Purine ribosides as anti-arrhythmic agents

FIELD: organic chemistry, heterocyclic compounds, purines, medicine.

SUBSTANCE: invention relates to a method for treatment of arrhythmia in mammal. Method involves administration of agonist of adenosine A1-receptors in the therapeutically effective minimal dose of the formula:

wherein R1 represents optionally substituted heterocyclic group. The indicated dose of agonist is in the range from 0.0003 to 0.009 mg/kg. Method shows the enhanced effectiveness and doesn't result to undesirable adverse effects.

EFFECT: improved treatment method, valuable medicinal properties of substances.

11 cl, 1 dwg, 2 ex

 

Background of the invention

The scope of the invention

This invention relates to a method for the treatment of atrial arrhythmias, which minimizes unwanted side effects and includes the introduction of agonist And1adenosine receptor in low doses.

Prior art

Atrial fibrillation, such as primary atrial fibrillation, atrial flutter and paroxysmal atrial tachycardia (PSVT), are abnormal heart rhythms that occur due to various factors. Arrhythmia can be in the range of incidental, asymptomatic clinical symptoms to life-threatening pathological conditions. For arrhythmia include a significant percentage of causes of death in humans. Thus, it is desirable to develop methods of mitigation arrhythmia.

Currently, there are various types of anti-arrhythmic drug therapy. However, these compounds have significant limitations. For example, digoxin has a delayed onset of action (about 30 min), and maximum effects were not observed within 3-4 h after injection. Other examples are widely used for the treatment of arrhythmias β-blockers and calcium channel blockers, which can cause hypotension and exert negative inotropic effects.

densin is a naturally occurring compound, which is highly effective for the relief of arrhythmia. However, adenosine has a wide variety of physiological effects. Multiple kinds of activity of adenosine mediated by its interactions with the family of adenosine receptors, known as A1, A2AAnd2Band a3adenosine receptors, each of which regulates certain types of biological activity. For example, adenosine is associated with A1the adenosine receptors in the heart, which leads to dromotropic effect, while linking And2Athe adenosine receptor leads to expansion of coronary vessels. Similarly, adenosine binds to And2Bthe adenosine receptor, affecting, therefore, a wide range of activities, including, as mention only some of them, angiogenesis, cell proliferation and apoptosis. On the other hand, adenosine binds to And3receptors on the fat cells, by stimulating the degranulation and release of histamine.

Antiarrhythmic effects of adenosine caused solely by its interaction with a subtype of A1adenosine receptor. However, the simultaneous binding of adenosine subtype And2AAnd2Band a3leads to undesirable side effects such as vasodilatation, changing frequency serdechnosti and degranulation of mast cells. Thus, the lack of selectivity of adenosine against subtype a1receptors makes adenosine unsuitable for the treatment of arrhythmias. In addition, adenosine has a short half-life (about 10 s), which makes it ineffective in any condition that requires long-term effects of the drug.

Therefore, there is a need for a method of treating arrhythmia therapies that election in respect of A1adenosine receptor, have sufficiently long half-life periods and have fewer adverse effects. The preferred connection must be active at very low doses, because lower doses provide less possibility of side effects.

New classes of agonists that are associated with A1the adenosine receptor and which can be used in the treatment of arrhythmias, as described in U.S. patent No. 5789416, full details of which are included here as a reference. These compounds have high specificity in relation to the subtype of A1adenosine receptor, but, like all compounds that have a therapeutic effect, they have the potential to cause side effects.

Disclosed in the document ‘416 effective dose of the compounds is in the range from 0.01 to 100 mg/kg Unexpectedly, the authors present the image is placed found the data connection is active in much lower doses (0,0003-0,009 mg/kg)than identified as effective in the document ‘416. Accordingly, a new and effective way to treat arrhythmias, which restores sinus rhythm without slowing the sinus frequency and essentially devoid of unwanted side effects, such as changes in mean arterial pressure, blood pressure, heart rate or other adverse effects.

The invention

The object of the present invention is an effective method for the treatment of atrial arrhythmias in a mammal, at the same time, minimizing unwanted side effects. Accordingly, in the first aspect of the invention relates to a method for the treatment of atrial arrhythmias in a mammal, comprising the introduction needs it the mammal a therapeutically minimum dose of agonist (A1adenosine receptor formula I:

where

R1represents an optionally substituted heterocyclic group, preferably monocyclic, and the specified minimum dose is in the range from 0.0003 to 0,009 mg/kg

In a more preferred embodiment, the implementation of R1is a 3-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-pyranyl and 4-dipiradol.

is soedineniya formula I exist as racemic mixtures or as individual isomers. Most preferred is (6-(R)-tetrahydrofuran-3-ylamino)polyribosyl.

The most preferred embodiment of the invention is a method for the treatment of atrial arrhythmias in a mammal, comprising introducing a therapeutically minimum dose of from 0.0003 to 0,009 mg/kg (6-(R)-tetrahydrofuran-3-ylamino)polyribosome, hereinafter referred to as CVT-510.

Description of the drawings

The dynamics of the effect of CVT-510 on an interval (conduction from the Atria to the bundle of his).

Table. Impact on PSVT CVT-510 in doses 0,3, 1,0, 3,0, 7,5, 10, 15 and 30 µg/kg

Abbreviations:

AV: atrioventricular

BP: blood pressure

HR: heart rate

HV: carrying out from the bundle of his to the ventricles

WCL: cycle time of Wenckebach

SH: the incentive to bundle of his (the duration time of the current through the AV node)

PSVT: paroxysmal atrial tachycardia

Definition

Used in the present description, the following words and phrases, in General, have the following meanings, except in those cases where the context in which they are used, there are other indications.

The term "heterocycle" or "heterocyclyl" refers to monologically saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably from 1 to 4 is of heteroatoms in the ring, selected from nitrogen, sulfur, phosphorus and/or oxygen. Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocycles include tetrahydrofuran, tetrahydrothiophene, pyranyl, 4-dipiradol, morpholino, piperidinyl and the like.

In the absence of other restrictions in the definition of the heterocyclic substituent, such heterocyclic groups can be optionally substituted by 1-5, preferably 1-3 substituents selected from the group comprising alkyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, substituted amino, cyano, halogen, hydroxyl, oxo, taketo, carboxyl, carboxylic, thiol, dialkoxy, aryl, aryloxy, heteroaryl, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl.

The term "halogen" refers to fluorine atoms, bromine, chlorine and iodine.

The term "oxo" refers to =O.

The term "hydroxyl" refers to the group-HE.

The term "alkyl" refers to monologically branched or not branched saturated hydrocarbon chain, having from 1 to 20 carbon atoms. This term is illustrated by such groups as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-hexyl, n-decyl, tetradecyl, etc.

The term "lower alkyl" relative to the tsya to monologically branched or unbranched saturated hydrocarbon chain, having from 1 to 6 carbon atoms. This term is illustrated by such groups as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, n-hexyl and the like.

The term "substituted lower alkyl" refers to lower alkyl as defined above, substituted by one or more groups selected from hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cyclogeranyl, substituted cyclogeranyl, acyl, carboxyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroalkyl, alkylalcohol, alkylamine, alkylcyclohexane, alkylcyclopentanes and cyano. These groups can be attached to any carbon atom of the group lower alkyl.

The term "cycloalkyl" refers to cyclic alkyl groups of from 5 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include as an example adnakolava patterns, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or poly-ring structure, such as adamantyl and bicyclo [2.2.1] heptane, etc.

The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 replace the Fort worth, selected from the group comprising alkoxy, cycloalkyl, acyl, acylamino, acyloxy, amino, substituted amino, cyano, halogen, hydroxyl, keto, taketo, carboxyl, carboxylate, thiol, dialkoxy, aryl, aryloxy, heteroaryl, heteroaromatic, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and-SO2-heteroaryl.

The term "alkoxy" refers to the group-OR where R represents an alkyl, lower alkyl or substituted lower alkyl as defined above.

The term "acyl" denotes the group-C(O)R, where R represents hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, amino and the like.

The term "amino" refers to the group-NH2.

The term "substituted amino" refers to the group-NRR where each R is independently selected from the group comprising hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl, provided that both R are not hydrogen. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nR, where R is an alkyl, aryl or heteroaryl, and n is 0, 1 or 2.

The term "aryl" refers to aromatic carbocyclic group having at least one aromatic ring (e.g., f the Nile or biphenyl) or multiple condensed rings, in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, antrel or financil).

The term "substituted aryl" refers to aryl, optionally substituted by one or more functional groups, for example, halogen, lower alkyl, lower alkoxy, lower akitio, trifluoromethyl, amino, amido, carboxyla, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "aryloxy" denotes the group-OAS, where AG represents aryl, substituted aryl, heteroaryl or substituted heteroaryl.

The term "heteroaryl" refers to an aromatic group (i.e. unsaturated)comprising from 1 to 15 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur, at least one ring which may be optionally substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyla, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol or sulfamido.

The compositions of this invention are agonists And1receptors, which can be used for the treatment of coronary electric disorders such as arrhythmia, including SVT, mercata is inuu fibrillation, atrial flutter, AV nodal tachycardia associated with circulation stimulation. Compositions can be administered orally, intravenously, through the epidermis or any other way known in this area for the introduction of therapeutic agents.

The treatment method includes introducing an effective amount of the selected compound, preferably dispersed in a pharmaceutical carrier. The standard dose of the active ingredient is selected from the range from 0.0003 to 0,009 mg/kg, depending on the route of administration, the age and condition of the patient. Data standard dose can be administered from one to ten times/day for acute or chronic disorders.

If the target compound in this invention contains a basic group can be obtained acid additive salt. Acid additive salts of compounds receive a standard manner in a suitable solvent of the generic compounds and an excess of acid, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methansulfonate. The form of the salts of hydrochloric acid are especially suitable for use. If the target compound contains an acid group can be obtained cationic salt. Usually a generic connection is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, terrasim the corresponding cation. Such cations as Na+To+, CA+2and NH

+
4
are examples of cations present in pharmaceutically acceptable salts. Some compounds form an internal salt or zwitterion, which can also be acceptable.

Pharmaceutical compositions comprising compounds of the present invention, and/or their derivatives can be prepared as solutions or liofilizovannyh powders for parenteral administration. Before applying to the powders can be added suitable thinners or other pharmaceutically acceptable carriers. When used in liquid form compositions according to this invention, preferably, included in the buffer, isotonic, aqueous solution. Examples of suitable diluents are isotonic saline solution, a standard 5% dextrose in water and buffer solution of sodium acetate or ammonium. Such liquid compositions suitable for parenteral administration, but they can also be used for oral administration. For pharmaceutical compositions comprising compounds according to this invention, it may be desirable to add excipients such as polyvinylpyrrolidine, gelatin, hydrocellulose, gum, poly is trangleball, mannitol, sodium chloride, sodium citrate or any other excipient known to the person skilled in the art. Alternatively, the compounds of formula I may be encapsulated, tableted or prepared in an emulsion syrup for oral administration. To enhance or stabilize the composition or to facilitate the obtaining of the composition can be added pharmaceutically acceptable solid or liquid carriers. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, white Teff, magnesium stearate or stearic acid, talc, pectin, resin of acacia, agar or gelatin. The carrier may also include material for sustained release, such as glycerol monostearate or glycerol distearate, alone or with a wax. The amount of solid carrier will vary, but preferably it is from about 20 mg to about 1 g per standard dose. Pharmaceutical dosage prepared using conventional methods, such as crushing, mixing, granulation and, if necessary, pressing for tablet forms; or crushing, mixing and filling forms in the form of hard gelatin capsules. When using a liquid medium, the drug will be in the form of a syrup, elixir, emulsija water or not water suspension. This liquid composition can be entered directly or filled into a soft gelatin capsule.

The following examples serve to illustrate the present invention. Examples are in no way intended to limit the scope of the claims in this invention, but are presented to illustrate how to obtain and use the compounds according to this invention. In the examples all temperatures expressed in degrees Celsius.

EXAMPLES

The compounds of formula I can be obtained by conventional means, as described in U.S. patent No. 5789416, full details of which are included here as a reference.

Example 1

A. Obtaining ((S)-tetrahydrofuranyl-3-amino)polyribosome

Stage 1. Dissolve (3-(S)-aminotetrahydrofuran

A mixture of the hydrochloride of 3-aminotetrahydrofuran (0.5 g, 4 mmol) and (S)-(+)-10-camphorsulfonate (1.1 g, 4.4 mmol) in pyridine (10 ml) is stirred for 4 h at room temperature and then concentrated. The residue is dissolved in EtOAc and washed with 0.5 n Hcl, sodium bicarbonate and saline. The organic layer is dried over gSO4filter and concentrate to obtain 1,17 g brown oil (97%), which chromatographic on silica gel (25 to 70% EtOAc/Hex). The obtained white solid is repeatedly recrystallized from acetone until then, until the achieved gain is of more than 90% of 1H NMR, obtaining (S)-camphorsulfonate 3-(S)-aminotetrahydrofuran.

Stage 2. Obtaining 3-(S)-aminotetrahydrofuran hydrochloride

(S)-Camphorsulfonic 3-(S)-aminotetrahydrofuran (170 mg, 0,56 mmol) was dissolved in conc. HCl/AcOH (2 ml each), stirred for 20 h at room temperature, washed three times CH2CL2(10 ml) and concentrated to dryness to obtain 75 mg of 3-(S)-aminotetrahydrofuran in the form of a white solid.

Stage 3. Obtain (6-(R)-tetrahydrofuran-3-ylamino)polyribosome

A mixture of 6-globulinemia (30 mg, 0.10 mmol), hydrochloride of 3-(S)-aminotetrahydrofuran (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol (0.5 ml) is heated to 80°C for 18 hours the Mixture is cooled, concentrated and chromatographic 95/5 (CH2Cl2/MeOH) to give 8 mg (24%) (6-(R)-tetrahydrofuran-3-ylamino)polyribosome in the form of a white solid.

C. Obtain ((R)-tetrahydrofuranyl-3-amino)polyribosome (CVT-510)

Similarly, following the above stages 1-3, but substituting (S)-(+)-10-camphorsulfonate (R)-(-)-10-camphorsulfonate receive the following connection: (6-(R)-tetrahydrofuran-3-ylamino)polyribosyl (CVT-510).

Similarly receive other enantiomers of the compounds of formula I.

Example 2

The effect of CVT-510 for lengthening an interval, an indicator of the effect of CVT-510-mediated sub> 1the adenosine receptor, and heart rate (frequency of sinus rhythm) patients with PSVT studied in patients undergoing clinically indicated electrophysiological study. In the first study patients-volunteers were administered a single bolus SVT-510. In the second study PSVT caused patients before the introduction of CVT-510.

Introduction of all antiarrhythmic drugs, including digoxin, beta-blockers and calcium channel blockers were discontinued before the study for a period of five half-life periods.

Patients were excluded from the study if the PR interval was >200 MS or heart rate at rest was <60 >100/min excluding Other indicators include data pre-excitation of the ventricles, heart failure II-IV classes or asthma. It was also required that patients had normal baseline electrophysiological parameters, including the duration of the AV nodal cycle Wenkebach by electrical stimulation, component 500 MS, an interval from 60 to 125 MS and HV interval from 35 to 55 MS. All patients were 18 years of age.

Four catheters were introduced through the skin and carried out under fluoroscopic control in the upper part of the right atrium and through the tricuspid ring valve to register potential of the bundle of his. Bipolar is e, intracardiac the recorded signals were filtered at 30 and 500 Hz and using surface ECG leads taken out on the digital display monitor. Data stored on an optical disc. All patients throughout the study conducted continuous monitoring of ECG and blood pressure non-invasive method.

Electrical stimulation of the heart was performed by a programmable stimulator using an isolated DC source. The stimulus was applied in the form of rectangular pulses of 2 MS, a value four times greater than the diastolic threshold. The study design was an open study with higher doses, the latter was determined by tolerance. A single bolus intravenous administration of CVT-510 was performed for each patient after the original electrophysiological measurements.

After bolus intravenous administration of CVT-510 blood pressure, heart rate, 12-lead ECGs and spacing of the Academy of Sciences and HV were recorded after 1, 5, 10, 15, 20 and 30 min, and then every 15 min for a period of time up to 1 h after a bolus injection or as long as the performance is not returned to the original level. Intervals and an HV was determined by measurement of the last interval for a series of 15 cuts the length of the loop electrical stimulation of 600, 500 and 400 MS (which if it was not preceded by Fes AV nodal period Wenkebach).

The introduction of CVT-510 was started at a dose of 0.3 ág/kg, the dose was continued with an additional group of patients receiving dose 1, 3, 7, 5, 10, 15 and 30 mg/kg on the basis of tolerability and the absence of atrioventricular nodal period Wenckebach or 3 AV blockade during sinus rhythm.

Data are expressed as the average value of the±the standard deviation. Based on the results of normality test to determine the significance of the effects of CVT-510 on heart rate, blood pressure, ECG and time atrioventricular nodal conduction (and an HV) for each group (for example, 0, 3, 1,0, 3,0, 7,5, 10,0, 15,0 and about 30.0 mg/kg) used a paired t-test or nonparametric marked the ranking criterion (SR). Similarly, for comparing an interval during sinus rhythm and atrial stimulation at all doses used analysis of variance (ANOVA) or the criterion of Well-Wallis (KW). Adjustments for multiple comparisons were not made, and the value of P <0.05 is used to determine the significance of differences between mean values.

The results are summarized as follows:

The drawing shows the dynamics of the effect of different doses of CVT-510 on an interval. The maximum effect of CVT-510 on an interval occurred after 1 min after a dose of 7.5 mg/kg

The table below shows the results of treatment of patients with SV Asami CVT-510 in the range of from 0.003 to 0.015 mg/kg, presented in the form of a bolus with an interval of at least 1 min before termination of the arrhythmia. Most patients (75%and 100%, an average value of 98%) rhythm turned into a sinus after the introduction of the first bolus CVT-510.

Level dose% conversion after 1 bolus% conversion after 2nd bolus% of total transformation95% confidence interval
3 (n=4)7525100You cannot define
5 (n=9)780780,400,96
7,5 (n=4)1000100You cannot define
10 (n=5)900900,381
12,5 (n=4)7525100You cannot define
15 (n=10)8010900,540,99
ALL0,980,980,980,980,98

Data show that CVT-510 slows AV nodal conduction dependent on the dose of the image is m Onset of action was rapid (observed for 1 minute after administration), and its effects are mainly eliminated to 20 minutes No impact on the frequency of sinus rhythm, which indicates a relatively greater sensitivity of the AV node than the sinoatrial node to this agonist (A1adenosine receptor.

CVT-510 also showed specificity in respect of A1adenosine receptor, i.e. no effects on systemic arterial pressure. Effects of CVT-510 on the AV node (but not on coronary conductance) is completely removed by the selective antagonist And1receptors CPX. It was also shown that CVT-510 does not affect the pressure in the left ventricle or dPdt-1max.

Thus, the data show that CVT-510 has a new and unusual properties that make it useful antiarrhythmic treatment for PSVT and to regulate the ventricular frequency during atrial fibrillation, atrial flutter. Its properties election And1agonist provide the opportunity CVT-510 to have a significant negative dromotropic effects on the AV node, causing a concomitant hypotension due to effects mediated And2the adenosine receptor. Its relatively long half-life, compared with adenosine, also makes possible the m to maintain a favorable therapeutic effect over a longer period of time.

At low concentrations CVT-510 also quickly terminate PSVT, without causing hypotension, lengthening HV or suppression of the sinus or AV nodal conduction after restoration of sinus rhythm. Selective depression time AV nodal conduction without hypotension indicates that continuous infusion of CVT-510 can also be used to regulate the frequency of contractions of the ventricles during atrial fibrillation, even in patients with impaired left ventricular function.

Now after a complete description of the invention the specialist should be clear that there can be made many changes and modifications without deviating from the essence or scope of the attached claims.

1. A method of treating arrhythmias in a mammal, including the introduction in need of such treatment to the mammal a therapeutically effective minimal dose of agonist And1adenosine receptor of the formula I

where

R1represents an optionally substituted heterocyclic group, and

this dose is in the range from 0.0003 to 0,009 mg/kg

2. The method according to claim 1, where R1is a 3-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-pyranyl or 4-dipiradol.

3. The method according to claim 2, where R1is a 3-tetrahydrofuranyl.

4. The method according to claim 3, where R1

5. The method according to claim 4, where the introduction is by intravenous infusion.

6. The method according to claim 4, where the introduction is one bolus.

7. The method according to claim 1, where the arrhythmia is selected from the group consisting of atrial fibrillation, atrial flutter and paroxysmal atrial tachycardia.

8. The method according to claim 7, where R1is a 3-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-pyranyl or 4-dipiradol.

9. The method of claim 8, where R1is a 3-tetrahydrofuranyl.

10. The method according to claim 9, where R1represents (R)-3-tetrahydrofuranyl, namely, (6-(R)-tetrahydrofuran-3-ylamino)polyribosyl.

11. The method according to claim 1, where the specified mammal is man.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to synthesis of new biologically active substance, namely, to γ-hydroxypropylammonium-5-hydroxynicotinate of the formula (I): , eliciting an anti-ischemic, anti-arrhythmic and hypolipidemic activity. This compound shows low toxicity and absence of cardiodepressive effect. Compound of the formula (I) is prepared by interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent at heating.

EFFECT: valuable medicinal properties of compound.

1 cl, 7 tbl, 3 ex

The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims

The invention relates to medicine, namely to create MiniPack emergency self - help and mutual aid

The invention relates to the field of pharmaceutical industry and relates to the production of solid dosage forms of drugs to reduce the resistance of the coronary arteries and increase coronary blood flow, ischemia of heart contractions, reducing the need of oxygen, increase energy reserves attacks

The invention relates to the section of experimental medicine and can be used to create a new antiarrhythmic drug

The invention relates to new derivatives of benzopyran formula (I)

where R1and R2each independently represent a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, a C1-6-alkoxygroup or a hydroxyl group; R3represents a hydroxyl group or a C1-6-alkylcarboxylic; R4represents a hydrogen atom, or R3and R4together form a bond, m is an integer from 0 to 4, n represents an integer from 0 to 4, Y is absent or represents CR11R12where R11and R12each independently represents a hydrogen atom or a C1-6is an alkyl group, R5represents an aryl group or heteroaryl group, such as thienyl, pyridyl or indolyl, where this aryl group may be optionally substituted(R10), where R10represents a halogen atom, a hydroxyl group, a C1-6-alkyl group, where this alkyl group may be optionally substituted by atom galactography, di-C1-6-alkylamino, C1-6-alkoxycarbonyl group, carboxyl group, q is an integer from 1 to 3, and each R10may be the same or different when q is 2 or 3, R6represents a hydrogen atom or a C1-6is an alkyl group, R10represents a hydrogen atom or a C1-6is an alkyl group, X is absent or represents C=O or SO2; R8represents a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, or WITH3-6-cycloalkyl group, and R9represents a halogen atom, a nitro-group, or cyano; or their pharmaceutically acceptable salts, as well as a drug on the basis of these compounds with anti-arrhythmic activity

The invention relates to a new group of pyrrole, in particular 1-(2,4,6-trimetilfenil)-2-[(2-hydroxy-3-phenyloxy)-N-substituted-aminomethyl]pyrrole General formula

where VI, R=-H, VIa R=-C(O)H, VIIб R=-C(O)CH3, VIIIa R=-CH3, VIIIб R=-C2H5and their pharmaceutically acceptable salts of dicarboxylic acids, which have anti-arrhythmic and anti-ischemic activity and intensity of effect exceeds applicable in the clinic verapamil, amiodarone and lidocaine

The invention relates to chemical-pharmacological industry and relates to new biologically active chemical compounds of the hydrochloride of 3-(2-hydroxyethyl)-1,5-dinitro-3-azabicyclo[3.3.1]non-6-ene of formula (1) with high antiarrhythmic activity and low toxicity

The invention relates to medicine and is a pharmaceutical combination containing antagonist of P2C-receptor and other antithrombotic agent, and their use for the treatment and prevention of thrombosis

The invention relates to medicine, namely to the development of new combinations Antiherpes virus effect of actions

The invention relates to medicine, specifically to pharmacology
The invention relates to medicine, particularly cardiology, and for the treatment of paroxysmal supraventricular tachycardia

The invention relates to medicine and can be used to obtain therapeutic agents with anti-ischemic activity in the prevention and treatment of ischemic heart disease

The invention relates to purine derivative of L-nucleoside of the formula (I), where R1, R2', R3' and R4- N; R2, R3and R5- HE; Z1- N; Z2selected from N and CH; Z3- NR-, -C(R)2, -S-, where R, same or different, selected from H, Br, NH2, alkyl and alkenyl; Z4selected from C=O, -NR-, -C(R)2- where R, same or different, selected from H and Br; Z5Is N; X is selected from H, HE, SH, -SNH2, -S(O)NH2, -S(O)2NH2Y from H and NH2; W is O, and Y represents NH2then Z3is not a-S-
The invention relates to medicine, in particular to gynecology

FIELD: organic chemistry, heterocyclic compounds, purines, medicine.

SUBSTANCE: invention relates to a method for treatment of arrhythmia in mammal. Method involves administration of agonist of adenosine A1-receptors in the therapeutically effective minimal dose of the formula:

wherein R1 represents optionally substituted heterocyclic group. The indicated dose of agonist is in the range from 0.0003 to 0.009 mg/kg. Method shows the enhanced effectiveness and doesn't result to undesirable adverse effects.

EFFECT: improved treatment method, valuable medicinal properties of substances.

11 cl, 1 dwg, 2 ex

Up!