Compounds of cyclic urethane or their pharmaceutically acceptable salts, the method of treatment of humans and other mammals suffering from cardiac arrhythmia and/or cardiac fibrillation, the pharmaceutical composition for the treatment of arrhythmia and atrial

 

(57) Abstract:

Describes the new cyclic urethanes of the formula I, where X is phenyl; R is a covalent bond; Y furylidene; R1, R2and R3is hydrogen or chlorine; L - lower alkylamino attached to a nitrogen atom to the nitrogen atom of the cyclic urethane; R4lowest alkylen; And - saturated six-membered heterocycle containing 1 or 2 nitrogen atom which may be substituted by lower alkyl or hydroxy(lower)alkyl, and one of the nitrogen atoms of the heterocycle And is associated with the radical R4; R5- methylene, or their pharmaceutically acceptable salts. Cyclic urethanes are active against heart fibrillatio and arrhythmias. 3 S. and 8 C.p. f-crystals, 1 PL.

The invention relates to cyclic urethane compounds and their pharmaceutical compositions suitable for the treatment of humans and other mammals with cardiac arrhythmia and cardiac fibrillation.

Cyclic urethanes are active against atrial fibrillation and arrhythmia. These compounds are highly effective against cardiac arrhythmia and fibrillation and can be applied to substantially alleviate and/or prevent arrhythmia and fibrillation. In addition, these soy is IMO also the advantage of the described compounds is that they have antifibrillatory and antiarrhythmic action.

As an example, see the work Coplen, S. E. et al., "Efficacy and Safety of Quinidine Therapy for Maintenance of Sinus Rhythm after Cardioversion - A meta - analysis, Circulation, Vol. 82, pp. 1106-1116, (1990); and Echt, D. S. et. al., "Mortality and Morbidity in Patiens recciving Ecainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial", N. Engl. J. Med., Vol. 324, pp. 781-788 (1991), both works are included as references.

In a healthy heart with a normal structure is consistent electrical activation and then deactivation of each muscle fiber of the heart muscle. This happens regularly, with each beat of the heart and is characterized as a normal heart rhythm. Arrhythmia is characterized by the presence of abnormal electrical activation, violating the normal heart rhythm. Abnormal electrical activity may violate the stimulation and/or uniform distribution of electric waves (i.e., depolarization, followed by repolarization of the heart muscle, causing contraction of the heart).

Violation of arrhythmia smooth cyclical process of cardiac activity associated with normal heart rhythm, and in some cases is life threatening. the x premature ventricular complexes [pVCs]) to life-threatening (consisting of ventricular fibrillation and sustained ventricular tachyarrhythmias).

An excellent review on arrhythmias and antiarrhythmic therapy see, for example, Bigger, Thomasj., "Antiarrhythmic Treatment : An Overview", American Journal of Cardiology, Vol. 53, pp. 8B-16B, February 27, 1984; Goldstein, S. "Toward a New Undestanding of tlu Mechanism and Prevention of Sudden Death in Coronary Heart Disease, Circulation, Vol. 82(1), pp. 284-88 (1990); and Woosley, R. L. , "Antiarrhythmic Drugs" Annu. Rev. Pharmacol. Toxical. Vol. 31: p. p. 427-455, (1991), all works are included as references.

Life-threatening arrhythmia is listed as the main causes of mortality in the world. For example, it is estimated that in the United States sudden death from ventricular fibrillation takes approximately 400000-600000 lives annually (Department of health and Health Care in the USA (1985) NCHS. Monthly statistical report 33:8-9).

Basically arrhythmia is divided into 2 types:

1) Supraventricular arrhythmia (for example, Adrianna fibrillation and atrial flutter-vibration fibrillation) and

2) Ventricular arrhythmias (such as ventricular tachyarrhythmia and ventricular fibrillation and vibration).

Supraventricular arrhythmia is usually not life threatening. Individuals with this arrhythmia can experience a wide range of symptoms, from mild to quite severe. These individuals may feel that skipping the blow, additional shock and/or vibration, may is actually in General not threatening the lives of more invasive methods of treatment, such as conventional antiarrhythmic drugs are sometimes not suitable because of their unacceptable side effects. Cyclic urethanes, basically, is transferred better, than many of the conventional anti-arrhythmic drugs used at the present time, therefore, they can be used to treat patients suffering from supraventricular arrhythmias and can greatly reduce their discomfort.

Ventricular fibrillation, on the other hand, is potentially more serious and is divided into three groups:

1) Light;

2) With a poor prognosis (potentially lethal);

3) life-Threatening (death).

See Morganroth, J. and Bigger J. T., "Pharmacological Management of Ventricular Arrhythmias after the Cardiac Arrhythmia Suppression on Trial", Amer. J. Cardiol. Vol. 65, pp. 1497-1503, 1990, (hereinafter Morganroth and Bigger) are included as references.

Individuals with mild fibrillation have a very small risk of sudden death, scarring of the heart and heart disease. Easy ventricular fibrillation is relatively frequent and is approximately 30% of all ventricular arrhythmias. That is easy to arrhythmias, such as premature ventricular complexes (PVCs), represents the minimum risk for individuai symptoms so carrying her individuals not to reassure the fact that this arrhythmia and its symptoms are not dangerous. They also may not be amenable to more conventional treatment, such as beta-blockers. In such cases, the treatment described here, the connection is likely to benefit these individuals.

Arrhythmia with a poor prognosis combined with some additional symptoms of heart disease such as mild heart failure, symptoms of ischemia and/or scarring of the heart. It is established that the arrhythmia with a poor prognosis approximately 65% of all ventricular arrhythmias (see, for example, Morganroth and Bigger, at 1497).

In patients with life-threatening arrhythmia may be fainting (sudden loss of consciousness is usually fainting combined with insufficient cerebral circulation), cardiac arrest, cardiac failure and/or myocardial ischemia structural heart disorders. Life-threatening arrhythmia is relatively rare, probably less than 10% of individuals suffering from arrhythmia, struck her with a lethal form (see, Morganroth and Bigger, at 1497).

However, because of the life-threatening nature of fatal ventricular arrhythmia and its serious symptoms should intensively lenticularly arrhythmia. In addition, these compounds have a weaker side effects than conventional anti-arrhythmic drugs, which have to be applied due to the lack of alternative means. For example, many common drugs are toxic to the lungs, causing cardiodepression and have a neurological effect, uncharacteristic of cardiac tissue. Discussion the side effects of traditional anti-arrhythmic drugs given works Bigger, J. T. and Hoffman, B. F., "Antiarrhythmic Drugs" in Goodman and Gilman''s The Pharmacological Basis of Therapeutics, 8 th edition, ed. A. G, Gilman, pp. 840-873, New York: Pergamon; and Woolsey, R. L. "Antiarrhythmic Agents", in The Heart, ed. J. W. Hurst, pp. 1682-1711. New York: Mc-Graw - Hill (1990), both works are included as references.

In addition, the described connections are easily digested, which facilitates treatment with oral medication and, therefore, it is convenient for patients.

In addition, the manufacture of the compounds described here is relatively cheap, and they exhibit a high degree of stability in dosage forms intended for oral administration.

New cyclic urethanes and their pharmaceutically acceptable salts and esters which are suitable as anti-arrhythmia and fibrillatio, have the following General structure is clam;

(b) R is selected from the group comprising covalent bond, a heteroatom, carbonyl, heterocyclic ring, carbocyclic ring, alkyl, alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy, acylamino, or is absent;

(c) Y is substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7-membered heterocyclic or carbocyclic ring or absent and in which, when R is absent, X and Y are systems of condensed rings, and when R is a covalent bond, X and Y are systems of rings connected by covalent bond, and when absent, R is a covalent bond, and X is carbocycle related to L through R;

R1, R2, R3are independently selected from the group Cl, F, Br, NH2, CF3, OH, SO3H, CH3SO2NH, COON, alkoxy, acyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, aminoalkyl, acylamino, acyloxy, or absent;

(e) L is selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino, arylamino, a nitrogen atom which is attached to the nitrogen atom in position 3 of the ring of the cyclic urethane;

(f) R4selected from the group comprising alkyl, alkenyl, quinil, alkyl heteroalkyl straight or branched chain, or a substituted or unsubstituted, saturated or unsaturated 6 - or 7-membered heterocycle, which may have an oxygen atom and A has one nitrogen atom, which is adjacent to R 4; and

(h) R5is substituted or unsubstituted C1and C2- alkyl.

Described cyclic urethanes include a group of cyclic urethane associated with a system of rings (X-R-Y) via a linking group L. Cyclic urethanes are in the 3 - position of the nitrogen atom, a 5-position (when the group is cyclic urethane is a 5-membered ring or 6-position (when the group is cyclic urethane is a 6-membered ring substituted amino group containing (A). A is separated from the carbon atom to which it is attached by means of spatial groups (R4).

This group (X-R-Y) is the group's system of rings and consists of one carbocyclic ring or two or more condensed or nscontainerbox, saturated or unsaturated carbocyclic rings or heterocyclic rings.

When on a plot of X-R-Y there is only one ring, this ring is carbocyclic. When two to the 5-, 6 - or 7-, preferably 5 - or 6-membered.

Preferably, the system rings (X-R-Y) was polycyclic and included two nscontainerbox rings and even more preferably, the ring representing the Y, which is adjacent to the linking group L, it heterocyclic, most preferably five-membered ring, which contains a heteroatom of oxygen in the 1-position.

In addition, when the ring system contains two rings, it is also preferred that the heterocycle (Y) was covalently linked to another ring (X) in the 5-position of the heterocycle (Y) and 1-position of the ring X and that the heterocycle Y was associated with group 1 in the 2-position of the heterocycle y

It is also possible, although not preferably, the polycyclic system of rings (X-R-Y) consisted of 2 rings (X and Y), separated by alkyl, carbonyl, or a heteroatom, most preferably oxygen (R). In addition, the ring system may be monocyclic and to consist of one carbocyclic ring; in this case, Y is absent, and R is the covalent bond is attached to L. However, when in the system there is only one carbocyclic ring, preferably, this ring is comprised of at least two, most STI and benzoyl.

When replacing any or all members of the system of rings (monocyclic or polycyclic) may have one or more substituents and substitution may be Cl, F, Br, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, aminoalkyl, acylamino or acyloxy.

L is a linking group announced new cyclic urethanes. Carbon-containing end of the L attached to the ring system X-R-Y for Y, but if Y is absent when X is most preferably in the 2-position of the ring Y or 1-position, ring X, if Y is missing.

The nitrogen atom of the group L is linked to the nitrogen atom in the 3 position of the plot of cyclic urethane.

This site L is selected from the group including, but not limited alkylamino, alkynylamino, alkylamino, alkynylamino, arylamino; preferably L is alkylamino, most preferably C1-alkylamino, CH=n

The group of cyclic urethane of new compounds of the present invention provides new compounds of the present invention characterize their name.

The plot of the cyclic urethane can be 5 - or 6-membered ring, preferably a 5-membered ring. Group cyclicality group of cyclic urethane. The group of cyclic urethane of new compounds of the present invention has the following structure:

< / BR>
in which R5is C1or C2the alkyl, preferably C1the alkyl. A must have one atom of nitrogen adjacent to the R4, A is heteroalkyl or 6 - or 7-membered heterocyclic ring, in which the heteroatoms are nitrogen atoms or sulfur, and oxygen can not be contained. When a is heteroalkyl, A can be straight or branched chain, saturated or unsaturated, substituted or unsubstituted. When a is a heterocycle, A represents a 6 - or 7-membered heterocyclic ring, which may have an oxygen atom and may contain one or two heteroatom nitrogen or sulphur, one of whom must be a nitrogen atom attached to R4. The specified ring can be substituted or unsubstituted, preferably substituted, saturated or unsaturated, preferably saturated. R4substituted 5 (when the plot of the cyclic urethane is a 5-membered ring or 6-position (when the plot of the cyclic urethane is a 6-membered ring) plot of cyclic urethane and is connected to the nitrogen atom A.

R4you is when A represents a substituted heteroalkyl, substituents selected from the group including, but not limited stands, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethanol and methanesulfonyl.

When the heterocycle has A two heteroatoms, both of which azoty, it is preferable that the nitrogen atom was not associated with R4being substituted by radicals selected from the group including, but not limited stands, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethanol and methanesulfonyl. When the heterocycle A is only 1 atom of nitrogen, it is preferable that the heterocycle was replaced (in the para - position to the nitrogen atom adjacent to R4if this heterocycle 6-membered) radicals selected from the group including, but not limited hydroxyethyl, hydroxy, oxo and stands.

In addition to these new cyclic urethanes of the invention relates to new pharmaceutical compositions containing these new compounds cyclic urethane and to a method of treating cardiac arrhythmia and fibrillation, using various compounds of cyclic urethanes.

The list used in the application of terms.

"Heteroatom is a nitrogen atom, sulfur or color represent an unsubstituted or substituted, linear or branched saturated hydrocarbon chain having from 1 to 8 carbon atoms, and preferably, unless otherwise stated, from 1 to 4 carbon atoms. A preferred group of alkyl include, but are not limited to groups: methyl, ethyl, propyl, isopropyl and butyl.

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

"Alkenyl" represents an unsubstituted or substituted, linear or branched hydrocarbon chain having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one etileno double bond.

"Quinil" represents an unsaturated or saturated hydrocarbons with straight or branched chain, having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms and having at least one triple bond.

"Rings" is used to denote containing ring of the area to which through a chemical bond L joined the group of cyclic urethane. Designated here as "X-R-Y" and may be a monocyclic group or globally, heterocycles, or both. Monocyclic rings, in the main, contain from 3 to 8 atoms, preferably from 5 to 7 atoms. Polycyclic system of rings, consisting of two rings usually contain from 6 to 16, preferably from 10 to 12 atoms. Polycyclic system of rings, consisting of three rings, usually contain from 13 to 17 atoms, preferably from 14 to 15 atoms.

"Carbocyclic ring" or "carbocycle" is used to denote unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring, typically containing from 3 to 8 atoms, preferably from 5 to 7 atoms.

"Heterocyclic ring" or "heterocycle" is used to denote unsubstituted or substituted, saturated or unsaturated or aromatic ring which consists of carbon atoms or one or more heteroatoms. Heterocyclic rings usually contain from 3 to 8, preferably from 5 to 7 atoms.

Unless otherwise noted, the heteroatom may be independently selected from nitrogen, sulfur or oxygen.

"Aryl" represents an aromatic carbocyclic ring. Preferably the aryl group include, but are not limited finallyclause ring. Preferably the aryl group include, but are not limited to tanila, fullam, pirrallo, pyridinyl, pyrazinium, oxazolium, thiazolium, hyalinella, pyrimidinium and tetrazolium.

"Alkoxy" represents an oxygen atom attached to a hydrocarbon chain that represents alkyl or alkenyl (i.e.,- o-alkyl or-o-alkenyl). Preferably the alkoxy group include, but are not limited to methoxy, ethoxy, propoxy and alkoxy.

"Hydroxyalkyl" represents a substituted hydrocarbon chain, which has a Deputy hydroxy (i.e.,- OH), and may have other substituents. Preferably the group hydroxyalkyl include, but are not limited to hydroxyethyl, hydroxypropyl, phenylhydroxylamine.

"Carboxylic" represents a substituted hydrocarbon chain, which has a carboxyl radical (i.e.,- COOH) and may have other substituents. Preferably the group carboxyethyl include carboxymethyl, carboxyethyl and their acids and esters.

"Aminoalkyl" represents a hydrocarbon chain (i.e., alkyl), substituted amine (i.e., NH-alkyl-), such as dimethylaminoethyl.

"Alkylamino" represents an amino group having about euwww one or two alkenyl Deputy (i.e., - N-alkenyl).

"Alkynylamino" represents an amino group having one or two etkinlik Deputy (i.e., - N-quinil).

"Alkylamino is aminogroup having one or two alkyl substituent (i.e., N-alkyl-).

"Arylalkyl" represents an alkyl plot, a substituted aryl group. Preferably, the group arylalkyl include benzyl or phenylethyl.

"Arylamino" represents the amino group, substituted aryl group (i.e., - N H/aryl).

"Aryloxy" represents an oxygen atom, aryl having a substituent (i.e.,- o-aryl).

"Acyl" or "carbonyl" is a group formed by removal of the hydroxyl of the carboxylic acid (i.e., R - C (= O) - ).

Preferably the group alkylaryl includes, but is not limited to acetyl, propionyl and butanoyl.

"Alkoxy" represents an oxygen atom, with the acyl substituent (i.e.,- o-acyl), for example,- O-C(=O)-alkyl.

"Acylamino" represents the amino group with the acyl substituent (i.e., - N - acyl), for example-NH-(C = O)-alkyl.

"Halo", "halogen" or "halide" is a radical chlorine atom, bromine, fluorine or iodine. Preferred is the La) represents a hydrocarbon chain, including, unless otherwise stated, from 1 to 6, preferably from 1 to 4 carbon atoms.

"Pharmaceutically applicable" salt is a cationic salt formed any acidic (e.g., carboxyl) group, or an anionic salt formed with any basic (e.g., amino) group. Many such salts are known, as described in World Patent Publication 87/05297, Johnston and others , published 11 September 1987 This work is included as a reference. Preferably cationic salts include alkali metal salts (such as sodium and potassium), and salts of alkaline earth metals (such as magnesium and calcium). Preferably anionic salts include halide salts (such as chloride).

"Biohydrology ester" is an ester compounds cyclic urethane, which does not preclude the antiarrhythmic activity of the compounds or which is easily absorbed by humans or other mammals, forming antiarrhythmic active cyclic urethane. Many such esters are known, as described in World Patent Publication 87/05297, Johnoston et. al., published on 11 September 1987, This work is included as a reference. Such esters include lower alkalemia esters, lower aryloxyalkyl esters (talkitive esters), esters lactone (such as Caligraphy and tittilicious esters), lower alkoxyalkanols esters such as esters methoxycarbonylmethylene, ethoxycarbonylmethylene and isopropoxycarbonyloxymethyl ethers, esters alkoxyalkyl, esters of choline and esters acylaminoalkyl (such as esters of atsetamidometil).

As defined above and as used here, a group of deputies, in turn, can be substituted. Such substitution may be one or more substituents. Such substituents are included, but not limited to the list shown in the following: C. Hansch and A. Leo, Substituent Constans for Correlation Analysis in Chemistry and Biology (1979). This work is included as a reference. Preferred substituents include, but are not limited to alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (i.e. aminomethyl and so on), cyano, halo, carboxy, alkoxyamino (i.e., carboethoxy and so on), thiol, aryl, cycloalkyl, heteroaryl, heterocyclization (i.e. piperidinium, morpholinium, piperazinil, pyrrolidinium and so on), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and their combinations.

The present invention covers some new cyclic urethanes, the way their polnie relates to a method for treatment of cardiac arrhythmia and/or cardiac fibrillation humans and other mammals using aminosilane cyclic urethanes, such as new compounds, the cyclic urethane of the present invention and cyclic urethanes as defined here. Special compounds and compositions used in the present invention should be pharmaceutically acceptable. Used the term "pharmaceutically acceptable" component means a component that is suitable for the treatment of humans and/or other mammals without obtaining side-effects (such as toxicity, irritation, allergic response) commensurate with a reasonable ratio of benefit/risk.

Described herein are new compounds aminosilanes cyclic urethane useful in the treatment of cardiac arrhythmia and/or serdechnoi atrial humans and other mammals and have the following General structure:

< / BR>
in which (a) X is a saturated or unsaturated 5-, 6 - or 7-membered heterocycle or carbocycle;

(b) R is selected from the group comprising covalent bond, a heteroatom, carboxyl, heterocyclic ring, carbocyclic ring, alkyl, alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy, acylamino, or is absent;

(c) Y is substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7-credentialing rings, and when R is a covalent bond, X and Y are systems of rings connected by covalent bond, and Y is absent, R is a covalent bond, and X is carbocycle related to L through R;

(d) R1, R2, R3are independently selected from the group comprising Cl, F, Br, NH2, CF3, OH, SO3H, CH3SO2NH, COON, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, aminoalkyl, acylamino, acyloxy;

(e) L is selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino, arylamino, in which the nitrogen atom attached to the nitrogen atom at the 3 - position of the group ring of the cyclic urethane;

(f) R is selected from the group comprising alkyl, alkenyl, quinil, alkylaryl and heteroalkyl;

(g) A is A substituted or unsubstituted, saturated or unsaturated heteroalkyl C1-C8with a straight or branched chain, or a substituted or unsubstituted, saturated or unsaturated 6 - or 7-membered heterocycle, which may have oxygen atom, and A has at least one nitrogen atom, which is adjacent to R4and

(h) R5is substituted or unsubstituted C1or C2- alkyl,

and takabatake useful for the treatment of cardiac arrhythmia and/or cardiac fibrillation and include a group of cyclic urethane, associated with a system of rings (X-R-Y) by a chemical bond (L). Cyclic urethanes are in the 3-position of the nitrogen atom, as in the 1-position is an oxygen atom; these cyclic urethanes substituted in the 5 position (when the plot of the cyclic urethane is a 5-membered ring [R5= C1-alkyl] ) and 6 position (when the plot of the cyclic urethane is a 6-membered ring [R5= C2-alkyl]) aminecontaining plot (A), separated from the carbon atom of the group (R4).

This system of rings (X-R-Y) represents the containing ring group and includes one, two or more carbocyclic fused or unfused, saturated or unsaturated, substituted or unsubstituted.

Thus, the system rings may be monocyclic (Y is missing) or polycyclic (rings are the X and Y or X, R and Y).

When there is only one ring, this ring - carbocycle. When there are two or more rings, these rings may be carbocycles and/or heterocycles and each ring may be either carbocycle or heterocycle, and may include 5, 6 or 7, preferably 5 or 6 members.

Preferably, the system rings polycyclic was and is(L), was a heterocycle, most preferably a 5-membered ring containing an oxygen atom in position 1. In addition, when the system rings represented by two rings, preferably a heterocycle (Y) was covalently linked (through R) with another ring (X) in the 5-position of the heterocycle Y in the 1-position of the ring (X) and that the heterocycle Y was associated with a carbon-containing end of the segment L in the 2-position of the heterocycle y

Although not preferred, but acceptable to the system of the rings was a polycyclic system of rings, consisting of two rings (X and Y), which would be separated by alkyl, carbonyl, or a heteroatom, preferably oxygen (R). In addition, an acceptable system of rings may include polycyclic system of rings comprising a two condensed (R no) the ring (X and Y) or three condensed rings (X, R and Y). When R is a ring, it is preferable that it is 5 - or 6-membered carbocycle or heterocycle.

Particularly suitable is a monocyclic system of rings, which consists of only one carbocycle (X), covalently linked to carbon-based plot of L (R is a covalent bond, and Y is absent). However, when the system rings more preferably substituted by at least two, and most preferably at least three, substituents, independently selected from the group including, but not limited to hydroxy, methyl, chlorine, methoxy and benzoyl.

When substituted for any or all of the members of the ring, monocyclic or polycyclic, there may be one or more substituents. These substituents can be independently selected from the group including, but not limited Cl, F, Br, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, alkoxy, alkoxycarbonyl, hydroxyalkyl, alkyl, aminoalkyl, acylamino, acyloxy and carboxyethyl, especially Cl, F, Br, OH and CH3.

Preferably the ring system (X-R-Y) new cyclic urethanes include, but are not limited to:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Preferred ring systems new cyclic urethanes of the present invention, which are useful for the treatment of cardiac arrhythmias and/or fibrillation include, but are not limited to, for example, monocyclic rings such as 2-acetoxy-5-chlorophenyl; 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl; 2-thienyl; 4-pyrimidinyl; 2-methanesulfonylaminoethyl, cyclohexyl; 5-chloro-2-hydroxyphenyl; 5-chloro-2-methoxyphenyl; 3-AMINOPHENYL, 3-methoxyphenyl; 2-amino the spent fuel from the two unfused rings, covalently associated with one another, include, for example, but not limited to: 5-(4-carboxyphenyl)-2-furanyl; 5-(4-methanesulfonyl)-2-furanyl; 5-(3,4-acid)-2-furanyl; 5-(4-methanesulfonylaminoethyl)-2-furanyl; 5-(4-bromophenyl)-2-oxazolyl; 5-(4-methoxyphenyl)-2-furanyl; 5-(1-cyclohexen-1-yl)-2-furanyl; 5-cyclohexyl-2-furanyl; 5-(3-triptoreline)-2-furanyl; 5-(4-were)-2-furanyl; 2-(4-course)-2-furanyl; 5-(4-course)-2-furanyl; 5-(4-forfinal)-2-furanyl. Suitable polycyclic ring system, which consist of two unfused rings connected via a heteroatom, alkyl or other acyclic carbon-containing groups include, for example, but not limited to: 2-benzyloxy-5-chlorophenyl; 4-benzyloxyphenyl; 3-(4-T-butylphenoxy)phenyl; 3-benzyl-2,4-dichlorophenyl; 2-chloro-3-benzyloxyphenyl; 3-(4-chlorophenoxy)phenyl. Suitable polycyclic ring system containing two or more condensed rings include, for example, but unlimited: 1H - indol-3-yl; 2-forfinal; 2-naphthyl; 2-hydroxy-1-naphthyl; 2-chinoline; 5-chloro-2-benzofuranyl.

L is a linking group of new compounds of cyclic urethane of the present invention. Carbon-containing end of the L attached to the ring system X-R-Y p is no. The nitrogen atom of the group L is attached to the nitrogen atom in position 3 plot of cyclic urethane. Group L selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino, arylamino, preferably alkylamino, most preferably C1-alkylamino, CH = n

The group of cyclic urethane of new compounds with cyclic urethane of the present invention provides compounds described herein characterize their name. The plot of the cyclic urethane may represent a 5 - or 6-membered ring, preferably a 5-membered ring. The plot of the cyclic urethane has the following structure:

< / BR>
in which R5is C1or C2the alkyl, preferably C1the alkyl. When R5is C1the alkyl, cyclic urethane is a 5-membered ring, and when R5is C2the alkyl, cyclic urethane is a 6-membered ring.

A is remotemachine or branched, substituted or unsubstituted, saturated or unsaturated C1-C8heteroalkyl or substituted or unsubstituted, saturated or unsaturated 6 -, or 7, preferably 6-membered heterocyclic ring.

A have sulfur, but may not contain heteroatoms of oxygen.

When A is replaced by heteroalkyl, preferably, the substituents are selected from the group including, but not limited stands, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethanol and methanesulfonyl.

When A has two nitrogen atom, preferably a nitrogen atom is not adjacent to R4(which in the case of 6-membered heterocycle is in the para - position to the nitrogen atom adjacent to R4), substituted by radicals selected from the group including, but not limited stands, hydroxyethyl, alkyl, aryl, mercaptoethanol, methanesulfonyl, heterocycle and arylalkyl. When the heterocycle A is only one nitrogen atom, and A is A 6-membered ring, the position of the pair with respect to the neighboring R4the nitrogen atom is preferably substituted by radicals selected from the group including, but not limited hydroxyethyl, hydroxy, oxo and stands.

Preferably, portions of A connection of a new cyclic urethane of the present invention include, but are not limited to:

< / BR>
< / BR>
< / BR>
< / BR>
Accordingly, suitable groups A new cyclic urethanes of this izopet is not limited to dimethylamino, diethylamino, bis-2-hydroxyethylamino, bis-[(1-methyl)ethyl]amino, N-benzyl-N-methylamino, N-(2-hydroxyethyl)-N-methylamino. Suitable groups A, where a is a heterocycle include, but are not limited to N-(1-methylethyl)-N-[2-hydroxy-2[(4-methanesulfonamido)phenyl] ethyl] amino, 4-phenyl-1-piperazinil, 4-(2-hydroxyethyl)-1-piperazinil; 4-[(1-methyl)ethyl]-1-piperazinil, 4-(2-methyl)-propyl-1-piperazinil, 4-hexyl-1-piperazinil; 4-benzyl-1-piperazinil, 1-piperazinil, 4-hydroxy-1-piperazinil, 4-methyl-1-piperazinil, 4-n-butyl-1-piperazinil, 4-ethyl-1-piperazinil, 3-(4-methyl-1-piperazinil)-3-oxopropyl, 4-phenyl-1-piperazinil, N-(2-pyridinyl)-1-piperazinil, N-(2-pyrimidinyl)-1-piperazinil, 4-(4-methoxyphenyl)-1-piperazinil-4-acetyl-1-piperazinil, N-methyl-N-phenylamino, 4-(2-were)-1-piperazinil, 4-(4-methanesulfonamido)-1-piperazinil, N-thiomorpholine, 4-oxo-1-piperazinil, 2-(t-butoxycarbonyl-4-(4-acetylphenyl)- 1-piperazinil, hexahydro-1H-azepin-1-yl.

R4attached to the cyclic group of urethane in 5-position (when the group is cyclic urethane is a 5-membered ring and a 6-position (when the group is cyclic urethane is a 6-membered ring group of the cyclic urethane and the nitrogen atom of the group A. R4selected from the group including, but n is drank, butyl, pentyl and hexyl.

As indicated above, the compounds of the cyclic urethane of the present invention include the group of cyclic urethane attached to the ring system via a bridging group. Accordingly, preferred compounds of cyclic urethane of the present invention include, but are not limited to the following compounds and their cleaners containing hydrochloride salts:

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-5-(1 - piperidinylmethyl)-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5-[3-(1- piperidinyl)propyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[4-(4- methyl-1-piperazinil)butyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[3-(4- methyl-1-piperazinil)propyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-5-[[4-(2- hydroxyethyl)-1-piperidinyl]methyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[(4-methyl - 1-piperazinil)methyl]-2-oxazolidinone.

New cyclic urethanes of the present invention can be administered to humans and other mammals in various ways, including but not limited to oral dosage forms and injections (intravenous, intramuscular, subcutaneous and intramural easily be obtained by the person skilled in the art using appropriate pharmaceutical excipients, as is described below.

For the patient's oral dosage forms are preferred.

The term "pharmaceutical composition" means a combination of safe and effective amount of the active ingredient cyclic urea or mixtures and pharmaceutically acceptable excipients.

The phrase "safe and effective amount" is used to denote the number of compounds or compositions, in General, sufficient for a significant positive modification of symptoms and/or condition that should be treated, but insufficient to produce serious side effects (at a reasonable benefit ratio/risk) from the point of view of medicine.

Safe and effective amount of the active component for use in the pharmaceutical composition or method that is proposed in the present invention, will vary depending on the specific conditions of treatment, age and physical condition of the patient, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the particular active component used, the features used pharmaceutically acceptable excipients, and related factors, assessment of inert, pharmaceutically inert materials that are compatible with the physical and chemical characteristics of the particular active component cyclic urethane selected for use.

Pharmaceutically acceptable excipients include, but are not limited to polymers, resins, plasticizers, fillers, binders, lubricants, galantai, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening additives, which impart taste and odor additives, pharmaceutical dyes or pigments and imparts viscosity additives.

The term "oral dosage form" is used to refer to any pharmaceutical composition intended for the systematic assignment of the individual through the mouth with a subsequent release of the specified composition in the gastrointestinal tract.

For the purposes of the present invention used form may be a tablet, coated or uncoated, solution, suspension or capsules coated or uncoated.

The term "injection" is used here in the meaning of any of the pharmaceutical compositions, prednaznacheniya active component, by piercing the skin of the specified channel to the specified solution or emulsion came into the circulation system of the individual intravenously, intramuscularly, subcutaneously or by intraperitoneally injection.

The norm of regular consumption can be controlled using one or more of the following factors:

a) the right of the active component;

(b) pharmaceutically acceptable excipients, as they do not interfere with the activity of the selected active ingredient;

c) the type of filler and the accompanying desirable thickness and permeability properties of swelling of the specified coverage;

d) time-dependent properties of the filler and/or properties within him;

e) the particle size of the granulated active ingredient;

f) pH-dependent properties of the fillers.

In particular, solubility, acidity and sensitivity to hydrolysis of the various active components of the cyclic urethane, such as an acid additive salts, salts formed with a carboxyl group and so on, salts of alkali metals, salts of alkaline earth metals, and so on, ethers such as alkyl, alkenilovyh, arrowy arylalkylamine can be used as a principle is inogo use by adding a suitable buffer to the active component.

Pharmaceutically acceptable excipients include, but are not limited to, resins, fillers, binders, lubricants, solvents, galantai, disintegrate, co-solvents, surfactants, preservatives, sweetening additives, which impart taste and odor additives, buffer systems, pharmaceutical dyes and pigments and imparts viscosity additives.

The preferred solvent is water.

Suitable additives, which impart taste and odor, include those described in Remington''s Pharmaceutical Sciences, 18 th Edion, Mack Publishing Company, 1990, pp. 1288-1300, the work is included as a reference.

Suitable for use here pharmaceutical compositions typically contain 0 - 2% gives taste and smell components.

Used dyes or pigments include those described in Handbook of Pharmaceuticol Excipients, pages 81-90, 1986 by the American Pharmaceutical Assotiation and Pharmaceutical Society of Great Britain, the work is included as a reference. Pharmaceutical compositions typically contain 0-2% dyes or pigments.

Preferred co-solvents include, but are not limited to ethanol, glycerin, propylene glycol, polyethylene glycols. Pharmaceutically who Ernie systems include, but not limited to acetic, boric, carbonic, phosphoric, succinic, maleic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts. Mostly preferred are phosphoric, tartaric, citric and acetic acid and their salts. The pharmaceutical compositions of the present invention typically include 0-5% buffer system.

Preferred surfactants include, but are not limited to esters of fatty acids of polyoxyethylenesorbitan, polyoxyethylene ethers of monoalkyl, monoamine sucrose, esters of lanolin and esters, salts alkylsulfate, salts of sodium, potassium and ammonium fatty acids.

The pharmaceutical compositions of the present invention include 0-2% surfactants.

Preferred preservatives include, but are not limited to phenol, alkyl esters of parahydroxybenzoic acid, o-phenylphenolate acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, thimerosal, finalstates acetate and nitrate, nitromersol, benzalkonium, cetylpyridinium is s, cetylpyridinium chloride, methylparaben and propylparaben. Compositions of the present invention typically include 0-2% preservatives.

Preferred sweetening substances include, but are not limited to sucrose, glucose, saccharin, sorbitol, mannitol and aspartame. The most preferred sucrose and saccharin. The pharmaceutical compositions of the present invention include 0-5% sweeteners.

Preferred giving the viscosity of the additive include, but are not limited to methylcellulose, Na - carboxymethyl cellulose, hypromellose, hydroxypropylcellulose, sodium alginate, Carbonera, povidone, acacia, yeasty resin, xanthan resin and Trianta.

Most preferred are methyl cellulose, carbomer, xanthan gum, yeasty resin, povidone, Na - carboxymethyl cellulose, and magnesium-aluminum silicate. Compositions of the present invention include 0-5% giving the viscosity of the components.

Preferred fillers include, but are not limited to lactose, mannitol, sorbitol, dibasic calcium phosphate, trehosnovnoy calcium phosphate, presswise sugar, starch, calcium sulfate, dextro and microcryst the global lubricants include, but not limited to magnesium stearate, stearic acid and talc. The pharmaceutical compositions of the present invention include a 0.5 - 2% lubricants.

Preferred glidant include, but are not limited to talc and colloidal silicon dioxide. Compositions of the present invention include 1-5% of glidants.

Preferred disintegrant include, but are not limited to starch, sodium starch glycolate, crosspovidone, croscarmellose sodium and microcrystalline cellulose. The pharmaceutical compositions of the present invention include 4-15% of disintegrant.

Preferred binders include, but are not limited to acacia, tragakant, hydroxypropylcellulose, pre relativedomainname starch, gelatin, povidone, hydroxypropylcellulose, hypromellose, methylcellulose, solutions of sugars, such as sucrose and sorbitol, ethylcellulose. Compositions of the present invention include 1-10% of binders.

Thus, the pharmaceutical compositions of the present invention include 15-95% of the active ingredient compounds of cyclic urethane, or mixtures thereof: 0-2% gives taste and scent additives; 0-50% carstvo% giving a viscosity additives; 0-75% fillers; 0.5 to 2% lubricants; 1-5% glidants; 4-15% of disintegrant and 1-10% of binders.

Suitable pharmaceutical compositions are described in examples G - K. Changing samples described here, you can get a wide range of pharmaceutical compositions.

Described cyclic urethanes effective in the treatment of humans and other mammals suffering from supraventricular arrhythmia, ventricular arrhythmia and/or cardiac fibrillation. Described herein are new compounds useful for the treatment of cardiac arrhythmia and fibrillation; in addition, connections aminosilanes cyclic urethane described in the following U.S. patents, incorporated as reference, are also useful for the treatment of cardiac arrhythmia and fibrillation:

2,798,068 issued 02.07.1957,; 2,802,002 issued 06.08.1985,

3,318,878 issued 09.05.1967 g and 4,393,204 issued 12.07.1983,

As stated above, believe that in addition to rare cases of supraventricular fibrillation is not life threatening and usually not treated intensively with conventional antiarrhythmic drugs because of their unwanted side effects. Thus, this type of arrhythmia is usually not treated seriously, and only ease the symptoms that happen from the definition drugs, as a rule, have less unwanted side effects and, accordingly, can be successfully used for the treatment of those individuals who are experiencing discomfort, even if there is no threat to their lives.

As stated above, compounds described herein aminosilanes cyclic urethane is also effective in the treatment of ventricular arrhythmias, which, as a rule, much more serious than Adrianna arrhythmia and, accordingly, requires intensive treatment. Due to the severity of ventricular arrhythmias have been many classifications depending on the type of patient.

Individuals suffering from ventricular fibrillation in the form of light from a philosophical point of view, such as those suffering from supraventricular arrhythmia. These individuals no pain in my heart, they may be fainting, dizziness, palpitations and frequent disturbance caused by feelings that they are experiencing. These individuals usually suffer from PVCs, which in most cases is safe, but cause anxiety.

Described herein cyclic urethanes typically produce less unwanted side effects that make unwanted treatment traditional antiarrhythmic is epidemol would be useful therapy, which is usually better tolerated.

Another class of individuals, which would be a useful therapy using compounds of cyclic urethane, are individuals who are characterized as suffering from arrhythmia with poor prognosis". These individuals usually suffer from myocardial infarction and may have PVCs and/or episodes of unstable ventricular tachyarrhythmias, symptomatic or asymptomatically. They do not experience the same degree of immediate life-threatening symptoms, as individuals, are described here below, and not by the fact that for them there is a threat of immediate or imminent death. However, there is a significantly greater risk of sudden death than for the rest of saturation and, therefore, therapy that uses described herein compounds of cyclic urethane, would reduce the risk of coronary insufficiency.

For other individuals, who for a long period of suffering life-threatening arrhythmia, there is a danger of immediate or imminent death. These individuals usually suffer from sustained ventricular tachyarrhythmia or ventricular fibrillation. Utricularia arrhythmia these individuals usually causes heard or hypotension. In these patients, the highest risk of sudden cardiac death and is usually the most serious form of heart disease. Cm. Morganroth and Bigger, page 1498.

Described herein cyclic urethanes and their pharmaceutical compositions are effective but have fewer undesirable side effects, compared to the still commonly used traditional means of complications. Certainly they have no alternative in the treatment of life-threatening arrhythmias, although intensive therapy is suitable for the treatment of this class of individuals.

As above described cyclic urethanes have less of many unwanted side effects associated with many conventional antiarrhythmic drugs. These side effects include, but are not limited to pulmonary toxicities, cardiac depression and neurological effects are not specific for cardiac tissue.

In addition, the above cyclic urethanes have as antiarrhythmic and antifibrillatory action; they warn of sudden cardiac death by prolongation of the period of devozbuzhdeniya heart in continuation of each heartbeat. Conventional therapeutic means proyavlyalsya.

Described here are the links cyclic urethane useful for the treatment of cardiac arrhythmia and/or cardiac fibrillation humans and other mammals. Accordingly, the present invention relates to a method of treatment of humans and other mammals suffering from cardiac arrhythmia and/or cardiac fibrillation, which includes the appointment of a specified person or other mammal a safe and effective amount of a pharmaceutical composition that includes 15-90% connection cyclic urethane having the General formula:

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in which (a) X is a saturated or unsaturated 5-, 6 - or 7-membered heterocycle or carbocycle;

(b) R is selected from the group comprising covalent bond, a heteroatom, carboxyl, heterocyclic ring, carbocyclic ring, alkyl, alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy, acylamino or missing;

(c) Y is substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7-membered heterocycle or carbocycle or missing;

and in which, when R is absent, X and Y are systems of condensed rings, and when R is a covalent bond, X and Y are systems of rings associated covalent bond, the om R;

(d) R1, R2and R3are independently selected from the group comprising Cl, F, Br, NH2, CF3, OH, SO3H, CH3SO2NH, COON, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, aminoalkyl, acylamino, acyloxy or absent;

(e) L is selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino, arylamino; in which the nitrogen atom of L is attached to the nitrogen atom at position < 3 the group ring of the cyclic urethane;

(f) R is selected from the group comprising alkyl, alkenyl, quinil, alkylaryl and heteroalkyl;

(g) A is A substituted or unsubstituted, saturated or unsaturated C1-C8heteroalkyl straight or branched chain, or a substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7-membered heterocycle, which may have oxygen atom and one nitrogen atom, which is adjacent to R4;

(h) R5is substituted or unsubstituted C1and C2- alkyl;

or their pharmaceutically acceptable salts esters;

and 10-85% of pharmaceutically acceptable fillers.

New cyclic urethanes of the present invention are useful for the treatment of cardiac arrhythmia and/or cardiac group (L). Cyclic urethanes are in the 3-position of the nitrogen atom, as in the 1 - position of the oxygen atom. These cyclic urethanes substituted aminecontaining group (A), separated from the carbon atom of the cyclic urethane group (R4).

This system of rings (X-R-Y) represents the containing ring section and includes one or more, preferably one or two condensed or unfused, saturated or unsaturated, substituted or unsubstituted rings.

Thus, the system rings may be monocyclic (Y is missing) or polycyclic (rings are the X and Y or X, R and Y).

Each ring can be either carbocycle or heterocycle, and may include 5, 6 or 7, preferably 5 or 6 members.

Preferably, the system rings was polycyclic and included two condensed rings. More preferably, the ring (Y) adjacent to the linking group (L), was a heterocycle, most preferably a 5-membered ring containing an oxygen atom in position 1. In addition, when the system rings represented by two rings, preferably a heterocycle (Y) was covalently linked (through R) with another ring (X) in the 5-position of the heterocycle Y is recicla y

Although not preferred, but acceptable to the system of the rings presents a polycyclic system of rings, consisting of two rings (X and Y), which would be separated by alkyl, carbonyl, or a heteroatom, preferably oxygen (R). In addition, an acceptable system of rings may include polycyclic system of rings comprising two condensed rings (X and Y) R is absent or three rings (X, R and Y). When R is a ring, it is preferable that it is 5 - or 6-membered carbocycle or heterocycle.

Particularly suitable is a monocyclic system of rings, which consists of only one carbocycle (X), covalently linked to carbon-based plot of L (R is a covalent bond, and Y is absent). However, when the system rings represented by only one ring, it is preferable that this ring was a 6-membered carbocycle, which is more preferably substituted by at least two, and most preferably at least three substituents, independently selected from the group including, but not limited to hydroxy, methyl, chlorine, methoxy and benzoyl.

When substituted for any or all of the members of the ring, monocyclic or Politechnicheskaya, including, but not limited Cl, F, Br, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, alkoxy, alkoxycarbonyl, hydroxyalkyl, alkyl, aminoalkyl, acylamino, acyloxy and carboxyethyl, especially Cl, F, Br, OH and CH3.

Preferably the ring system (X-R-Y) cyclic urethanes used in the treatment of cardiac arrhythmias and/or fibrillation, as defined here, include, but are not limited to:

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Preferred ring systems of cyclic urethanes used in the treatment of cardiac arrhythmias and/or fibrillation include, but are not limited to, for example, monocyclic rings: 2-acetoxy-5-chlorophenyl; 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl; 2-thienyl; 4-pyrimidinyl; 5-methoxycarbonyl-2-furanyl; cyclohexyl; 5-chloro-2-hydroxyphenyl; 5-chloro-2 - methoxyphenyl; 5-ethyl-2-furanyl; 3-methoxyphenyl; 2-AMINOPHENYL; 3,5-dimethyl - 4-hydroxyphenyl and 5-acetoacetyl - 2-furanyl. Suitable polycyclic ring system, which consist of two unfused rings covalently associated with one another, include, for example, but not limited to 5-(4-carboxyphenyl)-2-furanyl; 5-(4-methanesulfonyl)-2-furanyl; 5-(3,4-acid)-2-furanyl; 5-(4-methanesulfonyl the KSIL-2 - furanyl; 5-(3-triptoreline)-2-furanyl; 5-(4-were)-2-furanyl; 2-(4-course)-X-furanyl; 5-(4-course)-2-furanyl; 5-(4-forfinal)-2-furanyl. Suitable polycyclic ring system, which consist of two unfused rings connected via a heteroatom, alkyl or other acyclic carbon-containing groups include, for example, but are not limited to 2-benzyloxy-5-Harper; 4-benzyloxyphenyl; 3-(4-t-butylphenoxy)phenyl; 3-benzyl-2,4-dichlorophenyl; 2-chloro-3-benzyloxyphenyl; 3-(4-chlorophenoxy)phenyl. Suitable polycyclic ring system containing two or more condensed rings include, for example, but not limited to 1H-indol-3-yl; 2-forfinal; 2-naphthyl; 2-hydroxy-1-naphthyl; 2-chinoline; 5-chloro-2-benzofuranyl.

L is a linking group antiarrhythmic and antifibrillatory compounds cyclic urethane of the present invention. Carbon-containing end of the L attached to the ring system X-R-Y Y, but if Y is zero, X; most preferably in the 2-position of the ring Y and 1 - X, if Y is missing. The nitrogen atom of the group L is attached to the nitrogen atom in position 3 - phase cyclic urethane. Group L selected from the group consisting of alkylamino, alkynylamino, alkylamino, alkenone the PAP cyclic urethane may represent a 5 - or 6-membered ring, preferably 5-membered ring. The plot of the cyclic urethane has the following structure:

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in which R5is C1or C2the alkyl, preferably C1the alkyl. When R5is C1the alkyl, cyclic urethane is a 5-membered ring, and when R5is C2the alkyl, cyclic urethane is a 6-membered ring.

A is remotemachine or branched substituted or unsubstituted, saturated or unsaturated C1-C8heteroalkyl or substituted or unsubstituted, saturated or unsaturated 5-, 6 -, or 7, preferably 6-membered heterocyclic ring.

A, regardless of whether he heteroalkyl or heterocycle must have at least one nitrogen atom adjacent to R4.

When A is replaced by heteroalkyl, preferably, the substituents are selected from the group including, but not limited stands, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethanol and methanesulfonyl.

When A heterocycle has two nitrogen atom, preferably a nitrogen atom is not adjacent to R4(which in the case of a 6 membered nymi from the group including, but not limited stands, hydroxyethyl, aryl, mercaptoethanol, methanesulfonyl, heterocycle and arylalkyl. When the heterocycle A is only one nitrogen atom, and A is A 6-membered ring, the position of the pair with respect to the neighboring R4the nitrogen atom is preferably substituted by radicals selected from the group including, but not limited hydroxyethyl, hydroxy, oxo and stands.

Preferred amino compounds plots a compounds described herein cyclic urethanes of the present invention include, but are not limited to:

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Accordingly, the appropriate group A may include, but are not limited to the following:

Areas in which a is heteroalkyl include, but are not limited to dimethylamino; diethylamino; bis-2-hydroxyethylamino; bis-[(1-methyl)ethyl] amino; N-benzyl-N-methylamino; N-(2-hydroxyethyl)-N-methylamino. Suitable groups A, where a is a heterocycle include, but are not limited to N-(1-methylethyl)-N-[2-hydroxy-2[(4-methanesulfonamido)phenyl] ethyl]amino; 4-phenyl-1-piperazinil; 4-(2-hydroxyethyl)-1-piperazinil; 4-(1-methyl-ethyl]-1-piperazinil; 4-(2-methyl)-propyl-1-piperazinil; 4-hexyl-1-piperazinil; 4-benzyl-1-piperazinil; 1-piperazinil; 4-GI is oxopropyl; 4-phenyl-1-piperazinil; N-(2-pyridinyl)-1-piperazinil; N-(2-pyrimidinyl)-1-piperazinil; 4-(4-methoxyphenyl)-1-piperazinil; 4-acetyl-1-piperazinil; N-methyl-N-phenylamino; 1-imidazolyl; 4-(2-were)-1-piperazinil; 4-(4-methanesulfonamido)-1-piperazinil; N-morpholinyl; N-thiomorpholine; 4-oxo-1-piperazinil; 2-(t-butoxycarbonyl-1-piperazinil; pyrrolidinyl; 4-(4-acetylphenyl)-1-piperazinil; hexahydro-1H-azepin-1-yl.

R4attached to the cyclic group of urethane in 5-position (when R5is C2by alkyl), or 6-position (when R5is C2by alkyl) plot of cyclic urethane and the nitrogen atom of the site A. R4selected from the group including, but not limited to alkyl, alkenyl, quinil, alkylaryl and heteroalkyl, especially C3-C6alkali, that is, propyl, butyl, pentyl and hexyl.

As indicated above, these cyclic compounds include urethane group, a cyclic urethane attached to the ring system via a linking group. Accordingly, suitable connections cyclic urethane include, but are not limited to, the following compounds and their cleaners containing hydrochloride salts:

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-5-(1 - piperidinylmethyl)-2-oxaz(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[4-(4- methyl-1-piperazinil)butyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[3-(4- methyl-1-piperazinil)propyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-5-[[4-(2- hydroxyethyl)-1-piperidinyl]methyl]-2-oxazolidinone;

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[(4-methyl - 1-piperazinil)methyl]-2-oxazolidinone;

3-[[[5-(4-were)-2-furanyl] methylene] amino] -5-(1 - pyrrolidinyl)-2-oxazolidinone.

Examples of M-S show the situation with certain patients and illustrate methods of treating cardiac arrhythmia and fibrillation, which can be used compounds described herein cyclic urethane. The person skilled in the art, changing the examples described here, can treat a wide class of individuals suffering from cardiac arrhythmia and fibrillation.

The present invention is illustrated by the following examples:

An example of A

Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] - 5-(1-piperidinylmethyl)-2-oxazolidinone hydrochloride

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5-(4-chlorophenyl)-2-furancarboxaldehyde (F-1054) (to 3.92 g, 19.0 mmol) and 3-amino-5-(1-piperidinyl)methyl-2-oxazolidinone (EU-137) (of 3.78 g, 19.0 mmol) in 150 ml of ethanol is treated with 3 ml of concentrated hydrochloric acid (pH about 3). The reaction mixture Perea obtain the target product (NE 11715).

Analytically pure sample is obtained by one recrystallization from nitromethane (Darco) (3.2 g, 40%), so melting 285oC.

Elemental analysis: calculated for C20H22ClN3O3HCl: C 56,61; H 5,46; N 9,90.

Found: C 56,68; H 5,44; N 9,88.

Example B

Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-5- (1-(4-methylpiperazine)methyl]-2-oxazolidinone dihydrochloride

A. Synthesis of 3-[(phenylmethylene)amino]-5-1-(4-methyl-1'- piperazinil)methyl]-2-oxazolidinone hydrochloride

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A solution of 5-(chloromethyl)-3-[(phenylmethylene)amino]-2-oxazolidinone (EU-168), prepared as described in "Stereocpecific Synthesis of Opticolly Active 5-Substituted-3-Aralkylidene-amino-2-oxazolidinone," By N. D. Harris, J.Org. Chem., so 27, pages 745-748 (1963) (work included as a reference).

(5.0 g, 0,021 mol), dimethylformamide (50 ml) and N-methylpiperazine (25 ml) is heated under reflux for 4 hours. The solution is concentrated under reduced pressure to obtain oily sludge. The residue is dissolved in absolute ethanol (20 ml) and cooled in an ice bath. The solid is separated, collected and then dried in the air, receiving 2 g of the product of raw. The filtrate is concentrated under reduced pressure and then under high vacuum at 55-60oC. Clear the society. The solid is collected and partially dried on the air. This solid is combined with the above product is raw, triturated with acetonitrile (25 ml), collected and dried in the air, receiving of 4.05 g (0.012 mol) of the intermediate product.

B. Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]- 5-[1-(4-methyl-1-piperazinil)methyl]-2-oxazolidinone

< / BR>
A mixture of intermediate synthesized in part A (of 4.05 g, 0.012 mol), 2N HCl (125 ml) and 5% Pd/C 50% H. O. (1.0 g) is treated with hydrogen in a Parr apparatus at 40 psi pound per square inch (about 2.8 kg/cm2) at room temperature. After 1 hour shaking ceased. The catalyst was removed by filtration, and the filtrate concentrated under reduced pressure to obtain oily sludge.

The residue is suspended in dimethylformamide, are then added to a solution of 5-(4-chlorophenyl)-2-furancarboxaldehyde (F-1054), prepared as described in U.S. patent 4.882.354 issued 22.11.1984 g, (work is included as a reference) (2.5 g, 0.012 mol) in dimethylformamide (40 ml).

The resulting solution was stirred at room temperature overnight. The solid is collected and partially dried on the air. This solid material is recrystallized cibacen, the tub on the air, dried in vacuum at 100oC, receiving of 2.08 g (0,0044 mol), yield 36% of the target product. So melting 240oC (decomp.). Elemental analysis: Calculated for C20H23ClN4O32HCl:

C, 50.49; H, 5.30; N, 11.78.

Found: C, 50.52; H 5,41; N 11.59.

Example C

Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino-5- [[4-(2-hydroxyethyl)-1-piperidinyl]methyl]-2-oxazolidinone hydrochloride

A) Synthesis of 3-benzylamino-5-[4-(2-hydroxyethyl)-1-piperazinyl)- methyl]-4H-oxazolidinone hydrochloride

< / BR>
Stir the solution EU-168 (10.0 g, 0.04 mol) in 270 ml of dry DMF, treated with anhydrous sodium iodide (12,6 g, 0.08 mol) and heated for 1/2 hour. Then the reaction solution is treated with anhydrous potassium carbonate (5.8 g, 0.04 mol) followed by addition of 4-piperidinemethanol (5,43 g, 0.04 mol). The reaction mixture is heated almost to boiling under reflux for 2 hours and left at room temperature overnight. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to obtain an oily residue. The residue is treated with 300 ml of H2O and extracted with portions h ml of acetate. An ethyl acetate extracts are combined and dried over anhydrous magnesium sulfate. the aslo placed in absolute alcohol (100 ml) and treated with saturated mixture of ethanol/HCl.

The reaction solution is placed within 10 minutes prior to the crystallization of solid light brown color. The crystals are collected and washed with anhydrous ether to obtain 7,01 g of the crude intermediate product (1). Then the sample is recrystallized from absolute alcohol (activated charcoal) and obtain analytically pure intermediate compound 3-phenylethylamine - 5-[4-(2-hydroxyethyl)- 1-piperidinyl) methyl]- 2-oxazolidinone hydrochloride in the amount of 3.5 g (24%).

Elemental analysis: Calculated for C18H25N3O3HCl:

C 58,77; H 7,12; N 11,42.

Found: C 58,49; H 7,18; N 11,37.

B) Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]- 5-[[4-(2-hydroxyethyl)-1-piperidinyl]methyl]-2-oxazolidinone hydrochloride

< / BR>
A solution of intermediate substances (1), synthesized in part A (2.0 g, 0,006 mol) in 20 ml of 2N HCl is treated with 5% palladium on carbon [50% catalyst humidity (2.0 g)]. The reaction mixture was restored in the Parr apparatus in an atmosphere of hydrogen. The absorption of hydrogen ceases after 0.5 hours, averaging 140% of theoretical. The catalyst was removed and the filtrate is concentrated under reduced pressure to separate the off-white precipitate.

The precipitate is treated with nom 21.11.1984 g, work included as reference), (1,21 g, 0.006 mol) in 50 ml of dry dimethylformamide.

The reaction mixture was stirred over night at room temperature. The reaction mixture was filtered and washed with anhydrous ether to obtain 2,44 g (of 91.6%) of product. Analytically pure sample is obtained by recrystallization from absolute alcohol (add a little water) (charcoal/celite), yield 1.4 g so pl. 217 to 220oC.

Elemental analysis: Calculated for C22H28ClN3O4HCl:

C 56,42; H OF 5.81; N 8,97.

Found: C 55,47; H Of 5.84; N 8,84.

Calculated for the sample containing 0.5 mol (H2O) (1,89%):

C 55,35; H 5,91; N 8,80.

Example D

Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5- [3-(1-piperidinyl)propyl]-2-oxazolidinone hydrochloride

A) Synthesis of m-chloroperoxybenzoic acid

< / BR>
In a three-neck flask with a capacity of 5 liters with a mechanical stirrer are placed H2O (1000 ml), magnesium sulfate 7H2O (5,77 g, 0,0234 mol), then sodium hydroxide (138,5 g, 3.46 mol). The turbid solution is cooled in an ice bath to 10-15o. Add 30% hydrogen peroxide (340 ml, ALD.), with the subsequent addition of dioxane (1250 ml). With vigorous stirring at 10-15oslowly is cooled to 15-20oand stirred for 30 minutes Maintaining the temperature 15o, with stirring, add 20% H2SO4(chilled, fit of 3100 ml, prepared by pouring the H2SO4in ice). After 10 min the mixture is transferred into a 6-liter separating funnel, add remaining 20% H2SO4. The organic layer is separated and the aqueous phase extracted with CH2Cl2(2 x 500 ml 4 x 250 ml). The combined organic layers dried over MgSO4. The filtered solution is used as it is and assume that it contains -1,14 80-85 mol% of meta-chloroperoxybenzoic acid (I).

B) Synthesis of potassium salt of benzyliden of ethyl carbazate (II)

< / BR>
A solution of ethyl carbazate (50.0 g, 0,0480 mol, ALD.), acetic acid (350 ml) and benzaldehyde (49 ml, 50.9 mg, to 0.480 mol, ALD.) stirred for 2 hours. The mixture is then poured into H2O (approximately 3500 ml) and stirred for 1 hour. The solid is collected, washed with H2O and air-dried. Drying continued at 60oto obtain 85 g (0,4422 mol, yield 92%) of benzyliden of ethyl carbazate.

Benzyliden ethyl, carbazate (40,0 g, 0,2081 mol) is dissolved in absolute ethanol (500 ml), to this solution was added a solution of tert-butoxide potassium (23,4 g, 0,2081 mol, ALD.) in absolute atenonol the mixture is stirred for 1.5 hours at room temperature. The solid is collected, washed with anhydrous ether and dried in air. Drying continued at 60owith the receipt of 45.0 g (0,1954 mol, yield 94%) of the potassium salt of benzyliden of ethyl carbazate (II).

C) Synthesis 3-[[[5-(4-chlorophenyl)-2-furacin]methylene]amino]- 5-[3-(1-piperidinyl)propyl]-2-oxazolidinone hydrochloride

1) Synthesis of benzyl ester 4-penten-1-ol (III)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Stir a solution of 4-penten-1-ol (77 ml, 64,6 g, 0.75 mol, ALD.) in DMF (800 ml) portions treated with NaH 60% in mineral oil (30.0 g, 0.75 mol, ALD. ), for about 2 hours. Keep the temperature of 10-20omoderate cooling in an ice bath. After the addition the mixture is stirred for 2 h at room temperature, then 2 hours, heated at a temperature steam baths. After cooling to room temperature the mixture is cooled to 5-10o. Under stirring at 5-10oadded dropwise benzylchloride (86,3 ml, 0.75 mol, ALD.) for about 45 minutes Stirring is continued refrigerated for 1 hour, then at room temperature overnight. The mixture is heated at a temperature steam bath for 3 hours, then cooled to room temperature. The mixture is concentrated at the pony who comply with ethyl ether (4 x 250 ml). The ether extract was washed with H2O (4 x 150 ml), then dried over MgSO4. The filtered solution is concentrated under reduced pressure to get III (102 g, 0,579 mol, the yield of the crude substances 77%, note 1) in the form of liquid residue.

Note 1: This residue contains about 12 g of mineral oil.

2) Synthesis of benzyl ether (4,5-epoxy)pentane-1-ol (IV)

A solution of meta-chloroperoxybenzoic acid (1) (a solution prepared in stage A, containing 1,14 mol of percolate in CH2Cl2and dioxane) was stirred and cooled to 0-5o. Benzyl ether of 4-penten-1-ol (III) (102, 0,579 mol) are added dropwise at 0-5owithin 1 hour. The solution is stirred while cooling and allow to slowly warm to room temperature. Stirring is continued at room temperature for 5 days. The solution was washed with 1N NaOH (2 x 3500 ml, carried out by three washes that make up 1/3 of the volume parts). The organic layer is dried over MgSO4. The filtered solution is concentrated under reduced pressure to a liquid residue. His distil in vacuo, collecting the product at 95-120oand 1-0,5 mm RT.article obtaining 77,2 g (0,402 mol, 69%) IV.

3) Synthesis of 5-[3-(phenylmethoxy)propyl] -3-fenil is fragmented, as described in part B (34,0 g, 0.1476 mol), dimethylformamide (550 ml) and benzyl ether (4,5-epoxy)pentane-1-ol (IV) (prepared in accordance with part C 2) (42.6 g, 0,2214 mol, 1.5 square) is heated under reflux for 3 hours. After cooling, the mixture is concentrated under reduced pressure to an oily residue. This residue was dissolved in CH2Cl2(500 ml), then washed with H2O (4 x 200 ml), saturated NaCl solution (1 x 200 ml), then dried over MgSO4. The filtered solution is concentrated under reduced pressure to a maximum balance. The residue is triturated with anhydrous ether (500 ml), stir for 15 minutes. The solid is collected, washed with ether and dried in the air, getting 27,1 g (0,0801 mol, the yield of 54.3%) 5-[3-(phenylmethoxy)propyl]- 3-phenylethylamine-2-oxazolidinone (V).

4) Synthesis of 3-phenylethylamine-5-(3-hydroxy)propyl-2 - oxazolidinone (VI)

A mixture of 5-[3-(phenylmethoxy)propyl] -3-phenylmethylene-2 - oxazolidinone (V) (20,0 g, 0,0591 mol), 2N HCl (450 ml) and 5% Pd/C 50% H2O (about 5 g) is treated with hydrogen in a Parr apparatus at 40 psi (2.8 kg/cm2) at room temperature. After 2 hours the absorption of H2stops, constituting 100% of theoretical values. The catalyst disarmament reaction repeat the identical way, using 22,0 g (0,0650 mol) of 5-[3-(phenylmethoxy)propyl]-3-phenylethylamine - 2-oxazolidinone (V). The method gives an oily residue.

United aforementioned residues (0,1241 mol), dimethylformamide (500 ml), benzaldehyde (13,17 g, 0,1241 mol) and molecular sieves was stirred at room temperature overnight. The sieves are removed by filtration, the filtrate is concentrated under reduced pressure to an oily residue.

This residue chromatographic on a Waters Prep-500 on silica gel normal phase elute 2,5 MeOH/CH2Cl2. The fractions containing the product are combined and concentrated under reduced pressure to a semi-solid residue. The residue is triturated with anhydrous ether (400 ml), stirring for 30 minutes. The solid is collected and dried in the air, getting 23,68 g (0,0954 mol, yield 77%) of 3-phenylethylamine-5-(3-hydroxy)propyl-2-oxazolidinone (VI).

5) Synthesis of 5-(3-chlorpropyl)-3-phenylethylamine-2-oxazolidinone (VII)

A mixture of 3-phenylethylamine-5-(3-hydroxy)propyl-2-oxazolidinone (VI) (10,88 g, 0,0438 mol), CHCl3(200 ml) and pyridine (4,25 ml of 4.16 g, 0,0526 mol, 1.2 EQ.) stirred at room temperature. Added dropwise thionyl chloride (11.2 ml of 18.2 g, 0,1533 mol; 3.5 equiv.) within 30-45 mine is actor heated under reflux for 2 hours. After cooling, the solution is concentrated under reduced pressure to a solid residue, which azeotropic distillation with toluene (2 x 50 ml). The solid residue was dissolved in CH2Cl2(250 ml), then washed with water (3 x 100 ml). CH2Cl2dried over MgSO4, filtered, then concentrated under reduced pressure and get 5-(3-chlorpropyl)-3 - phenylethylamine-2-oxazolidinone (VII) (11.2 g, 0,0420 mol, yield 96%) as a solid residue.

6) Synthesis of 3-phenylethylamine-5-[3-(1-piperidinyl)propyl]-2 - oxazolidinone (VIII)

Stir a solution of 5-(3-chlorpropyl)-3-phenylethylamine-2 - oxazolidinone (VII) (2.7 g, 0,0101 mol), dimethylformamide (75 ml) and piperidine (2.15 g, 0,0253 mol, 2.5 EQ.) heated under reflux for 2 hours (TCX shows the complete disappearance of the chlorine-containing compounds). After cooling, the solution is concentrated under reduced pressure to obtain solid oily residue. This residue is suspended in H2O (200 ml), then extracted with ethyl acetate (3 x 100 ml). The ethyl acetate is dried over MgSO4, filtered, then concentrated under reduced pressure to an oily-solid residue. The residue is triturated with hexane, and stirring for one hour. The solid is collected and su is II).

7) Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]- 5-[3-(1-piperidinyl)propyl]-2-oxazolidinone hydrochloride (NE-10118).

A mixture of 3-phenylethylamine-5-[3-(1-piperidinyl)propyl]-2 - oxazolidinone (VIII) (1,67 g, 0,0053 mol), 2N HCl (125 ml) and 5% Pd/C 50% H2O (approximately 2 g) is treated with hydrogen in a Parr apparatus at 40 psi (2.8 kg/cm2) at room temperature. After 1 hour, the absorption of hydrogen ceases, constituting 100% of theoretical values. The catalyst is removed by filtration. The filtrate is concentrated under reduced pressure to an oily residue, which forms an azeotropic mixture with absolute alcohol (2 x 25 ml), get a solid residue.

The solution of the above residue, dimethylformamide (50 ml) and 5-(4-chlorophenyl)-2-furancarboxaldehyde (F-1054) (prepared as described in U.S. patent 4.882.354 issued 21.11.1984, the work is included as a reference) (1.10 g, 0,0053 mol) during the night stirred at room temperature. The mixture is filtered, the collected solid residue, which is recrystallized from a mixture of absolute ethanol/H2O boiling absolute ethanol, then add water to obtain a solution. The solution is filtered, then cooled on ice. The solid is collected, dried in 2-furanyl] methylene] amino]-5-[3- (1-piperidinyl)propyl] -2-oxazolidinone hydrochloride (NE-10118). So pl. 231-232oC.

Elemental analysis:

Calculated for C22H26ClN3O3HCl: C, 58.41; H, 6.02; N, 9.29.

Found: C 57,99; H Equal To 6.05; N 9,00.

Found: C 58,07; H 6,16; N 9,04.

Example E

Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5- [3-(4-methyl-1-piperazinil)propyl]-2-oxazolidin dihydrochloride

A) Synthesis of 3-phenylethylamine-5-[4-methyl-1-piperazinil)propyl]- 2-oxazolidinone (1)

< / BR>
Stir a solution of 5-(3-chlorpropyl)-3-phenylethylamine-2 - oxazolidinone (5.0 g, 0,0187 mol), dimethylformamide (100 ml) and 1-methylpiperazine (5,62 g, 0,0561 mol) is heated under reflux for 2.5 hours. After cooling, the dark solution is concentrated under reduced pressure to an oily residue. This residue is suspended in a saturated NaHCO3(200 ml) and extracted with CH2Cl2(3 x 100 ml). Extract CH2Cl2washed with saturated NaHCO3(1 x 200 ml), then dried over MgSO4. The filtered solution is concentrated under reduced pressure to obtain a solid residue, which is triturated with hexane, collected and dried in the air, get equal to 4.97 g (0,0150 mol, yield 80%) of 3-phenylethylamine-5-[3-4-methyl-1 - piperazinil)propyl]-2-oxazolidinone (1).

B) Synthesis Of 3-[.

< / BR>
A mixture of 3-phenylethylamine-5-[3-(4-methyl-1-piperazinil)-propyl] - 2-oxazolidinone (1) (2.5 g, 0,0076 mol), 2N HCl (125 ml) and 5% Pd/C 50% H2O (2 g) is treated with hydrogen in a Parr apparatus at 40 psi (2.8 kg/cm2) at room temperature. After 2 hours the absorption of hydrogen ceases, constituting 100% of theoretical values. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to a gummy residue.

This residue, dimethylformamide (50 ml) and 5-(4-chlorophenyl)-2 - furanecarboxaldehyde (F-1054) (prepared as described in U.S. patent N 4.882.354 issued 21.11.1984, the work is included as a reference) (1,57 g, 0,0076 mol) during the night stirred at room temperature. The obtained solid is collected, air-dried and recrystallized from absolute EtOH and H2O, collected, air-dried, then dried in vacuum at room temperature, receiving a 1.96 g (0,039 mol, 51% yield) NE-10178. So plvl. = 232-238oC.

Elemental analysis:

Calculated for C22H27ClN4O32HCl 1/4H2O:

C, 51.98; H, 5.85; N, 11.01; H2O 0.90.

Found: C, 51.98; H, 5.92; N, 11.09; H2O 0.75.

C, 51.85; H, 6.03; N, 11.00.

Example F

Synthesis 3-[[[5-(4-chlorophenyl)-2-furanyl] metilen-1-ol

< / BR>
Stir a solution of 5-HEXEN-1-ol (75 g, 0,749 mol, ALD.) in DMF (800 ml) is treated with portions of 60% NaH in mineral oil (30.0 g, 0.75 mol, ALD.) within 1.5 hours, maintaining a temperature of 0-5o. After complete addition the mixture is stirred for 1 hour in the cold, then heated at a temperature steam baths (90o) for 2.5 hours. Brown the mixture is cooled in an ice bath to 0-5o. Added dropwise benzyl chloride (87 ml, 0.75 mol, ALD. within 45 min, keeping the temperature between 0-5o. After complete addition the mixture is stirred at room temperature overnight. The mixture is heated at a temperature steam bath for 3.5 hours, then cooled to room temperature. The mixture is concentrated under reduced pressure to an oily residue. This residue is suspended in H2O (500 ml), then extracted with ether (2 x 300 ml, 2 x 100 ml). The ether extract was washed with H2O (4 x 200 ml), dried over MgSO4, filtered, then concentrated under reduced pressure to an oily liquid residue (1) 126 g to about 12 g is a mineral oil, giving approximately 114 g (of 0.60 mol with yields of 80%).

B) Synthesis of benzyl ester of 5,6-epoxyhexane-1-ol

< / BR>
3-chloroperoxybenzoic CIS layers (think that is H2O). The solution is dried over MgSO4and then filtered. Clear filtrate is cooled in a bath with ice to 5 to 10oC. is added benzyl ether of 5-HEXEN-1-ode (1) (126 g of 0.60 mol) dropwise over 1.5 hours. Received the cooled mixture is stirred for several hours, allow it to warm to room temperature and again stirred overnight. The mixture was washed with 1N NaOH (2 x 2000 ml 6 x 1000 ml), H2O (3 x 600 ml), saturated NaHCO3(1 x 600 ml), then dried over MgSO4. The filtered solution is concentrated under reduced pressure to obtain a liquid residue. This distil the residue under vacuum, get one major faction, collect it at 100-120oC at 0.5 mm Hg (70 g, 0.34 mol, 56% yield).

The second distilling 2 gives the fraction of the benzyl ester of 5,6-epoxyhexane-1-ol (II), 16,1 g collected at 102-110oC at 0.3 mm Hg and 31.9 per g collected at 110-114oC at 0.3 mm Hg (total output - 48g, 0,233 mol, 39%).

Each faction represents a desired product, with different amounts of unidentified impurities.

C) Synthesis of 5-[4-(phenylmethoxy)butyl]-3-phenylethylamine-2 - oxazolidinone (III)

< / BR>
Stir the solution benzylidenemalonate prepared as opiso in example D part B (2,03 g, 0,0088 mol, (see NE-10118)), benzyl ether 5,6-atoxigenic-1-ol (1) (38 g, 0,1842 mol) and dimethylformamide (800 ml) is heated under reflux for about 2.5 hours, then cooled to room temperature. The solution is concentrated under reduced pressure to an oily residue. This residue was dissolved in CH2Cl2(500 ml), then washed with H2O (4 x 200 ml), saturated NaCl (2 x 200 ml), dried over MgSO4(activated charcoal), filtered and concentrated under reduced pressure to an oily residue. This residue is dissolved in anhydrous ether (600 ml) and stirred for 2 hours. The precipitated solid is collected, washed with anhydrous ether, air-dried, get 38,18 g (0,1083 mol) of 5-[4-(phenylmethoxy)butyl]-3-phenylethylamine-2-oxazolidinone (III).

D) Synthesis of 3-phenylethylamine-5-(4-hydroxybutyl)-2 - oxazolidinone

< / BR>
A mixture of 5-[4-(phenylmethoxy)butyl] -3-phenylethylamine-2 - oxazolidinone (III) (23.0 g, 0.0653 mol), 2N HCl (625 ml) of 5% Pd/C 50% H2O (about 5 g) is treated with H2in the Parr apparatus at 40 psi (2.8 kg/cm2) at room temperature. After 2 hours the absorption of H2stops, constituting 100% of theoretical values. The catalyst was removed by filtration and the Phi is nabludaetsa no further absorption of hydrogen. The catalyst was removed by filtration, and the filtrate concentrated under reduced pressure to an oily residue.

This reaction is repeated under the same conditions, with the same load and the product combined with the balance mentioned above. This consolidated balance azeotrope is distilled with absolute ethanol (4 x 50 ml), receiving semi-solid residue.

This residue, dimethylformamide (600 ml), benzaldehyde (13,9 g, 0,1305 mol) and molecular sieves during the night stirred at room temperature. The sieves are removed by filtration, and the filtrate is then concentrated under reduced pressure to an oily residue, which partially crystallizes upon standing with obtaining 50.4 g (yield > 100%) 3-phenylethylamine-5-(4-hydroxybutyl)-2 - oxazolidinone (IV).

E) Synthesis of 6-(4-chlorobutyl)-3-phenylethylamine-2-oxazolidinone (V)

< / BR>
Thionyl chloride (23,8 ml, to 38.8 g, 0,3165 mol) is added dropwise during 1 hour to a stirred solution of 3-phenylethylamine-5- (4-hydroxybutyl)-2-oxazolidinone (IV) (50,4 g, 0,1306 mol), CHCl3(600 ml) and pyridine (22,7 g, 0,2873 mol). After complete addition, the solution is refluxed for 3.5 hours. After cooling, the solution is concentrated under reduced pressure until the residue is dissolved in CH2Cl2(500 ml), washed with H2O (4 x 200 ml), saturated NaCl (2 x 100 ml), then dried over MgSO4filter and concentrate under reduced pressure to a solid residue. The residue is triturated with anhydrous ether (500 ml), stirring for several hours. The solid is collected, washed with ether and dried in the air, getting to 29.7 g (0,1058 mol, yield 81%) of 5-(4-chlorobutyl)-3-phenylethylamine-2-oxazolidinone (V).

F) Synthesis of 5-[4-(4-methyl-1-piperazinil)butyl] -3 - phenylethylamine-2-oxazolidinone (VI)

< / BR>
Stir a mixture of 5-(4-chlorobutyl)-3-phenylethylamine-2 - oxazolidinone (V) (29,7 g, 0,1058 mol), dimethylformamide (600 ml) and 1-methylpiperazine (26.5 g, 0,2645 mol) is heated under reflux for 3.5 hours. After cooling to room temperature the solution is concentrated under reduced pressure to a semi-solid residue. This residue was dissolved in CH2Cl2(600 ml), washed with saturated NaHCO3(2 x 300 ml 2 x 200 ml), H2O (2 x 100 ml), saturated NaCl (1 x 200 ml) and dried over MgSO4. The filtered solution is concentrated under reduced pressure to a solid residue. His triturated with hexane (2 x 300 ml), decanted the supernatant liquid is then evaporated to dryness, obtaining 31.0 g (0,090 mol, vyho who yl)-2-furanyl] methylene] amino]-5- [4-(4-methyl-1-piperazinil)butyl]-2-oxazolidinone hydrochloride (NE-10188)

< / BR>
A mixture of 5-[4-(4-methyl-1-piperazinil)butyl] -3-phenylethylamine-2 - oxazolidinone (VI) (2,88 g, 0,0087 mol), 2N HCl (125 ml) and 5% Pd/C 50% H2O (2 g) is treated with hydrogen in a Parr apparatus at 40 psi (2.8 kg/cm2) at room temperature. After 2 hours the absorption of hydrogen ceases, constituting 100% of theoretical values. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to an oily residue. The remainder constantly azeotrope is distilled with absolute ethanol (4 x 20 ml), get a semi-solid residue.

This residue, dimethylformamide (75 ml) and 5-(4-chlorophenyl)- 2-furanecarboxaldehyde (F-1054) (prepared as described in U.S. patent 4.882.350 issued 21.11.1984 g) (1.8 g, 0,0087 mol) during the night stirred at room temperature. After cooling in a bath with ice, the solid is collected and air-dried. It is recrystallized from absolute EtOH/H2O, collected, washed with absolute ethanol (20 ml), air-dried, then dried at 90oC and dried in vacuum at 77oC, obtain 2.8 g (0,0070 mol, yield 69%) 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5- [4-(4-methyl-1-piperazinil)butyl] -2-oxazolidinone hydrochloride (NE-10198). So pl. > 250oC.

Ale Is O 0,9.

Found: C 52,77; H 6,12; N 10,61; H2O 0,6.

Found: C 52,97; H 6,20; N 10,67.

2. Data on biological activity.

Description of the test methods

Shot CAL-R rats with an open chest with superimposed coronary artery ligature with subsequent reperfusion is used as a model to determine the antiarrhythmic efficacy of the inventive compounds.

Compounds injected in dosed form. Data corresponding to a dose of 10 μm, are presented in the table. The efficiency value determined based on the compound's ability to inhibit anti-arrhythmic condition after reperfusion. A value less than 100 indicates the efficiency of the connection.

Safety factor of Ferret (Ferret) (FSI) is a measure of the overall toxicity of the compounds. Compounds are administered intravenously at 1 mg/kg/min FSI is a quantitative assessment of how behavioral response to toxicity and effect on the electrocardiogram and blood pressure.

A value of 0 indicates the absence of toxicity, whereas a value of 16 indicates significant toxicity.

Example G

Getting 3-[[[5-(4-chlorphenyl oral

Tablets, including a connection 3-[[[5-(4-chlorophenyl)- 2-furanyl] methylene] amino] -5-[3-(4-methyl-1-piperazinil)propyl]- 2-oxazolidinone dihydrochloride [prepared as described in example E] have the following composition:

THE ACTIVE INGREDIENT

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5- [3-(4-methyl-1-piperazinil) propyl]-2 - oxazolidinone dihydrochloride - 350 mg

FILLERS

Lactose - 197 mg

Na Glycolate, starch 50 mg

Preferably gelatinising starch 30 mg

Talc - 12 mg

Magnesium stearate 6 mg

Ten thousand tablets of the above composition is prepared as described below:

3.50 kg 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5- [3-(4-methyl-1-piperazinil)propyl]-2-oxazolidinone dihydrochloride, 1,92 kg of lactose, 0.50 kg Na glycolate, starch and 0.30 kg pre gelatinising starch are mixed in a mixer Patterson-Kelly and then granularit with water, using intensifying rod.

The granules are then dried on trays in the oven or in a fluidized bed dryer.

Granules are milled using sieves having cell 12 mesh., using a vibrator or other suitable grinder.

The granules are mixed with 120 g of talc and 60 g ETS the

The patient suffering from cardiac arrhythmia and/or cardiac fibrillation, appoint the above tablets on the appropriate regimen.

Example H

Getting 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]- 5-[3-(1-piperazinil)propyl] -2-oxazolidinone dihydrochloride in the form of tablets for oral administration

Tablets for oral administration, comprising 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[3-(1-piperazinil) propyl]-2-oxazolidinone hydrochloride, prepared as described in example D, have the following composition:

THE ACTIVE INGREDIENT

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5- [3-(1-piperazinil)propyl]-2-oxazolidinone the dihydrochloride 300 mg

FILLERS

Dibasic calcium phosphate 219 mg

Crosspovidone 60 mg

Povidone - 12 mg

Talc - 6 mg

Magnesium stearate 3 mg

Ten thousand tablets, including the above composition is prepared as described below:

3.00 kg 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5- [3-(1-piperidinyl)propyl] -2-oxazolidinone hydrochloride, 219 kg of dibasic calcium phosphate, 0.60 kg of crosspovidone and 0.12 kg of povidone are mixed in the mixer Patterson-Kelly and then granularit with water, using intensifying rod.

the use of sieves, having cell 12 mesh., using a vibrator or other suitable grinder.

The granules are mixed with 60 g of talc and 30 g of magnesium stearate. Finally, the mixture of granules, talc and magnesium stearate is pressed into tablets weighing 600 mg on a suitable teletrauma machine.

The patient suffering from cardiac arrhythmia and/or cardiac fibrillyatsy prescribed tablets, using the appropriate regimen.

Example I

Getting 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] - 5-[4-(4-methyl-1-piperazinil)butyl] -2-oxazolidinone dihydrochloride in the form of capsules for oral administration

Capsules for oral administration comprising 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5-[4-(4-methyl-1 - piperazinil)butyl]-2-oxazolidinone the dihydrochloride, prepared as described in example F, have the following composition:

THE ACTIVE INGREDIENT

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5- [4-(4-methyl-1-piperazinil)butyl]-2-oxazolidinone the dihydrochloride 300 mg

FILLERS

Lactose - 92 mg

Na Glycolate, Starch 40 mg

Pre gelatinising Starch 25 mg

Talc - 12 mg

Magnesium stearate 3 mg

Hard gelatin shell capsule - 1 capsule

Ten thousand capsules for oral]methylene]amino]-5- [4-(4-methyl-1-piperidinyl)butyl]-2-oxazolidinone hydrochloride, 0.92 kg of lactose, 0.40 kg Na glycolate, starch and 0.25 kg pre gelatinising starch are mixed in a mixer Patterson-Kelly and granularit with water, using intensifying rod.

The granules are dried on trays in an oven or in a fluidized bed dryer type.

Granules are milled using sieves with cells in 12 mesh 12-cell sieve and using a vibrator or other suitable grinder. The granules are mixed with 120 g of talc and 30 g of magnesium stearate.

Finally, the mixture of granules weight of 472 mg of talc and magnesium stearate are placed in each capsule shell on a suitable machine for filling capsules.

The patient suffering from cardiac arrhythmia and/or cardiac fibrillation prescribed capsules, prepared as described above using the appropriate dosage.

Example J

Preparation 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]- 5-[4-(4-methyl-1-piperazinil)butyl] -2-oxazolidinone dihydrochloride in the form of tablets for oral administration

Capsules for oral administration comprising 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-5-[4-(4-methyl-1 - piperazinil)butyl]-2-oxazolidinone the dihydrochloride [prepared as described in example F] have the following status is oxazolidine the dihydrochloride - 175 mg

FILLERS

Microcrystalline cellulose - 110 mg

Crosspovidone 25 mg

Povidone - 5 mg

Talc 5 mg

Magnesium stearate 2 mg

Hard gelatin shell capsule - 1 capsule

Ten thousand capsules having the above composition is prepared as described below:

1.75 kg 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5- [4-(4-methyl-1-piperazinil)butyl] -2-oxazolidinone dihydrochloride, 1.10 kg microcrystalline cellulose, 0.25 kg of crosspovidone and 0.05 kg of povidone are mixed in the mixer Patterson-Kelly or other suitable mixer and then granularit with water, using intensifying rod.

The granules are dried on trays in an oven or in a fluidized bed dryer type.

Granules are milled using sieves 12 mesh., using a vibrator or other suitable grinder. The granules are mixed with 50 g of talc and 20 g of magnesium stearate.

The mixture of pellets weighing 322 ml talc and magnesium stearate fill each capsule shell on a suitable machine for filling capsules.

The patient suffering from cardiac arrhythmia and/or cardiac fibrillation, appoint capsules for oral administration, prepared as described above using appropriate but]- 5-[3-(4-methyl-1-piperazinil) propyl]- 2-oxazolidinone the dihydrochloride, lyophilized for injection

Solution suitable for intravenous injection (I. V.), including 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5-[3-(4- methyl-1-piperazinil)propyl] -2-oxazolidinone the dihydrochloride, prepared as described in example D, has the following composition:

THE ACTIVE INGREDIENT

3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[3-(4- methyl-1-piperazinil)propyl]-2-oxazolidinone the dihydrochloride 400 mg

FILLERS

Mannitol 500 mg

Citric acid/sodium citrate - Quantity sufficient to maintain the pH=5.5-6.5

Method of preparation of 1,000 capsules of the above solution for I. V. injection described below.

400 g 3-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-5-[3-(4- methyl-1-piperazinil)propyl]-2-oxazolidinone dihydrochloride, 500 g of mannitol and the amount of citrate and/or citric acid required to maintain the pH = 5.5 - 6.5, dissolved in 10.0 liters of sterile water for injection.

The resulting solution was aseptically passed through a filter of 0.2 micron and bottled in vials of 10 ml per ampoule.

The ampoule is placed in lyophilizator, frozen, dried and sealed. The lyophilized product was diluted with 10 ml of sterile water neposredsgvennye solution, prepared as described above using the appropriate dosage.

Example L

Any connection cyclic urethane prepared as described in examples A - F may be used as the active component in the preparation of any dosage form, prepared as described in examples G-K.

Example M

57-year-old man was discovered at home without consciousness and without a clear pulse. Family members caused cardiopulmonary the ambulance. First rhythm recorded by ambulance, pointed to ventricular fibrillation. The patient regained consciousness.

Three years ago, the patient suffered a myocardial infarction and since then he had stable angina.

During subsequent hospitalization, the patient was not found myocardial infarction. Program electrical stimulation caused the monomorphic ventricular tachyarrhythmia.

The cardiologist has prescribed to the patient 3-[[[5-(4-chlorophenyl)-2-furanyl] - methyl] amino] -5-[3-(4-methyl-1-piperazinil)-propyl] -2-oxazolidinone the dihydrochloride for oral administration the dose of 350 mg twice a day, after meals. Four days after treatment repeated electrical stimulation did not cause arrhythmias. LASS="ptx2">

Example N

The 65-year-old man, a Negro, was faint, followed by a heart attack. Over the previous few months the patient suffered from frequent palpitations, once with attack or status. The patient suffers from hypertensive cardiovascular disease, diabetes, old myocardial infarction and obesity.

Programmed electrical stimulation induces long-term monomorphic ventricular tachycardia. Cardiologist assigns the patient 3-[[[5-(4-chlorophenyl] methylene] -amino] -5-(3-(piperidinyl) propyl] -2-oxazolidinone hydrochloride for oral administration the dose of 300 mg, once a day, after meals. After a few days of treatment repeated electrical stimulation fibrillation is not induced. Over the next three years of syncope or presyncope States were observed.

Example O

58-year-old Oriental woman suffers from cardiomyopathy with recurrent syncope. Her ejection fraction is 35%. Programmed electrical stimulation (PES) induces a weak portable sustained the ventricular tachyarrhythmia, impervious to three different antiarrhythmic drugs. A fourth drug, moricizine, systematically cardioverter defibrillator (AICD).

The defibrillator is discharged twice a year after the implantation of AICD. During defibrillation device registers continually monitor the ventricular tachyarrhythmia. After the second discharge, the patient was hospitalized. PES induces continuous the monomorphic ventricular tachyarrhythmia. The cardiologist stopped treatment moricizine and appointed 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5-[3-(4- methyl-1-piperazinil)-propyl] -2-oxazolidinone the dihydrochloride for oral 350 mg, twice a day, after meals.

When re-PES few days later fibrillation is not induced and the defibrillation threshold remains the same. When viewed in a year further AICD discharge had not occurred.

Example P

Within 15 years, the 35-year-old woman happen private (2 per month) frequent attacks of palpitation, lasting several hours, in combination with dizziness and fatigue. These attacks cause her to miss work.

The results transtelephonic observations indicate paroxysmal supraventricular tachycardia. Your doctor has prescribed for the patient 3-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -5-[3- (piperidinyl)propyl]-2-oxazolidinone hydrochloride in the form of an oral dose of 175 mg, once derouchey her condition.

Example Q

75-year-old male, Caucasian, securewave 50 packs per year, suffers from atrial fibrillation, confirmed by transtelephonic monitoring during treatment digoxin and quinidine, episodes of atrial fibrillation are repeated 3 times in a month. These attacks continue, sometimes for eight hours and the resulting weakness hinders the normal daily activities of the patient, such as gardening classes.

The doctor replaces quinidine on 3-[[[5-5-(4-chlorophenyl)-2-furanyl] methylene] amino]-5-[3-(piperidinyl)propyl]-2-oxazolidinone the dihydrochloride for oral administration dose of 175 mg, once a day, after meals. In the next four months the frequency of attacks is reduced to one per month.

Example R

For several years the 40-year-old male, Caucasian, suffers frequent palpitations. During seizures, the patient feels anxiety, shortness of breath, and think about death. Careful examination reveals the absence of structural abnormalities in the heart. Holter monitoring shows 2500 PVCs a day single and 50 double on the day. Neither reassurance nor subsequent treatment with propranolol is not effective.

Doctor prescribes 3-[[[5-(4-chlorophenyl)-2-furanyl]-methylene]amino is Ni, after a meal.

The heart rate decreases, also decreases anxiety and shortness of breath. Now Holter monitoring shows 250 PVCs a day without repeating forms. The thought of death does not visit in a few months. The patient is carefully examined, it continues to feel good over the next five years.

Example S

58 - year-old man, a Negro, suffered a myocardial infarction, for ten years he suffered from diabetes in the form, not requiring insulin, cholesterol was over 300 mg/DL. Two weeks after the heart attack he had no symptoms, except for shortness of breath during exercise. His ejection fraction is 29% and 24 hour surveillance on Holter show 50 single PVCs per hour, a rare double and one times five strokes, evidence of ventricular tachyarrhythmias.

Cardiologist prescribes him 3-[[[5-(4-course)-2-furanyl] methylene]amino] -5-[3-(4-methyl-1-piperazinil)propyl] -2-oxazolidinone the dihydrochloride for oral administration the dose of 350 mg, once a day, after meals. Repeated Holter monitoring shows the disappearance of all shapes and an average of 9 PVCs per hour. The patient feels good in the next three years.

1. Compounds of cyclic urethane of the formula I
R1, R2and R3independently selected from hydrogen or chlorine;

L is a lower alkylamino attached to a nitrogen atom to the nitrogen atom of the cyclic urethane;

R4represents the lowest alkylen;

A is A saturated six-membered a heterocycle containing 1 or 2 nitrogen atom which may be substituted by lower alkyl or hydroxy (lower) alkyl, and one of the nitrogen atoms of the heterocycle A is associated with the radical R4;

R4is methylene,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R is a covalent bond and is attached to X in 1 position X and Y in the 5-position y

3. Connection under item 1 or 2, in which Y is connected with carbon end L in the 2 position y

4. Compounds according to any one of paragraphs.1 to 3, in which the heteroatom Y is oxygen in the 1 position specified heterocycle.

5. Compounds according to any one of paragraphs.1 to 4, in which one of R1, R2and R3is chlorine, and two of R1, R2and R3are hydrogen.

6. Compounds according to any one of paragraphs.1 to 5, which is a 3-///5-(4-chlorophenyl)-2-furanyl/methylene/-amino/-5-(1-piperidinylmethyl)-2-oxazoline/methylene/-amino/-5-/4-(4-methyl-1-piperazinil)butyl/-2-oxazolidinone; 3-///5-(4-chlorophenyl)-2-furanyl/methylene/-amino/-5-/3-(4-methyl-1-piperazinil)propyl/-2-oxazolidinone; 3-///5-(4-chlorophenyl)-2-furanyl/methylene/-amino/-5-//4-(2-hydroxyethyl)-1-piperidinyl/-methyl/-2-oxazolidinone; 3-///5-(4-chlorophenyl)-2-furanyl/methylene/amino/-5-/(4-methyl-1-piperazinil)-methyl/-2-oxazolidinone, or their pharmaceutically acceptable cleaners containing hydrochloride salt.

7. The compound according to any one of paragraphs.1 to 6, in which A nitrogen atom not attached to R4is substituted and the substituents are selected from the group comprising methyl, hydroxyethyl, lower alkyl.

8. The method of treatment of humans and other mammals suffering from cardiac arrhythmia and/or cardiac fibrillation, characterized in that the method comprises the introduction of a specified person or mammal a pharmaceutical composition comprising 15 to 90% of compounds of cyclic urethane, or mixtures thereof, under item 1 and from 10 to 85% of pharmaceutically acceptable fillers, in an effective amount.

9. Pharmaceutical composition for the treatment of arrhythmia and fibrillation, characterized in that it comprises from 15 to 90% of compounds of cyclic urethane under item 1 or mixtures thereof, and from 10 to 85% of pharmaceutically acceptable fillers.

10. The pharmaceutical composition under item 9, the General taste and odor additives, not more than 50% of alcohol, no more than 5% of buffer systems, no more than 2% of surface-active substances, not more than 2% preservatives, no more than 5% of the sweetening additives, no more than 5% giving a viscosity additives, no more than 75% of fillers, of 0.5 - 2% lubricants 1 - 5% glidants, 4 - 15% of disintegrant and 1 - 10% of binders.

11. The pharmaceutical composition according to p. 9, wherein the pharmaceutically acceptable excipients selected from the group comprising polymers, resins, plasticizers, fillers, binders, lubricants, glidant, disintegrators, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening additives, which impart taste and odor additives, dyes and pigments pharmaceutical quality and imparts viscosity additives.

 

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< / BR>
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< / BR>
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< / BR>
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