Cyclic compounds of urea, pharmaceutical composition and method of treatment

 

(57) Abstract:

Cyclic compounds of urea of the formula I, where R1, R2, R3is hydrogen, chlorine, fluorine or bromine; R4- C3-6-alkylen; And - dimethylamino, diethylamino, bis-2-hydroxyethylamino, bis-[(1-methyl)ethyl] amino, N-(2-hydroxyethyl)-N-methylamino, 4-(2-hydroxyethyl)-1-piperazinil, 4-[[(1-methyl)ethyl] ]-1-piperazinil, 4-[(2-methyl)-propyl] -1-piperazinil, 4-hexyl-1-piperazinil, 1-piperazinil, 4-methyl-1-piperazinil, 4-n-butyl-1-piperazinil, 4-ethyl-1-piperazinil; R5- C1-2alkylene; or their pharmaceutically acceptable salts or esters, exhibit antiarrhythmic and antifibrillatory activity. 3 c. and 4 C.p. f-crystals.

The present invention relates to new cyclic urea compounds and their pharmaceutical compositions, which can be used for the treatment of humans or other mammals suffering from cardiac arrhythmia and/or cardiac fibrillation.

New cyclic compounds urea of the present invention have antifibrillatory and antiarrhythmic activity. The considered compounds find wide range of actions against cardiac arrhythmia and atrial and can successfully be used in the to have less unwanted side effects, than many well-known antiarrhythmic therapeutic drugs. Another advantage of the compounds described in this application, is that they have as antifibrillatory and antiarrhythmic activity, whereas the majority of known therapeutic drugs have only antifibrillatory action (see, for example, the work Copley (S. E. Coplen and others (Efficacy and Safety of Quinidine Therapy for Maintenance of Sinus Rhethm after Cardioversion: A meta-analysis, Circulation, vol. 82, p. 1106 - 1116 (1990)) and the work Echt (Echt D. S.) and others (Mortality and Morbidity in Patients receiving Ecainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial", N. Engl. J. Med., vol. 324, p. 781 - 788 (1991), both of these works are included here as a reference).

In a healthy heart, normal tone strictly sequential electrical activation and then deactivation of the entire heart of the machine, which invariably occur with each heartbeat, characterized as a normal heart rhythm. Arrhythmias are characterized as manifestations of abnormal electrical activity, which can disrupt normal heart rhythm. Abnormal electrical activity may affect the initiation and/or uniformity of distribution of electric waves (i.e., depolarization and subsequent repolarization senichenkov process of the functioning of the heart, normal heart rhythm is in some cases the phenomenon, life threatening.

The gravity of the arrhythmia is classified as relatively benign (consisting of asymptomatic and infrequent ventricular extrasystoles) to life threatening (consisting of ventricular fibrillation and persistent ventricular tachyarrhythmias). Arrhythmia and ways of antiarrhythmic therapy are described in detail in the literature (see, for example, Bigger, Thomas J., "Antiarrhythmic Treatment: An Overview", American Journal of Cardiology, vol. 53, p. 8B-16B, February 27, 1984; Goldstein, S., "Towardas New Understanding of the Mechanism and Prevention of Sudden Death in Coronary Heart Disease, Circulation, vol. 82(1), p. 284 - 88 (1990); Woosley, R. L., "Antiarrhythmic Drugs", Annu. Rev. Pharmacol. Toxicol., vol. 31, p. 427 - 455 (1991)), and all these works are introduced in the present description by reference. Life-threatening arrhythmia are the leading cause of death worldwide. For example, it was found that sudden death from a heart attack caused by ventricular fibrillation, is in the United States the cause of death of about 400000 - 600000 people annually (monthly demographic statistical report N 33:8-9 National center for health statistics (NCHS) of the Department of health and human Sciences USA (1985)).

In General, arrhythmias are divided into two types: 1) supraventricular arrhythmias (for example, Phi is inhibiting fibrillation and atrial flutter).

Supraventricular arrhythmias mostly are not life-threatening. Individuals with these types of arrhythmia can experience a wide variety of symptoms from mild to severe intensity. These individuals can physically feel interruptions, increased frequency and/or a pounding heart, sometimes a slight or significant dizziness, shortness of breath and/or chest pain. Because in fact this situation is not life-threatening, in such cases usually do not resort to more radical treatments, such as use of standard antiarrhythmic drugs because of the side effects of these drugs cannot be used in cases that do not pose a danger to life. However, the new compounds of the present invention mainly migrated easier than many common, currently available antiarrhythmic drugs; therefore they can be used to treat individuals suffering from supraventricular arrhythmias, which will greatly reduce the discomfort from these individuals.

Ventricular fibrillation, on the other hand, are potentially much more serious and meaning/BR> 3) life threatening (lethal) (see , for example, work Morganroth (Morganroth J. ) and Bigger (Bigger, J. T.) ("Pharmacological management of ventricular arrhythmias after the Cardiac Arrhythmia Syppression Trial", Amer. J. Cardiol., vol. 65, p. 1497 - 1503 (1990)), which is introduced in the present description by reference (and is referred to below as Morganroth and Bigger).

Individuals with arrhythmias light forms are very small risk of death, the appearance of scars on the heart and cause heart disease. Ventricular fibrillation light forms are fairly common disease, and approximately 30% of all ventricular arrhythmias. Similarly arrhythmia mild, such as ventricular extrasystoles, pose minimal risk to individuals and rarely require the use of antiarrhythmic therapy. However, ventricular extrasystoles may be of such frequency or complexity, or may be associated with a sufficiently threatening symptoms that individuals experiencing them, will cease to respond to assurances that arrhythmia and symptoms are not dangerous. They may also not perceive the most common types of treatment (for example, not to take the beta blockers). In these cases, the treatment of previously unknown compounds, oeticheskii serious arrhythmias are usually associated with a number of other clinical symptoms of heart disease, such as mild heart failure, the symptoms of ischemic heart disease and/or scarring of the heart. Claim that approximately 65% of all ventricular arrhythmias are prognostically serious (see, for example, work Morganroth and Bigger S. 1497).

Patients with life-threatening arrhythmias may experience fainting (sudden loss of consciousness, usually dizziness associated with cerebral blood flow), delay heart rhythm, heart failure, and/or ischemia of mikrada due to the presence of organic heart disease. Life-threatening arrhythmias occur relatively infrequently; it is possible that less than 10% of individuals suffering from arrhythmias, suffer lethal form of arrhythmia (see Morganroth and Bigger, S. 1497). However, given the life-threatening nature of lethal ventricular arrhythmias and the severity of the symptoms associated with these diseases, they must undergo intensive therapy.

The new compounds of the present invention are very effective tools against heart fibrillation and supraventricular or ventricular arrhythmias. Furthermore, the new compounds of the present invention are characterized by lower expression of mekoi therapy due to the lack of acceptable alternative treatment options. For example, many existing treatments cause pulmonary toxicity, inhibition of cardiac and neurological effects that are not specific to cardiac tissue. A detailed discussion of the side effects associated with conventional anti-arrhythmic drugs, contains, for example, in the work of Bigger (Bigger, J. T. and Hoffman (Hoffman, B. F.) ("Antiarrhythmic Drugs" in Goodman and Gilman''s The Pharmacological Basis of Therapeutics, 8th edition, ed. A. G. Gilman, p. 840 - 873, (New York: Pergamon) and in the work of Musli (Woosley, R. L. ("Antiarrhythmic Drugs, 1682 - 1711, New York: Mc Graw-Hill (1990)), and both these works included here with links to them.

Furthermore, the new compounds of the present invention are biologically readily available. This feature can be treated by oral administration, and therefore these new tools are convenient for the patient. Furthermore, the new compounds of the present invention are relatively inexpensive to manufacture, and their oral dosage forms have a high degree of stability.

Previously unknown cyclic urea and pharmaceutically acceptable salts and esters can be used as antiarrhythmic and antiphony 5-, 6 - or 7-membered heterocycle or carbon cycle;

b) R is absent or is selected from the group consisting of a covalent bond, heteroatom, carbonyl group, heterocyclic ring, carbocyclic ring, alkyl groups, alkenylphenol group, alkoxygroup, alkylamino, arylalkyl group, alloctype, acyl group, alloctype and alluminare;

c) Y either represents a substituted or unsubstituted, saturated or unsaturated, 5-, 6 - or 7-membered heterocyclic ring or a carbon ring or absent and when R is absent, X and Y represent a condensed ring system, as in the case when R is a covalent bond, X and Y represent a ring system, linked through covalent bonds, and, in the case when Y is absent, R is a covalent bond, and X is linked to L through R;

d) R1, R2and R3either absent or independently selected from the group consisting of chlorine, fluorine, bromine, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, alkoxygroup, alkyl groups, alkoxycarbonyl group, hydroxyalkyl group, carboxialkilnuyu group, aminals is s, alkenylamine, alkylamino, alkynylamino and alluminare, where the nitrogen atom of these groups linked to the nitrogen atom of the cyclic part of the urea in the 1-position.

f) R4is selected from the group consisting of alkyl, alkenylphenol, alkenylphenol and heteroalkyl group;

g) A substituted or unsubstituted, saturated or unsaturated, straight or branched (C1-C8)heteroalkyl group, either substituted or unsubstituted, saturated or unsaturated heterocyclic group having 5, 6 or 7 members, which contains one nitrogen atom directly connected to the R4;

h) R5substituted or unsubstituted alkyl group having 1 or 2 carbon atoms.

Ring system (X-R-Y). New cyclic compounds urea of the present invention contain a portion of the cyclic urea attached to the ring system (X-R-Y) via a connecting part (L). Cyclic urea contains nitrogen atom in the 3-position which is substituted aminecontaining part (A), consisting of amino group, separated from the nitrogen atom of the cyclic part of the urea in the 3-position of the separating group (R4). The part having the form (X-R-Y) represents a ring system and Susannah or unsaturated carbocyclic rings or heterocyclic rings, as defined in this description. Each carbocyclic ring or heterocyclic ring containing 5, 6 or 7 (preferably 5 or 6) members.

Preferably, the ring system (X-R-Y) was polycyclic and consisted of two unfused rings, more preferably a ring, denoted by the letter Y and associated with the group L represents a heterocycle, and most preferably, they had a five-membered ring containing an oxygen heteroatom in position 1. In addition, if the ring system has two rings, it is preferable that the heterocycle Y was covalently bound with the ring in position 5 of the heterocycle and Y position 1 of the ring X and that the heterocycle Y was associated with a group L in position 2 of the heterocycle y

It is also possible, although this option is not preferred that the ring system (X-R-Y) will consist of two rings (X and Y), divided alkyl group, a carbonyl group or a heteroatom, and most preferably, in such a heteroatom was an oxygen atom (R). In addition, the ring system may be monocyclic; in this case, Y is absent, and R is covalently associated with L. However, if sistere two, and most preferably at least three substituents selected from the group consisting of (but not limited to) hydroxy-group, methyl group, chlorinated group, metoxygroup and bentilee group.

If rings are substituted, any or all members of the ring systems (regardless of whether it is a monocyclic or polycyclic) may have one or more substituents and may be substituted by chlorine, fluorine, bromine, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, alkoxygroup, alkyl group, alkoxycarbonyl group, hydroxyalkyl group, carboxialkilnuyu group, aminoalkyl group, allmineral or alloctype.

The connecting part (L). L represents a linking part of the new cyclic urea compounds of the present invention. Carbon end L is associated with a ring system of Y; but, if Y is not present, this end is connected to the system X, and most preferably in position 2 of the ring Y, or if Y is absent, in position 1 of the ring X. the nitrogen Atom of L-part is connected with the nitrogen atom located at position 1 of ring of urea. Part L is selected and is reliminary and alluminare; in this preferred component of the L-part is alkylamino, and most preferably alkylamino with one carbon atom, having a form CH = n

Cyclic kochevinova component. Cyclic kochevinova component of the new compounds of the present invention adds to the above compounds, their distinctive name. Cyclic kochevinova component can represent a 5 - or 6-membered ring, preferably a five-membered ring was. Cyclic kochevinova component is related to the nitrogen atom of the group L through its nitrogen atom, which is in position 1. Cyclic kochevinova component has the following structure

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in which R5is an alkyl group with one or two carbon atoms, and preferably alkyl group with one carbon atom, A represents heteroalkyl or heterocyclic ring, and must always contain at least one nitrogen atom associated with the group R4. If A is heteroalkyl group, then A can be straight or branched, saturated or unsaturated, substituted or unsubstituted. If A is a heterocyclic ring, then A I is m, and preferably substituted, saturated or unsaturated, preferably saturated. The group R4linked to the nitrogen atom located at position 3 cyclic macewindow component, and with the nitrogen atom of the group A. R4is selected from the group consisting of, but not limited to, alkyl, alkenylphenol, alkenylphenol, alkylsilanes and heteroalkyl group.

If A is a substituted heteroalkyl group, the substituents are selected from the group consisting of (but not limited to) methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol, and methanesulfonyl group.

If A heterocycle contains two heteroatoms, and they both represent nitrogen atoms, preferably a nitrogen atom that is not associated with the group R4was substituted by substituents selected from the group consisting of (but not limited to) methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol and methanesulfonyl group. If A heterocycle contains only one nitrogen atom, preferably a heterocycle was replaced (in the position para - with respect to nitrogen, prioities (but not limited to) hydroxyethylene group, hydroxy-group, carbonyl group and a methyl group.

Below is a list of definitions of terms used in this description.

"Heteroatom is a nitrogen atom, sulfur or oxygen. Group containing one or more heteroatoms, may contain heteroatoms.

"Alkyl" group is an unsubstituted or substituted, straight chain or branched saturated hydrocarbon chain having 1 to 8 carbon atoms, preferably, unless otherwise stated, to the number of carbon atoms comprised of 1 to 4. Preferred alkyl groups are not limited to, methyl, ethyl, sawn, ISO-propyl and bucilina group.

"Heteroalkyl" group is an unsubstituted or substituted saturated chain having from 3 to 8 members and containing carbon atoms and one or two heteroatoms.

"Alchemilla" group is an unsubstituted or substituted, straight chain or branched hydrocarbon chain having from 2 to 8 carbon atoms, and preferably 2 to 4 carbon atoms and containing at least one olefinic double bond.

"Alchemilla" group represents the volume of carbon and preferably from 2 to 4 carbon atoms, and containing at least one triple bond.

Used in the present description, the term "ring system" means containing ring component, which through a linking group L is attached a circular kochevinova component. This system is denoted by "X-R-Y" may be a monocyclic ring component or the condensed containing bridge connection or polycyclic ring spinosissima and may contain carbon cycles, heterocycles, or both. Monocyclic rings usually contain from 3 to 8 otomops, and it is preferable that the number of atoms ranged from 5 to 7. Polycyclic ring system consisting of two rings usually contain from 6 to 16 atoms, preferably the number of atoms ranged from 10 to 12. Polycyclic ring system consisting of three rings, usually contain from 13 to 17 atoms, preferably the number of atoms ranged from 14 to 15.

Used in the present description, the terms "carbocyclic ring" or "carbocycle" means unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring, about the ins "heterocyclic ring", or "heterocycle" means unsubstituted or substituted, saturated or unsaturated or aromatic ring consisting of carbon atoms and one or more heteroatoms, in the ring. Heterocyclic rings usually contain from 3 to 8, and preferably from 5 to 7 atoms. The heteroatom may be independently selected from nitrogen atoms, sulfur, and oxygen, if it is not specifically mentioned.

"Aryl" group is an aromatic carbocyclic ring. Preferred aryl groups are not limited to, phenyl, Tomilina, xylella, cominella and naftalina group.

"Heteroaryl" group is an aromatic heterocyclic ring. Preferred heteroaryl groups are not limited to, thienyl, furilla, pyrrolidine, pyridinoline, piratininga, oxazolidine, thiazolidine, hyalinella, pyrimidinamine and tetrataenia group.

"Alkoxy" group is an oxygen atom with a substituent in the form of a hydrocarbon chain, where the hydrocarbon chain is an alkyl or alkenylphenol group (for example, -O-alkyl or-O-alkenylphenol group). Preferred alkoxy is"ptx2">

"Hydroxyalkyl group" is a substituted hydrocarbon chain, which contains hydroxysultaine (for example, a group-OH), but may contain other substituents. Preferred hydroxyalkyl groups are not limited to, hydroxyethylene, hydroxiproline, phenylhydroxylamine group.

"Carboxialkilnuyu" group is a substituted hydrocarbon chain, which contains carboxylesterase (for example, a group-COOH), but may contain other substituents. Preferred carboxialkilnuyu groups are carboxymethyl, carboxyaniline group, and their acid and esters.

"Aminoalkyl" group is a hydrocarbon chain (for example, alkyl chain), substituted amine component (for example, a group NH-alkyl-), such as dimethylaminoethyl group.

"Alkylamino" group represents aminosilanes containing one or two alkyl substituents (for example, -N-alkyl group).

"Alkynylamino" group represents aminosilanes containing one or two alkenyl substituent (for example, -N-Alchemilla group).

"Alkylamino" group I group).

"Alkylamino" group represents kinosostavlyayuschaya containing one or two alkyl substituent (for example, a group of form N-alkyl-y

"Arylalkyl" group is an alkyl component, a substituted aryl group. Preferred arylalkyl groups are benzyl and phenylethylene group.

"Arylamino" group is an amine component, a substituted aryl group (e.g.,- NH-aryl group).

"Aryloxy" group represents an oxygen atom, aryl having a substituent (for example, -O-aryl group).

"Acyl" or "carbonyl" group is a component formed by removal of the hydroxy-group of the carboxylic acid (for example, the group R-C(=O)-). Preferred alkylsilane groups are not limited to, acetyl, propylaniline and buchanania group.

"Acyloxy" group represents an oxygen atom, containing the acyl substituent (for example, -O-acyl group); for example, -O-C(=O)-alkyl group.

"Acylamino" group represents aminosilanes containing the acyl substituent (for example, N-acyl group); for example, -NH-(C is th radical, a chlorine atom, bromine, fluorine or iodine. The preferred guidami are chlorine, bromine and fluorine.

In addition, used in the present description, the term "lower" hydrocarbon group (for example, "lower alkyl group) represents a hydrocarbon chain containing, unless otherwise stated, from 1 to 6, and preferably from 1 to 4, carbon atoms.

"Pharmaceutically acceptable" salt is a cationic salt formed with any acidic (e.g., carboxyl) group, or an anionic salt formed with any basic (e.g., amino) group. Many such salts are known in the art and described in the publication World Patent Publication N 87/05297, Johnston (Johnston) and other published September 11, 1987, which is incorporated into the present description by reference. Preferred cationic salts are alkali metal salts (such as sodium or potassium), and salts of alkaline earth metals (such as magnesium and calcium). Preferred anionic salts are halide (such as chlorides).

"Biohydrology ester" is an ester of a cyclic mochevinoi compounds which do not adversely affect the antiarrhythmic activity of the compounds is eat antiarrhythmic active cyclic urea. Many of these esters are known in the art and described in the publication World Patent Publication N 87/05297, Johnston (Johncston) and other published September 11, 1987, which is mentioned here with reference to it. Such esters are the lower alkalemia esters, lower aryloxyalkyl esters (such as acetoxymethyl, ecotoxicology, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl esters), lactonase esters (such as Caligraphy and tittilicious esters), lower alkoxyalkanols esters (such as methoxycarbonylmethyl, ethoxycarbonylmethyl and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, kalinovye esters and acylaminoalkyl esters (such as acetamidomethyl esters).

As defined above and used hereinafter, the substituting groups may themselves be substituted. These groups may have one or more substituents. Such substituents are not limited to, are the substituents listed in the job's Wife (C. Hansch and Leo (Leo A.) (Substituent Constants for Correlation Analysis in Chemistry and Biology (1979)), which is introduced in the present OPI is Alchemilla group, alkoxygroup, the hydroxy-group, oxoprop, amino group, aminoalkyl group (for example, aminomethyl group, and so on), cyano, halogen-containing group, carboxypropyl, alkoxyamine group (for example, carboethoxy and so on), Tolna group, aryl group, cycloalkyl group, heteroaryl group, heterocytolysine group (for example, piperidinyl, piperazinilnom, morpholinyl, pyrrolidinyl group, and so on), aminogroup, tocograph, hydroxyalkyl group, alloctype, arylalkyl group and a combination thereof.

The present invention describes the new cyclic urea, methods for their preparation, pharmaceutical compositions containing these urea, and a method of treating cardiac arrhythmias and/or fibrillyatsy in humans or other mammals using the aforementioned novel compounds and their pharmaceutical compositions. Used in the present invention specific compounds and compositions should be pharmaceutically acceptable. Used in the present description, the term "pharmaceutically acceptable" component refers to a component that is suitable for administration to humans and/or other mammal, does not provide the and reasonable utility and risk.

Compounds of the present invention, hereinafter referred to as "cyclic ureas", include a number of cyclic urea compounds having the following General structural formula:

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in which

a) X represents a saturated or unsaturated 5-, 6 - or 7-membered heterocycle or carbon cycle;

b) R is selected from the group consisting of a covalent bond, heteroatoms, carboxyl group, heterocyclic ring, carbocyclic ring, alkyl groups, alkenylphenol group, alkoxygroup, alkylamino, arylalkyl group, alloctype, acyl group, alloctype and alluminare; or R is absent;

c) Y is a substituted or unsubstituted, saturated or unsaturated, 5-, 6 - or 7-membered heterocycle or carbocycle; or Y is absent, and, if R is absent, X or Y represents a condensed ring system; if R is a covalent bond, then X and Y represent a ring system, connected through a covalent bond; and if Y is absent, R is a covalent bond, and X is linked to L through R;

d) R1, R2and R3either absent or independently selected PPI, alkyl group, alkoxycarbonyl group, hydroxyalkyl group, carboxialkilnuyu group, aminoalkyl group, alluminare and alloctype;

e) L is selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino and alluminare, where the nitrogen atom of L is related to the nitrogen atom in the 1-position cyclic ring component urea;

f) R4is selected from the group consisting of alkyl, alkenylphenol, alkenylphenol, alkylsilanes and heteroalkyl group;

g) A is a substituted or unsubstituted, saturated or unsaturated, straight or branched (C1-C8)heteroalkyl group or a substituted or unsubstituted, saturated or unsaturated heterocyclic group having 5, 6 or 7 members and containing at least one nitrogen atom associated with the group R4;

h) R6represents a substituted or unsubstituted alkyl group with one or two carbon atoms;

and their pharmaceutically acceptable salts and esters.

Ring system (X-R-Y). New connections urea of the present invention consists of a cyclic component of urea, prisoedinenii 1 and also in position 3. The nitrogen atom at position 3 is substituted aminecontaining group (A), separated from the nitrogen atom in the 3-position of the cyclic urea component by separating the groups (R4).

Ring system (X-R-Y) represents the containing ring component and consists of one or more, and preferably one or two fused or unfused, saturated or unsaturated, substituted or unsubstituted rings, as they have been defined here. In accordance with this ring system may be monocyclic (education Y is absent) or polycyclic (X and Y represent a ring or all of X, R and Y represent the ring). Each ring can be either carbocyclic or heterocyclic and may contain 5, 6 or 7, preferably 5 or 6 members.

Preferably, the ring system was polycyclic and consisted of two unfused rings. More preferably, the ring (Y) adjacent to the binder component (L), is a heterocyclic, and most preferably, the ring was five-membered and contains an oxygen atom in position 1. In addition, if there are two rings in the ring system, it is desirable that Goethe is NII 1 ring X and to the heterocycle Y was associated with carbon end component L in position 2 of the heterocycle.

Acceptable, though not preferred, is when the ring system is a polycyclic ring system consisting of two rings (X and Y), which are separated alkyl group, a carbonyl group or a heteroatom, preferably oxygen atom of (R). In addition, acceptable ring system may be polycyclic ring system consisting of two rings (X and Y), which are condensed (education R is absent), or three rings (X, R and Y), which are condensed. If R is a ring, it is preferable that it is 5 - or 6-membered carbocyclic or heterocyclic ring.

Especially acceptable ring system is monocyclic system consisting, therefore, only one ring (X), which is covalently bound to carbon part L (R is a covalent bond, and Y is absent). However, if there is only one ring in the ring system, preferably a ring represented a 5-membered carbocycle that would be that the performance of selected from the group consisting of (but limited to) hydroxy-group, methyl group, chlorinated group, metoxygroup and bentilee group.

In the case of replacement of any or all members of the ring system regardless of whether it is a monocyclic or polycyclic, and may contain one or more substituents. The above substituents may be independently selected from the group consisting of, but not limited to chlorine, fluorine, bromine, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, CNS group, alkoxycarbonyl group, hydroxyalkyl group, alkyl group, aminoalkyl group, alluminare, alloctype, and carboxialkilnuyu groups, and special interest chlorine, fluorine, bromine, OH, and CH3.

Preferred ring systems new cyclic urea are not limited to, for example, monocyclic ring, which includes, not agrarias them, 2-acetoxy-5-chloraniline, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl, 2-thienyl, 4-pyrimidinyl, 5-methoxycarbonyl-2-fornillo, tsiklogeksilnogo, 5-chloro-2-hydroxyphenyl, 5-chloro-2-metoksifenilny, 2-methanesulfonylaminoethyl, 3-AMINOPHENYL, 2-myoxinol and 5-acetoacetyl-2-fornillo system. Acceptable polycyclic ring systems, which consist of two unfused rings covalently linked to each other, for example, are not limited to, 5-(4-carboxyphenyl)-2-furazilina, 5-(4-methanesulfonyl)-2-furazilina, 5-(3,4-acid)-2-furazilina, 5-(4-methanesulfonylaminoethyl)-2-furazilina, 5-(4-bromophenyl)-2-oxazolinone, 5-(4-methoxyphenyl)-2-furazilina, 5-(1-cyclohexen-1-yl)-2-furazilina, 5-cyclohexyl-2-furazilina, 5-(3-triptoreline)-2-furazilina, 5-(4-were)-2-furazilina, 2-(4-chlorophenyl)-3-furazilina, 5-(4-chlorophenyl)-2-furazilina, 5-(4-forfinal)-2-furazilina system. Acceptable polycyclic ring systems, which consist of two unfused rings connected to each other via a heteroatom, alkyl groups or other acyclic carbon-containing group, for example, are not limited to, 2-benzyloxy-5-chloraniline, 4-benzyloxyphenyl, 3-(4-tert-butylphenoxy)phenyl, 3-benzoyl-2,4-dichloraniline, 2-chloro-3-benzyloxyaniline, 3-(4-chlorophenoxy)phenyl system. Acceptable polycyclic ring systems containing two or more condensed rings are, for example, not limited to a lot of systems.

Preferred ring systems (X-R-Y) new cyclic ureas, as defined in this description are not limited to, the following systems:

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< / BR>
< / BR>
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The connecting part (L). L represents a linking part of the new cyclic urea compounds of the present invention. Carbon-containing end of part L is associated with X-R-Y-ring system via a Y-piece, and if Y is absent, then by part X; preferably in 2-position of the ring Y and 1-X, unless Y is absent. The nitrogen atom of L-part is connected to the nitrogen atom in 1 cycle macewindow component. Part L is selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino and alluminare, and it is desirable that it was alkylamino, but, most preferably, (C1) alkylamino type CH = n

The cyclical component of the urea. The cyclical component of the new urea compounds of the present invention determines the characteristic name of these compounds. Cyclic kochevinova component can represent a 5 - or 6-membered ring, preferably a five-membered ring was. Tsiklicheski is a (C1) or (C2)alkyl group, and preferably (C1)alkyl group. If the group R5is a (C1) alkyl group, a cyclic urea is a five-membered ring, and, if R5is a (C2)alkyl group, a cyclic urea is a six-membered ring.

A represents a straight or branched, substituted or unsubstituted, saturated or unsaturated (C1-C8) heteroalkyl group or a substituted or unsubstituted, saturated or unsaturated, 5-, 6 - or 7-membered (preferably 5 - or 6-membered) heterocyclic ring. Regardless of whether heteroalkyl or heterocyclic group, it must contain at least one nitrogen atom associated with the group R4.

If A is replaced by heteroalkyl, the substituents are selected from the group consisting of (not limited to) methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol and methanesulfonyl group.

If A contains two atoms of nitrogen, then it is desirable that the nitrogen atom not attached to the group R4(which in the case of the UB>4), was substituted by substituents selected from the group consisting of (not limited to) methyl, hydroxyethylene, alkyl, aryl, mercaptoethanol, methanesulfonyl, heterocyclic and arylalkyl group. If A heterocycle contains only one atom of nitrogen and the formation of A represents a 6-membered ring, preferably parapolitica relative to the nitrogen atom, which is adjacent to the group R4was replaced by Deputy selected from the group consisting of (not limited to) from hydroxyethylene group, a hydroxy-group, carbonyl group and a methyl group.

In accordance with the above acceptable components of A can be, not limited to, groups specified below. For components where A is heteroalkyl group include, without limitation, dimethylaminopropyl, diethylaminopropyl, bis-2-hydroxyethylamino, bis[(1-methyl)ethyl] amino group, N-benzyl-N-methylaminopropane, N-(2-hydroxyethyl)-N-methylaminopropyl. To be acceptable A-pillars, where A represents a heterocycle include, not limited to, N-[(1-methyl)ethyl]-N-[2-hydroxy-2- [4-methanesulfonamido)phenyl] ethyl]amino group, 4-phenyl-1-piperazinilnom group, isolina group, 4-hexyl-1-piperazinilnom group, 4-benzyl-1-piperazinilnom group, 1-piperazinilnom group, 4-hydroxy-1-piperidinyl group, 4-methyl-1-piperazinilnom group, 4-n-butyl-1-piperazinilnom group, 4-ethyl-1-piperazinilnom group, 3-(4-methyl-1-piperazinil)-3-oxopropyl group, 4-phenyl-1-piperazinilnom group, N-(2-pyridinyl)-1-piperazinilnom group, N-(2-pyrimidinyl)-1-piperazinilnom group, 4-(4-methoxyphenyl)-1-piperazinilnom group, 4-acetyl-1-piperazinilnom group, N-methyl-N-phenylaminopropyl, 1-imidazolidinyl group, 4-(2-were)-1-piperazinilnom group, 4-(4-methanesulfonylaminoethyl)-1-piperazinilnom group, N-morpholinyl group, N-thiomorpholine group, 4-oxo-1-piperidinyl group, 2-(tert-butoxycarbonyl)-1-pyrrolidinyl group, pyrrolidinyl group, 4-(4-acetylphenyl)-1-piperazinilnom group, hexahydro-1H-azepin-1-ilen group.

Preferred aminecontaining components (A) new cyclic ureas, as defined in this description are not limited to, the following components:

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The group R4linked to the nitrogen atom located at position 3 of the cyclical component of urea, and with the nitrogen atom A-part. R4and heteroalkyl group, especially (C3-C6)alkenylphenol group, i.e., through butilkoi, Pintilei and hexylene group.

As mentioned above, the new cyclic compounds urea of the present invention consist of cyclic macewindow component connected to the ring system via a binder component. In accordance with the above-mentioned suitable compounds of the present invention are not limited to, the following compounds and their pharmaceutically acceptable esters and salts, particularly maleate and hydrochloride: 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-dimethylamino) propyl]-2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl] -methylene] -amino]-3-[4-(dimethylamino)butyl]- 2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1 - piperazinil)butyl]-2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[2-(dimethylamino) ethyl]-2-imidazolidinone, 1-[[[3-(4-chlorophenoxy)phenyl] the methylene] amino] -3-[3-(dimethylamino) propyl[-2-imidazolidinone, 1-[[5-chloro-2-benzofuranyl)methylene] amino] -3-[3-(dimethylamino)propyl] - 2-imidazoline, 1-[[3-benzoyl-2,4-(dichlorophenyl)methylene]amino]-3- [3-(dimethylamino)propyl]-2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino] -3-[3-(dimethylamino) propyl] t-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino]-3-[3-(4-methyl-1-piperazinil)propyl]-2-imidazolidinone, 1-[[cyclohexyl)methylene]amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone.

Examples A-D, shown in this description, illustrate the preferred methods of obtaining new cyclic urea compounds described in this application.

Pharmaceutical compositions containing previously not known cyclic mcevenue connection.

New cyclic compounds urea of the present invention can be administered to the human or other mammal in a variety of ways, including, but not limited to, oral administration dosage forms and injections (intravenous, intramuscular, subcutaneous and intraperitoneal). Using suitable fillers, as defined below, specialists can be easily obtained and numerous other dosage forms containing the new cyclic compounds urea of the present invention as active ingredients. While oral dosage forms are preferred in respect of ease of use.

Used in the present description, the term "pharmaceutical composition" on Amenemope as an active ingredient, or mixtures thereof and pharmaceutically acceptable excipients.

The term "safe and effective amount", as used herein, means an amount of compound or composition, which are large enough to significantly positively modify the symptoms and/or condition being treated, but small enough to create serious side effects (at a reasonable ratio of benefits and risks) in accordance with the medical testimony. Safe and effective amount of active ingredient in pharmaceutical compositions intended for use in the method of the present invention may vary depending on the specific condition, affected, age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, specifically used active ingredient, specifically used pharmaceutically acceptable excipients, and other factors in accordance with the competence and experience of the treating physician.

Used in the present description, the term "pharmaceutically acceptable excipients" includes any physiologically initializegame characteristics of a specific cyclic compounds of urea, selected for use as the active ingredient. Pharmaceutically acceptable excipients are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, oil, disintegrators, solvents, co-solvents, buffer systems, surfactants, preservatives, sweeteners, flavouring agents, pharmaceutically acceptable dyes or pigments and thickeners.

The term "oral dosage form", as used herein, means any pharmaceutical composition intended for the system introduction to the individual by delivering these compositions in the gastrointestinal tract of the individual through the mouth of the mentioned individual. In accordance with the present invention, the insertion can be in the form of tablets, coated or uncoated, solution, suspension or capsules coated or uncoated.

The term "injection" as used herein, means any pharmaceutical composition intended for system introduction to human or other mammal in the form of a solution or emulsion containing the active ingredient, by piercing the skin of the mind or intravenously, either intramuscularly or subcutaneously, or intraperitoneally.

Dose ingestion of a drug can be successfully determined by the specialist with regard to one or several factors, namely:

(a) the amount of the active ingredient;

b) number of pharmaceutically acceptable fillers, if they do not have any adverse effect on the activity of the selected active ingredient;

c) the type of filler and the corresponding desired consistency and permeability (swelling characteristics) of the above-mentioned filler;

d) time-dependent characteristics of the filler itself and/or in combination with other fillers;

e) the particle size of the granulated active ingredient;

f) pH-dependent characteristics of the fillers.

In particular, for the correct choice should take into account important factors, such as solubility, acidity, and susceptibility to hydrolysis of various cyclic ureas used as the active ingredients, such as additive salts, salts formed carboxylic group, for example salts of alkali metals, salts of alkaline earth metals, etc. and esters, such as Ala is presented pH values) can be created in the oral dosage forms by adding a suitable buffer to the active ingredient in accordance with the desired scheme of its release.

As mentioned above, the pharmaceutically acceptable filler is not limited to, resins, fillers, binders, oil, solvents, substances that reduce friction, desintegrator, co-solvents, surfactants, preservatives, sweeteners, flavouring agents, buffer systems, pharmaceutically acceptable dyes or pigments and thickeners.

The preferred solvent is water.

As the fragrances can be used aromatic substances described in the Handbook (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, p. 1288-1300), which is incorporated into this description by reference. Pharmaceutical compositions suitable for use in the present invention usually contain 0-2% flavoring agents.

As dyes or pigments may be used dyes, described in the Handbook (Handbook of Pharmaceutical Excipients, p. 81-90, 1986), released by the American pharmaceutical Association and the pharmaceutical society of great Britain, which is included in the present description by reference. The pharmaceutical compositions of the present invention typically contain 0 to 2% of dyes or pigmentaion, the glycols. The pharmaceutical compositions of the present invention contain 0-50% co-solvents.

Preferred buffer systems are not limited to, acetic, boric, carbonic, phosphoric, succinic, maleic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric, and glutamic acid and their sodium, potassium and ammonium salts. Especially preferred are phosphoric, tartaric, citric and acetic acids and their salts. The pharmaceutical compositions of the present invention typically contain 0 to 5% buffer systems.

Preferred surfactants are not limited to, polyoxyethylenesorbitan esters of fatty acids, polyoxyethylene monoalkyl ethers, complex monetary sucrose and lanolin esters and ethers, alkylsulfate salt, sodium, potassium and ammonium salts of direct acid. The pharmaceutical compositions of the present invention contain 0 to 2 percent surface-active substances.

Preferred preservatives are not limited to, phenol, alkalemia esters by parahydroxybenzoic acid, o-phenylphenol, benzoi the RT thimerasol, phenylacetate and vanilmirth mercury, nitromersol, benzylaniline, cetylpyridinium, methylparaben and propylparaben. Especially preferred are salts of benzoic acid, cetylpyridinium, methylparaben and propylparaben. Compositions of the present invention typically contain 0 - 2% preservatives.

Preferred sweetening agents are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol and aspartame. Especially preferred are sucrose and saccharin. The pharmaceutical compositions of the present invention typically contain 0 to 5% sweeteners.

Preferred thickening agents are not limited to, methylcellulose, sodium carboxymethyl cellulose, oksipropilmetiltselljuloza, oxypropylation, sodium alginate, carbomer, povidone, Arabian gum, hoerova gum, xanthan gum and tragacanth gum.

Especially preferred are methyl cellulose, carbomer, xanthan gum, hoerova gum, povidone, sodium carboxymethyl cellulose and the magnesium aluminosilicate. Compositions of the present invention contain 0 to 5% thickening agents.

Predice, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, extracellular and microcrystalline cellulose. Compositions of the present invention contain 0 to 75% fillers.

The preferred sizing are not limited to, magnesium stearate, stearic acid and talc. The pharmaceutical compositions of the present invention contain 0.5 - 2% lubricants.

Preferred slip agents are not limited to, talc, and colloidal silicon dioxide. Compositions of the present invention contain 0 to 5% of sizing.

The preferred disintegrators are not limited to, starch, sodium starch glycolate, crosspovidone, sodium crosscarmellose, and microcrystalline cellulose. The pharmaceutical compositions of the present invention include 4 - 15% baking powder.

Preferred binders are not limited to, Arabian gum, tragakant, oxypropylation, preferably gelatinizing starch, gelatin, povidone, oxypropylation, oksipropilmetiltselljuloza, methylcellulose, solutions of sugars, such as sucrose and sorbitol, and ethylcellulose. diversified pharmaceutical compositions of the present invention contain from 15 to 95% of active ingredient in the form of a circular motivirovalo compounds or mixtures thereof, 0 - 2% flavoring agents, 0 to 50% co-solvents, 0 to 5% of a buffer system, 0 - 2% preservatives 0 - 2% surfactant, 0 to 5% sweeteners, 0 to 5% of a thickening agent, 0 to 75% filler, 1 to 5% of agents that reduce friction, 0.5 to 2% oil, 4 - 15% of desintegration and 1 - 10% binding substances.

Acceptable pharmaceutical compositions described below in the examples, E-J. it Should be noted that any expert can make some modifications in the described variants, does not extend, however, beyond the scope of the present invention, in order to obtain pharmaceutical compositions wide range of applications.

Not previously known compounds of the present invention are effective for the treatment of humans or other mammals suffering from supraventricular arrhythmias and ventricular arrhythmias and/or cardiac fibrillation. As mentioned above, except in rare cases of supraventricular arrhythmias are not life-threatening and usually not subjected to intensive treatment with conventional antiarrhythmic drugs because of their unwanted side effects. In accordance with the foregoing, this type of arrhythmia is usually not exposed to intense the organisations present invention are basically quite portable, and have less unwanted side effects, than many common antiarrhythmic drugs, so they can successfully be used in order to facilitate physical and emotional symptoms of individuals suffering from supraventricular arrhythmias, because these individuals are in fact in a state of discomfort, even if this condition is not life-threatening.

As mentioned above, the new cyclic mcevenue compounds of the present invention are also effective for the treatment of ventricular arrhythmias, which, as a rule, are much more serious than atrial fibrillation, and therefore require intensive treatment. Because of the potential severity of some ventricular arrhythmias appeared numerous classifications of types of patients.

For individuals suffering from benign ventricular arrhythmias, i.e., subject to a philosophical thesis "And whether they should be treated?", can be assigned individuals with supraventricular arrhythmias. These individuals there is no heart disease, but they may experience fainting, dizziness and palpitations, and often suffer from a certain amount of emotional distress, wasn the PVCs, which for the most part are physically harmless, but for obvious reasons, are the grounds for some concern. New cyclic mcevenue compounds of the present invention mainly cause less unwanted side effects than many traditional antiarrhythmic drugs, which, though considered undesirable, but is still practiced in the case of more serious and/or life-threatening diseases. Therefore, individuals of this type are likely to benefit from more easily portable method of treatment.

Another class of individuals who may benefit from treatment with the use of new cyclic mochevinoi compounds of the present invention, are those individuals who are characterized as having "prognostically serious arrhythmia. These individuals usually suffered a myocardial infarction, and they are characterized by the presence of ventricular extrasystoles and/or attacks implicit ventricular symptomatic or asymptomatic tachyarrhythmias. These patients do not require immediate action, because they do not have an acute, life-threatening symptoms in the extent of their experience individuals opican is charged to the group with a significantly higher risk of sudden death, than other people, and therefore the risk of them heart failure can be reduced in the case of treatment using the new compounds of the present invention (see Morganroth and Bigger, S. 1498).

But there are individuals who continuously suffer life-threatening arrhythmia and exposed to immediate danger and imminent death. These individuals are usually characterized by the existence of stable ventricular tachyarrhythmias or ventricular fibrillation. Ventricular arrhythmia experienced by these individuals, usually accompanied by a manifestation of hemodynamically significant signs or symptoms, such as fainting, heart failure, myocardial ischemia or hypotension. These patients are characterized by the highest risk to die suddenly from a heart attack, and usually suffer the most acute form of the underlying disease of the heart (see. Morganroth and Bigger, S. 1498). The new compounds of this invention are effective strong anti-arrhythmia, suitable for the treatment of this class of individuals, and at the same time, these compounds find less unwanted side effects than common antiarrhythmic drugs, which is linked to the life of arrhythmias.

As mentioned above, a new antiarrhythmic means of the present invention are unwanted side effects to a much lesser extent than is typical of many common antiarrhythmic drugs. Such side effects include, without limitation, pulmonary toxicity, inhibition of cardiac and neurological effects, not characteristic of cardiac tissue.

In addition, previously unknown compounds of the present invention have antifibrillatory and antiarrhythmic effect; they prevent the possibility of sudden death from heart attack by uniform prolongation newsbureau period of the heart during each beat. Standard drugs have anesthetic properties and/or properties that inhibit cardiac function, and make the heart less susceptible, but not less fibrillar.

In accordance with the above new cyclic mcevenue compounds of the present invention are suitable for the treatment of cardiac arrhythmias and/or cardiac fibrillation in humans and other mammals. Therefore, the present invention relates to a method of treatment which involves the introduction mentioned person or other mammal a safe and effective amount of the pharmaceutical composition, contains 15 - 90% of the active ingredient in the form of a circular motivirovalo compounds or mixtures thereof, and 10 to 85% of pharmaceutically acceptable fillers.

Examples of K-R illustrate some cases of treatment of patients and the ways in which pharmaceutical compositions containing the new cyclic mcevenue compounds of the present invention can be used to treat cardiac arrhythmias and/or fibrillyatsy. Specialist working in this field of technology can make changes in the described examples, not limiting the scope of the invention for treatment of a wide class of individuals suffering from cardiac arrhythmias and/or fibrillation.

The following examples are an additional illustration of the present invention.

Example A.

Synthesis of hydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]-methylene]amino]-3-[3-(dimethylamino) propyl]-2-imidazolidinone

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Hydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] -methylene] amino] -3-[3-(dimethylamino) propyl]-2-imidazolidinone was prepared as follows.

I. Synthesis of dimethylaminopropylamine. Dimethylaminopropylamine was obtained by neutralizing the hydrochloric salt in an aqueous solution of NaOH in H2

II. Synthesis of 1-[(phenylmethylene)amino] -2-imidazolidinone. Mix a solution of 65 g (0.75 mol) of 2-imidazolidinone in 2000 ml of 2 n sulfuric acid solution was cooled to 0oC. part of the NaNO2in the amount of 53 g (0.77 mol) in portions over 15 min was added to the solution, keeping the temperature at 0oC. the resulting mixture was stirred at 0oC for 2 hours Servings of zinc dust in the amount of 108 g (of 1.65 mol) parts for 1 h was added to the solution, keeping the temperature at 0oC. the Reaction mixture was stirred at 0oC for 0.5 h and then at ambient temperature for 1 h, the Excess zinc was removed by filtration. The filtrate was completely treated with a solution of 80 g (0.75 mol) of benzaldehyde in 400 ml of substance S. D. A. N 32, and the resulting solution was stirred for 16-18 h at ambient temperature. The solid is collected by filtration, washed with water and dried by air, resulting in a received 124 g (yield 87%) of 1-[(phenylmethylene)-amino]-2-imidazolidinone.

III. Synthesis of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)-amino]-2-imidazolidinone. The solution 9,46 g (0,050 mol) 1-[(phenylmethylene)amino-2-imidazolidinone practically dissolved in 125 ml of dimethylformamide was treated with portions of 2 g (0,050 Go the mixture was stirred at ambient temperature for 15 min with the formation of solids. A portion of dimethylformamide in the amount of 100 ml, stirring, was added to the solution, and the resulting mixture was stirred at 80-90oC for 30 minutes the Mixture was cooled to ambient temperature and the whole was treated with 12.2 g (0,100 mol) of chloride dimethylaminopropyl (obtained as described above in part I). The resulting mixture was heated at 80-90oC for 3 h, reaching almost complete dissolution. The solvent was removed in vacuum. The residual semi-solid product was dissolved in water (150 ml) and was extracted with ethyl acetate (2 x 200 ml). The combined extracts were dried with magnesium sulfate, and the solvent was removed in vacuum. The residual solid was washed simple with ether, and dried by air, receiving 4.8 g of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone.

IV. Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[3-(dimethylamino)propyl] -2 of imidazolidinone hydrochloric. A solution of 4.8 g (of 0.017 mol) of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone (obtained as described in part III) in 125 ml of 2 n HCl solution was treated with 1 g of 5% palladium carbon (50% water suspension) and was placed in the apparatus of the recovery Parra, feeding for 30 min theory is and the solvent was removed in vacuum. The residual oily substance was dissolved in 100 ml of dimethylformamide and the whole was treated 3.51 g (0,0170 mol) of 5-(4-chlorophenyl)-2-furancarboxaldehyde (obtained as described in U.S. patent N 4882354 issued to Huang (Huang and others (21 November 1989), the rights to which belong to the company "Norwich Eaton pharmaceuticals, Inc.; see example 3, columns 7 and 8; the patent is incorporated into this description by reference), which was accompanied by dissolution. Then added portion in 0.1 g of molecular sieve 3 , and the reaction mixture was stirred for 16 - 18 h at ambient temperature. The resulting mixture was heated in a vessel under reflux with addition of dimethylformamide to dissolve. The molecular sieves were removed by filtration and the solvent was removed in vacuum. The residual semi-solid substance was led by rubbing with simple ether. The solid is recrystallized from a substance S. D. A. N 32 (activated charcoal) and dried by spraying in vacuum, ethyl acetate, which was obtained 2.7 g 1[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-(3-dimethylaminopropyl)-2-imidazolidinone hydrochloride.

Example B.

Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-(4-methyl-1-piperazinyl-1-piperazinil) butyl] -2-imoduleinitializer received so as is described below.

I. Synthesis of 1-phenylethylamine-3-(4-chlorobutyl)-2-imidazolidinone. Stir mixture consisting of 1 phenylethylamine-2-imidazolidinone (27,6 g, 0,1453 mol) (obtained as described in example a, part II) in dimethylformamide (500 ml), was treated with portions of 60% NaH in mineral oil (5.8 g, 0,1458 mol), within 30 minutes the resulting mixture was stirred at ambient temperature for 30 min, then was heated at 80-90oC for 30 minutes produced thick mixture was cooled to ambient temperature and one portion was added 1-bromo-4-chlorobutane (50.0 g, 0,2916 mol, 2 equivalents). The mixture was heated at 80-90oC. after 30 min after achieving almost complete dissolution of the gradual deposition of small amounts of solids. The mixture was heated at 80-90oC for 3 h, then stirred at ambient temperature for 18 hours the Mixture was filtered (celite), removing a small amount of insoluble matter. The filtrate was concentrated under reduced pressure to education oily residue. The residue is triturated with water, resulting in the obtained solid substance. The solid is collected and dried by air. This vexes who has suhali air, resulting received of 36.4 g (0,130 mol) 1-phenylethylamine-3-(4-chlorobutyl)-2-imidazolidinone.

II. Synthesis of 1-phenylethylamine-3-(4-iodobutyl)-2-imidazolidinone. The stirred mixture of 1-phenylethylamine-3-(4-chlorobutyl)-2-imidazolidinone cases (36.4 g, 0,1301 mol), acetone (700 ml) and sodium iodide (42.9 g, 0,2862 mol), was heated in a vessel under reflux for 24 hours the Mixture was filtered in hot condition, removing solid. After cooling, the filtrate was poured into water (2000 ml) and was stirred for 1 h, the Solid was collected, washed with water, dried with air, resulting in received of 31.4 g (0,0845 mol) 1-phenylmethylene-amino-3-(4-iodobutyl)-2-imidazolidinone.

III. Synthesis of 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil)butyl]-2-imidazolidinone. The stirred solution of 1-phenylethylamine-3-(4-iodobutyl)-2-imidazolidinone (10.0 g, 0,0269 mol), dimethylformamide (150 ml) and 1-methylpiperazine (6,0 ml, 3.4 g, 0,0539 mol) was heated in a vessel with reflux condenser. The heating in the vessel under reflux was continued for 2.5 hours the Solution was concentrated under reduced pressure before the formation of semi-solid residue. This residue was dissolved in CHCl3(300 ml) and then washed with saturated solution of NaHCO3(3 eigendom pressure before the formation of oily residue. The residue is triturated in hexane (300 ml) by stirring. The solid is collected and dried by air, which was obtained 8.0 g (0,0233 mol) 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil)butyl]-2-imidazolidinone.

IV. Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)- butyl] -2-imidazolidinylideneamino salt. A mixture of 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil)butyl]-2-imidazolidinone (3.0 g, 0,0087 mol), 2 n HCl solution (125 ml) and 5% palladium carbon (50% water suspension) (2.0 g) was subjected to hydrogen in the apparatus parry at ambient temperature under a pressure of 40 lb/in2(2,812 kg/cm2). After 3 h was 100% absorption of hydrogen from theoretical values. The filtrate was concentrated under reduced pressure to education oily residue. The residue was converted into the azeotrope of absolute ethanol (g ml), then concentrated under high vacuum to education oily residue.

The solution consisting of the residue obtained above, dimethylformamide (50 ml) and 5-(4-chlorophenyl)-2-furancarboxaldehyde (obtained as described in U.S. patent N 4882354, issued November 21, 1989, the Huang (Huang and others, PR is the reference to it) (1.80 g, 0,0087 mol), stirred at ambient temperature for 17-18 hours the Mixture was concentrated under reduced pressure before formation of the solid residue. The residue is suspended in water (250 ml), then was extracted with ethyl acetate (4 x 75 ml). The aqueous phase was podslushivaet by adding a saturated solution of NAHCO3. This cloudy mixture was extracted with ethyl acetate (3 times 100 ml). The extract was washed with water (2 times 50 ml), then were dried with magnesium sulfate (activated charcoal). The filtered solution was concentrated under reduced pressure before formation of the solid residue (1.28 g, 0,0028 mol). This residue was dissolved in absolute alcohol (50 ml), then treated with a solution of maleic acid (9,673 g, 0,0053 mol) dissolved in absolute ethanol (5 ml). The resulting mixture was stirred at ambient temperature for 1 h, the Solid was collected and dried by air. After an additional 24 hours of drying in vacuum at ambient temperature received 1,74 g (0,0026 mol) 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1 - piperazinil)butyl]-2-imidazolidinylideneamino salt.

Example C.

Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino)butyl] -2-imidazole)butyl] -2-imidazolidinone hydrochloric received so as is described below.

1. Synthesis of 1-phenylethylamine-3-[4-(dimethylamino)butyl]-2-imidazolidinone. The stirred solution of 1-phenylethylamine-3-(4-iodobutyl)-2-imidazolidinone (obtained as described in example b, part II) (7.0 g, 0,0189 mol), dimethylformamide (125 ml) and dimethylamine monohydrochloride (x 6.15 g of 0.075 mol) was heated on the steam bath. In the conditions of heating for 2 h portions was added sodium methoxide (of 4.05 g of 0.075 mole). After adding the heating continued for another 2 h, then the mixture was cooled to ambient temperature. The mixture was concentrated under reduced pressure to education oily residue. The residue is suspended in a saturated solution of NaHCO3(300 ml) and was extracted with CH2Cl2(3 times 100 ml). The dichloromethane extract was washed with water (2 times 100 ml), then were dried with magnesium sulfate. The filtered solution was concentrated under reduced pressure to education oily liquid residue, which is triturated in hexane (2 times 100 ml), decantation, and then dried under vacuum, obtaining 4.6 g (0,016 mol) 1-phenylethylamine-3-[4-(dimethylamino)butyl]-2-imidazolidinone in the form of a solid substance.

II. Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-idine, representing the solid obtained as described above in part II (4.6 g, to 0.016 mol), was dissolved in 2 N. HCl solution (125 ml). A cloudy solution was immediately extracted with ethyl acetate (2 x 75 ml). The aqueous phase was treated with 5% palladium carbon (50% water suspension) (2 g), and subjected to the influence of hydrogen in the apparatus parry at ambient temperature under a pressure of 40 lb/in2(285,8 kN/m2). After 1 h was added an additional amount of catalyst (2 g) and continued to hydrogenation. After shaking for 15 to 16 hours, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to education oily residue, which was turned into an azeotrope by adding acetone (1 x 25 ml).

The above residue, dimethylformamide (100 ml) and 5-(4-chlorophenyl)-2-furanecarboxaldehyde (obtained as described in U.S. patent N 4882354, issued November 21, 1989, the Huang (Huang and others, the rights to which belong to the company "Norwich Eton pharmacuticals, Inc.; see example 3, columns 7 and 8; the patent is incorporated into this description by reference) (3,30 g, 0,0160 mol) was stirred at ambient temperature for several days. Received Rastogi (200 ml), then was extracted with ethyl acetate (3 times 100 ml). The aqueous phase was podslushivaet by adding a saturated solution of NaHCO3. Cloudy solution was extracted with ethyl acetate (4 times 100 ml) and the organic extract was dried with magnesium sulfate. The filtered solution was concentrated under reduced pressure before formation of the solid residue. This residue was recrystallized from a mixture of ethyl acetate with hexane. The collected solid was dried air, was dissolved in absolute ethanol (50 ml) and acidified by treatment with ethanol/hydrochloric acid. After cooling for several hours, the solid was collected, dried by air and then in vacuum at 100oC for 2 h, resulting in a received 1.92 g (0,0045 mol) 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-(dimethylamino) butyl]-2-imidazolidinone hydrochloric.

Example D.

Synthesis of I-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[2-(dimethylamino)ethyl]-1 - imidazolidinone hydrochloride

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The above-mentioned compound was obtained as described below.

I. Synthesis of dimethylaminoethoxide. Mix a solution of hydrochloric dimethylaminoethoxide (36,73 g, 0.26 mol) in water (65 ml) was cooled on what I (10.6 g, 0.26 mol) in water (90 ml) so that the temperature always remained equal to 10oC. the Reaction mixture was stirred for 15 min, and then was extracted with three portions of simple ether 150 ml each. The extracts were combined and dried with anhydrous magnesium sulfate. The mixture formed by the extracts were filtered, and the filtrate was concentrated under reduced pressure, resulting in a net oily substance, which was dimethylaminoethanol (18.2 g).

II. Synthesis of 1-phenylethylamine-3-[2-(dimethylamino)ethyl]-2-imidazolidinone. A solution of 1-phenylethylamine-2-imidazolidinone (obtained as described in part II of example (A) (14.4 g, 0,076 mol) in dry dimethylformamide (338 ml) was stirred for 3 min was treated with portions of sodium hydride (60% dispersion in mineral oil) (3.0 g, is 0.023 mol). Adding maintained constant stream of nitrogen. After complete addition, the reaction mixture was heated on the steam bath for 15 min and then was cooled to ambient temperature. The flow of nitrogen was stopped and the reaction mixture is entirely handled by dimethylaminoethanol (17,66 g, 0.16 mol), obtained as described in part I. the Reaction mixture plumage is within 3 hours The reaction mixture was filtered while hot and the filtrate was cooled and concentrated under reduced pressure, resulting in the obtained oily residue. The residue was treated with 300 ml of water and was extracted with three portions of chloroform and 300 ml each. The extracts were combined and dried with anhydrous magnesium sulfate. The extract was filtered, and the filtrate was concentrated under reduced pressure, resulting in a received reddish-brown semi-solid substance. Semi-solid substance was ground with anhydrous simple ether, resulting in received 1 phenylethylamine-3-[2-(dimethylamino)ethyl]-2-imidazolidinone in the number of 6.17 g

III. Synthesis 1-[[[5-(4-chlorophenyl)2-furanyl] methylene] amino] -3-[2-(dimethylamino)ethyl]-2 - imidazolidinone cleaners containing hydrochloride. A mixture of 1-phenylethylamine-3-[2-(dimethylamino)ethyl] -2-imidazolidinone, obtained as described in part II above (6,17 g, is 0.023 mol), 2 N. HCl solution (166 ml) was treated with 5% palladium carbon (50% aqueous catalyst) (1.3 g). The reaction mixture was restored in the apparatus parry in an atmosphere of hydrogen. The flow of hydrogen was stopped after 0.5 h at 100% absorption from theoretical values. The catalyst was removed, and the filtrate was concentrated under reduced pressure is of elegida (obtained, as described in U.S. patent N 4882354, issued November 21, 1989, the Huang (Huang and others , the rights to which belong to the company "Norwich Eaton pharmaceuticals, Inc.; see example 3, columns 7 and 8; the patent is incorporated into this description by reference) (to 4.81 g, is 0.023 mol) in dry dimethylformamide (137 ml). The reaction mixture was stirred at ambient temperature overnight. Then the mixture was filtered and washed with simple ether, resulting in the received 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[2-(dimethylamino)ethyl]-2-imidazolidinone hydrochloric.

Example E.

Preparation of tablets for oral administration containing 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[3-(dimethylamino)-propyl - 2-imidazoline hydrochloride

Oral tablet containing 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino] -3-[(3-dimethylamino)propyl)] -2-imidazoline hydrochloride (obtained as described in example a), had the following composition.

The active ingredient

1-[[[(4-Chlorophenyl)-2-furanyl] methylene] amino]-3-[3-(dimethylamino)propyl] -2 - imidazolidinone hydrochloride - 350 mg

Fillers

Lactose - 197 mg

Sodium glycolate starch 50 mg

Pre gelatinizing kauchali so, as is described below.

In the homogenizer Patterson-Kelly (Patterson-Kelly) was mixed 3,50 kg 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-(dimethylamino)propyl]-2-imidazolidinone hydrochloride, 1,92 kg of lactose, 0.50 kg of sodium starch glycolate and 0.30 kg pre gelatinizing starch, and then granulated with water, using stimulating knife.

The granulated material was dried on trays in an oven or in a fluidized bed dryer.

Granular material was grinded by passing through a sieve with holes the size of 12 mesh (1,68 mm), using a vibrator or another mill that is suitable for this purpose.

Granular material was mixed with 120 g of talc and 60 g of magnesium stearate.

Magnesium powder and the granulated mixture was pressed into tablets weighing 440 mg on a suitable teletrauma machine.

So manufactured tablets were administered to the patient suffering from cardiac arrhythmia and/or cardiac fibrillation, in accordance with a proper regimen of the drug.

Example F.

Preparation of tablets for oral administration containing 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(dimethy is phenyl)-2-furanyl] methylene] amino] -3-[4-(dimethylamino) butyl]-2-imidazolidinone hydrochloride (obtained, as described in example C), had the following composition.

The active ingredient

1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino) butyl] -2-imidazolidinone hydrochloride 300 mg

Fillers

Dibasic calcium phosphate 219 mg

Crosspovidone 60 mg

Povidone - 12 mg

Talc - 6 mg

Magnesium stearate 3 mg

Ten thousand tablets of the above composition was prepared as described below.

In the homogenizer Patterson-Kelly (Patterson-Kelly) was mixed 3.00 kg 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinone hydrochloride, 219 kg of dibasic calcium phosphate, 0.60 kg of crosspovidone and 0.12 kg of povidone, and then granulated with water, using stimulating knife.

The granulated material was dried on trays in an oven or in a fluidized bed dryer.

The granulated material is then grinded, passing through a sieve with holes the size of 12 mesh (1,68 mm) and using a vibrator or other suitable mill.

Granular material was mixed with 60 g of talc and 30 g of magnesium stearate. And, finally, a mixture consisting of granular material, talc and magnesium stearate were pressed into tablets weighing 600 is technoi arrhythmia and/or cardiac fibrillation in accordance with the assigned regimen medicines.

Example G.

Preparation of capsules for oral administration of 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(dimethylamino) butyl]-2-imidazolidinone hydrochloride

Oral capsule containing 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino] -3-[4-(dimethylamino) butyl]-2-imidazolidinone hydrochloride (obtained as described in example C), had the following composition

The active ingredient

1-[[[5-(4-Chlorophenyl)-2-furanyl] methylene]amino-3-[4-(dimethylamino) butyl] -2-imidazolidinone 300 mg

Fillers

Lactose - 92 mg

Sodium glycolate, starch 40 mg

Pre gelatinizing starch 25 mg

Talc - 12 mg

Magnesium stearate 3 mg

Hard gelatin capsule shell - 1 capsule

Ten thousand oral capsules described above composition was prepared as described below.

In the homogenizer Patterson-Kelly (Patterson-Kelly) was mixed 3.00 kg 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4- (dimethylamino)butyl]-2-imidazolidinone hydrochloride, 0,92 kg of lactose, 0,40 kg sodium glycolate, starch and 0.25 kg pre gelatinizing starch, and granulated with water, using stimulating knife.

Granulated the ial group grinded by passing through sieves with openings 12 mesh (1,68 mm) and using a vibrator or other suitable mill. Granular material was mixed with 120 g of talc and 30 g of magnesium stearate.

And, finally, a mixture consisting of granular material, talc and magnesium stearate, and taken in quantities of 472 mg, filled every capsule, using a machine for filling capsules.

Thus obtained capsule oral was administered to a patient suffering from cardiac arrhythmia and/or cardiac fibrillation in accordance with the assigned treatment regimen.

Example H.

Preparation of capsules for oral administration of 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[3-(dimethylamino)-propyl]-2-imidazolidinone hydrochloride

Oral capsule containing 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[(3-dimethylamino)propyl)-2-imidazolidinone hydrochloride (obtained as described in example A), had the following composition.

The active ingredient

1-[[[5-(4-chlorophenyl)-2-furanyl] -methylene] amino] -3-[3-(dimethylamino) propyl]-2-imidazolidinone hydrochloride - 175 mg

Fillers

Microcrystalline cellulose - 110 mg

Crosspovidone 25 mg

Povidone - 5 mg

Talc 5 mg

Magnesium stearate 2 mg

Hard gelatin capsule shell - 1 capsule

Ten is she-Kelly (Patterson-Kelly) or in another suitable homogenizer mixed 1,75 kg 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino] -3-[3-(dimethylamino)propyl]-imidazolidinone hydrochloride, 1,10 kg microcrystalline cellulose, 0.25 kg of crosspovidone and 0.05 kg of povidone, and then granulated with water, using stimulating knife.

The granulated material was dried on trays in an oven or in a fluidized bed dryer. Granular material was grinded by passing through sieves with openings 12 mesh (1,68 mm), for which we used a vibrator or other suitable mill. Granular material was mixed with 50 g of talc and 20 g of magnesium stearate.

A mixture consisting of granular material, talc and magnesium stearate and taken in quantities of 322 mg, filled every capsule shell using a machine for filling capsules.

Thus obtained capsule oral was administered to a patient suffering from cardiac arrhythmia and/or cardiac fibrillation in accordance with the assigned treatment regimen.

Example I.

Preparation of liofilizirovannogo 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(dimethylamino)butyl]-2-imidazolidine hydrochloride for injection

The solution prepared for use as an intravenous injection and containing 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-(dimethylamino)butyl] -2-imidazol-Chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(dimethylamino) butyl] -2-imidazolidinone hydrochloride 400 mg

Fillers

Mannitol 500 mg

Citric acid/sodium citrate In sufficient quantity to establish the pH to 5.5-6.5

The following describes the method of preparation of 1,000 capsules of the above composition, intended for intravenous injection.

In 10 l of sterile water for injection was dissolved 400 g 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(dimethylamino) butyl]-2-imidazolidinone hydrochloride, 500 g of mannitol and a certain amount of sodium citrate and (simultaneously or separately) of citric acid sufficient to obtain the desired pH.

The resulting solution was aseptically filtered through the filter hole size 0.2 μm and was introduced in an amount of 10 ml per ampoule.

Vials were loaded into lyophilizator, frozen, dried and closed. Liofilizovannye product was dissolved in 10 ml of sterile water immediately before injection.

The patient suffering from cardiac arrhythmia and/or cardiac fibrillation, did the injection solution prepared as described above in accordance with the assigned treatment regimen.

Example

Any of the compounds synthesized in accordance with the description in examples A-D may be used is in the examples E-I

Example K

White male 57 years old was discovered at home without consciousness and without a palpable pulse. A family member initiated the restoration of cardiac activity and respiration. The initial rhythm, documented by ambulance, was a ventricular fibrillation. The patient was successfully resuscitated.

Patient three years ago suffered a myocardial infarction, ever since suffered from angina.

During hospitalization the patient had not discovered myocardial infarction. Monomorphic persistent ventricular tachyarrhythmia was initiated by programmed electrical stimulation.

The cardiologist has prescribed to the patient 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino] -3-[3-(dimethylamino)propyl] -2-imidazolidinone hydrochloride oral dose of 350 mg, twice a day, after meals. After treatment for four days arrhythmia was not initiated the study with re-programmable electrical stimulation. Subsequently the patient experienced episodes of heart failure for more than 2 years, and the treatment was continued.

Example L.

Black man 65 years experienced fainting, which was preceded by feelings of Castlevania, once with presyncope. In his medical history was recorded hypertension cardiovascular origin, diabetes, old myocardial infarction and obesity.

Stable monomorphic ventricular tachycardia was initiated by programmed electrical stimulation. The patient's cardiologist prescribed 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[(4-dimethylamino)butyl]-2-imidazolidinone hydrochloride oral dose of 350 mg once daily, during meals. After several days of treatment arrhythmia was not initiated re-programmed electrical stimulation. Over the next three years similar attacks syncope or presyncope state was not observed.

Example m

The woman 58 years, a resident of the East, was diagnosed with cardiomyopathy with recurrent syncope. Share ejection she was 35%. Programmed electrical stimulation was initiated by the appearance of poorly tolerated resistant ventricular tachyarrhythmias who do not respond to the application of three different antiarrhythmic drugs. The fourth drug, moricizine, reduced speed tachyarrhythmias, and its reception lasted, but when Easter defibrillator.

The defibrillator is discharged twice a year after implantation of the automatic implantable cardioverter-defibrillator. Monitor registered persistent the ventricular tachyarrhythmia in moments of defibrillation. After the second discharge defibrillator patient was hospitalized. Stable monomorphic ventricular tachyarrhythmia was initiated by programmed electrical stimulation. Treatment moricizine was discontinued and instead was prescribed 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] -amino] -3-[3-(dimethylamino) propyl] -2-imidazolidinone hydrochloride oral dose of 350 mg twice a day, after meals.

When you trigger programmed electrical stimulation after a few days arrhythmia was not observed and defibrillation threshold remained unchanged. At follow-up within 1 year of discharge of the defibrillator was not observed.

Example n

Female 35 years experienced for 15 years, frequent (twice a month) attacks heart palpitations, lasting several hours and accompanied by dizziness and fatigue. These attacks do not allow her to work.

Working through the telephone network maul her 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] -amino]-3-[3-(dimethylamino) propyl] -2-imidazolidinone hydrochloride at a dose of 175 mg, once a day, after meals.

During the subsequent observation period of 1 year, it was found that the frequency of these attacks has fallen to one attack in two months if there is a noticeable improvement in her card registration requests for medical aid at work.

Example O.

The man is 75 years old, who for 50 years has smoked a pack a day, suffered installed bouts of atrial fibrillation, documented monitoring via the telephone network, with a repetition frequency of three times per month in terms of treatment with digoxin and quinidine. These attacks are sometimes continued for 8 h and because of the weakness prevented the patient to do his normal daily activities such as work in the garden.

Then the doctor replaced quinidine on 1-[[[5-(4-chlorophenyl)- 2-furanyl] methylene] amino] -3-[3-(dimethylamino)propyl] -2-imidazolidinone hydrochloride oral dose of 175 mg once a day, after meals. Over the next four months of monitoring, the frequency of attacks has fallen to one per month.

Example P.

Male 40 years old, black, for several years suffered from frequent bouts of palpitations. Patient experienced anxiety and shortness of breath during usagemessage heart disease. Monitoring Holter (Holter) was found to 2500 ventricular extrasystoles per day, univocally form with 50 pairs a day. Neither beliefs nor the subsequent therapy with the use of propranolol has not been effective.

Doctor has prescribed 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[4-(4-methyl-1-piperazinil)butyl]-2-imidazolidinedione in oral dose of 350 mg, once a day, after meals.

The heart rate decreased and weakened related anxiety and shortness of breath. After conducting monitoring Holter was found to 250 ventricular extrasystoles per day and found no re-forms. After a few months began to disappear thoughts about death. The patient was under constant supervision and continued to feel satisfactorily over the next five years.

Example Q.

Black man 58 years, within 10 years, suffering from insulin-dependent diabetes mellitus and cholesterol greater than 300 mg/DL, history of myocardial infarction. Two weeks after the heart attack he had no symptoms except that he felt short of breath during physical activity. Its share vybroshennyh ventricular extrasystoles in 1 h, sometimes steam forms, and one series of five beats of ventricular tachyarrhythmias. His cardiologist put him on 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-(dimethylamino)butyl]-2-imidazolidinone hydrochloride at oral doses of 300 mg after meals. After re-Holter monitoring was established the absence of all pairs of the form and having an average of 9 ventricular extrasystoles in 1 hour the Patient felt satisfactorily over the next three years.

Example R.

Any dosage form prepared as described in examples E-I, and containing any of the active ingredients, synthesized in examples A-D can be used to treat individuals described in examples K-Q in accordance with the assigned regimen of these drugs.

1. Cyclic compounds urea of General formula

< / BR>
where (a) R1, R2and R3independently represent hydrogen, chlorine, fluorine or bromine;

(b) R4represents a C3-C6-alkylen;

(c) A is chosen from the group consisting of dimethylamino, diethylamino, bis-2-hydroxyethylamino; bis-[(1-methyl)ethyl] -amino, N-(2-hydroxyethyl)-N-methylamino, 4-(2-hydroxyethyl)-1l, 4-methyl-1-piperazinil, 4-n-butyl-1-piperazinil, 4-ethyl-1-piperazinil;

(d) R5represents a C1-C2alkylen;

or their pharmaceutically acceptable salts or esters.

2. Cyclic compounds of urea under item 1, where A is selected from dimethylamine and 4-methyl-1-piperazinil.

3. Cyclic compounds of urea under item 1 or 2, having antiarrhythmic and antifibrillatory activity.

4. Cyclic compounds of urea according to any one of paragraphs.1 to 3, selected from the group consisting of 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylamino)propyl-] -2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-(dimethylamino)butyl]-2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-(4-methyl-1-piperazinil)butyl]-2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-[4-(2-hydroxyethyl)-1-piperazinil] butyl] -2-imidazolidinone, 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(4-methyl-1-piperazinil)propyl]-2-imidazolidinone, and their pharmaceutically acceptable cleaners containing hydrochloride and maleate salt.

5. Pharmaceutical composition for the treatment of arrhythmia and fibrillation, characterized in that it contains a safe and effective amount of from 15 to 90% cyclic with the surrounding 0,5 - 2% of a lubricating agent, 1 to 5% of glidants, 4 - 15% loosening agents, 1 - 10% binding substances, not more than 2% of agents gives taste and smell, not more than 50% of alcohol, no more than 5% of a buffer system, no more than 2% of surface-active substances, not more than 2% preservative agents, not more than 5% of the sweetening matter, not more than 5% of a thickening agent, not more than 75% of the media.

6. The pharmaceutical composition according to p. 5, characterized in that it further includes a pharmaceutically acceptable polymers, resins, plasticizers, solvents, dyes or pigments, suitable for pharmaceutical purposes.

7. The method of treatment of a human or other mammal suffering from cardiac arrhythmia and/or cardiac fibrillation, characterized in that it includes an introduction to the specified person or other mammal a safe and effective amount of a compound according to any one of paragraphs.1 to 4 or a pharmaceutical composition according to p. 5 or 6.

 

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