UA76959C2 - Use of salicylic acid derivatives, pharmaceutical composition, method for treating heart arrhythmias - Google Patents

Abstract

The invention relates to the medicine and the pharmacology, in particular to the anti-arrhythmic drugs. The salicylic acid derivatives or pharmaceutically acceptable salts thereof are used as the active components of the pharmaceutical composition. The method for treating the heart arrhythmias is also disclosed.

Description

Description of the invention

The invention relates to medicine and pharmacology, in particular to means for the treatment of cardiac arrhythmias. More specifically, this invention relates to the use of salicylic acid derivatives as an active component of a pharmaceutical composition with antiarrhythmic activity, new pharmaceutical compositions and a method of treating cardiac arrhythmias.

Currently, there is a wide variety of pharmacological drugs that have a normalizing effect on the disturbed rhythm of heart contractions. Various 70 classifications are proposed for antiarrhythmic drugs, the most common of which is currently the Vaughan-Williams classification |Mashkovsky M.D. Medicines. - Kharkiv: Torsing, 1998. - Volume 1. - P.370-371). According to this classification, antiarrhythmic drugs are divided into 4 classes: membrane stabilizing agents (blockers of Mo" channels); D-adrenoblockers; drugs that slow down repolarization (blockers of K" channels), and blockers of calcium channels. 15 In the mechanism of action of all antiarrhythmic drugs, the leading role is played by the influence on cell membranes, on the transport of ions through them (Mo", K", Ca?"), as well as the interconnected effect on electrophysiological processes in the myocardium, on depolarization and repolarization electric membrane potential of cardiomyocytes.

Disturbances in the electrical properties of cardiac myocytes and heart rhythm occur as a result of intracellular ionic imbalance, which is pathogenetically related to transmembrane ionic flow disorders. The electrical potentials of rest and the excitation phase of cardiomyocytes are determined by the properties of ion channels through which a certain number of Mo, Ca, K, Ma, ions enter the cell, and also leave the cell.

SI, the ratio of concentrations of which determines the value of the electrical potential of the cell in different phases of the cardiac cycle. The sarcolemma of cardiomyocytes not affected by the pathological process exerts strict control over the function of ion channels and the intracellular ion balance. But with various pathological processes of Ge 25, the regulatory function of the sarcolemma is disturbed, ion channels and pumps become dysfunctional, and the permeability of cell membranes increases (5), which leads to intracellular ion imbalance. At the same time, the concentration of Mo and Ca ions increases in the plasmalemma, which accumulate in cells due to the dysfunction of ion channels and pumps or penetrate into the sarcoplasm along a concentration gradient. At the same time, the number of K ions decreases in the cells, since its concentration in the intercellular fluid is 30 times lower than in Me. 30 cytoplasm of cardiomyocytes. Pathological ionic imbalance leads to increased cell excitability and impaired conduction of bioelectrical impulses through the conduction system of the heart, which causes cardiac arrhythmias.

One of the main antiarrhythmic drugs used to correct intracellular ionic Me. imbalance, there is amiodarone, which blocks K", Ma"- and Ca"-channels, as well as so- and p-adrenergic receptors of the heart. (Se)

Pharmacological blockade of pathologically activated ion channels in most cases normalizes their function, 35 reduces intracellular ion imbalance and leads to normalization of electrical activity - myocardial cells and heart rhythm. But the use of amiodarone in effective antiarrhythmic doses causes side effects, the frequency of which reaches 5795, as well as dangerous complications that require complete cessation of treatment in 15-1795 patients. Interstitial pneumonia (in 10-1790 patients) and arrhythmogenic effects (2-595) are considered the most dangerous complications. In addition, there are liver lesions with a 2-4 times increase in the level of liver enzymes, deposition of promelanin and lipofuscin in the corneal epithelium, hypo- or hyperthyroidism, etc. At present, despite the significant achievements of experimental and clinical arrhythmology, as well as a significant number of antiarrhythmic drugs, the effectiveness of drug therapy for cardiac arrhythmias does not exceed 70,965.

It is also known that cyclooxygenase inhibitors are used in antiarrhythmic therapy | E.I. Mytchenko, - 15 O.M. Mayakova, A.P. Viktorov, A.I. Frolov "Antiarrhythmic therapy with preexcitation syndromes using cyclooxygenase inhibitors!".- IM national congress of cardiologists of Ukraine. Abstracts of scientific reports. - Kyiv. - 200 Or. - P.174). The antiarrhythmic effectiveness of indomethacin and movalis, which were prescribed to 58 patients with ventricular preexcitation syndrome with frequent paroxysms of tachyarrhythmias, was investigated. The authors found that cyclooxygenase inhibitors, which are not an alternative to antiarrhythmic therapy, increase the effectiveness of basic treatment with sodium channel blockers and D-adrenoblockers. However, due to the low antiarrhythmic effectiveness of indomethacin and movalis, the authors did not even prescribe them to patients with cardiac arrhythmias.

Due to the numerous side effects of the above-mentioned drugs and their insufficient therapeutic effectiveness, there is still a need to develop more effective and safer antiarrhythmic drugs. Based on the above, the basis of this invention was the task of offering a new (F) active component of a pharmaceutical composition that would be effective in the treatment of cardiac arrhythmias and therefore

To increase the safety and effectiveness of antiarrhythmic therapy.

When creating the invention, it was unexpectedly established that derivatives of salicylic acid of the general formula 60 b5

!

Her that and and and I that EIi Si

She and. Same residential complex

M where

МЖХИХ in which

B" means the formula group

MH-- in", where 85 is selected from the group that includes hydrogen, alkyl, oxyalkyl, dialkylaminoalkyl, phenyl, oxyphenyl, aminophenyl; or with

B means a group of the formula He) o-687, where B" is selected from the group consisting of hydrogen, alkali or alkaline earth metals such as sodium, potassium, calcium, magnesium; amino, alkyl, oxyalkyl, dialkylaminoalkyl, phenyl, aminophenyl, acylaminophenyl Fo zo 2 is selected from the group consisting of hydrogen, alkyl, acetyl, succinyl, aminoalkyl;

BZ is hydrogen, OH or oxyalkyl; at

B" represents hydrogen, amino group, acetylamino group or benzoylamine, 2,4-difluorophenyl; (o)

IN? represents hydrogen, an amino group, an acetylamino group, 2,4-difluorobenzene or benzoylamine, or their pharmaceutically acceptable salts; show antiarrhythmic activity. -

Accordingly, the object of this invention is the use of salicylic acid derivatives of the general formula I, in which the substituents have the values indicated above, as an active component of a pharmaceutical composition with antiarrhythmic activity. "

Another object of this invention are pharmaceutical compositions with antiarrhythmic activity, which as an active component contain at least one derivative of salicylic acid of the general formula I, in which the substituents tc have the values indicated above, or its pharmaceutically acceptable salt, in an effective amount, necessarily in combination with pharmaceutically acceptable excipients and/or carriers. Also, the object of this invention is a method of treating arrhythmias, which involves administering to the patient a pharmaceutical composition, which as an active component contains at least one derivative of salicylic acid of the general formula I, in which the substituents have the values indicated above, in an effective amount. - Salicylic acid and its derivatives are well known from the state of the art Mashkovsky M.D. Medicines. - b Kharkiv: Torsing, 1998. - Volume 1. - P.164-169). They show a specific anti-inflammatory effect, as well as an analgesic and antipyretic effect. Salicylic acid, salicylic ester of acetic acid (acetylsalicylic acid), acelysine (a mixture of O, -lysine with 20 acetylsalicylate and glycine in a ratio of 9:1), sodium salicylate, salicylic acid amide, methyl salicylate and salicylsalicylic acid have become widely used in medical practice. acid (salsalate). The antipyretic effect, which is accompanied by an increase in heat transfer and 3e) due to the expansion of skin vessels and increased sweating, is significantly associated with a calming effect on the excitability of the thermoregulatory centers of the midbrain, which has changed under the influence of the pathological process.

The anti-inflammatory effect of salicylates is associated with the effect on various links of homeostasis regulation. One of the main elements of their anti-inflammatory action is the normalizing effect on the increased permeability of capillaries and on

Gee! microcirculation processes. They also have an inhibitory effect on the synthesis of prostaglandins. Salicylates are widely used for various forms of rheumatic diseases, for headache, dental and other types of pain. Aspirin is also used as an antiplatelet agent. Salicylates are mainly biotransformed in the liver into water-soluble conjugates, which are quickly removed from the body by the kidneys. The alkaline reaction of urine increases the ionization of 60 salicylates, which reduces their reabsorption in the epithelium of the renal tubules and increases the excretion of INil M in the urine.

J. Supervised pharmacology. - M. - GZOTAR Medicine, 1999. - P.70-711.

During the creation of the invention, it was unexpectedly established that derivatives of salicylic acid of the general formula exhibit antiarrhythmic activity, possibly due to a decrease in the penetration of Ma ions into cardiomyocytes and

Ca?" in arrhythmogenic concentrations directly through the sarcolemma. Over the past decade, it has been established that during myocardial ischemia, reperfusion, and stress conditions, as well as during inflammatory and some toxic damage to the heart, lipid peroxidation (LPO) and free radical damage to cell membrane proteins are activated. Products LPOs, in turn, activate tissue lipases and proteases, which also damage the lipid bilayer of the sarcolemma and its protein skeleton, as a result of which defects appear in the cell membrane (tidrophilic clusters"), through which Ca 25 ions enter the cell outside the ion channels.

The driving force of these transmembrane ion flows is the Ca concentration gradient, the content of which in the intercellular fluid is 20 times greater than in the protoplasm of cardiomyocytes. It is obvious that blockers of ion channels do not affect extrachannel ion flows, cannot curb them, and do not have a positive effect on the course of cardiac arrhythmias. The use of salicylic acid derivatives according to the invention allows to reduce damage to the 70 sarcolemma by lipid products and proteases. The antiarrhythmic activity of salicylic acid derivatives according to the invention is manifested both in Ma"- and Ca"-dependent heart arrhythmias, which greatly simplifies the individual choice of an antiarrhythmic agent and reduces the possibility of dangerous arrhythmogenic effects. Salicylic acid derivatives can show synergism in antiarrhythmic activity when combined with other antiarrhythmic drugs. The use of salicylic acid derivatives according to the invention allows to significantly expand the range of existing antiarrhythmic agents.

In the above general formula I, the term "alkyl" means a C4i-C3 monovalent linear hydrocarbon fragment, in particular methyl, ethyl, propyl.

Such derivatives of salicylic acid of the general formula I have proven themselves to be particularly effective, in which

B" means a group of the formula mn--pe where 89 is selected from the group consisting of dialkylaminoalkyl, oxyphenyl; 22, 23, B and 2" are hydrogen.

More effective are such derivatives of salicylic acid of the general formula I, in which

B" means a group of the formula o-bB87 o where B" represents magnesium or dialkylaminoalkyl;

Selected from the group consisting of hydrogen, acetyl;

VZ is hydrogen; (at)

He represents hydrogen, an amino group or benzoylamine; yu

IN? represents hydrogen, amino group, acetylamino group, 2,4-difluorobenzene or benzoylamine.

As the most effective derivatives of salicylic acid of formula I, selected from the group that includes:

Yi and Su! - rent reni

And HER iy

IS

She Her and how g ay r A), KE tai a «

Zh t zhi Be pot. Sya tata ee IC e s will drop such a burden and Zhe se EH: s . re Mem sv) Vitya dune Ya

IS; Because tomorrow's IZH B sia -A---Ya g

Х І Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х Х

Shch de lev lk: ЗB ok I "Be same ddtNh uki HL. -And | | M magnesium salt of 2-oxybenzoic acid (in particular, in the form of tetrahydrate); (o) zate: (That; ko v ly i s

GOES: I eat: I and "In Shk, in- And and shk pe her sya nu and not y BO zi ON - "shcha how I s: Y s--yy y y j Me and what Nm she I

ГФ) h---- V y I : e t still tni ih a ИЙ x EK bo U : : . 2",4-difluoro-4-oxybiphenylcarboxylic acid;

KI sia Se i pli i I E z i Z le ih

So stschiver. zani an ran -sh- factories rt ge sut In nN- u-e33 re in V sa a YAK; in and tt sk. i 7170 "V o schi -ХХ in it with M-(lara-oxyphenyl)-salicylamide;

In a certain way with EE No: I-y I tey rak inn GU y:

And you KE zkyitestk sh vky g; ИЙ dm Kopa - I is y 7 s Ж sr ka lyy Dok karti: yy shkunprtyli t i, p; ST I to which their sha and yang: there are still

And what Yah sa te a zksny I oz oh EE Zk y Ka y . хи, НИ and: same ss t sudi tia ne ih p - S i

A kt sha Bern sok: eat- s vo What. | at

And and, tivy - that's you

KINE ko me and more

Ii that ih: po VE AK zak g y y-yai -e F tik ih

In : : pd: 2,4-difluoro-4-oxybiphenyl magnesium carbonate; IF) with A ration I she | ee, : S Be TYA r ey o drntkttt Zovari is food and: st sv "shche ko chi I Y pr Kaya - Bash M "koe n h ki ; and read ТЯ ТЕ her reyaty which carried ТЕ Song, yad thu at 7 Es "

NE V rt: t y GI ge: U | - s Ya eh y ch o ki sa

Para-acetaminophenyl ether of 2-oxybenzoic acid.

Derivatives of salicylic acid of the general formula !, according to the invention, can be used individually or as part of a suitable pharmaceutical composition for the treatment of arrhythmias. b Derivatives of salicylic acid and their pharmaceutically acceptable salts proposed in the invention are suitable for obtaining appropriate pharmaceutical compositions based on them. Similar pharmaceutical compositions, respectively (Ce) therapeutic agents contain as an active substance one or more compounds according to the invention or their salts, optionally sl 50 in a mixture with other pharmacologically, respectively pharmaceutically active substances. Pharmaceutical compositions are obtained according to the usual technology, while it is possible to use known and commonly used in iChe) pharmaceutical auxiliary substances, as well as other usual carriers and diluents.

Preferred pharmaceutical compositions according to the invention as an active ingredient include magnesium salicylate, 5-aminosalicylate, magnesium acetylsalicylate or magnesium 2"4"-difluoro-4-oxybiphenylcarbonate.

Pharmaceutical compositions such as magnesium salicylate, 5-aminosalicylate, magnesium acetylsalicylate or magnesium 2',4"-difluoro-4-oxybiphenylcarbonate in combination with novocainamide are also preferred.

A pharmaceutical composition containing magnesium salicylate and 5-aminosalicylate is also preferred. ime) Pharmaceutical compositions according to the invention include active components in an effective amount. More preferred are compositions that contain the specified components in a mass ratio from 20:11 to 1:20, 60 especially preferably from 5:1 to 1:5.

The compounds proposed in the invention can be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously.

Capsules, tablets, dragees, etc. are suitable for oral administration. In addition to the latter, medicinal forms that contain a single dose of the active substance may also include a pharmaceutically acceptable carrier, such as, for example, starch, sugar, sorbitol, gelatin, a lubricant, silicic acid, talc, etc.

The compounds proposed in the invention also allow their use in the form of medicinal forms that provide a slow (prolonged) release of the active substance, which are the most preferable for long-term treatment.

For parenteral administration, active substances can be presented in a dissolved or suspended form in a physiologically acceptable diluent. Aqueous and alcoholic solutions of the active substance are suitable for parenteral administration.

In addition to active substances, the compositions proposed in the invention may additionally include various components generally accepted for dosage forms, such as antimicrobial preservatives, means for adjusting osmolarity, thickeners, excipients for adjusting the pH value or buffer systems. 70 In addition, the compositions proposed in the invention may include pharmaceutically acceptable buffer substances that allow you to set the pH value to approximately 4-8, preferably 5.5-7.5, and maintain this value within the specified limits. Similar buffer substances are citrate, phosphate, tromethamine, histidine, glycine, borate or acetate. These buffer substances can also represent derivatives of such substances as citric acid, primary or secondary sodium phosphate, glycine, boric acid, sodium tetraborate /5, acetic acid and sodium acetate. Other excipients, such as hydrochloric acid or sodium hydroxide, can be used to adjust the pH value.

The amount of salicylic acid derivatives of general formula I that is administered to the body can vary widely, including any effective amount. The dosage of active substances can be changed depending on the method of administration, the effectiveness of the compound used, the age and weight of the patient, the type and severity of the relevant disease, and similar factors. The daily dose is approximately from mg to 25Omg per kg of body weight, and this dose can be prescribed as a single dose or at the rate of two or more doses.

The above-described compositions and preparation forms are also an object of this invention.

The salicylic acid derivatives of the general formula | and pharmaceutical compositions that contain them are most suitable for the treatment of arrhythmias, especially in myocardial infarction (parenteral and oral administration), paroxysmal forms of supraventricular and ventricular arrhythmias (parenteral and) administration), arrhythmias in sinus node weakness syndrome (since salicylates improve its function |D.

Mandel. Heart arrhythmias. In 3 volumes. T.2. - 1996.- P.2111), as well as for the prevention and treatment of attacks of atrial fibrillation, ventricular extrasystole in combination with other antiarrhythmic drugs. Gee! z The appointment for atrial fibrillation is all the more justified, which will allow controlling the risk of thromboembolic complications. at

The method of treatment of arrhythmias according to the invention involves the administration of a pharmaceutical composition to the patient, which Ge! contains as an active component at least one derivative of salicylic acid of the general formula I according to the invention in an effective amount. ise)

Compounds according to the invention can be obtained by methods known to experts in this field |V.G. Belenkov. uh-

Pharmaceutical Chemistry. M. Higher School - 1985. - P.330-353.)|. So, for example, the compound of the formula I 70 х KE и ve p С хх шк zfrtyakya - ч» я ся Bo DY Ж я вкях kta t і - і і о - | them

AND

Siyan E; they are) magnesium salt of 2-oxybenzoic acid (in particular, in the form of tetrahydrate); sl 50 is obtained by the interaction of salicylic acid and magnesium hydroxide or oxide in a suitable environment under certain conditions, followed by isolation of the target product by generally accepted methods (for example, iChe) by evaporation and recrystallization. |Gytis S.S., Glaz A.I., Ivanov A.V. Workshop on organic chemistry.

Organic synthesis. M.: Higher School. -1991.-S.17-21 |).

By the interaction of 2'4"-difluoro-4-oxybiphenylcarboxylic acid with hydroxide or magnesium oxide in a certain environment and under appropriate reaction conditions, it is possible to obtain a substance of the formula

Ф) име) 60 b5 panst, y N sche s kh zhyy g. y ie SEah y shchi ; ; o : ay - yah ry y y zhe per zh : A t y zhe y

Yar i: b pd 710 i v la o KU res Y g t I u shik ee magnesium 2,4-difluoro-4-oxybiphenylcarbonate; which is allocated according to generally known methods

Esters of salicylic acid can be obtained by carrying out an etherification reaction on a carboxyl or hydroxyl group (ors. Gitis S.S., Glaz A.I., Myvanov A.V. Workshop on organic chemistry. Organic synthesis. M.: Vyissaya Shkola. - 1991 . - P.17-21 | when the necessary substances interact in the appropriate environment under certain conditions with the use of substances for binding water (for example, sulfuric acid) and the subsequent isolation of the target product according to generally accepted methods.

The production of amides and amide derivatives of salicylic acid is based on the interaction of complex esters with nitrogen-containing substances in the aminolysis reaction. For example, the substance of the formula c ze i o yati

And in the role of khdivtsoei re il Z fev V osti: ЧИ Me schy and 9 "y tm Y - - in the east with Ks pkt Y from traps IF) more soy: fr ennnYasya yar ee o 2 ti: rai z SHY "Where

SK I ke shchi sia and about SHO

NVNININININSHOTNN (Co) is obvious and -

SHE dO zhrultyat mouth SN KATE LK Kiya vetvsy, DY i ia g t aty same Veperaksirentrealtsipamya; " is obtained by fusing phenylsalicylate with paraaminophenol, followed by isolation of the target product from c.

Aminosalicylates are obtained by hydrogenation of nitrophenol and subsequent carboxylation according to Kolbe's method. After that, the salt of aminosalicylic acid is obtained by interaction with the corresponding metal salt. Upon further interaction with benzoic acid chloride, a benzoyl derivative of aminosalicylic acid is obtained

ACIDS. Many of the substances used are commercially available.

For example, the magnesium salicylate used in the studies was obtained from Mopagp Miigiirpai

Me, I arogaiyugiez, Ips. (OA), which indicates the industrial capacity of obtaining this product, especially since

Ge) this substance is included in the Pharmacopoeia of the USA 2000 (OBR 24 ME 19, R.1008).

Examples o The examples presented below are given so that specialists in this field can more clearly understand and

Ge) put this invention into practice. They are not intended to limit the scope of the invention, but are provided only for the purpose of illustrating representative embodiments.

Examples of pharmaceutical compositions. 5B a) Tablets

GF) Component Content per tablet, mg ka Active substance 250

Corn starch 160 in Lactose 502

Microcrystalline cellulose c)

Magnesium stearate 0.5

Methyl hydroxyethyl cellulose 2,3

A total of 472 b5 , , y and NYA also y

The finely divided active substance is mixed with a part of the entire amount of corn starch, lactose, microcrystalline cellulose, the resulting mixture is sieved and, together with another amount of corn starch, processed into a granulate, which is dried and sieved. Then methylhydroxyethyl cellulose and magnesium stearate are added, mixed and tablets of the required size are pressed from the resulting mixture. b) Capsules

Component Content per capsule, mg

Active substance 250

Lactose anhydrous 71 76 Talc b

Aerosil 3

A total of 360

The components are mixed in the traditional way and packaged in capsules. c) Solution in ampoules

Active substance 250 mg

Sodium chloride ABmMg

Water at the rate of one injection bml

The active ingredient at its own pH or, if necessary, at a pH of 5.5 to 6.5 is dissolved in water and mixed with sodium chloride as an isotonic agent.

The resulting solution is filtered under pyrogenic conditions and the filtrate is packaged in ampoules under aseptic conditions, which are then sterilized and sealed. Such ampoules can contain the required amount of active substance.

The antiarrhythmic effect of the compounds according to the invention was evaluated in the studies described below using different models of cardiac arrhythmias on experimental animals. Gee)

Application examples

Aconitine model of cardiac arrhythmias.

Example Ta.

A rat weighing 150 g, under nembutal anesthesia (4 Ω/kg), registers an ECG in the 2nd standard lead. A solution of oaconitine in a dose of ZOmkg/kg is injected into the femoral vein b. After 1.5 min. registered ventricular and extrasystolic arrhythmia according to the type of bigeminy. The rat is slowly injected with O.bml of 2.595 magnesium salicylate solution (10Omg/kg). Restoration of sinus rhythm was immediately registered. b"

Example 16. Ge

A rat weighing 16b0g under nembutal anesthesia (4Omg/kg) records an ECG in the 2nd standard lead. IN

A solution of oaconitine in a dose of ZOmkg/kg is injected from the femoral vein. After 2.1 min. registered ventricular - extrasystolic arrhythmia according to the type of bigeminy. The rat is slowly injected with 0.32ml of 195 solution of novocainamide at a dose of 2Omg/kg, respectively. Violation of intraventricular conduction, development of idioventricular rhythm was registered. Through the Record the animal died from apnea and ventricular fibrillation. "

Example in

A rat weighing 130g under nembutal anesthesia (4Omg/kg) records an ECG in the 2nd standard lead. A solution of aconitine in a dose of ZOmkg/kg is injected into the femoral vein. After 1.3 min. registered ventricular extrasystolic arrhythmia of the bigeminy type. The rat was slowly injected with a mixture of 0.28 ml of 2.595 mg of magnesium salicylate solution and 0.1 ml of 195 mg of novocainamide solution in doses of 5 mg/kg and 1 mg/kg, respectively. Stable restoration of sinus rhythm was registered immediately.

Example 1g. - A rat weighing 130g, under nembutal anesthesia (4Omg/kg), registers an ECG in the 2nd standard lead. IN

A solution of oaconitine in a dose of ZOmkg/kg is injected into the femoral vein. After 1.3 min. registered ventricular extrasystolic arrhythmia according to the type of bigeminy. The rat is slowly injected with 0.22 ml of a 2.595 solution of 5-aminosalicylate and magnesium in a dose of 5Omg/kg. Restoration of sinus rhythm lasting 1.4 minutes was registered immediately. "p. 50 Calcium chloride model of cardiac arrhythmias.

Example 2 c A rat weighing 150g, under nembutal anesthesia (4Omg/kg), registers an ECG in the 2nd standard lead. O0.bml of 2.595 magnesium salicylate solution (1OOmg/kg) is injected into the femoral vein. Through them an injection of 1090 calcium chloride solution at a dose of 20 Ωg/kg was made. Complete AV blockade and a single ventricular 25 extrasystolic arrhythmia were registered. After 0.5 min. sinus rhythm was restored.

HF) Chloridebarium model of cardiac arrhythmias.

Example With a guinea pig weighing 650g, under Nembutal anesthesia (4Omg/kg), an ECG is recorded in the 2nd standard lead. 195 barium chloride solution at a dose of 4 mg/kg is injected into the femoral vein. After 0.5 min. registered 60 ventricular extrasystolic arrhythmias according to the type of bigeminy. Animals are slowly injected with 1.2 ml of 2.595 magnesium salicylate solution (5Omg/kg). Restoration of sinus rhythm was immediately registered.

Strophantin model of cardiac arrhythmias.

Example 4.

A guinea pig weighing 730g, under Nembutal anesthesia (4Omg/kg), records an ECG in the 2nd standard lead. 0.8 ml of 0.02595 strophanthin-K solution at a dose of 0.0 mg/kg is injected into the femoral vein. After 1.3 min.

registered ventricular extrasystolic arrhythmia, with paroxysms of ventricular tachycardia. Animals are slowly injected with a mixture of 1.4 ml of 2.595 magnesium salicylate solution and 0.7/5 ml of 195 novocainamide solution in doses of 50 mg/kg and 10 mg/kg, respectively. The restoration of a stable sinus rhythm was immediately registered.

Membrane-destructive model of cardiac arrhythmias.

Example 5a.

A rat weighing 130g under nembutal anesthesia (4Omg/kg) records an ECG in the 2nd standard lead. 0.22 ml of 195 solution of novocainamide in a dose of 20 mg/kg is injected into the femoral vein. After 1 min. an injection of 0.000 ml of 1090 ml of ascorbic acid solution at a dose of 5 mg/kg was made, and also through IV. 0.1 ml of 195 iron sulfate solution at a dose of 7/0 LOmg/kg. When the amplitude of the T wave increased, an injection of 0.1 ml of 1095 calcium chloride solution at a dose of 10 Ωg/kg was performed. Complete AV blockade and a single ventricular extrasystolic arrhythmia were registered, which after 3.5 min. ended with the development of ventricular fibrillation and the death of the animal.

Example 56.

A rat weighing 150 g, under nembutal anesthesia (4 Ω/kg), registers an ECG in the 2nd standard lead. 0.35 ml of 2.570 magnesium salicylate solution is injected into /5 btegov vein. In a minute an injection of 0.0 ml of 1095 ascorbic acid solution at a dose of 5 mg/kg was made, and also through IV. 0.15ml of 195 iron sulfate solution at a dose of 1Omg/kg. When the amplitude of the T wave increases, an injection of calcium chloride is made at a dose of 100 mg/kg. Complete AV blockade and a single ventricular extrasystolic arrhythmia were registered. After 0.5 min. stable sinus rhythm was restored.

Strophanthin-caffeine model of cardiac arrhythmias

An example of

A rat weighing 160 g, under nembutal anesthesia (4 Ω/kg), registers an ECG in the 2nd standard lead. 0.02595 ml of strophanthin K solution at a dose of 1.5 mg/kg is injected into the femoral vein, and after 3 minutes slowly through the same needle for 2 minutes. inject 0.bml 1095 caffeine-sodium benzoate solution at a dose of 40mg/kg. The animal develops paroxysmal bidirectional ventricular tachycardia. The rat was intravenously injected with 0.3 ml of 195 ml of Novocainamide solution at a dose of 20 mg/kg. After 20 seconds, a violation of intraventricular conduction was registered, which led to the development of ventricular tachycardia of a different type, which lasted until the end of the experiment. and)

Sinus rhythm was not restored.

Example 66.

A rat weighing 150 g, under nembutal anesthesia (4 Ω/kg), registers an ECG in the 2nd standard lead. In Ge! 0.025905 ml of strophanthin K solution at a dose of 1.5 mg/kg is injected from the femoral vein, and after 3 minutes slowly through the same needle for 2 minutes. inject 0.bml 1095 caffeine-sodium benzoate solution at a dose of 400 Омг/kg. The animal is experiencing paroxysmal bidirectional ventricular tachycardia. The rat is slowly injected with 0.bml of 2.590 mg of magnesium salicylate solution at a dose of 10mg/kg. After 10 seconds, the restoration of the sinus rhythm was registered with a duration of Zhv.

The calculation of the doses of the experimental substance used in the laboratory was carried out without taking into account the bound water, given the impossibility of determining its quantitative content. Since the real ED in a laboratory substance is about bOmg/kg, and EDioo is about 200mg/kg on the aconitine model of cardiac arrhythmias, theoretical | Methodological recommendations for preclinical and clinical testing of medicinal products. Ed. A. V. Stefanova. Kyiv. - "Avicenna". - 2000. - P.112-120| doses of other antiarrhythmic drugs on this model to prevent the development of arrhythmia are: "- disopyramide - "10 Омг/kg; with c - novocainamide - "10Omg/kg;, - lidocaine - 10Omg/kg; with - mexiletine - 5Omg/kg; - Quinidine - 5Omg/kg; - propranolol - 5Omg/kg; -I - nifedipine - 10Omg/kg; - timolol - 10mg/kg body weight) At the same time, the doses of these drugs used for humans vary from 1-2mg/kg for lidocaine

Ge) for single administration, the daily dose can reach 1-2 g | (AN Okorokov. Diseases of internal organs.

In 4 volumes. M.: 2000. T.3. P.216-218) up to 15-20mg/kg for novocainamide for single administration (daily dose can reach 4Hg).

Ge) Magnesium salicylate (magnesium salt of salicylic or 2-oxybenzoic acid) is a white crystalline powder with a sweet-bitter taste, exists in the form of tetrahydrate. The antiarrhythmic activity of magnesium salicylate in the conducted studies is found in all used experimental two models of cardiac arrhythmias (see Table 1.).

The following abbreviations are used in the tables below:

F) AS - cardiac arrhythmia, and DR - the substance under investigation,

S/r - sinus rhythm, in FS - ventricular fibrillation,

HE - ventricular extrasystole,

ST - ventricular tachycardia, х - p«0.05 in comparison with the control, Ях - p«e0.01 in comparison with the control. b5

Table 1

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The effectiveness of magnesium salicylate is superior to the effectiveness of amiodarone in aconitine (Ki) membrane-destructive models of cardiac arrhythmias, compared with amiodarone in chloride-calcium and strophantin-caffeine models, and slightly inferior in the chloride-barium model of cardiac arrhythmias. Since the pathogenesis of the membrane-destructive model of cardiac arrhythmias lies in the activation of lipid peroxidation and its damage by membrane products structures, the protective effect of magnesium salicylate should be sought in the membrane-protective effect of the anionic component of the compound, which necessitates its allocation to the class of membrane and cardioprotectors.

Significant effectiveness on the aconitine model of cardiac arrhythmias, in accordance with the recommendations (Kaverina N.V., Senova

Z.P. Methodological recommendations for the experimental (pharmacological) study of drugs proposed as means for the prevention and treatment of heart rhythm disorders. M.:

Medicine 1981.-71p.| allow to assign it to the group of membrane-stabilizing antiarrhythmic drugs.

Magnesium salicylate also exhibits anti-inflammatory and antipyretic properties associated with the blockade of Ge) prostaglandins, an antiaggregant effect associated with a blocking effect on platelet cyclooxygenase, an analgesic effect associated with an effect on the prostaglandin system and a direct effect on the central nervous system. It is indicated that the effects are enhanced when combined with other anti-inflammatory, antipyretic, antiplatelet agents and drugs that affect the central nervous system (for example, celecoxib, ibuprofen, paracetamol, dipyridamole, trental, caffeine, etc.)

In addition to magnesium salicylate, other derivatives of salicylic acid according to the invention were also studied as antiarrhythmics, in particular, the sodium salt of salicylic acid, the magnesium salt of acetic ether (magnesium acetylsalicylate) and the complex salt of acetylsalicylic acid with lysine. The results are presented in table 3. h 4 Z - So Glen etnteninnyu noeyunnntyunn ns oyu. g» det 00000011 6011636010 yuyu 8 1 Moro o

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Ф (Acetyl-salicylate of lysine 10) 4" | 3 z | 5) 2 | 1 /6|2m| m m 62) 2 (se) It is clear from the given data that the sodium salt of salicylic acid and its esters have less antiarrhythmic effectiveness , than magnesium salicylate in all models, except for the membrane-destructive model. Moreover, among salts

Less antiarrhythmic activity of Mn ether was noted in the lysine salt. (Che) Known | New possibilities of metabolic therapy in cardiology. Orotic acid and matium. Symposium.

TOP "Medicine".-1996.-Mo6.-S.27-30), that magnesium ions have a non-specific antiarrhythmic effect. To date, the main indications for the use of magnesium sulfate as a magnesium preparation in cardiology are myocardial infarction, in which there is a threat of the development of "pirouette" - tachycardia. For this rhythm disorder, magnesium ions are the drugs of the first line. From the point of view of evidence-based medicine, magnesium significantly reduces the mortality of such patients. o For this, it is recommended to introduce 2-5 g of magnesium at once, and up to 22 g per day. Organic magnesium salts (asparaginate, orotate, lactate, pivalate) are used as adjuncts in the treatment of cardiac arrhythmias. For these purposes, magnesium asparaginate in the composition of the drug "Panangin", magnesium orotate 60 Smagnerot"), magnesium lactate and pivalate ("magne-B5") are most often used. However, different magnesium salts have different antiarrhythmic activity (A.V. Dolgov, 1990).

Among the studied compounds, magnesium salicylate shows the highest activity on experimental models.

It is possible that such antiarrhythmic activity is due to the synergistic effect of the anionic and cationic components of the compound. The activity of salicylic acid on the aconitine and membrane-destructive models is enhanced by the use of magnesium salt on experimental models with calcium arrhythmogenesis. It is known that magnesium ions are antagonists of calcium ions, so it is obvious that a compound in which each of the components would have its own antiarrhythmic activity would have an advantage over other compounds.

Our comparative assessment of the antiarrhythmic activity of magnesium salicylate and magnesium acetylsalicylate showed significantly more pronounced (approximately 2.5 times) effectiveness of the non-acetylated drug. The analysis of the results of different effectiveness allowed us to assume that a significant role in the molecular antiarrhythmic effect of magnesium salicylate belongs to the presence of a free hydroxyl group of salicylic acid. This is confirmed by the even lower antiarrhythmic activity of benzoic acid in the form of a magnesium salt, which lacks radicals in the benzene ring. It is possible that the presence of the hydroxyl group of salicylic acid contributes to its stronger interaction with the components of the membrane, since in the magnesium salicylate molecule it is due to them that the magnesium ion is stabilized. Therefore, it is possible that 2,3-dioxybenzoic acid (two free hydroxyl groups) and its magnesium salts will have an even more pronounced antiarrhythmic effect. (Especially because the specified acid was approved for clinical use as an anti-inflammatory agent, and was excluded from the register of medicinal products as having no advantage over modern anti-inflammatory drugs).

Pharmacokinetics and pharmacodynamics of non-acetylated salicylates and aspirin (acetylsalicylic acid or acetic ester of 2-oxybenzoic acid), despite having a lot in common, have significant differences.

Absorption of non-acetylated salicylates in the gastrointestinal tract is faster than that of aspirin.

The anti-inflammatory effect of salicylates is based on the effect on the synthesis of prostaglandins in the arachidonic acid cycle.

The main role in this process is assigned to the enzyme cyclooxygenase. Aspirin irreversibly blocks the enzyme by transferring its acetic (acetyl) group to its active center, thereby hydrolyzing 2o to salicylic acid, which also interacts with the enzyme in the allosteric center, causing blocking of its activity. However, under the influence of esterases, salicylic acid is quickly (within 5 days) "disconnected" from cyclooxygenase, while its function remains inhibited due to acetylation until the synthesis of a new enzyme (3-5 days). Blocking the activity of the enzyme by aspirin in platelets and endothelium leads to the inhibition of the synthesis of thromboxane (a prostaglandin that causes vasospasm and aggregation) and the accumulation of prostacyclin (a substance with opposite properties to thromboxane), since thromboxane synthase is more sensitive to acetylation than prostacyclin synthase. That is why high doses of aspirin do not give a more pronounced i) antiplatelet effect. The same mechanisms underlie the ulcerogenicity and nephrotoxicity of high doses of aspirin, since long-term blocking of the production of prostacyclin in the vessels of the gastric mucosa and the endothelium of the kidney vessels contributes to local vasospasm and ischemia. Hence the recommendation to use aspirin as Ge! with an antiplatelet agent in a dose of up to 50 Ωg/day. However, in some patients (about 2,095) significantly larger doses are needed to achieve the antiplatelet effect (A.I. Dyadyk. Sovremen'e podhod'ye k provdenii antitromboticheskoho scho) therapy for coronary artery disease. Donetsk. 2000). Salicylic acid to a greater extent than aspirin, reveals the ulcerogenic effect of Ge! due to a direct irritating effect on tissues, and to a lesser extent through the prostaglandin system, since the activity of prostacyclin synthase is restored quite quickly. ise)

When using magnesium salicylate, the risk of irreversible inhibition of the enzyme is reduced if it is necessary to use large doses of the substance. It is known that salts of salicylic acid and its amide are in some cases better tolerated than acetylsalicylic acid |M.D. Mashkovsky. Medicines. Aid for doctors.

Edition 11, corrected, supplemented and reworked. 2000. - 1.1. - P.165-167)|, In numerous randomized studies on the safety of long-term treatment with anti-inflammatory drugs, it has been proven that "the lowest "toxicity index" was in non-acetylated derivatives of salicylic acid. The development of enteric-soluble forms of aspirin made it possible to reduce this indicator compared to acetylsalicylic acid in tablets. (AN Okorokov. Treatment of diseases of internal organs. In 4 volumes. M. 2000. - 7.2. - :z» P.27-371.

In addition, the presence of an antiaggregative effect is very valuable for a cardiology remedy. It is this property of aspirin that made it possible to recommend it to the protocol for the management of patients with myocardial infarction and ischemic heart disease. In addition, a decrease in the severity of reperfusion arrhythmias (that is, provoked by the resumption of coronary blood flow during thrombolysis) was also noted. It is recognized that the basis of the development of these rhythm disturbances lies in damage to membranes by products of lipid and protein peroxidation. Noted

Ge) ID. V. Preobrazhensky, 1994. In the book: Treatment of diseases of internal organs. Ed. A.N. Okorokova. In 4 volumes. 5o M: 2000. T.3. P. 1861 the positive effect of aspirin on the mortality of patients with myocardial infarction in the distant term, although the authors did not draw a conclusion about the direct antiarrhythmic effect of aspirin. The same effect was observed by others

Ge) authors, and the early appointment of aspirin after thrombolysis in myocardial infarction reliably reduced the development of ventricular arrhythmias (O. Egeitagk, 5. MaiyeysgKu, .I eog e( aI./ At Sagayo!. - 2002. - M.89. - R. 381-3851.

The development of new dosage forms made it possible to create water-soluble aspirin analogues for oral and parenteral administration. The complex salt of aspirin with the amino acid lysine ("acelisin", "aspiol") is well soluble in water, has a lower ulcerogenic effect, can be administered intravenously in cases of need (F, obtaining a rapid therapeutic effect in doses up to 100 ml per day of 195 solution (1Og/day) |M.D. Mashkovsky. ka Lekarstvennye, srednat. Posobie dlya vrachei. Izdaniye 11, ispravlennoe, dopolnennoe i pererabotannoe. 2000. Vol. 1. P. 165-167Y. In addition to its antiplatelet effect, it has a pronounced analgesic, antipyretic, and anti-inflammatory effect.

Among the derivatives of salicylic acid, 5-aminosalicylic acid has also been studied as an antiarrhythmic agent (Table 4). 65 Antiarrhythmic effectiveness of the studied substances on experimental models of AS in rats

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It was established that BB-aminosalicylic acid has a pronounced antiarrhythmic effect, especially on the aconitine and 7/0 membrane-destructive heart arrhythmia models, surpassing the comparator drug amiodarone. Membranoprotective and anti-inflammatory effects play a significant role in the mechanism of action of 5-aminosalicylic acid. Cardiotoxic effects are not observed when using it.

Since 5-aminosalicylic acid is used in medicine for autoimmune connective tissue diseases, and in case of acute myocardial infarction, the possible development of Dressler's autoimmune syndrome, it was appropriate /5 to study the antiarrhythmic activity of the combination of magnesium salicylate and 5-aminosalicylic acid in an equimolar ratio, which in such a combination could be detected complex anti-inflammatory and antiarrhythmic effect (see table 5.) Bamkosapicitetto 19787 70808883 5 wk i 11111yamodaon o 4") from 1 from | 5) 313 65) 4 | from milestones) o

Thus, the conducted studies indicate that the specified combination exhibits pronounced antiarrhythmic activity, which, given the theoretical prerequisites, may prove to be an effective means of F for the long-term therapy of cardiac arrhythmias, especially in patients with systemic inflammatory diseases, in which the use of other antiarrhythmic agents is contraindicated . and what)

It is known that antiarrhythmic therapy in 2590-3095 is ineffective. To overcome resistance to Ge! combined therapy of antiarrhythmic drugs is carried out. However, the combination of antiarrhythmic drugs often leads to undesirable side effects (including arrhythmogenic effects). Therefore, according to the recommendations of Section 35 of the RKPR-2000, in acute myocardial infarction, it is prescribed to administer novocainamide (procainamide), amiodarone or chalidocaine, and it is recommended to use only one drug, avoiding the simultaneous use of AAP

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Thus, as a result of the conducted research, a pronounced potentiation of the effectiveness of the drugs on experimental models of cardiac arrhythmias is noted, which will allow to reduce the doses used

Ge of each of them, because when taking novocainamide in large doses, the development of lupus syndrome is possible.

In addition, novocainamide lengthens the OT interval, which is a factor of arrhythmogenic action according to the type of development of "pirouette" - tachycardia. In the clinic, magnesium salts are used to correct the specified effect of novocainamide. Therefore, the combination with magnesium salicylate allows to reduce the risk of developing the syndrome of prolonged OT interval.

Thus, the use of salicylic acid derivatives according to the invention as active components (F) of the pharmaceutical composition allows effective and safe treatment of arrhythmias, which

GI is confirmed by the above information.

Claims (19)

60 Formula of the invention 1. Application of salicylic acid derivatives of the general formula I b5 : SHO) ZE BEK: PEN hi gi and A same states B B-e5 then in which B' means a group of the formula where 5 is selected from the group which includes hydrogen and oxyphenyl; or B" means a group of the formula B, where B! is selected from the group consisting of hydrogen, alkali or alkaline earth metals such as sodium, potassium, calcium, magnesium; B? means hydrogen, OH or acetyl; EZ means hydrogen or OH ; ВЕ? means hydrogen or OH; 2? means hydrogen, an amino group or an acetylamino group, or their pharmaceutically acceptable salts; as an active component of a pharmaceutical composition with antiarrhythmic activity. 2. Application according to claim 1, which differs in that in the general formula I B" means a group of the formula o where K5 means oxyphenyl; 22, 23, B and 2? stand for hydrogen. 3. The application according to claim 1, which differs in that in the general formula I 2" means the group of the formula Me with B, where B" means magnesium; b" In? selected from the group consisting of hydrogen, acetyl; VZ stands for hydrogen; ise) B" means hydrogen; cha VE means hydrogen, an amino group, or an acetylamino group. 4. Application according to item C, which differs in that B means magnesium; 22, 23, 27 mean hydrogen; " VE means hydrogen, amino group or acetylamino group. 5. Application according to point C, which differs in that not) c B means magnesium; :z" In? means acetyl; VZ stands for hydrogen; B" means hydrogen; -and 2? means hydrogen, an amino group, or an acetylamino group. b 6. Application according to claim 1, which differs in that the salicylic acid derivative of the formula I! selected from the group consisting of: (se) magnesium salt of 2-oxybenzoic acid; ml 50 M-(para-oxyphenyl)-salicylamide. | | that J 7. A pharmaceutical composition with antiarrhythmic activity, which is characterized by the fact that as an active component iChe) contains at least one derivative of salicylic acid of the general formula | according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, in an effective amount, together with pharmaceutically acceptable excipients and/or carriers. 8. Pharmaceutical composition according to claim 7, which differs in that it contains magnesium salicylate as an active component. o 9. Pharmaceutical composition according to claim 7, which differs in that it contains 5-aminosalicylate as an active component. 10. Pharmaceutical composition according to claim 7, which differs in that it contains 60 magnesium acetylsalicylate as an active component. 11. Pharmaceutical composition according to any of claims 8-10, which is characterized by the fact that it additionally contains novocainamide. 12. Pharmaceutical composition according to claim 8, which is characterized by the fact that it additionally contains 5-aminosalicylate. 13. Pharmaceutical composition according to claim 11, which is characterized by the fact that it contains the specified components in a mass ratio of 20:1 to 1:20. 14. Pharmaceutical composition according to claim 12, which is characterized by the fact that it contains the specified components in a mass ratio of 5:1 to 1:5. 15. Pharmaceutical composition according to any one of claims 7-14, which differs in that it is presented in the form of a dosage form for oral administration. 16. Pharmaceutical composition according to claim 15, which differs in that it is presented in the form of tablets or capsules. 17. Pharmaceutical composition according to any of claims 7-14, which differs in that it is presented in the form of a dosage form for parenteral use. 18. Pharmaceutical composition according to claim 17, which differs in that it is presented in the form of a solution for 7/0 injections. 19. A method of treating arrhythmias, which is characterized by the fact that the patient is administered an effective amount of the pharmaceutical composition according to any of claims 7-18. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated 7/5 Microcircuits", 2006, M 10, 15.10.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c schi 6) (o) IS) (o) (Se) and - - with . and? -I (o) se) c 50 3e) ime) 60 b5