Vasopressor agent

FIELD: chemistry.

SUBSTANCE: invention refers to N, S-substituted isothiourea derivatives of the general formula (1) in the form of salts with pharmacologically acceptable acids as a NOS-inhibitory and vasopressor agent wherein: n=1, 3, i.e. an acyl substitute represents cyclobutanoyl or cyclohexanoyl; R represents an alkyl group: C2H5, i-C3H7; HX represents a pharmacologically acceptable inorganic or organic acid: HCl, HBr, HI, hydrogen methyl sulphate, oxalic, succinic acids, etc.

EFFECT: extending the range of products of the vasopressor action.

6 cl, 7 tbl, 10 ex

 

The invention relates to the field meet vital human needs, namely to medicines, which can find application in pharmaceutical industry and medicine.

Development of new effective tools and methods for the treatment of hypotension (States with low blood pressure) remains an ongoing challenge. For example, in North America only in septic shock annually develops in 700 thousand people that, despite the high level of medicine on the continent, is fatal 30-50% of these patients (Ward, R. A., M. Bosmann A historical perspective on sepsis // Am. J. Pathol. 2012. v.181, n. 1. p.2-7). The complexity of treatment for these conditions are associated not only with their weight, but with the disadvantages of existing medicines.

In the treatment of hypotension are important drugs that affect blood pressure by increasing vascular tone - Pressor means. As these drugs are currently used α1-adrenergic agonists (norepinephrine, dopamine, epinephrine, phenylephrine, midodrine, etc.) and peptide vasoconstrictors (vasopressin, terlipressin, angiotensin, Octopussy, etc.) (Mashkovsky M. D. Medicines: in 2 vol, 14th ed. / M.: New Wave, 2002; L. Brunton, Chabner V., Knollman B. Goodman & Gilman''s The Pharmacological Basis of Therapeutics / 12th ed. NY: McGraw Hill Professional, 2010, pp 1808).

Common disadvantages of these p�of aparatow is a short duration of action and the presence of many of them, especially agonists, side effects. So, in the application of agonists, along with increased vascular tone, the possible development of arrhythmias and metabolic acidosis, Central nervous system excitation, and in the case of peptide vasopressors - deepening of myocardial ischemia (Delmas A., Leone M, Rousseau S. et al. Clinical review: Vasopressin and terlipressin in septic shock patients // Crit. Care. 2005. v.9, N. 2. p.212-22; E. C. Boerma, Ince C. The role of vasoactive agents in the resuscitation of microvascular perfusion and tissue oxygenation in critically ill patients // Intensive Care Med. 2010. v.36, N 12. p.2004-18; Ferquson-Myrthil N. Vasopressor use in adult patients // Cardiol. Rev. 2012. v.20, N. 3. p.153-58).

The pharmacological properties of the prototype is the drug phenylephrine (phenylephrine) is a hydrochloride of 1-(m-oxyphenyl)-2-methylaminoethanol (Mashkovsky M. D. Medicines: in 2 vol, 14th ed. M.: New Wave, 2002, Vol. 1. Pp. 233-234). It causes constriction of arterioles and increases blood pressure, selectively acting on the α1adrenergic receptors.

The disadvantage mezatona, like other vasopressors, is small (no more than 20 minutes) duration of action, which reduces its therapeutic efficacy and significantly limits the possibility of its application, for example, the provision of emergency, urgent care in the prehospital phase and in the treatment of severe shock conditions (Avakian O. M. Pharmacological regulation of the function of adrenergic receptors. / M.: Medicine, 1988. 256 p.; V. E. Volkov, Volkov S. V. Shock. Sepsi�. Multiple organ dysfunction. / Cheboksary: SP L. A. Naumov, 2009. 348 p.).

The technical result of the invention is to create a new vasopressor funds has significantly greater length antihypotensives operation, in comparison with the existing prototype, which allows to expand possibilities of therapy hypotonic conditions, especially in the provision of emergency medical care and treatment of critical conditions.

In recent decades, it has been shown that the tone of blood vessels depends on the activity of the synthesis of nitric oxide (NO) in vascular endothelium (Dudzinski D., Michel, T. Life history of eNOS: Partners and pathway // Cardiovasc. Res. 2007. v.75, N. 2. p.247-60; K. Bian, M. F. Doursout, Murad F. Vascular system: role of nitric oxide in cardiovascular diseases // J. Clin. Hypertens. (Greenwich). 2008. v.10, N. 4, p.304-10). In this regard, vasopressor action can be expected from chemical compounds with specific biochemical properties, namely the ability to inhibit the catalytic activity of NO-synthase (NOS) enzymes which synthesize nitric oxide.

Earlier, the authors of the present invention it is shown that some linear and cyclic N,S-disubstituted isothiourea capable of inhibiting NOS and show vasopressor effect in various hypotonic conditions (Proskuryakov, S. Y., Kucherenko N. G., Filimonova, M. V. et al. NO-inhibiting and vasotropic Akti�of some compounds, containing diamidino group. // Bull. experi. Biol. honey. 2002. T. 134, No..10. S. 393-96; Proskuryakov, S. Y., M. V. Filimonova, Verkhovsky, Y. G. et al. The effect of the inhibitor oxide synthase, 2-ADT on endotoxin-induced changes in hemodynamics and respiration of rats // bull. experi. Biol. honey. 2004. T. 138, No..10. S. 446-49; Filimonova, M. V.; Shevchenko, L. I., Surikova V. I. et al. The effect of N-propionyl-S-isopropyl-isothiourea for the products of biogenic nitric oxide (NO)and hemodynamic parameters of the animals at endotoksicski shock // Vopr. Biol. honey. and Pharm. chemistry. 2011. No..9. S. 35-9; Filimonova, M. V., Trofimova T. P., Borisova G. S. et al. Antihypotensive activity of N-2-acetylamino-5,6-dihydro-4H-1,3-thiazine. // Chem.-Pharm. log. 2012. Vol. 46, No..3. P. 39-41). The experience we have acquired synthesis (Filimonova, M. V.; Shevchenko, L. I., Makarchuk V. M., Shevchuk, A. S., G. A. Lushnikov Vasoconstrictor agent. The patent for the invention № 2475479. 2013) identified a group of compounds having a more favorable pharmacological properties than phenylephrine available and vasopressor drugs.

The invention consists in the synthesis of new N,S-substituted derivatives of estimacion of the General formula (1) in the form of salts with pharmacologically acceptable acids and their use as inhibitors of NOS and vasopressor funds.

The term "pharmacologically acceptable acid" encompasses all �farmacologicas acceptable acid, as inorganic (e.g., hydrochloric, Hydrobromic, phosphoric, sulfuric, etc.) and organic (e.g., oxalic, succinic, tartaric, metallinou, salicylic, etc.).

Synthesized it exhibits a pronounced and long-lasting Pressor effect due to inhibition of the catalytic activity of NOS.

List of figures.

Fig.1. Structural formula 1.

in which: n=1, 3, i.e. acyl Deputy has a cyclic saturated hydrocarbon group with 4 or 6 ring carbon atoms, and represents cyclobutanol and cyclohexanol;

R represents an alkyl group: C2H5i-C3H7;

HX is a pharmaceutically acceptable acid: HCl, HBr, HI, metallinou, oxalic, tartaric, succinic, etc., as above.

Fig.2. The influence mezatona at a dose of 0.5 mg/kg on the dynamics of systolic (ADF) and diastolic (Add) blood pressure of animals in a state of severe hemorrhagic shock: 1 - BP readingsWithcontrol animals (not treated with "treatment"), 2 - BP readingsDcontrol animals, a 3 BP readingsWithanimals treated with phenylephrine, a 4 BP readingsDanimals who received phenylephrine.

Fig.3. The joint effect of T-1020 at a dose of 10 mg/kg on the dynamics of arterial pressure�Oia animals in a state of severe hemorrhagic shock: 1 - BP readingsWithcontrol animals, 2 - BP readingsDcontrol animals, 5 - BP readingsWithanimals treated with T-1020, 6 - BP readingsDanimals treated with T-1020.

Fig.4. The joint effect of T-1049 dose of 10 mg/kg, on arterial blood pressure dynamics of animals in a state of severe hemorrhagic shock: 1 - BP readingsWithcontrol animals, 2 - BP readingsDcontrol animals, 7 - BP readingsWithanimals treated with T-1049, 8 - BP readingsDanimals treated with T-1049.

Fig.5. The joint effect of T-1059 in the dose of 10 mg/kg, on arterial blood pressure dynamics of animals in a state of severe hemorrhagic shock: 1 - BP readingsWithcontrol animals, 2 - BP readingsDcontrol animals, a 9 - BP readingsWithanimals treated with T-1059, 10 - BP readingsDanimals treated with T-1059.

Synthesis of salts of N,S-substituted estimacion formulas (1)

Compounds of the formula (1) according to the invention is obtained using methods known in the field of science and technology to obtain similar substances. The basis for obtaining compounds of formula (1) is the reaction, namely that of thiourea of formula (TM), in which n=1, 3,

subjected to reaction with an equivalent amount or an excess (200%) resp�relevant alkylating agent of the formula R-X (in which R represents an alkyl group, C 2H5or i-C3H7; and X represents a leaving group such as halide, sulfate, alkylsulfonate, arylsulfonate, triflic, alkylsulfate, alkylphosphate, dialkylphosphate, acetate) in a polar inert solvent (such as dimethylformamide, dimethylsulfoxide, sulfolane, acetone, acetonitrile) at a temperature from ambient to the boiling point of the reaction mixture.

Intermediate thiourea of formula (TM) (1-cyclobutanemethanamine and 1-cyclohexanediamine) are obtained by acylation of thiourea with equimolar amounts of the corresponding carbonylchloride in a solution of toluene.

The structures of compounds and their purity confirmed by the data of the chemical, elemental and spectral analysis. Control of the reaction course and purity of the obtained compounds is carried out using thin-layer chromatography on plates Silufol UV-254 in the system ammonia-chloroform-isopropanol. The PMR spectra obtained on a Bruker DRX-500 at 500 MHz. Examples of synthesis of compounds of formula (1)

Example 1. Synthesis of 1-cyclobutanol-2-isopropylethylene hydrobromide (hereinafter T-1049).

A mixture of 2.0 g (12.6 mmol) of 1-cyclobutanemethanamine, 3.0 g of 25.2 mmol) Isopropylamine and 8.0 ml of dry acetonitrile in a sealed tube was heated in a boiling water bath for 30 hours. The solvent was evaporated, the residue was filtered and feathers�crystallizable from 4-methyl-2-pentanone. Yield 1.0 g (39%). TPL118-120°C.

Range PMR (DMSO-d6, δ): 1,3 (t, 6H); 1,95 (C, 2H); 2,2 (m, 4H); and 3.8 (s, 1H); 4,1 (C, 1H); 10,9 (W, 3H).

Calculated, %: C 38,43; H 6,09; N 9,96.

Found, %: C 38,52; H 6,27; N 10,14.

Example 2. Synthesis of 1-cyclobutanol-2-utilizationin hydrobromide (hereinafter T-1020).

A mixture of 2.0 g (12.6 mmol) of 1-cyclobutanemethanamine, 2.8 g (26 mmol) of ethylbromide and 7 ml of dry acetonitrile in a sealed tube was heated in a boiling water bath for 15 hours. The solvent was evaporated, the residue was filtered and twice recrystallized from 4-methyl-2-pentanone. Yield 2.5 g (73.5 per cent). TPL120-123°C.

Range PMR (DMSO-d6, δ): 1,3 (t, 3H); 1,95 (C, 2H); or 3.28 (2H); 3,38(m, 1H); 11,0 (W, 3H).

Calculated, %: C Of 35.96; H For 5.66; N 10,48.

Found, %: C 36,19; H 5.78% Was Established; N 10,48.

Example 3. Synthesis of 1-cyclohexanol-2-utilizationin hydrobromide (hereinafter T-1059).

A mixture of 3.7 g (20 mmol) 1-cyclohexanediamine, 4.4 g (40 mmol) of ethylbromide and 10 ml dry acetonitrile was heated in a boiling water bath in a sealed tube for 20 hours. The precipitate was filtered and twice precrystallization from 4-methyl-2-pentanone. Yield 2.8 g (48.5 per cent). TPL123-125°C.

Range PMR (DMSO-d6, δ): 1,3 (m, 9H); 1,62-of 1.84 (m, 5H); 3,65 (m, 1H); to 10.8 (W, 3H).

Calculated, %: C 40,68; H Of 6.49; N Of 9.5. C10H19BrN2OS.

Found, %: C 40,6; H 6,56; N 9,44.

Example 4. Synthesis of 1-cyclohexanol-2-isopropylethylene hydrobromide (hereinafter T-1064).

Mixture� 3.7 g (20 mmol) 1-cyclohexanediamine, 4.8 g (40 mmol) of Isopropylamine and 10 ml dry acetonitrile was heated in a boiling water bath in a sealed tube for 70 hours. The precipitate was filtered, washed with a large volume of ether and precrystallization from 4-methyl-2-pentanone. Yield 2.0 g (36%). TPL163-165°C.

Range PMR (DMSO-d6, δ): 1,3 (m, 11H); 1,63-of 1.84 (m, 5H); 4,1 (C, 1H); 10,9 (W, 3H).

Calculated, %: C 42,71; H 6,84; N A 9.05. C11H21BrN2OS.

Found, %: C 42,77; H 7,0; N 9,06.

Another aspect of the invention is the compounds of formula (1) ability to inhibit the catalytic activity of NO-synthase (NOS) enzymes, synthesizing in biological tissues nitric oxide, which is confirmed by the results of biological research.

Example 5. Assessment of NOS-inhibitory activity of the compounds of formula (1) presented in examples 1, 2, 3 and 4, conducted in-vitro experiments on isolated isoforms of NOS radiometric method for the rate of accumulation of [3H]-L-citrulline (van Eijk N. M. Y. C. Luiking, Deutz N. E. Method using stable isotopes to measure nitric oxide synthesis in the L-arginine/NO pathway in health and disease // J. Chromatogr. In Analyt. Technol. Biomed. Life Sci. 2007. v.851, N. 1-2. p.172-85). Using recombinant isoforms of NOS (Alexis Biochemicals) and a set of reagents NOSdetect Assay Kit (Alexis Biochemicals). The measurements were carried out on the radiometric complex Wollac-1414 (Vinspectral).

The results show that all of the claimed compounds exhibit SP�the capacity to NOS inhibition. Moreover, as shown in table 1, the compounds possess significant selectivity (selectivity) of the action to the inducible (iNOS) and endothelial (eNOS) isoforms, inhibiting their 8 to 20 times more active than the neuronal isoform (nNOS).

The selectivity of the compounds of formula (1) is essential to achieve the technical result of the invention because it provides the claimed compounds high vasopressor activity and minimal risks of side effects (caused by the suppression of nNOS), such as increased excitability of the myocardium, hypertonicity of skeletal muscle, disorders of the Central nervous system (K. Bian et al. Vascular system: role of nitric oxide in cardiovascular diseases // J. Clin. Hypertens. (Greenwich). 2008. v.10, N. 4. p.304-10; W. K. Alderton et al. Nitric oxide synthases: structure, function and inhibition // Biochem. J. 2001. v.357, Pt.3. p.593-615).

Table 1
The concentration of the compounds of formula (1), inhibiting by 50% the activity of different isoforms of NOS
ConnectionnNOSiNOSeNOS
µmolmg/lµmolmg/l µmolmg/l
T-1020328,52,70,73,81,0
T-10493810,72,50,73,10,9
The t-10593710,91,80,52,30,7
T-10644112,74,71,56,52,0

A necessary condition for achieving the technical result of the invention is the determination of the toxic properties of the compounds of formula (1).

Example 6. The toxicity of compound (1) was studied in outbred white rats-males weighing 21-23 g on a standard test of acute toxicity after a single dose. The substance was dissolved in saline and injected intraperitoneally. SRO� observation of experimental animals was 14 days. Assessment of toxicity was performed according to the method of Litchfield-Wilkinson (Litchfild J. T., Wilcoxon F. A. Asimplified method of evaluating dose effect experiments // J. Pharm. Exp. Ther. 1947. v.95. p.99-113). The results showed that LD50compounds of formula (1) is 400-700 mg/kg (Tab.2).

Table 2
Rates of acute toxicity of the compounds of formula (1).
Chemical compoundLD50(LD16÷LD84), mg/kg
T-1020542 (136÷1150)
T-1049708 (528÷868)
The t-1059380 (246÷475)
T-1064650 (324÷962)

In accordance with the classification of the toxicity of chemical compounds of the General formula (1) classes are moderately toxic and low-toxic. Moreover, the toxicity of the claimed compounds is significantly lower than that of the agonists used in the treatment of hypotonic conditions (for example, with this method of introduction of LD50mezatona 191 mg/kg). Moreover, a comparison of the range of toxic and NOS-inhibiting doses (performance�introduced in Table.1) suggests that what a test substance capable of providing high inhibition activity of eNOS and iNOS necessary for the development of the vasopressor effect, already at doses 50 to 100 times below the minimum lethal dose (LD16).

To explore vasopressor properties of the claimed compounds used in the experimental model of hemorrhagic shock caused by acute massive blood loss (47-50% of circulating blood volume within 5-8 minutes), similar in its flow with severe clinical forms of hypotension.

Studies conducted on male Wistar rats weighing 300-400 g. Before surgery, the animal was anesthetized by thiopental sodium (60 mg/kg/b). It was further established tracheostomy, catheterizable jugular veins and both carotid arteries were plugged invasive blood pressure sensor, ECG electrodes. I injected heparin 100 units After stabilization of the animal with the help of a polygraph (RM-6000 (Nihon Kohden) was recorded baseline heart rate (HR), respiratory movements (NPV), systolic and diastolic blood pressure (BPWithADD) in the left carotid artery. To create severe hemorrhagic shock in the right carotid artery was performed blood sampling in the amount of 2.5 ml per 100 g weight of the animal. After repeated blood loss Ryougi�centration of indicators of external respiration and Central hemodynamics. Then the animals of experimental groups were injected intraperitoneally one of the compounds in solution at the rate of 0.1 ml per 100 g body weight. Monitoring physiological indicators continued during the following 120 minutes.

Used in this model of acute blood loss leads to the development of severe shock (Table.3) and in the absence of treatment is accompanied by loss of many experimental animals within the first two hours (Sarkisov D. S., P. Remezov I. Reproduction of human diseases in the experiment / edited by A. A. Vishnevsky, M.: 1960. 780 S.).

As shown in Table.3, the end of blood loss in the experimental animals was observed very pronounced decline in blood pressure: BPWithreduced more than 3 times (186,3±3,5 to 56.7±6,9), ADD- almost 5 times (from 132,9±2.3 to 28,1±9,0). For the first 60-70 minutes of the severity of hypotension partially decreased due to the compensatory increase in vascular tone and heart rate. However, a substantial compensation of the deficit of blood flow did not occur, and profound hypotension in further violation of the pumping function of the heart that caused the deaths of many experimental animals. Of the 11 control animals 5 animals (45%) were lost to the 120 minute observation.

Table 3
The hemodynamic and respiratory anesthetized animals after severe acute blood loss (control group; n=11)
Time after blood lossAPWith, mm Hg. articleAPD, mm Hg. articleHeart rate, beats minNPV, et/min
Source186,3±3,5132,9±2,3413,1±10,462,4±4,9
Blood loss56,7±6,928,1±9,0348,1±10,074,1±8,2
2 minutes59,7±6,927,9±9,0
5 minutes65,2±6,927,0±6,7355,3±12,273,8±8,4
10 minutes67,4±4,931,1±5,0Of 359.5±12,973,4±8,7
20 minutes76,4±8,042,9±8,3 358,7±13,368,6±7,7
30 minutes88,4±10,053,5±9,4372,2±17,168,5±7,8
40 minutes96,8±10,157,7±9,6383,2±14,362,4±6,7
50 minutesOf 101.3±8,458,5±7,6387,9±11,967,4±7,7
60 minutesTo 108.3±6,962,9±6,3402,7±11,567,7±7,8
70 minutes113,0±5,565,5±5,1416,3±8,469,3±7,3
80 minutes116,7±5,567,5±5,0429,3±8,969,4±5,2
90 minutes117,1±4,767,3±4,1434,2±9,470,8±6,3
100 minutesTo 118.0±5,9439,4±9,768,3±7,4
110 minutes118,9±6,568,5±6,3440,3±8,868,5±6,9
120 minutesOf 119.8±7,968,8±7,7439,1±8,568,9±6,7

Example 7. To obtain an objective evaluation of vasopressor properties of the claimed compounds on the model of hemorrhagic shock was investigated therapeutic potential of the drug-prototype - α1-adrenomimetic phenylephrine. Experienced animal phenylephrine was administered intraperitoneally at high dose (0.5 mg/kg) immediately after blood loss.

The results showed (Table.4, Fig.2) that the introduction of mezatona animals in a state of severe hemorrhagic shock was accompanied by a rapid increase in blood pressure. 5 minutes after injection BP readingsWithand HELLDin the experimental animals were significantly higher than in controls. The maximum effect was developed by the 10 minute, the degree of increase in blood pressureWithwas 25-40%, BPD- 65-75% relative indices of control animals. However, significant influence mezatona were observed during the short�of the second period - from 5 to 20 min after injection. With 30 minutes to end of the observation period all controlled parameters in experimental and control animals were statistically indistinguishable. Thus, when used method of administration mezatona the duration of vasopressor action is about 20 minutes. Short and relatively weak improvement of hemodynamic parameters under the influence mezatona in this experiment is essentially not affected during the shock - mortality in this group was 50% within 120 minutes of observation.

Table 4
The hemodynamic and respiratory anesthetized animals after severe acute blood loss when exposed mezatona at a dose of 0.5 mg/kg (n=8)
Time after blood loss/ injectionsAPWith, mm Hg. articleAPD, mm Hg. articleHeart rate, beats/minNPV, et/min
Source181,9±3,8128,2±5,9434,1±11,5To 66.3±5,7
Blood loss/ Injection55,9±4,0 26,4±3,7364,4±12,970,3±8,5
2 minutes70,5±4,237,5±5,1
5 minutes80,5±4,5*43,7±5,4*Of 362.6±10,072,2±8,1
10 minutes96,0±6,8*58,7±7,9*Of 369.5±9,770,5±8,9
20 minutes107,9±11,1*67,3±10,6*365,8±5,169,6±7,9
30 minutes112,0±11,971,6±13,1372,1±9,869,3±6,8
40 minutesTo 114.1±13,671,3±14,3378,7±7,466,1±6,3
50 minutes115,3±13,270,6±14,4387,9±8,269,2±7,6
60 minutesA total of 115.4±14,667,9±14,6Of 381.1±9,569,7±7,0
70 minutesTo 122.2±5,473,7±6,5391,0±15,768,8±7,9
80 minutes130,3±12,380,7±13,8395,9±18,067,9±7,2
90 minutesOf 123.2±12,173,2±11,9380,3±24,568,3±6,7
100 minutes122,1±12,573,7±10,5397,3±27,169,2±7,3
110 minutesTo 124.7±11,875,5±11,7Is 399.6±24,568,5±6,9
120 minutes125,2±12,276,3±12,3408,2±20,368,7±6,6
* - statistically significant difference (p<0,05) with the control group (Tab.3) non-parametric Q-�riteria Dunn's multiple comparisons.

Example 8. A different pattern of flow shock was observed when using compounds of formula (1). The introduction of experimental animals in a state of severe hemorrhagic shock connection T-1020 at a dose of 10 mg/kg (less than 14 times LD16and 50 times less than the LD50) caused a rapid increase in blood pressure (Table.5, Fig.3).

From table 5 it is seen that already at 2 minutes after injection BP readingsWithand HELLDin the experimental animals were significantly higher than in controls. Fully vasopressor effect T-1020 was developed approximately 20 minutes, the degree of pressure rise was significantly higher than under the action mezatona - ADWithincreased to 100-120% and BPD- at 200-220% relative to the control animals. Duration antihypotensive activity of a compound T-1020 also 5-6 times the duration of mezatona. The effect began to wane with only 100 minutes, and a statistically significant effect of T-1020 blood pressure was maintained until the 110th minute of the experiment. Long and powerful increase in blood pressure under the action of T-1020 stabilized hemodynamics and qualitatively changed over the shock throughout 120 minutes of observation. None of the 8 experimental animals that received T-1020, despite the severe blood loss, not killed.

Table 5.
The hemodynamic and respiratory anesthetized animals after severe acute blood loss when exposed connections T-1020 at a dose of 10 mg/kg (n=8)
Time after blood loss/ injectionsAPWith, mm Hg. articleAPD, mm Hg. articleHeart rate, beats/minNPV, et/min
Source184,5±2,8130,3±1,9429,8±9,1To 66.3±5,7
Blood loss/Injection55,1±1,326,1±1,8348,1±9,970,3±8,5
2 minutes79,1±5,0*53,5±5,7*
5 minutes92,1±8,2*68,2±8,3* m371,9±10,172,2±8,1
10 minutes118,9±7,5*94,7±6,8* m397,5±10,7* 70,5±8,9
20 minutes175,5±15,3* m134,0±7,8* m404,4±12,8*69,6±7,9
30 minutes177,9±7,3* m140,0±4,6* m407,9±10,769,3±6,8
40 minutes181,5±7,6* mOf 143.5±3,9* m410,9±14,466,1±6,3
50 minutes168,7±7,6* m134,7±4,5* m414,8±13,969,2±7,6
60 minutes166,4±5,9* m134,0±4,2* m417,9±16,269,7±7,0
70 minutes171,9±7,5* m135,5±4,2* m433,8±18,068,8±7,9
80 minutes155,6±5,5* m125,5±4,7* m 422,6±18,167,9±7,2
90 minutesRate of 162.4±6,6*To 131.4±5,1* m448,0±20,968,3±6,7
100 minutes157,8±7,4* mOf 124.5±4,5* m419,4±16,369,2±7,3
110 minutes146,3±10,0*114,8±8,4* m439,2±19,568,5±6,9
120 minutes138,1±10,5106,3±10,0* m449,9±15,868,7±6,6
* - statistically significant difference (p<0,05) with the control group (Tab.3) non-parametric Q-test Dunn's multiple comparisons;
m- statistically significant difference (p<0.05) in the group treated with phenylephrine (Table.4), non-parametric Q-test Dunn's multiple comparisons.

Example 9. The introduction of experimental animals in a state of severe hemorrhagic shock connection T-1049 in the dose of 10 mg/kg (50 times LD 16and 70 times less than the LD50) also caused a rapid increase in blood pressure (Table.6, Fig.4).

The dynamics of the effect was similar to the action of a compound T-1020: 10 minute ADWithincreased by 100% and BPDby 220% relative to the control. The duration of vasopressor activity of a compound T-1049 more than 5 times the duration of mezatona. The effect began to wane with only 110 minutes, however, a significant influence on blood pressure of experimental animals was maintained until the end of the experiment. And the long-term stabilization of pressure under the influence of T-1049 prevented the development of compensatory tachycardia, pronounced the control animals in the late stages of observation. Like T-1020, the connection of the T-1049 in these experiments was provided by 100% anti-shock protection - within 120 minutes of observation none of the experimental animal that received T-1049, died.

Table 6
The hemodynamic and respiratory anesthetized animals after severe acute blood loss when exposed connections T-1049 in the dose of 10 mg/kg (n=4)
Time after blood loss/ injectionsAPWith, mm Hg. article APD, mm Hg. articleHeart rate, beats/minNPV, et/min
Source185,5±3,7To 126.3±4,3414,3±8,672,3±5,8
Blood loss/ Injection52,8±3,531,3±4,8366,0±32,560,5±5,9
2 minutes77,3±7,353,5±8,1*
5 minutes101,5±14,1*78,8±14,8* m394,0±33,067,5±6,9
10 minutes134,0±21,6*To 108.5±20,2* m406,0±37,663,1±5,5
20 minutes133,5±20,6*To 108.5±18,3* m389,0±27,365,3±7,1
30 minutesTo 150.3±16,8* m122,5±12,5* m 401,3±21,579,5±7,0
40 minutes163,3±5,8* mHR 132.5±4,5* m391,3±13,777,3±7,9
50 minutes160,0±5,9* m129,0±5,4* m381,5±8,568,4±5,9
60 minutes163,8±7,6* mHR 132.5±5,0* mRUR 403.0±14,371,5±6,1
70 minutes157,8±7,6* m127,0±7,5* m401,3±15,678,8±9,2
80 minutes158,3±9,3* mTo 126.8±7,3* m391,5±19,375,0±9,3
90 minutes146,3±14,1* m120,8±13,2* m395,3±14,5*78,0±10,4
100 minutes147,3±4,9* m119,3±2,9* m Hanging Assembly are h 386.0±13,5*75,8±10,5
110 minutes151,5±5,0* m121,8±2,9* m382,5±6,6*74,1±10,5
120 minutes140,8±8,0*111,0±6,9* m373,8±2,4*74,3±9,6
* - statistically significant difference (p<0,05) with the control group (Tab.3) non-parametric Q-test Dunn's multiple comparisons;
m- statistically significant difference (p<0.05) in the group treated with phenylephrine (Table.4), non-parametric Q-test Dunn's multiple comparisons.

Example 10. Among the compounds of formula (1) is the most potent vasopressor action demonstrated derived T-1059. The introduction of experimental animals in a state of severe hemorrhagic shock connection T-1059 in the dose of 10 mg/kg (25 times less than the LD16and 38 times less than the LD50) also caused a sharp rise in blood pressure (Table.7, Fig.5).

The initial dynamics of the vasopressor action of T-1059 was similar to the action of the T-1049, but the degree of pressure rise was significantly you�e - to 20 minute ADWithincreased by 140% and BPD- 250% relative to the control. The duration of the connection T-1059 also more than 5 times the duration of mezatona - significant vasopressor effect was observed with 2 minutes from injection to the end of the observation period. As shown in Fig.4, the result is a powerful Pressor action of T-1059 BP readings of animals that have lost 50% of circulating blood that rose to the level of HELL healthy animals and was maintained at this level until the end of the experiment. Prolonged stabilization of hemodynamic parameters under the influence of T-1059 also provided 100% anti-shock protection - within 120 minutes of observation not lost any experimental animal.

Table 7
The hemodynamic and respiratory anesthetized animals after severe acute blood loss when exposed connections T-1059 in the dose of 10 mg/kg (n=6)
Time after blood loss/ injectionsAPWith, MRT. articleAPD, mm Hg. articleHeart rate, beats/minNPV, et/min
Source19,2±3,6 Of 124.8±3,1409,0±8,263,3±4,5
Blood loss/Injection44,5±3,518,3±2,8348,7±11,263,3±5,5
2 minutes63,5±5,037,0±4,6*
5 minutes86,7±7,2*59,0±8,7*367,3±17,0To 66.3±5,6
10 minutes141,2±12,8* mTo 107.8±9,4* m389,3±16,058,0±4,1
20 minutes181,5±9,3* m136,7±5,9* m416,6±16,3*63,0±8,9
30 minutes166,8±11,8* m127,5±7,5* m404,3±16,759,7±5,9
40 minutesTo 157.5±20,9* m113,5±15,9 * m384,5±15,058,7±5,3
50 minutes160,2±19,6* m117,3±12,4* m377,8±17,358,0±5,2
60 minutes174,5±17,4* mOf 128.8±10,0* m389,0±19,262,7±6,2
70 minutesTo 187.5±6,4* m141,8±4,8* m409.8 mln±16,558,7±5,9
80 minutes189,7±12,2* mTo 137.5±7,6* m396,7±14,3*59,0±5,8
90 minutesOf 188.3±11,9* m138,8±5,3* m399,5±15,1*63,7±5,5
100 minutes169,8±18,9* mOf 124.8±16,0* m396,7±16,6*65,7±6,5
110 minutesFor 180.2±10,1* m To € 132.2±8,9* m399,2±16,1*62,7±5,1
120 minutes173,7±6,2* m130,3±6,1* m397,0±17,8*63,0±6,4
* - statistically significant difference (p<0,05) with the control group (Tab.3) non-parametric Q-test Dunn's multiple comparisons;
m- statistically significant difference (p<0.05) in the group treated with phenylephrine (Table.4), non-parametric Q-test Dunn's multiple comparisons.

Examples 7-10 demonstrate not just a significant advantage, and qualitative superiority of the claimed compounds over adrenomimetic drug on the prototype, because it proves the ability of the compounds of formula (1) to provide effective assistance when in a state of shock (traumatic, hemorrhagic) in the prehospital phase, which is impossible by mezatona and other vasopressor means used currently.

The evidence of achieving the stated results

As a result of studies on novel isothiourea derivative first synthesized and characterized compounds of the General fo�formula (1), having the ability to selective inhibition of catalytic activity of eNOS and iNOS - those NOS isoforms, the activity of which leads to the development of hypotension. Thanks to this capability, the inventive compounds have strong vasopressor properties with minimal risk of adverse effects. Compounds of formula (1) are moderately toxic, and their toxicity is 2 times lower than that of the widely used vasopressor adrenomimetic action of the drug phenylephrine.

The study vasopressor properties of the compounds of formula (1) held at reproducing the severe clinical form of hypotension experimental models of shock in acute, massive blood loss. The results show that a single administration to animals in a state of severe shock (BP level 55/25) compounds of formula (1) in the notoriously non-toxic dose of 10 mg/kg (1/50-1/14 LD16) accompanied by a powerful and long-lasting Pressor effect. The effect is from the first minutes after injection, with no visible changes in the condition of the animals. After 10-20 minutes BPWithincrease by 100-140% and BPD- 200-250% of the level of control animals not receiving "treatment", and meet 90-100% of indicators to bleeding. Stabilization of blood pressure under the influence of the compounds of formula (1) very long - Pressor effect with�unity T-1020 T-1049 starts to wane only 100-110 minutes after injection and the connection T-1059 continued unabated and after 120 minutes. Stable improvement of hemodynamics qualitatively alters shock-within 120 minutes of observation none of the animals that received the claimed compound, despite heavy blood loss (1/2 of the volume of circulating blood), not killed, while in the control of mortality by that time reaches 45%.

In these studies, the compounds of formula (1) showed a significant superiority over mezatona. Although this drug is one of the most long-acting α1-agonists, a single injection of mezatona in the high dose (0.5 mg/kg) causes a Pressor effect in animals, no more than 20 minutes, and the degree of rise in blood pressure in 1,5-2 times weaker than the action of the claimed compounds. Short and relatively mild improvement in hemodynamics in action mezatona, essentially, does not affect the course of shock - to 120-minute observation of mortality in this group of animals reached 50%.

It is known that the most effective way of treatment of hemorrhagic shock is extra compensation for the lost volume of blood or blood substitutes. However, these activities are not always available, especially outside of clinical conditions. It should therefore be emphasized that the prolonged and powerful "anti-shock" protection provided in the data ISS�egomaniac single injections of the claimed compounds, demonstrates their quality advantage - the ability to provide effective assistance when in a state of shock (at least in traumatic and hemorrhagic) in the prehospital phase, which is impossible vasopressor means used currently. This creates new possibilities in the treatment of acute and possibly chronic arterial hypotensions, as well as in cases of emergency and ambulance services, and in therapy of critical conditions.

In this regard, the authors have reason to offer as another aspect of this invention a new vasopressor agent, containing as active substance a compound of the formula (1). New vasopressor means it is advisable to keep in several dosage forms, convenient to be used in different cases: in the form of a solid dosage form with a dose of active substance 5 to 30 mg, in the form of an injectable solution containing 1-10% of active substance, in the form of an infusion solution containing 0.01-0.1% active ingredient. A new tool can be used for the treatment of hypotonic States alone at a dose that provides the dose of active ingredient of 0.1-20 mg/kg or as part of a pharmaceutical composition providing a dosage of active ingredient of 0.1-20 mg/kg. the New tool can be used to comfort�of blood pressure in acute arterial hypotension, caused by injuries, wounds, burns, poisoning, bleeding, surgical intervention. Moreover, the ability of the compounds of formula (1) to implement the vasopressor action, bypassing the α1-adrenoretseptory, allows us to expect that the proposed means of therapeutic efficiency in hypotonia, developed on the background of epidural anesthesia, overdose of ganglionic, α-blockers, antipsychotics, anesthetics, when the refractory stage of shock and other conditions when the agonists are ineffective or are contraindicated.

The inventive tool can be used in the form of a solid or liquid dosage form containing as active substance a compound of the formula (1) used alone or in pharmaceutical compositions for the treatment of hypotonic States. Such a vasopressor agent creates new possibilities in the treatment of acute and possibly chronic arterial hypotensions, as well as in cases of emergency and ambulance services, and in the treatment of critical conditions.

New vasopressor tool can be used to increase blood pressure in acute arterial hypotension caused by injuries, wounds, burns, poisoning, bleeding, surgical intervention. A full range of pharmacological challenge�th proposed vasopressor funds of course, can only be appreciated with further detailed studies. However, the ability of the compounds of formula (1) to implement the vasopressor action, bypassing the α1-adrenoretseptory, allows us to expect that the proposed means of therapeutic efficiency in hypotonia, developed on the background of epidural anesthesia, overdose of ganglionic, α-blockers, antipsychotics, anesthetics, when the refractory stage of shock and other conditions when the agonists are ineffective or are contraindicated.

1. N, S-substituted isothiourea derivatives of the General formula (1) in the form of salts with pharmacologically acceptable acids as NOS-inhibitory and vasopressor means:

in which:
n=1, 3, i.e. acyl Deputy is cyclobutanol or cyclohexanol;
R - represents an alkyl group: C2N5i-C3N7;
HX is a pharmaceutically acceptable inorganic or organic acid: HCl, HBr, HI, metallinou, oxalic, succinic, etc.

2. The compound of formula (1) according to claim 1, characterized in that it has the ability to inhibit the catalytic activity of NO-synthase.

3. The compound of formula (1) according to claim 1, characterized in that it has a vasopressor effect, manifested Bui�m in vascular tone and elevation of blood pressure in hypotonic conditions.

4. The compound of formula (1) according to claims. 1 and 3 to obtain pharmaceutical compositions in the form of solid dosage forms at the dose of active substance 5-30 mg for the treatment of hypotonic States.

5. The compound of formula (1) according to claims. 1 and 3 for obtaining the pharmaceutical composition in the form of an injectable solution containing 1-10% of active ingredient, for treatment of emergency conditions.

6. The compound of formula (1) according to claims. 1 and 3 for obtaining the pharmaceutical composition in the form of an infusion solution containing 0.01-0.1% active ingredient, for treatment of emergency conditions.



 

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