Medicinal preparation for treatment of chronic cardiac insufficiency

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to a medicinal preparation used in treatment of chronic cardiac insufficiency. The preparation represents 3-methyl-5-[2-(3-tert.-butylamino-2-oxypropoxy)- phenoxymethyl]-1,2,4-oxadoazole hydrochloride. The preparation provides expanding assortment of medicinal agents used in treatment of chronic cardiac insufficiency.

EFFECT: valuable medicinal properties of drug.

5 tbl

 

The invention relates to the field of medicine and concerns the application of the hydrochloride of 3-methyl-5-/2-(3-trebutien-2-oxopropoxy)phenoxymethyl/ 1,2,4-oxadiazole formula I as drugs in chronic heart failure.

Previously the connection I know a biologically active compound which has a β- and α-adrenoceptor blocking properties (1), and also as a medicinal means of providing an antihypertensive, antiarrhythmic, koronarorasshiryayuschee, antiischemic and antiglaucoma action (2). The agent based on the compound I is used in medical practice under the name of practolol (3).

The closest pharmacological analogue of the claimed compounds in the presence of β- and α-adrenoceptor blocking action is labetalol, which has found application as an antihypertensive (4), but not in congestive heart failure (5), and carvedilol used as an antihypertensive, antianginal drug and medication for the treatment of congestive heart failure (6). However the lack of convincing evidence of the ability carvedilola (monotherapy) to improve the survival of patients with chronic heart failure due to ischemic heart disease is (7).

In addition, in our country carvedilol is rarely used, primarily because of the high cost.

The purpose of the invention is a new tool with efficiency in congestive heart failure.

This goal is achieved by the application of known compounds hydrochloride 3-methyl-5-/2-(3-trebutien-2-oxopropoxy)phenoxymethyl/1,2,4-oxadiazole as drugs used in congestive heart failure.

The study of the pharmacological activity of compound I (practolol) was performed in comparison with its pharmacological analogue of the carvedilola.

In rats with ischemic model of chronic heart failure in response to occlusion of the left descending coronary artery intraperitoneal administration of practolol at a dose of 2 mg/kg 2 times a day, starting from the first day after coronary occlusion and within 28 days resulted in a decrease in the frequency of deaths (table 1), the volume and area of necrosis of the myocardium post-mi scar (table 2), as well as indexes mass (hypertrophy of the myocardium) of the right and left ventricles (table 3). Similar results were obtained when studying carvedilola. If this is not established significant differences in the effect of practolol and carvedilola influence on the above mentioned parameters.

Table 1

The influence of proxodila and coverdill on mortality in rats with ischemic model of chronic heart failure
GroupThe number of operated animalsThe number of dead animals
Linopirdine animals (without coronary occlusion)130
Control (coronary occlusion)244
Practolol191
Carvedilol140

Table 2

The influence of praxagora and carvedilola on the size of the necrosis of the myocardium in rats with ischemic model of chronic heart failure
GroupVolume postinfarction scar ratio in % of the area of necrotic segments and sliceThe area of post-infarction scar (ratio in % length of outer surfaces postinfancy scars and circles slices)
Control (n=14)35,0±3,642,6± and 4.9
Practolol (n=13)16,3±1,5*19,6±2,1*
Carvedilol (n=10)16,6±3,7*23,1±4,5*
*P<0,001 compared to control 



Table 3

The influence of practolol and coverdill on myocardial hypertrophy in rats with ischemic model of chronic heart failure
GroupMass index left ventricular ratio (in % of mass of the ventricle and the animal's body)The mass index of the right ventricle (the ratio in % of mass of the ventricle and the animal's body)
Linopirdine animals (n=11)2,082±0,0680,6±0,734
Control (n=11)2,424±0,05610,926±0,0851
Practolol (n=13)2,204±0,07*0,715±0,082*
Carvedilol (n=10)2.281±0,096*0,655±0,059*
1P<0,001 compared with linearizovannykh animals

*P<0,001 compared to control

Data on the effectiveness of practolol in an experimental model of heart failure was conducted on the basis of his clinical studies in patients with chronic heart failure.

Clinical randomized, blind, placebo-controlled of isokinetically (in the form of tablets, 10 mg) was conducted on 90 patients with chronic heart failure II-III functional class and ejection fraction of the left ventricle is less than 40%Bolnye within 1 week after admission were distributed in two groups of observations based on randomization. The first group of patients received practolol, patients from the second group a placebo. The average daily dose was 49,8±18,8 mg Patients received concomitant therapy, with the exception of beta-blockers and calcium antagonists, which are cancelled at least 1 week. prior to the inclusion of patients in the study. The observation period was 12 weeks.

It is established that the treatment practolol led to improvement in clinical status of patients, which was reflected in the decrease of the functional class of chronic heart failure, the increase of the distance, giving patients and improving quality of life (decrease of the average score" Minnesota questionnaire quality of life') (Table 4). In addition, under the influence of practolol noted a significant increase in ejection fraction of the left ventricle, and reduced systemic blood pressure and a tendency to decrease heart rate (table 4). In the group of patients receiving placebo, the above parameters were not significantly changed, except for the decrease in diastolic blood pressure at study end (table 5).

For the whole observation period in both groups did not reveal any changes in the monitoring of biochemical parameters of blood, the total is about analysis of urine and blood. Among the side effects of practolol noted bradycardia (5 patients), arterial hypotension (2 patients), the occurrence of pronounced weakness (4 patients) and severe headache (1 patient).

Table 4

The influence of practolol on the main parameters in patients with chronic heart failure
Baseline(n=45)Within 4 weeks after the start of treatment (n=43)After 12 weeks after the start of treatment (n=43)
Functional class2,38±0,5 2,05±0,4
6-minute walk test, m315,2±61,4343,3±69,4358±73*
End-diastolic volume of the left ventricle, ml197,4±45,3 192±50,9
End-systolic volume of the left ventricle, ml132,3±62,2 to 121.6±58,6
The ejection fraction of the left ventricle, %32,8±4,3 37,12±5,4*
Quality of life scores41,3±18,935,93±21*32,9±21,8*
The heart rate, the/min 77,5±a 12.772,3±13,670,2±12,8
Systemic arterial pressure(mm Hg): systolic diastolic131, 5mm±13,5

83,2±8,0
123,5±14,6*

76,5±10,2*
122,4±17,1*

75,4±9*
*P<0.05 compared with the initial level



Table 5

The effect of placebo on the main parameters in patients with chronic heart failure
Baseline (n=45)Within 4 weeks after the start of treatment (n=42)After 12 weeks after the start of treatment (n=40)
Functional classof 2.26±0,4 2,22±0,36
6-minute walk test, m323,8±48,6to 326.1±63,7322,6±57
End-diastolic volume of the left ventricle, ml201,7±89,8 192,6±73,6
End-systolic volume of the left ventricle, ml139,4±81 127,5±75,9
The ejection fraction of the left ventricle, %33,1±7,9  34,9±7,4
Quality of life scores32,2±17,637,2±27,627,8±21,7
Heart rate, beats/min75,8±12,574,7±10,972,1±11,2
Systemic arterial pressure (mm Hg): systolic diastolic133,6±16,7

83,5±10,6
131, 6mm±12,0

82,5±8,1
132,1±9,2

79,3±6,3*
*P<0.05 compared with the initial level

Thus, the claimed drug in patients with mild and moderate chronic heart failure causes a decrease in the functional class of heart failure, the increase in the ejection fraction of the left ventricle and endurance load, and improved quality of life with good endurance. The first drug with these properties are revealed in a series of derivatives of 5-phenoxyethylacrylate.

The creation of the proposed drug allows you to expand the Arsenal of safe and effective domestic remedies for the treatment of chronic heart failure.

Literature

1. RF patent N 1132505, class 07 D 271/06, a 61 K 31/41, published 1994

2. RF patent N 1827067, class a 61 K 31/41, published 1994

3. Mashkovsky PPM Medicines. Moscow, "But the second Wave", 2000, vol. 1, s.

4. Levy G.P, Richards D.A. - Labetalol-Pharmacology of Antihypertensive Drugs., 325-347, Raven Press, New York, 1980.

5. Drug information for the Health Care Professional, 605, Micromedex, 20-th edition, 2000.

6. Encyclopedia of drugs, 2002, 9th edition, s.

7. DV Preobrazhensky,. Basearea - Successes and failures in the development of new approaches to drug therapy of chronic heart failure. Cardiology, 2001, N 5, p.65-73.

Drug for the treatment of chronic heart failure, representing the hydrochloride of 3-methyl-5-/2-(3-trebutien-2-hydroxy-propoxy)phenoxymethyl/-1,2,4-oxadiazole formula



 

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FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to a medicinal preparation used in treatment of chronic cardiac insufficiency. The preparation represents 3-methyl-5-[2-(3-tert.-butylamino-2-oxypropoxy)- phenoxymethyl]-1,2,4-oxadoazole hydrochloride. The preparation provides expanding assortment of medicinal agents used in treatment of chronic cardiac insufficiency.

EFFECT: valuable medicinal properties of drug.

5 tbl

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