2-(1-(2-(2-chloro-10h-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1h-1,2,4-triazol-3-yl)phenol, having hypotensive and antiarrhythmic activity

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

 

The invention relates to new derivatives in the series fenotiazina, namely 2-(1-(2-(2-chloro-10H-phenothiazines-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3-yl)phenol of the formula I:

having an antihypertensive and antiarrhythmic actions of intraperitoneal injection of the substance.

Most drugs phenothiazine series have neuroleptics, antihistamines (promethazine), cholinergic (Dinesen), sedative, antiemetic (tietilperazin), antiarrhythmic (etmozin, ethacyzin) and koronarorasshiryayuschee action (nonahlazin) [1].

It is known that the phenothiazines exhibit high antioxidant, antiradical, neuroprotective and anti-tumor activity[2], [3].

The most similar structure to the compound I is the hydrochloride of 2-chloro-10-(3-diethylaminopropyl)-fenotiazina (hloratsizin) II [4], with koronarorasshiryayuschee action.

The technical result of the invention is a new connection in series fenotiazina exhibiting hypotensive and antiarrhythmic effect, more effective than the known anti-arrhythmic drug - atalina.

The technical result of the invention is achieved by connecting I - 2-(1-(2-(2-chloro-10H-phenothiazines-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3-yl)phenol, with g potenziani and antiarrhythmic action. Table 1 shows the effect of compound I and atalina on the level MLID, HR, + dP/dt, - dP/dt, dp/dt/PI, dp/dt/PD, KDD in awake normotensive rats in percentage to the baseline at a dose of 1 mg/kg, where p<0.05 compared with the original data (by the t - student test for independent rows), n is the number of animals in the experience. In table 2 and 3 shows the acute toxicity of I and tablets atalina 0.5 g, respectively (D - index difference between the number two adjacent doses, Z - score difference between the number of dead animals when using two consecutive doses).

The first stage of the synthesis of a substance I is in the interaction perchlorate 2-methyl-4-oxo-1,3-benzoxazine III with hydrazine hydrate by heating in acetic acid with the formation of the product IV. The reaction occurs by recyclization on ANRORC mechanism [5] with the initial attack by the amino group of the second position oxazinones cycle.

Further boiling triazole IV in acetone in the presence of potash 2-chloro-10-(chloroacetyl)-10H-phenothiazines V leads to substance I - the second stage:

The following is the procedure for the synthesis of the proposed connection.

Stage 1. 2-(3-Methyl-1H-1,2,4-triazole-5-yl)phenol IV. Obtained by heating perchlorate 2-methyl-4-oxo-1,3-benzoxazine with hydrazine hydrate in glacial acetic acid [5].

Stage 2. 2-{1-[2-(2-Chloro-10H-phenothiazines-10-yl)-2-oxoethyl]-5-methyl-1H-1,2,4-triazole-3-yl} phenol I. To a solution of 1.75 g (10 mmol) of triazole IV in 15 ml of acetone are added 5.52 g (40 mmol) of calcined potash, boiled for 15 min, cooled and added 3.1 g (10 mmol) of 2-chloro-10-(chloroacetyl)-10H-fenotiazina V. the Reaction mixture is boiled for 1.5 h, dilute with water. Released colorless precipitate is filtered off (3.59 g, 83%). So pl. 188-190°C.

Found, %: C 63,80; N 3,40; Cl 8,50; N 12,60; S 7,10.

C23H17ClN4OS.

Calculated, %: C 63,82; N 3,93; Cl 8,21; N 12,95; S 7,40.

IR-spectrum (vaseline oil), cm-1: 1710 (C=O); 1600 (C=C).

Range1H NMR (acetone-d6, J/Hz), δ ppm: 2.50 (3H, s, CH3); 5.45 (2H, DuserN-CH2, J=5.3); 6.81-7.96 (11N, m, arene. N); 10.95(1H, s, O-H).

Range13With NMR (DMSO-d6, J/Hz), δ, ppm: 11.24 (1C, K, CH3, J=130.4), 50.38 (1C, t, CH2, J=143.6), 113.74 (1C, t, Cap, J=7.02), 116.70 (1C, m, Cap), And 119.21 (1C, m, Cap), 126.05 (1Car, d, J=6.9), 126.81 (1C, m, Cap), 126.96 (2C, d, Cap, J=4.5), 127.46 (1C, m, Cap), 127.76 (2C, m, Cap), 128.17 (1C, d, Cap, J=8.4), 129.14 (1C, m, Cap), 130.65 (1C, d, Cap, J=5.0), 131.22 (1C, d, Cap, J=6.6), 131.85 (1C, d, Cap, J=8.9), 136.65 (1C, d, Cap, J=9.0), 138.34 (1C, s, Cap), 153.75 (1C, mTrias,2J=7.2 Hz,3J=2.7), 156.09 t (1C, t, C=O, J=7.6), 158.35 (1C, q, jTrias, J=4.5), 164.61 (1C, t, Cap, J=4.8).

All screening studies were conducted according to the guidelines for experimental the material (preclinical) study of new pharmacological substances with the definition of LD 50[6].

The experiments were carried out in accordance with article 11 of the Declaration of Helsinki of the world medical Association (1964), "International guidelines for the conduct of biomedical research using animals" (1985) and good laboratory practice in the Russian Federation (order of the Ministry of the Russian Federation No. 267 from 19.06.2003,).

The experiment began with a study of the influence of the investigated compounds at different doses on cardiohemodynamic laboratory animals: blood pressure and heart awake normotensive rats (Wpisane. // Guidance on experimental (preclinical) study of new pharmacological substances. M., 2004. - S-224).

Acute toxicity was investigated [determined the median lethal (lethal) dose - LD50] in experiments on mice with intraperitoneal injection of substances previously suspended with tween-80, defined medium lethal dose (LD50) [7], [8], [9]. Expected acute toxicity, following the recommendations of the state pharmacological Committee for the study of General toxic action of biologically active substances [10]. As Comparators mapped connection I was taken ethacyzin. The substance I, as ethacyzin, has a mild hypotensive effect, substantially without affecting the heart rate (HR) waking normotensive outbred rats. It has been found that a dose of 1 mg/kg (1/3000 of LD50) studied the connection I significantly increases the rate of relaxation of the heart muscle, the rate of contraction increasing end - diastolic pressure was significantly decreased (table 1). Drug comparison ethacyzin at a dose of 0.002 mg/kg (1/3000 of LD50) has virtually no effect on indices of Central hemodynamics: significantly increases the rate dP/dt is the rate of relaxation of the myocardium at 5, 10, 15 min; increases KDD, significantly increases the rate of +dP/dt only 45 and 60 min of the experiment; no effect on the performance of dp/dt/PI contractility index Veraguth (KIV) and dp/dt/PD - modified index Veraguth (table 1).

Comparison of results of studies on acute toxicity suggests that according to the classes tab of toxicity[10], [11], [12] the substance I may be referred by Hodge and Sterner and classification Kev to 5 toxicity class and is practically non-toxic compound, and it helped to explain the rationale for further study of its biological activity (table 2). Indeed, based on the formula:

,

(where n is the number of animals in the experiment, equal to 12, LD100- the minimum dose of the substance, which leads to 100% death of the entire group of animals), for tablets, Atari the ina 0.5 g (50 mg) therefore, LD50=55 mg/kg (table 3). For substances I

Thus, the results of the study cardioprotective activity showed that the substance I has a significant advantage compared to the comparison drug atalina and after clinical trials in medical institutions can be used as drugs with hypotensive and antiarrhythmic effect.

Sources of information

1. Great medical encyclopedia [30 Tons of medical Sciences of the USSR]. CH. Ed. CH. - 3rd ed. - M.: Soviet encyclopedia. - V.5. 1985, 560 S., Medmaravis. // Medications: a Handbook for physicians. M., 2005. S-367.

2. K. Fukuzumi, N. Ikeda, M. Egawa, J. Am. Oil Chem. Soc., 1976, No 53, pp.623.

3. S. Nagy, G. Argyclan, J. Molnar, M. Kawase, N. Motohashi, Anticancer Res., 1996, No 16, pp.1916.

4. Medmaravis. // Medicines. M, 1972, s-369.

5. Hendrieth, Wherewhen, Sebborheic, VII, Owenahincha. // Zhur.org.chem., 1977, Vol.13, No. 11, s-2460.

6. Manual on experimental (preclinical) study of new pharmacological substances. // Edited Fisenko VP and others - M.: UAA "Remedium", 2004. - S-224.

7. Mpelembe. // Elements of a quantitative evaluation of the pharmacological effect. L., 1963, s.

8. Methodical recommendations for the study of General toxic action of pharmacological agents. Decl. 25.12.97. / Lead, pharmacopceia. - 1998. No. 1. - P.27-32.

9. Ivinice. // Methods for determining the toxicity and hazards of chemicals. M., 1970, s.

10. Kid, K.K. Methods for the determination of acute toxicity and hazards of chemicals. (Toxicology). / Div. - M.: Medicine, 1970, 171 S.

11. Izmerov NF Parameters toxicometric industrial poisons in a single exposure. / Nfessio, Ivinice, Kid. - M.: Medicine, 1977. - 197 S.

12. Hodge H.C., Sterner L.H., Am. industr. Hyg, Ass. Quart., 1943, 10, 4, 93.

5,3±3,8
Table 1
The influence of I and atalina on the level MLID, HR, +dP/dt, -dP/dt, dp/dt/PI, dp/dt/PD, KDD in awake normotensive rats in percentage to the baseline at a dose of 1 mg/kg (M± m, n=6, Δ%)
SubstanceSource MLID, mm HgAfter 5 minAfter 10 minAfter 15 minAfter 30 minAfter 45 minAfter 60 minAfter 90 min
Ethacyzin120,6±12,1-2,4±2,3-0,3±1,5of-1.5±2,2 -0,1±2,11,0±1,00,0±1,21,6±1,1
I144,1±8,4-2,2±2,4-4,6±2,7-5,5±2,8-7,8±4,2-9,3±4,2*vs.-7.9bn±2,7*-5,8±1,6*
Source HR, beats./min
Ethacyzin376,4±18,9-1,8±1,1and-0.6±0,8-0,3±0,8-0,2±0,4-0,4±0,5of-1.0±0,5-0,2±0,7
I408,3±11,11,3±1,4and 2.8±5,6-4,8±6,1-0,5±7,4-3,3±6,60,8±5,12,5±4,7
Source +dP/dt, mm Hg/sec
Ethacyzin9776,2±2475,42,2±5,97,8±5,65,9±6,07,8±5,210,5±3,5*9,0±4,4*2,2±7,2
I10872/7±1118,8to-4.5±6,3-5,4±6,9-9,5±6,9-12,2±8,b-11,5±7,5-4,9±3,8is 3.5±1,7
Source-dP/dt, mm Hg/sec
Ethacyzin-6560,5d±1468,410,6±2,2*8,3±1,9*9,6±2,4*7,3±3,57,0±3,35,7±2,6
I-7962,4±1031,79,1±3,3*10,5±3,7*12,1±3,9*21,1±4,8*21,0±8,3*17,8±7,6*13,4±4,6*

Continuation of table 1
The original dp/dt/PI, 1/s
Ethacyzin209,4±25,2and-0.6±0,8-1,1±1,9-2,2±1,3-1,7±1,80,8±2,40,2±1,71,3±1,9
I169,7±14,8-2,6±3,93.3V±5,40,3±4,64,1±5,24,1±7,0,3±3,1* 11,7±5,7
The original dp/dt/PD, 1/s
Ethacyzin229,6±20,9-0,1±0,71,9±0,9-0,1±0,90,7±1,4to 1.2±1,4and-0.6±1,7and-0.6=1,4
I204,6±16,4-3,4±4,3and 2.8±5,9to-4.0±6,8-1,3±8,5-5,2±1,4-3,0±6,4-0,2±4,7
The original KDD mm Hg
Ethacyzin8,6±2,116,8±16,917,2±17, 10,3±1,412,4±10,4-1,8±5,66,9±2,5*12,9±3,9*
I10,6±2,320,7±32,13,2±25,22,7±19,7-16,3±20,9-44,1±12,1*-45,2±13,0*-8,2±32,1

Table 2
Determination of the acute toxicity of compound I
ResultDose mg/kg
1010050010003100
The number of animals1212121212
Survived 1212121212
Died00000
D-904005002000
Z-0000
DZ-0000
Table 3
Determination of acute toxicity of tablets atalina 0.5 g(50 mg)
ResultDose, mg/kg
6055504540
The number of animals1212121212
Survived0681112
Died126410
D-555 5
Z-6231
DZ-3010155

2-(1-(2-(2-Chloro-10H-phenothiazines-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazole-3-yl)phenol of formula I

possessing hypotensive and antiarrhythmic effect.



 

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16 cl, 27 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmacology. Application of preparation which contains combination: 1) fermented and/or hydrolysed protein material, and 2) one or several compounds, which contain unoxidisable structural unit of a fatty acid, for obtaining pharmaceutical or food composition, as well as composition for prevention and/or treatment of resistance to insulin, obesity, diabetes, fatty infiltration of the liver, hypercholesterolemia, dyslipidemia, atherosclerosis, coronary heart disease, thrombosis, stenosis, secondary stenosis, myocardium infarction, stroke, hypertension, endothelial dysfunction, state of hypercoagulability, polycystic ovary syndrome, metabolic syndrome, malignant tumour, inflammatory disorder and proliferative skin disturbance. Application of animal food containing common food components and combination of: 1) fermented and/or hydrolysed protein material, and 2) one or several compounds which contain structural elements of fatty acids which cannot be β-oxidised for improvement of general lipid composition in animal organism. Method of obtaining product of animal origin with improved composition of fatty acids, which includes feeding of the animal intended for product obtaining, with animal food which contains common food components and combination of: 1) fermented and/or hydrolysed protein material, and 2) one or several compounds which contain structural elements of fatty acids which cannot be β-oxidised. Invention also relates to application of preparation which contains combination of: 1) protein material and 2) oil or fish oil for prevention of said diseases, and to composition for prevention and/or treatment of hypercholesterolemia and states which are negatively influenced by said diseases, which contains said combination.

EFFECT: invention ensures increase of efficiency of prevention and treatment of said diseases.

82 cl, 12 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology, cardiology, endocrinology, and can be applied for normalisation of microvesicle level in blood in case of glucose tolerance disturbance. For this purpose introduced is pioglitazone 30 mg 1 time in the morning and dosed physical loadings are prescribed. Duration of treatment is not less than 6 weeks.

EFFECT: method results in normalisation of microvesicle level in blood of patients of said category, reducingmanifestations, including, endothelial dysfunction, as well as considerably reducing hemocoagulation potential of blood, reducing risk of thrombotic complications.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, and deals with normalisation of functional reactivity of cardio-vascular system (CVS) in case of crisis course of arterial hypertension with disturbance of glucose tolerance. For this purpose estimation of CVS functional reactivity state under psychoemotional load is carried out by registration of systolic diastolic everage dynamic pressure (APav.dyn.) and heart rate (HR). On the basis of obtained data functional reactivity index (FRI) is determined before and after load, using the formula: FRI= APav.dyn.x HR)100 (conv. units). If FRI value after load increases on more than 20 conv.units, treatment including irbersartan 150 mg in the morning 1 time and lacidipine 4 mg in the morning 1 time during not less than 2 months.

EFFECT: such complex of medicamentary therapy in combination with empirically selected treatment duration ensures normalisation of CVS functional reactivity in said group of patients due to potentiation of therapeutic effect of applied medications.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology, endocrinology, and can be used for decreasing the blood microvesicle concentration in the patients with arterial hypertension and impaired glucose tolerance. That is ensured by administration of Valsartan 80 mg once in the morning, Pioglitazone 30 mg once in the morning and prescribed graduated physical activity.

EFFECT: invention provides normalisation of the blood microvesicle level in the case patients that allows considerably lowering hemocoagulation potential of blood, reducing risk of thrombotic complications.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology, endocrinology, and can be used for correction of the blood microvesicle level in the patients with arterial hypertension and abdominal obesity. That is ensured by administration of Valsartan 80 mg once in the morning, Metformin 500 mg twice a day, and graduated physical activity. The length of treatment is at least 5 weeks.

EFFECT: invention provides normalisation of the blood microvesicle level in the case patients that allows considerably lowering hemocoagulation potential of blood, reducing risk of thrombotic complications.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and can be used for correction of the blood microvesicle level in the patients with dyslipidemia and abdominal obesity. That is ensured by individual hypocaloric diet, graduated physical activity and administration of preparation Lovastatin 40 mg once a day in the evening at mealtimes. The length of treatment is at least 10 weeks.

EFFECT: invention provides normalisation of the blood microvesicle level in the case patients that allows considerably lowering hemocoagulation potential of blood, reducing risk of thrombotic complications.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns optimisation of thromboplastin formation activity in the patients with arterial hypertension and impaired glucose tolerance. That is ensured by the integrated treatment including graduated static and dynamic physical activity, daily swimming in a pool for at least 20 minutes, and introduction of metformin in dosage 500 mg 2 times a day and lisinopril in dosage 10 mg once a day in the morning for 1 month.

EFFECT: complex of specific medicines and physical activity combined with empirically prescribed length of treatment provides normalisation of thromboplastin formation that in turn reduces risk of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to cardiology, and concerns optimising the functional responsiveness of the cardiovascular system in arterial hypertension, dislipidemia and abdominal obesity in elderly and senile patients. That is ensured by estimating the condition of functional responsiveness of the CVS in psychoemotional load by recording systolic, diastolic, average dynamic pressure (BPav.dyn.) and heart rate (HR). These data are used to evaluate a functional responsiveness index (FRI) before and after load by formula: FRI=(BPav.dyn. x HR)100 (standard units). The post-load PFR increased more than by 20 standard units requires the integrated treatment including individually prescribed hypocaloric diet calculated by formula considering sex, age and body weight, swimming, morning hygienic gymnastics and therapeutic exercises throughout the day, divided physical activity throughout the day, and administration of irbesartan 150 mg for at least 3 months.

EFFECT: integrated drug-induced and drug-free therapy combined with empirically prescribed length of treatment provides optimisation of functional responsiveness of the CVS in the given group of patients due to potentiation of therapeutic effect of separate components of an individual care.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and endocrinology, and concerns normalisation of thrombocyte sensitivity to aggregation inducing factors in the patients with arterial hypertension and impaired glucose tolerance. That is ensured by the integrated treatment including graduated physical activity, including daily swimming in a pool for at least 20 minutes a day, and administration of lisinopril in dosage 10 mg once a day in the morning and metformin in dosage 500 mg once a day. The therapeutic course is at least 5 weeks.

EFFECT: complex of specific medical products and physical activity combined with empirically prescribed length of treatment provides complete normalisation of thrombocyte sensitivity to aggregation inducing factors that in turn reduces risk of thrombolytic complications in the given group of patients.

1 ex, 3 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and cardiology, and concerns decreasing microvesicles in blood in crisis course of arterial hypertension. That is ensured by administration of Irbesartan in dosage 150 mg once in the morning and Nebivolol in dosage 2.5 mg once in the morning for at least 7 weeks.

EFFECT: method ensures normalised blood concentration of microvesicles that in turn allows reducing risk of thrombotic complications in said group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to out-patient anaesthesiology, also can be used as an anaesthesia care in out-patient dental interventions. That is ensured by premedication with administered hypoxen in dosage 1g, 60 minutes prior to the intervention.

EFFECT: method ensures correction of stress-specific cardiac rhythm disturbance in the given category of patients due to antiarrhythmic actions of hypoxen, caused by decreased spontaneous activity of the cardiac pacemaker in a healthy and ischemic heart.

1 ex

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