * 78.5 ± 6.81 40 minutes 383.2 ± 14.26 112.8 ± 10.05 * 79.7 ± 9.58 * 72.4 ± 5.67 50 minutes 387.9 ± 11.89 111.3 ± 8.40 * 78.5 ± 7.62 * 77.4 ± 6.71 60 minutes 402.7 ± 11.51 P8.3 ± 6.85 * 82.9 ± 6.32 * 77.7 ± 6.76 70 minutes 416.3 ± 8.41 123.0 ± 5.50 * 85.5 ± 5.13 * 79.3 ± 6.27 80 minutes 429.3 ± 8.85 126.7 ± 5.49 * 87.5 ± 4.96 * 79.4 ± 4.17 90 minutes 434.2 ± 9.41 127.1 ± 4.73 * 87.3 ± 4.10 * 80.8 ± 5.30 Note: * - significance of differences with the original value according to the t-criterion of student (P≤0,05) n is the number of animals

Table 2.
Hemodynamics and respiration rates of anesthetized rats after severe blood loss and administration of T-975 (10 mg / kg ip) (n = 8). Groups, time after administration Heart rate (bpm) ADS (mmHg) ADD (mmHg) NPV (per minute) Originally 416.0 ± 11.15 179.9 ± 4.22 130.2 ± 1.41 73.50 ± 4.85 After blood loss 5 minutes 326.5 ± 11.14 * 71.5 ± 5.53 * 43.4 ± 6.35 * 83.62 ± 4.85 T-975 10 mg / kg iv 2 minutes - 104.0 ± 8.89 * '' m 79.6 ± 9.73 * '' m - 5 minutes - 141.2 ± 9.34 * '' m 116.7 ± 7.26``m - 7 minutes 296.2 ± 29.50 * m 148.9 ± 7.53 * '' m 123.2 ± 5.33``m 80.2 ± 6.42 10 minutes 326.2 ± 7.18 * 154.1 ± 11.90``m 124.0 ± 9.84``m 81.4 ± 5.67 15 minutes 351.7 ± 7.75 * 164.0 ± 6.61``m 133.8 ± 4.04``m 77.1 ± 5.53 20 minutes 362.4 ± 13.24 * 158.1 ± 5.18 * '' m 129.1 ± 4.23``m 77.4 ± 4.43 30 minutes 370.7 ± 4.92 * '' 161.2 ± 6.68 * '' m 130.5 ± 3.98``m 73.7 ± 4.36 40 minutes 370.2 ± 6.57 * '' 153.3 ± 6.38 * '' m 123.3 ± 3.82``m 72.7 ± 5.13 50 minutes 352.7 ± 6.64 * 137.0 ± 9.77 * '' m 107.7 ± 7.36``m 75.7 ± 5.19 60 minutes 368.8 ± 9.94 * '' 142.5 ± 9.90 * '' m 109.5 ± 8.60 * '' m 77.0 ± 5.43 Note: the significance of differences by t-student test (P≤0,05) * - with the original value; '' - with blood loss, m - with the corresponding time model of blood loss. n is the number of animals

Table 3.
Hemodynamics and respiration rates of anesthetized rats after severe blood loss and administration of T-977 (5 mg / kg ip) (n = 7). Groups, time after administration Heart rate (bpm) ADS (mmHg) ADC (mmHg) NPV (per minute) Originally 439.7 ± 12.76 194.1 ± 5.74 135.4 ± 2.7 68.0 ± 2.69 After blood loss 5 minutes 360.8 ± 16.26 * 66.4 ± 7.83 * 41.3 ± 7.48 * 68.3 ± 4.13 T-977 5 mg / kg iv 2 minutes - 83.8 ± 9.03 * 60.8 ± 10.56 * - 5 minutes - 100.6 ± 7.26 * '' m 81.1 ± 7.71 * '' m - 10 minutes 371.1 ± 23.52 * 118.8 ± 9.36 * '' m 98.4 ± 8.41 * '' m 75.4 ± 2.85 20 minutes 374.1 ± 8.81 * 133.0 ± 6.47 * '' m 112.3 ± 6.10 * '' m 72.8 ± 3.76 30 minutes 380.0 ± 15.95 * 142.3 ± 7.72 * '' 116.3 ± 5.98 * '' m 71.1 ± 6.63 40 minutes 388.1 ± 14.89 * 147.7 ± 8.20 * '' m 120.1 ± 6.88``m 67.6 ± 4.94 50 minutes 388.8 ± 14.93 * 145.6 ± 7.07 * '' m 115.3 ± 6.01 * '' m 67.0 ± 3.80 60 minutes 398.8 ± 14.89 148.1 ± 10.05 * '' m 114.6 ± 8.16 * '' m 69.0 ± 3.93 70 minutes 401.4 ± 13.36 140.6 ± 12.83 * '' 108.6 ± 11.57 * '' 70.3 ± 2.98 80 minutes 403.8 ± 12.74 * 155.0 ± 5.83 * '' m 120.0 ± 5.71``m 68.3 ± 3.32 90 minutes 410.7 ± 10.77 '' 159.5 ± 5.68 * '' m 124.7 ± 3.95 * '' m 69.3 ± 1.33 Note: the significance of differences by t-student test (P≤0,05) * - with the original value; '' - with blood loss, n - number of animals m - with the corresponding time model of blood loss.

Table 4.
Hemodynamics and respiration rates of anesthetized rats after severe blood loss and administration of T-982 (5 mg / kg ip, n = 7). Groups, time after administration Heart rate ADs ADD NPV recipes (bpm) (mmHg.) (mmHg.) (per minute) Originally 428.7 ± 19.47 184.1 ± 3.77 137.0 ± 4.45 75.1 ± 3.32 After blood loss 10 minutes 369.1 ± 15.25 * 92.1 ± 7.03 * 67.8 ± 8.14 * 92.6 ± 7.48 T-982 5 mg / kg iv 2 minutes - 106.4 ± 9.63 * m 83.1 ± 9.54 * m - 5 minutes - 133.8 ± 8.84 * '' m 107.4 ± 9.24 * '' m - 10 minutes 362.8 ± 20.08 * 141.6 ± 9.63 * '' m 116.0 ± 8.28 * '' m 92.8 ± 6.41 * 15 minutes - 129.8 ± 7.65 * '' m 109.0 ± 6.10 * '' m - 20 minutes 347.1 ± 24.16 * 117.0 ± 7.24 * 97.7 ± 6.14 * 88.1 ± 6.86 25 minutes 110.4 ± 7.24 * 90.8 ± 6.68 * " Note: the significance of differences by t-student test (P≤0,05) '' - with the original value; * - with blood loss; m - with the corresponding time model of blood loss. n is the number of animals

Claims (4)

1. The use of derivatives of isothioureas and their salts of the structural formula

where R ₁ = H, CH ₃ CO, C ₂ H ₅ CO, CH ₂ = CHCO, CH ₂ = C (CH ₃ ) CO, C ₆ H ₅ CO, m-FC ₆ H ₄ CO, m-ClC ₆ N ₄ CO, BrC ₁₁ H ₂₂ CO;
R ₂ = CH ₃ , C ₂ H ₅ , n-C ₃ H ₇ , i-C ₃ H ₇ , C ₄ H ₉ , C ₄ H ₈ F, C ₂ H ₄ F, C ₂ H ₄ OH, CH ₂ = CH-CH ₂ -, CH ₂ -CH-CH ₂ ;
X = Cl, Br, I, dialkyl phosphate, methanesulfonate as antihypertensive agent. 2. A pharmacological composition for the treatment of antihypertensive conditions, containing the active substance and a pharmacologically acceptable carrier, characterized in that as the active substance it contains a pharmacologically acceptable salt of isothiourea according to claim 1. 3. The pharmacological composition according to claim 2, characterized in that bromide is used as a pharmacologically acceptable salt. 4. The pharmacological composition according to claim 2, characterized in that it is intended for the treatment of hypotensive state caused by blood loss, trauma or shock.