4-oxocyclohexa compounds of urea, pharmaceutical composition and method of treatment

 

(57) Abstract:

4-Oxocyclohexa connection urea of General formula I

< / BR>
where X is an unsaturated 6-membered carbocycle;

R is a covalent bond or is absent;

Y - unsaturated 5-membered heterocycle, or 6-membered carbocycle, or absent and when R is absent, X and Y are condensed ring systems; when R is a covalent bond, X and Y are ring systems connected through a covalent bond, and Y is absent, R is a covalent bond and X is connected to L through R;

R1; R2and R3is independently chlorine, fluorine, bromine, HE, alkyl; or R1; R2; R3- no;

L - alkylamino, in which the nitrogen atom of the group linked to the nitrogen atom in 1,4 oxocyclohexa ring component urea;

R4- alkylen;

And - alkyl or hydroxyalkyl, possibly substituted saturated 6-membered heterocycle or heteroaryl containing two nitrogen atom;

R5- -CH2-;

or its pharmaceutically acceptable salts or esters.

The compounds of formula I or pharmaceutical composition based on it is suitable for treatment of a human or other mammal suffering from cardiac azikliceski of urea compounds and pharmaceutical compositions suitable for treatment of the human or other mammal suffering from cardiac arrhythmia and/or cardiac fibrillation.

New 4-oxocyclohexa connection urea of the present invention are active as antifibrillatory and antiarrhythmic drugs. These compounds are characterized by efficiency, broad-spectrum in relation to cardiac arrhythmia and fibrillation and can be applied to substantially mitigate and/or eliminate arrhythmias and fibrillation. In addition, these compounds find less unwanted side effects than is typical of many common complications. Additional benefits from the use of the compounds described here are that they are as antifibrillatory and antiarrhythmic activity; the most common treatments typically do not have the efficiency of antifibrillatory funds. On this issue, see the literature (see, for example, Coplen, S. E. et al., "Efficacy and Safety of Quinodine Therapy for Maintenance of Sinus Rhythm After Cardioversion: A meta-fnalysis", Circulation, Vol. 82, pp. 1106-1116 (199); Echt, D. S. et al., "Mortality and Morbidity in Patients Receiving Ecainide, Flecainide, or Placebo. The Cardiac Arrhythmia Suppression Trial," New England Journal of Medicine, Vol. 324, pp. 781-788 (1991), edutella electrical activation and then deactivate all of the heart muscle, which invariably occur with each heartbeat, characterized as a normal heart rhythm. Arrhythmias are characterized as manifestations of abnormal electrical activity, which can disrupt normal heart rhythm. Abnormal electrical activity may affect the initiation and/or uniformity of distribution of electric waves (i.e., depolarization and subsequent repolarization of the heart muscle), under the influence of which is compression of the heart. Violation smooth cyclical process of functioning of the heart, normal heart rate for adults is in some cases a phenomenon that is life-threatening.

Arrhythmia on its severity ranges from relatively mild (consisting of asymptomatic and infrequent ventricular extrasystoles [PVCs]) to life threatening (consisting of ventricular fibrillation and persistent ventricular tachyarrhythmias). Very good overview of types of arrhythmia and treatment of arrhythmia available in the literature (see, for example, Bigger, Thomas J., "Antiarrhythmic Tveatment: An Overview", Amevican Journal of Cardiology, Vol. 53, pp, 8B-16B, February 27, 1984; Galdstein, S. "Toward A New Understanding of the Mechanism and Prevention of Sudden Death in Coronary Heart Disease", Circulation, Vol. 87 (I), pp. 284 the ve links.

Life-threatening arrhythmia is considered the leading cause of death in the world. For example, according to estimates, sudden death from a heart attack caused by ventricular fibrillation, is in the United States the cause of death of about 400,000 - 600,000 people annually (monthly demographic statistical report N 33:8-9 National Committee for human Sciences (NCHS) of the Ministry of health and social security of the USA (1985).

Arrhythmia in the General case is divided into two types: 1) supraventricular arrhythmias (such as atrial fibrillation and atrial flutter) and 2) ventricular arrhythmia (e.g., ventricular tachyarrhythmia and ventricular fibrillation, and atrial flutter).

Supraventricular arrhythmia in the General case are not life-threatening. Individuals with these types of arrhythmia can experience a wide variety of symptoms from mild to severe intensity. These individuals may feel a physical sense of disruption, acadeny and/or pounding can sometimes feel a little uncomfortable or feel dizzy and may feel shortness of breath and/or chest pain. Because in essence this situation in General is not dangerous to life, not the drugs, because side effects that usually accompany the use thereof, may not be acceptable to States that do not pose a danger to life. However, the new compounds of the present invention in General are transferred much easier than many common, currently available antiarrhythmic drugs; therefore, they will, apparently, acceptable to treat individuals suffering from supraventricular arrhythmias and largely relieve feelings of discomfort in these individuals.

Ventricular fibrillation, on the other hand, are potentially much more serious and can be divided into three groups:

1) mild;

2) prognostically significant (potentially fatal) and

3) life threatening (lethal). Cm. for example, the work Morganroth (Morganroth, J. and Bigger (Bigger, J. T.) ("Pharmacological Management of Ventricular Arrhythmias After the Cardiac Arrhythmia Suppression Trial", American Journal of Cardiolagy, Vol. 65, pp. 1497 - 1503? 1990), which is incorporated by reference (hereinafter referred to as Morganroth and Bigger).

Individuals with arrhythmias light forms are very small risk of dying, to buy a scar on the heart and to get heart disease. Ventricular Ari the AEB ventricular arrhythmias. Similarly arrhythmia mild, such as ventricular premature contraction (PVCs), represent minimal risk to individuals and rarely requires the use of antiarrhythmic therapy. However, ventricular extrasystoles may be of such frequency or complexity, or may be associated with a sufficiently threatening symptoms that individuals experiencing them, will cease to respond to assurances that arrhythmia and symptoms are not dangerous. They may also not perceive the most common types of treatment (for example, not to take the beta blockers). In these cases, treatment with novel compounds of the present invention will become apparently desirable for these individuals.

Prognostically significant arrhythmias are usually associated with some additional clinical manifestations of heart disease, such as mild heart failure, ischemic symptoms and/or scarring of the heart. Claim that approximately 65% of all cases of ventricular arrhythmias are prognostically significant. See, for example, the work Morganroth and Bigger S. 1497.

Patients with life-threatening arrhythmias may experience fainting (sudden loss of consciousness, usually the accuracy and/or myocardial esimil due to the presence of organic heart disease. Life-threatening arrhythmias are relatively uncommon; it is possible that less than 10% of an individual suffering from arrhythmias, suffer from a lethal form of arrhythmia (see Morganroth and Bigger, S. 1497). However, given the life-threatening nature of lethal ventricular arrhythmias and the severity of symptoms associated with such, they must undergo intensive therapy.

The new compounds of the present invention are effective means of combating heart fibrillation and supraventricular or ventricular arrhythmias. Furthermore, the new compounds of the present invention are characterized by a smaller number of some of the unwanted effects that usually have to put up with many traditional antiarrhythmic drugs due to the lack of acceptable alternative means for treatment. For example, many existing treatments cause pulmonary toxicity, cardiac depression and neurological effects that are not specific to cardiac tissue. A very good discussion of the side effects associated with conventional antiarrhythmic treatments, contains, for example, in the work of Bigger (Bigger J. T. and Hoffman (Hoffman B. F.) "Antiarythmic Agents", in The Heart, ed. J. W. Hurst, pp. 1682-1711, New York, McGraw-Hill (1990)), and both of these works are included as references.

Furthermore, the new compounds of the present invention are readily bioavailable. This feature contributes to the treatment by oral administration and, therefore, contributes significantly to that patient conditions and treatment regimens. Furthermore, the new compounds of the present invention are relatively inexpensive to manufacture, and they exhibit a high degree of stability in the forms, dosage per oral administration.

New 4-oxocyclohexa connection urea of the present invention and pharmaceutically acceptable salts and esters thereof are suitable for use as antiarrhythmic and antifibrillatory funds General structural formula

< / BR>
in which

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

b/ R are selected from the group consisting of covalent bond, heteroatom, carbonyl group, heterocyclic ring, carbocyclic ring, alkyl groups, alkenylphenol group, alkoxygroup, alkylamino, arylalkylamine a substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7-membered heterocyclic ring or carbocyclic ring, or absent and when education R is absent, X and Y are systems of condensed rings, when education R is a covalent bond, X and Y are ring systems connected through a covalent bond; and when Y is absent, R permutes a covalent bond, and X is bound to L via R;

d) R1, R2and R3independently selected from the group consisting of chlorine, fluorine, bromine, NH2, CF3, OH, SO3H, CH3SO2NH, COOH, alkoxygroup, alkyl groups, alkoxycarbonyl group, hydroxyalkyl group, carboxialkilnuyu group, aminoalkyl group, alluminare and alloctype; or is absent

e) L is chosen from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino and alluminare, while the nitrogen atom of the group is bound to the nitrogen atom located at position 1 and 4 oxocyclohexa urea component;

f) R4selected from the group consisting of alkyl, alkenylphenol, alkyl, alkylsilanes and heteroalkyl group;

g) A is a substituted or unsubstituted, a substituted or unsubstituted, saturated or unsaturated heterocycle containing 5, 6 or 7 members; and A is characterized by the presence of one nitrogen atom, which is connected to the group R4;

h) R5represents a substituted or unsubstituted (C1) or (C2)alkyl group.

Ring system (X-R-Y). New 4-oxocyclohexa connection urea consist of 4-oxocyclohexa urea component connected to the ring system (X-R-Y) through the binder component (L), 4-oxocyclohexa connection ureas are characterized by a nitrogen atom located at position 3, which is substituted aminecontaining component (A) consisting of an amino group separated from the nitrogen atom located at position 3 in a 4-oxocyclohexa urea component separating group (R4). Component, depicted by a combination of (X-R-Y) represents a component in the form of a ring system, and it consists of one or more, preferably one or two condensed or unfused, saturated or unsaturated, substituted or unsubstituted carbocyclic rings or heterocyclic rings, as defined in this description. Each carbocyclic or heterocyclic, Sistema (X-R-Y) was polycyclic and consisted of two unfused rings, and more preferably, ring, denoted by Y, which is adjacent to the binder component L, was a heterocycle, and most preferably five-membered ring with a heteroatom of oxygen in position 1. In addition, when the ring system contains two rings, it is also preferable that the heterocycle (Y) was covalently linked with another ring (X) in position 5 of the heterocycle and in position IX, and that the heterocycle Y was associated with the component of L in position 2 of the heterocycle y

For ring system (X-R-Y) is also possible such an option, though it is not preferred when it consists of two rings (X and Y), which are separated by an alkyl group, a carbonyl group or a heteroatom, and most preferably, this heteroatom was an oxygen atom (R). In addition, the ring system may be monocyclic; in this case, Y is absent and education R is a covalent bond that is connected with L. However, when the system has only one ring, it is preferable that the above-mentioned ring was substituted by at least two and best of all, at least three substituents selected from the group consisting of">

In the case of replacement of any member or all members of the ring systems (regardless of whether it is a monocyclic or polycyclic), may have one or more substituents and may be substituted by chlorine, fluorine, bromine, NH2, CF3, OH, O3H, CH3O2NH, COOH, alkoxygroup, alkyl group, alkoxycarbonyl group, carboxialkilnuyu group, aminoalkyl group, allmineral or alloctype.

Binder component (L). Education L represents a connecting component of the new 4-oxocyclohexa of the urea compounds of the present invention. Carbon end L is bound to the ring system at the location of Y; if Y is absent, then the location of X; and most preferably in position 2 of the ring Y or in article IX, if Y is missing. The nitrogen atom component of L is bound to the nitrogen atom located at position 1 4-oxocyclohexa urea component. Component L is chosen from the group consisting of, but not limited to, alkylamino, alkynylamino, alkylamino, alkynylamino and alluminare; preferably, component L was alkylamino, Naya. 4-Oxocyclohexa urea component of the new compounds of the present invention provides new compounds of the present invention the characteristic name. 4-Oxocyclohexa urea component can represent a 5 - or 6-membered ring, preferably a 5-membered ring. 4-Oxocyclohexa urea component is attached to the nitrogen atom binding component (L) of nitrogen atom located at position 1 4-oxocyclohexa urea component. 4-Oxocyclohexa urea component has the structural formula

< / BR>
in which R5is a (C1) or (C2)alkyl group, preferably (C1)alkyl group. But heteroalkyl or heterocyclic ring, and must always contain at least one nitrogen atom that is attached to R4. When A represents heteroalkyl group A can be straight or branched chain, saturated or unsaturated, substituted or unsubstituted. When A represents a heterocycle, it is a 5-, 6 - or 7-membered heterocyclic ring. The said ring may be substituted or unsubstituted, and saturated or unsaturated, and predmosti urea component, and to the nitrogen atom in A. R4is selected from the group consisting of, but not limited by them, from alkyl, alkenylphenol, alkenylphenol, alkylsilanes and heteroalkyl group.

When A represents a substituted heteroalkyl group, the substituents are selected from the group consisting of, but not limited by them, from methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol and methanesulfonyl group.

When A heterocycle contains two heteroatoms, and they both represent nitrogen, then it is preferable that the nitrogen atom, but adjacent to R4was substituted by substituents selected from the group consisting of, but not limited by them, from methyl, hydroxyethylene, alkyl, aryl, heterocyclic, Uralkali, mercaptoethanol and methanesulfonyl group. When A heterocycle contains only one nitrogen atom, then it is preferable that the heterocycle A was replaced (in the para-position relative to the nitrogen atom connected to R4if the heterocycle is A six-membered)substituents selected from the group consisting of, but not limited by them, from hydroxyethylene group, a hydroxy-group, carbonyl group and a methyl group.

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

"Alkyl" represents an unsubstituted or substituted, straight or branched saturated hydrocarbon chain containing from one to eight carbon atoms, and preferably, unless otherwise stated, from one to four carbon atoms. Preferred alkyl groups include, but are not limited to, methyl, ethyl, sawn, ISO-propyl or bucilina group.

"Heteroalkyl" represents an unsubstituted or substituted, saturated chain with the number of members from three to eight, consisting of carbon atoms and one or two heteroatoms.

"Alkenyl" represents an unsubstituted or substituted, straight or branched hydrocarbon chain containing from two to eight carbon atoms, preferably two to four carbon atoms, and having at least one olefinic double bond.

"Quinil" represents an unsubstituted or unsubstituted straight or branched, hydrocarbon chain containing from two to eight carbon atoms, preferably PTA" refers to containing ring component, to which via a connecting component L is attached at the 4-oxocyclohexa urea component. It is indicated here in the form X-R-Y" and may be a monocyclic ring component or condensed, connected by a bridge or spirobicyclic annular component, and may contain carbocycle, heterocycles, or both. Monocyclic rings usually contain from three to eight atoms, preferably from five to seven atoms. Polycyclic ring system consisting of two rings usually contain from 6 to 16 atoms, preferably from 10 to 12 atoms. Polycyclic ring system consisting of three rings, usually contain from 13 to 17 atoms, preferably 14-15 atoms.

"Carbocyclic ring" or "carbocycle" represents an 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" represents an unsubstituted or substituted, saturated, unsaturated or aromatic ring containing ring carbon atoms and one or more heteroatoms. Heterocyclic ring about is independently selected from nitrogen atoms, sulfur and oxygen.

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

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

"Alkoxy"group is an atom of oxygen with the hydrocarbon chain - Deputy, where the hydrocarbon chain is an alkyl or alkenylphenol group (for example, -O-alkyl or-O-alkenylphenol group). The preferred alkoxygroup is, but not limited to, methoxy, ethoxy-, propoxy - and alkyloxy.

"Hydroxyalkyl" represents a substituted hydrocarbon chain, which contains hydroxysultaine (for example, a group-OH) and may contain other substituents. Preferred hydroxyalkyl groups include, but are not limited to, hydroxyethylene, hydroxypropyl the second circuit, which contains carboxylesterase (for example, a group-COOH) and may contain other substituents. Preferred carboxialkilnuyu groups are carboxymethyl group, carboxyaniline group, and their acid and esters.

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

"Alkylamino"-the group represents aminosilanes with one or two alkyl substituents (e.g.,- N-alkyl).

"Alkynylamino"-the group represents aminosilanes with one or two alkenylamine substituents (for example, N-alkenyl).

"Alkynylamino"-the group represents aminosilanes with one or two alkenylamine substituents (e.g.,- N-quinil).

"Alkylamino"group represents kinosostavlyayuschaya with one or two alkenylamine substituents (for example, N-alkyl-).

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

"Arylamino"group is the place of an oxygen atom from the aryl substituent (for example, O-aryl).

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

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

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

"Halo", "halogen" or "halide" is a radical chlorine atom, bromine, fluorine or iodine. Radicals, chlorine atoms, bromine and fluorine are the preferred halides.

In addition, the "lower" hydrocarbon component (for example, "lower alkyl group) is uglevodorodno chain containing, unless otherwise stated, from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.

"Pharmaceutically acceptable" salt is a cationic salt formed with participation of any acidic (e.g., carboxyl) group, or an anionic salt formed with participation of any principal (e.g., amino) Publication 87/05297, Johnston et al. , published September 11, 1987), cited here as reference. Preferred cationic salts are alkali metal salts (such as sodium and potassium), and salt seachnasaigh metals (such as magnesium and calcium). Preferred anionic salts are salts of halogen-containing acids (such as chloride).

"Biohydrology ester" is an ester 4-oxocyclohexa compounds of urea, which does not have a deleterious effect on the antiarrhythmic activity of the compounds or which is easily metabolized by a human or other mammal with education protivoaritmicheskih 4-oxocyclohexa compounds of urea. Many of these esters are known in this technical field, as they are described in the literature (World Patent Publication 87/05297, Johnston et al., published September 11, 1987), cited here as reference. Such esters are the lower alkyl esters, lower aryloxyalkyl esters (such as acetoxymethyl, ecotoxicology, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl esters), lastonline esters (such as fteely and totalitarnyi complex EPE is oxicology and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, kalinovye esters and acylaminoalkyl esters (such as acetamidomethyl esters).

As defined above and as used in the description of substituting groups may be substituted. Such substitution may be performed by one or more substituents. Such substituents include, but are not limited to, substituents listed in (C Hanasch and A. Leo, Substituent Constants for Correbation Analysis in Chemistry and Biology (1979)), referred to here as a reference. Preferred substituents include, but are not limited to, an alkyl group, Alchemilla group, alkoxygroup, oxoprop, amino group, aminoalkyl group (for example, aminomethyl group, and so on), cyano, halogen-containing group, carboxypropyl, alkoxyamine group (for example, carboxitherapy and so on ), Tolna group, aryl group, cycloalkyl group, heteromalla group, heterocytolysine group (for example, piperidinyl, morpholinyl, piperazinilnom, pyrrolidinyl group, and so on), aminogroup, tocograph, hydroxyalkyl group, alloctype, arylalkyl group, and combinations thereof.

The present invention katiuscia on their basis and method of treatment using the novel compounds and compositions for the treatment of cardiac arrhythmias and/or cardiac fibrillyatsy in humans or other mammals. Certain compounds and compositions used in the invention should be pharmaceutically acceptable. As used here, such a "pharmaceutically acceptable" component is a component that is suitable for human use and/or other mammals without unwanted signs of harmful side effects (such as toxicity, irritation and allergic response) at a reasonable ratio of benefit and risk.

4-oxocyclohexyl compounds of urea cover all the variety of 4-oxocyclohexa compounds of urea with the General structural formula of the form

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in which

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

b) R is chosen from the group consisting of a covalent bond, heteroatoms, carboxialkilnuyu group, heterocyclic ring, carbocyclic ring, alkyl groups, alkenylphenol group, alkoxygroup, alkylamino, arylalkyl group, alloctype, acyl group, alloctype and alluminare or missing:

c) Y is a substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7 is Auda condensed ring systems; and, when R represents a covalent bond, X and Y are ring systems connected through a covalent bond; and when Y is absent, R is a covalent bond and X is related to L through R;

d) R1, R2and R3independently selected from the group consisting of chlorine, fluorine, bromine, NH2, CF3, OH, SO3H, CH3, SO4NH, COOH, alkoxygroup, alkyl groups, alkoxycarbonyl group, hydroxyalkyl group, carboxialkilnuyu group, aminoalkyl group, alluminare and alloctype; or is absent;

e) L is chosen from the group consisting of alkylamino, alkynylamino, alkylamino, alkynylamino, and alluminare, with the nitrogen atom L is bound to the nitrogen atom located at the position 1 in 4-oxocyclohexa urea component;

f) R4selected from the group consisting of alkyl, alkenylphenol, alkenylphenol, alkylsilanes and heteroalkyl group;

g) A is a substituted or unsubstituted, saturated or unsaturated, straight chain or branched (C1-C8) heteroalkyl, or substituted or unsubstituted, saturated or unsaturated heterocycle containing 5, 6 or 7 members; and A content of sennou or unsubstituted (C1) or (C2)-alkyl group;

and pharmaceutically acceptable salts and esters thereof.

Ring system (X-R-Y). New 4-oxocyclohexa connection urea of the present invention consists of a 4-oxocyclohexa urea component connected to the ring system (X-R-Y) through the binder component (L). 4-Oxocyclohexa connection urea contains nitrogen atom located at position 1 and in position 3. The nitrogen atom located at position 3 is substituted aminecontaining group (A), separated from the nitrogen atom located at position 3, the separating group (R4).

Ring system (X-R-Y) represents the containing ring component, and it consists of one or more, preferably one or two fused or unfused, saturated or unsaturated, substituted or unsubstituted rings, as it is defined here. Accordingly, the ring system may be monocyclic (Y is missing) or polycyclic (as the X and Y represents a ring or all of X, R and Y are the rings). Each ring can be either carbocycle, or heterocycle, and may contain 5, 6 or 7 members, preferably 5 or 6 members who denserank rings. More preferably, ring (Y) adjacent to the binder component (L), represents a heterocycle, and most preferably five-membered ring containing an oxygen atom in position 1. In addition, when the ring system has two rings, preferably a heterocycle (Y) was covalently linked (through R) with another ring (X) in position 5 of the heterocycle and Y in position 1 of the ring X, and that the heterocycle Y was associated with carbon end component L in position 2 of the heterocycle.

For ring systems are acceptable, though not preferred, is the option with the formation of polycyclic ring system consisting of two rings (X and Y), which are separated by an alkyl group, a carbonyl group or a heteroatom, preferably oxygen atom of (R). In addition, a suitable ring system may be a polycyclic ring system consisting of two rings (X and Y), which are condensed (R no), or three rings (X and R and Y), which are condensed. When R is a ring, preferably so that it represents a 5 - or 6-membered carbocycle or heterocycle.

Especially predpochtitel, Valentino associated with carbonaceous part L (R represents a covalent bond, and Y is absent). However, when the ring system has only one ring, it is preferable that this ring was a 6-membered carbocycle, which, preferably, is substituted at least two and most preferably at least three substituents, independently selected from the group consisting of, but not limited by them, hydroxy groups, methyl group, chlorine, metoxygroup and benzene group.

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

Predpochtitelney ring, to which can be attributed, but not limited to, 2-acetoxy-5-chloraniline, 3-hydroxy-5-hydroxy-methyl-2-methyl-4-pyridinoline, 2-thienyl, 4-pyrimidinamine, 5-methoxycarbonyl-2-furazilina, tsiklogeksilnogo, 5-chloro-2 - hydroxyproline, 5-chloro-2-metoksifenilny, 2-methanesulfonylaminoethyl, 3-aminoaniline, 2-metoksifenilny, 5-ethyl-2-furazilina, 3-metoksifenilny, 2-aminoaniline, 2-furazilina; 3,5-dimethyl-4-hydroxyproline and 5-acetoacetyl-2-furazilina system. Suitable polycyclic ring systems, which consist of two unfused rings covalently linked to each other, are, for example, but not limited to, 5-(4-carboxyphenyl)-2-furazilina, 5-(4-methanesulfonyl)-2-furazilina, 5-(3,4-acid)-2 - furazilina, 5-(4-methanesulfonylaminoethyl)-2-furazilina, 5-(4-bromophenyl)-2-oxazolinone, 5-(4-methoxyphenyl)-2-furazilina, 5-(1-cyclohexen-1-yl)-2-furazilina, 5-cyclohexyl-2-furazilina, 5-(3-triptoreline)-2-furazilina, 5-(4-were)- 2-furazilina, 2-(4-chlorophenyl)-3-furazilina, 5-(4-chlorophenyl)-2 - furazilina, 5-(4-forfinal)-2-furazilina ring system. Suitable polycyclic ring systems, which consist of two unfused ¡group, are, for example, but not limited to, 2-benzyloxy-5 - chloraniline, 4-benzyloxyphenyl, 3-(4-tert-butylphenoxy) phenyl, 3-benzoyl-2,4-dichloraniline, 2-chloro - 3-benzyloxyaniline, 3-(4-chlorophenoxy)phenyl ring system. Suitable polycyclic ring systems containing two or more condensed rings are, for example, but not limited to, 1H-indol-3-ilen, 2-fluoroaniline, 2-naftalina, 2-hydroxy-1-naftalina, 2-hyalinella, 5-chloro-2-benzofuranyl ring system.

Preferred ring systems (X-R-Y) new 4-oxocyclohexa compounds of urea, as defined in this description, include, but are not limited to, the following systems:

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Binder component (L). L represents a connecting component in the new 4-oxocyclohexa the urea compounds of the present invention. Carbon-containing end of the L is connected with the ring system X-R-Y at the location of Y; however, if Y is absent, then the location of X; it is most preferable that this happened in position 2 of the ring Y or in position 1 X if Y is missing. The nitrogen atom in component L is associated with at the C group, consisting of alkylamino, alkynylamino, alkylamino, alkynylamino and alluminare; preferred alkylamino, most practically (C1)alkylamino CH=II.

4-Oxocyclohexa urea component. 4-Oxocyclohexa urea component of the new compounds of the present invention provides new compounds of the present invention the characteristic name. 4-Oxocyclohexa urea component can represent a 5 - or 6-membered ring, preferably a 5-membered ring. 4-Oxocyclohexa urea component has the structural formula:

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in which R5is a (C1) or (C2)alkyl group, preferably (C1)alkyl group. When R5is a (C1)alkyl group, 4-oxocyclohexa urea is a 5-membered ring and, when R5is (C2)alkyl group, 4-oxocyclohexa urea is a 6-membered ring.

A represents promoteyou or branched, substituted or unsubstituted, saturated or unsaturated (C1-C8) heteroalkyl group or a substituted or unsubstituted, saturated or unsaturated 5-, 6 - or 7-membered, predpochtitelnei group or a heterocycle, must contain at least one nitrogen atom, which must be associated with R4.

When A represents a substituted heteroalkyl group, preferably, substituents selected from the group consisting of, but not limited by them, from methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol and methanesulfonyl group.

When A heterocycle contains two nitrogen atom, preferably a nitrogen atom not attached to the group R4(which in the case of a 6 membered heteroclita is in the para-position relative to the nitrogen atom adjacent to R4), was substituted by substituents selected from the group consisting of, but not limited by them, from methyl, hydroxyethylene, alkyl, aryl, mercaptoethanol, methanesulfonyl, heterocyclic and arylalkyl group. When A heterocycle contains only one nitrogen atom, and A represents a 6-membered ring, preferably a para-position relative to the nitrogen atom adjacent to R4was substituted by substituents selected from the group consisting of, but not limited by them, from hydroxyethylene group, a hydroxy-group, carbonyl group and metalno the urea, defined in this description, include, but are not limited to, the following education:

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Suitable components A, therefore, can be, but are not limited to, the following components. Components, in which A represents heteroalkyl group include, but are not limited to, dimethylamino, diethylamino-, bis-2 - hydroxyethylamino, bis-[(1-methyl)ethyl] amino, N-benzyl-N-methylamino-, N-(2-hydroxyethyl)-N-methylaminopropyl. Suitable components A, where a is a heterocycle, be, but are not limited to, N-(1-methylethyl)-N-[2-hydroxy-2-[(4 - methanesulfonamido)phenyl] -ethyl]amino group, 4-phenylpiperidine, 4-(2-hydroxyethyl)piperazinilnom, 4-(1-methylethyl)piperazinilnom, 4-(2-methylpropyl)piperazinilnom, 4-hexylpyridine, 4-benzylpiperidine, 1-piperazinilnom, 4-hydroxy - 1-piperidinyl, 4-methyl-1-piperazinilnom, 4-n-butyl-1 - piperazinilnom, 4-ethyl-1-piperazinilnom, 3-(4-methyl-1-piperazinil)- 3-oxopropyl, 4-phenyl-1-piperazinilnom, N-(2-pyridinyl)-1 - piperazinilnom, N-(2-pyrimidinyl)-1-piperazinilnom, 4-(4-methoxyphenyl)-1-piperazinilnom, 4-acetyl-1-piperazinilnom group, N-methyl-N-phenylaminopropyl, 1-imidazolidinethione, 4-oxo-1 - piperidinyl, 2-(tert-butoxycarbonyl)-1-pyrrolidinyl, pyrrolidinone, 4-(4-acetylphenyl)-1-piperazinilnom, hexahydro - 1H-azepin-1-ilen group.

The group R4connected to the nitrogen atom in position 3 of the 4-oxocyclohexa urea component, and nitrogen nitrogen in A. R4is selected from the group consisting of, but not limited by them, from alkyl, alkenylphenol, alkenylphenol, alkylsilanes and heteroalkyl group, and particularly preferred is a (C3-C6)alkyl group, i.e., through bucilina, pentilla, and exilda group.

As mentioned above, the new 4-oxocyclohexa connection urea of the present invention consists of a 4-oxocyclohexa urea component connected to the ring system via a binder component. Accordingly, suitable compounds conforming to the present invention, include, but are not limited to, the following compounds in their pharmaceutically acceptable esters and salts, particularly their hydrochloride:

1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl - 1-piperazinil)butyl] -2,4-imidazolidinedione, 1-[[[4-hydroxy-3, 5dimethylphenyl]methylene] amino] -3-[4-(4-methyl-1-piperazinil)-butyl] - 2,4-imidazole(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-[4-(2- hydroxyethyl)-1-piperazinil] propyl] -2,4-imidazolidinedione, 1-[[[5- (4-chlorophenyl)-2-furanyl] methylene] amino]-3-[6-(4-methyl-1-piperazinil) hexyl]-2,4-imidazolidinedione,

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[5-(4-methyl-1 - piperazinil)pentyl]-2,4-imidazolidinedione, 1-[[[5-(4-forfinal)-2 - furanyl]methylene] amino] -3-[4-(4-methyl-1-piperazinil)-butyl] -2,4 - imidazolidinedione, 1-[[[5-(4-chlorophenyl)-2-furanyl] -methylene] amino] - 3-[4-[4-(2-hydroxyethyl)-1-piperidinyl] butyl] - 2,4-imidazolidinedione, 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] -3-[3-[4-(2-hydroxyethyl)-1 - piperidinyl]propyl]-2,4-imidazolidinedione, 1-[[[5-(4-chlorophenyl)-2 - furanyl]methylene]amino]-3-[3-[4-(2-mercaptoethyl)-1-piperazinil] propyl] -2,4-imidazolidinedione, 1-[[[5-(4-bromophenyl)-2-oxazolidinyl] methylene] amino]-3-[4-[4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione, 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-(dimethylamino)- propyl] dihydro-2,4-(1H, 3H) pyrimidinedione, 1-[[[5-(4-chlorophenyl)-2 - furanyl] methylene] amino] -3-(3-dimethylaminopropyl)-2,4-imidazolidinedione, 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-(4-methyl-1 - piperazinil)propyl]-2,4-imidazolidinedione, 1-[[[5-(4-forfinal)-2 - furanyl]methylene]amino]-3-[3-[4-(2- hydroxyethyl)-1-piperazinil] propyl] -2,4-imidazolidinedione, 1-[[[5- (4-chlorophenyl)-2-furanyl] methylene] amino]-3-[8-(4-morpholinyl)octyl]- 2,4-imidazolidinedione.

Examples A - L, privedennyh here.

New 4-oxocyclohexa connection urea of the present invention can be administered to the human or other mammal in a variety of ways, including, but not limited to, oral dosage forms and injections (internal, intramuscular, intraperitoneal and subcutaneous). Numerous other dosage forms containing the new 4-oxocyclohexa connection urea of the present invention can be easily prepared by a specialist working in this field of technology, using suitable pharmaceutical napalitano, as defined below. From the point of view of convenience for the patient dosage forms for oral administration are presented in the General case the most preferred.

The term "pharmaceutical composition" means a combination that includes safe and efficient active amount of the active ingredient is 4-oxocyclohexa compounds of urea or mixtures thereof and pharmaceutically acceptable excipients.

The phrase "safe and effective effective amount" means an amount of compound or composition that are large enough to significantly positive modification of symptoms and/or condition in the treatment, yet small enough that patentei medical point of view. Safe and efficient active amount of the active ingredient intended for use in pharmaceutical compositions, which should be applied in a way that meets the present invention should vary depending on the specific conditions of treatment, age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific characteristics of the active ingredient, which must be applied, the specific characteristics of the pharmaceutically acceptable fillers and the like factors within the knowledge and experience of the attending physician of the hospital.

The term "pharmaceutically acceptable excipients" includes any physiologically inert, farmacologicas inactive substances known to the specialists working in this field of technology that are compatible with the physiological and chemical characteristics of the active ingredient is 4-oxocyclohexa connection urea selected for use. Pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, swasey is esta, preservatives, sweeteners, fragrances, dyes or pigments pharmaceutical purity and thickeners.

The term "oral dosage form" means any pharmaceutical composition intended for the system introduction to the individual by making the above-mentioned composition in the gastrointestinal tract of the individual through the mouth of the mentioned individual. For the purposes of the present invention are made form may be in the form of tablets, coated or uncoated, solution, suspension or capsules coated or uncoated.

The term "injection" as used in this description, means a pharmaceutical composition intended for the systematic introduction to the human or other mammal in the form of a solution or emulsion containing the active ingredient, by piercing the skin in question an individual with the purpose of introducing the above-mentioned solution or emulsion in the circulatory system of the individual or intravenously, or intramuscularly, or intraperitoneally, or subcutaneously.

The rate of systemic delivery of a drug can be monitored by a specialist working in this field of technology by matching od is m pharmaceutically acceptable excipients, while there is no impact on the activity of this active ingredient;

c) type of filler and the associated required thickness and permeability (swelling) of the above-mentioned filler;

d) time-dependent conditions for the existence of the filler and/or in combination with other fillers;

e) the particle size of the granulated active ingredient and

f) depending on the pH of the fillers.

In particular, solubility, acidity, and susceptibility to hydrolysis of various 4-oxocyclohexa urea active ingredients, such as salt accession acid, salts formed with a carboxyl group, for example salts of alkali metals, salts of alkaline earth metals, etc. and esters, for example alkyl, alkeline, aryl, kalkilya, can be used as a guide to achieve the correct choice. In addition, the appropriate value of pH can be created in the oral dosage forms by adding a suitable buffer mixture to the active ingredient in accordance with the desired scheme of its release.

As noted above, pharmaceutically acceptable voltage is agrihotel, the co-solvents, surfactants, preservatives, sweeteners, flavouring agents, buffer systems, dyes or pigments pharmaceutical frequency and thickeners.

The preferred solvent is water.

Odorants from among those that can be used here represent the substances described in the Handbook (Remirgton''s Pharmaceutical Science, 18th Edition, Mack Publishing Company, 1990, pp. 1288 - 1300), which is included as a reference. Pharmaceutical compositions acceptable here, usually contain 0 to 2% of odorous substances.

Dyes or pigments, which can be used here, are described in the Handbook (Handboor of Pharmaceutical Excipients, pp. 81 - 90, 1986), released by the American pharmaceutical Association and the pharmaceutical society of great Britain, which is included as a reference. The pharmaceutical compositions described herein typically contain 0 to 2% of dyes or pigments.

Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycols. The pharmaceutical compositions of the present invention contain 0 to 50% of cosolvent.

Preferred b is new, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric, and glutamic acid and their sodium, potassium and ammonium salts. Particularly preferred systems are systems consisting of phosphoric, tartaric, citric and acetic acids and salts. The pharmaceutical composition of the present invention typically contains 0-5% buffer system.

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

Preferred preservatives include, but are not limited to, phenol, alkyl esters by parahydroxybenzoic acid, o-phenylpropanamine acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorbutanol, benzyl alcohol, thimerosal, fenilsalicilat and venertalented, nitromersol, chloride benzalkonium, cetylpyridinium, meth is d, methylparaben and propylparaben. Compositions of the present invention typically contain 0 - 2% preservatives.

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

Preferred thickening agents are, but are not limited to, methylcellulose, sodium carboxymethyl cellulose, hypromellose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, Arabian gum, gummibar, humectants and tragakant. Especially preferred are methyl cellulose, carbomer, humectants, gummibar, povidone, sodium carboxymethyl cellulose and alumomagnesium silicate. Compositions of the present invention contain 0 to 5% thickening agents.

Preferred fillers include, but are not limited to, lactose, mannitol, sorbitol, rejonowy calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, extracellular and microcrystalline cellulose. The composition of this izopet theart magnesium, stearic acid and talc. The pharmaceutical compositions of the present invention, containing 0.5 - 2% lubricants.

Preferred for facilitating the sliding agents are, but are not limited to, talc and colloidal silicon dioxide. Compositions of the present invention contain 1 to 5% of sizing.

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

Preferred binders include, but are not limited to, Arabian gum, tragakant, hydroxypropylcellulose, pre gelatinizing starch, gelatin, povidone, hydroxypropylcellulose, hypromellose, methylcellulose, solutions of sugars, such as sucrose and sorbitol, and ethylcellulose. The composition of the present invention contains 1 to 10% of binders.

Accordingly, the pharmaceutical compositions of the present invention contain 15 to 95% of active ingredient in the form of 4-oxocyclohexa compounds of urea or mixtures thereof, 0 to 2% of perfume oils, 0 - 50% corstvet, 0 to 5% of a thickening agent, 0 to 75% filler and 0.5 - 2% lubricants 1 to 5% of substances that facilitate the sliding, 4 - 15% baking powder and 1 to 10% of binders.

Suitable pharmaceutical compositions are described herein in the examples, M - Q. it Can be argued that any expert working in this field of technology, it is able to carry out the modification examples, not limiting the scope of the present invention described herein, and to obtain a wide range of pharmaceutical compositions.

The new compounds of the present invention are effective in the treatment of a human or other mammal suffering from supraventricular arrhythmias and ventricular arrhythmias and/or cardiac fibrillation. As mentioned above, with rare exception, supraventricular arrhythmias are not life threatening and usually do not undergo radical treatment using common antiarrhythmic drugs due to adverse side effects. Accordingly, with this type of arrhythmia is usually not conduct an intensive treatment to simply remove the symptoms, which are characterized by mild to severe. However, the new compounds of the present invention in General Pasprostaranenie antiarrhythmic drugs, and therefore, they may be quite acceptable for treatment to alleviate the symptoms experienced by individuals suffering from supraventricular arrhythmias who actually experience discomfort, even if the situation is not life-threatening.

As mentioned above, the new 4-oxocyclohexa connection urea of the present invention are also effective for the treatment of ventricular arrhythmias, which, as a rule, are much more serious than supraventricular arrhythmias, and, therefore, require intensive therapy. Because of the potential severity of some ventricular arrhythmias appeared numerous classifications of types of patients.

Individuals suffering from benign ventricular arrhythmias, from a philosophical point of view: "And whether they should be treated?!", be similar to individuals who are experiencing supraventricular arrhythmias. These individuals there is no heart disease, and they may experience dizziness and palpitations and often suffer from a certain amount of emotional distress arising from uncertainties due to the perceived physical symptoms. These individual who for obvious reasons are the grounds for some concern. New 4-oxocyclohexa compounds of urea present invention generally cause less unwanted side effects than many common antiarrhythmic drugs are still used in the case of more serious and/or life-threatening conditions, these unwanted individuals. However, these individuals are likely to benefit from treatment, which in the General case, be better tolerated.

Another class of individuals who may be benefit from treatment using the new 4-oxocyclohexa of the urea compounds of the present invention, is those individuals who are characterized as having "prognostically significant arrhythmias. These individuals usually have had a heart attack and they are characterized by the presence of ventricular extrasystoles and/or seizures unstable ventricular tachycardia, or with symptoms or without them. They do not feel require immediate action, sharp, dangerous to lower symptoms in the extent to which their experience of the individuals described here, and the generally accepted view is not in danger of immediate or imminent death. They, however, are characterized by considerably the of heart failure in the case of treatment of the new compounds of the present invention (see Morganroth and Bigger, S. 1498).

There are also individuals who continuously suffer life-threatening arrhythmia and are in danger of immediate or imminent death. These individuals usually observed persistent ventricular tachycardia or ventricular fibrillation. Ventricular arrhythmia experienced by these individuals, usually accompanied by hemodynamic manifestation of significant signs or symptoms, such as fainting, heart failure, myocardial ischemia or gipotenzia. These patients are characterized by the highest risk to die suddenly from a heart attack and usually suffer the most acute form of the underlying disease of the heart. Cm. Morganroth And Bigger, S. 1498. The new compounds of the present invention are the means for effective intensive antiarrhythmic treatment, suitable for use by this class of individuals, but with fewer unwanted side effects usually experienced when using common antiarrhythmic drugs out of necessity and lack of adequate alternative remedies for the treatment of life-threatening arrhythmias.

As mentioned the recreational side effects typical of many common methods for treating arrhythmia. These side effects include, but are not limited to, pulmonary toxicity, heart failure, and neurological effects, not characteristic of cardiac tissue.

Furthermore, the new compounds of the present invention are antifibrillatory, and antiarrhythmic agents; they eliminate the possibility of sudden death from a heart attack, evenly prolonging newsbody period of the heart during each beat. Ordinary treatments are characterized by the manifestation of anesthetic and/or cardiac depressive properties, which make the heart less susceptible, but not less than fibrillarin.

Accordingly, the new 4-oxocyclohexa connection urea of the present invention are suitable for the treatment of cardiac arrhythmias and/or cardiac fibrillation in humans or other mammals. Therefore, the present invention relates to a method of treatment of a human or other mammal suffering from cardiac arrhythmia and/or cardiac fibrillation, which includes the introduction of the aforementioned person or other mammal a safe and effective action is th compounds of urea or mixtures thereof, from 10 - 85% of pharmaceutically acceptable fillers.

Examples of S-Z replicate some of the patients and illustrate the ways in which pharmaceutical compositions containing the new 4-oxocyclohexa connection urea of the present invention, can be used to treat cardiac arrhythmias and fibrillation. Specialist working in this field of technology, it is able to modify the examples, not limiting the scope of the invention that are described here, so that could be the treatment of a wide class of individuals suffering from cardiac arrhythmia and fibrillation.

The following examples provide further illustration of the present invention.

An example of A

Synthesis dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione

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The above-mentioned connection receive and synthesize as described below.

1. Synthesis dihydrochloride 1-phenylethylamine-3-(4-chlorobutyl)-2,4-imidazolidinedione. The dihydrochloride of 1-phenylethylamine-3-(4-chlorobutyl)-2,4-imidazolidinedione produced by adding 60% sodium hydride in mineral oil (7.8 g, 0,1944 mol) for h is ll. Czech. Chem. Commun., Vol 33, pp. 2087 - 2096 (No. 7), 1968), included as a reference (39.5 g, 0,1944 mole) in dimethylformamide (1000 ml). After complete addition, the solution warm when the temperature of the steam bath (at about 100oC) for 1.5 hours the resulting mixture is allowed to cool to ambient temperature (30oC). Spending stirring at ambient temperature in one portion was added 1-bromo-4-chlorobutane (100 g, 0,5832 mol, 3 EQ.). The mixture generates heat, and about 30 min the temperature of the mixture reaches approximately 35oC. Almost completely dissolved, the mixture is warm at about 80oC on a steam bath for 4 h, cooled and stirred for about 8 hours at ambient temperature (30oC). The cloudy mixture is filtered, removing a small amount of insoluble substances. The filtrate is concentrated under reduced pressure to obtain a semi-solid residue. This residue is treated with water (400 ml), collected, recrystallized from acetonitrile and then dried in air, resulting in a gain of 43.1 g (0,1467 mole) 1-phenylethylamine-3-(4-chlorobutyl)-2,4-imidazolidinedione.

II Synthesis of 1-phenylethylamine-3-(4-iodobutyl)-2,4-imidazolidinedione. A mixture consisting of 1-phenylmethylene) and sodium iodide (48,4 g, 0,3227 mol), refluxed. Boiling is maintained for 5 hours the Mixture is filtered, collecting the insoluble substances. The filtrate is again added sodium iodide (10 g), and resume boiling under reflux, which continued for 15 hours After cooling to ambient temperature the mixture is filtered, removing the insoluble NaCl (full extraction, 9.5 g, 110%). The filtrate was poured into water (2000 ml) with stirring. After stirring for 30 min collect the solid and dry in the air, resulting in a gain of 51.5 g (0,1337 mole) 1-phenylethylamine-3-(4-iodobutyl)-2,4-imidazolidinedione.

III. Synthesis dihydrochloride 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione. A solution consisting of 1 phenylethylamine-3-(4-iodobutyl)-2,4-imidazolidinedione (10.0 g, 0,0260 mol) (obtained as described above in part II), dimethylformamide (150 mg) and 1-methylpiperazine (11.5 ml, 10.4 g, 0,1040 mole) is refluxed. Boiling is maintained for 3 hours After cooling to 40oC the solution is concentrated under reduced pressure in a rotary evaporator to education oily solid residue. This residue is dissolved in water (200 ml), then alkalinized, add ardoe substance harvested and dried in air; then it is dissolved in absolute ethanol (150 ml), then filtered, then acidified with installing on wet litmus paper, adding a mixture of EtOH/HCl. After cooling for several hours, the solid is collected and air-dried, resulting in a gain of 8.04 g (0,0187 mole) of the dihydrochloride of 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil) butyl]-2,4-imidazolidinone.

IV. Synthesis of hydrochloride of 1-amino-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione. A mixture of the dihydrochloride of 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil)butyl] -2,4 - imidazolidinedione (8,04 g, 0,0187 mol), 2N HCl solution (125 ml) and 50% aqueous suspension of 5% palladium-on-coal (1.5 g), is exposed to hydrogen in the apparatus parry at a pressure of 40 lb) square inch (235,8 kN/m2and ambient temperature. After 2 h, the catalyst was removed by filtration. The filtrate is divided into two different portions. Each portion was concentrated under reduced pressure in a rotary evaporator to education oily residue, representing the hydrochloride of 1-amino-3-/4-(4-methyl-1-piperazinil) butyl/-2,4-imidazolidinedione.

V. Synthesis dihydrochloride [[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinil) butyl]-2,4-ia (0,0094 mol), of dimethylformamide (75 ml) and 5-(4-chlorophenyl)-2-furancarboxaldehyde (obtained as described in U.S. patent N 4882354, issued November 21, 1984 Huang (Huang and others, the rights to which are attracted to the firm "Normalities, Inc.; see columns 7 and 8; the patent is included here as a reference) (1,94 g, 0,0094 mol), stirred at ambient temperature for 72 hours the Mixture is filtered, collecting the solid. By recrystallization from a mixture of absolute ethanol with water and air drying receive 2,63 g (0,0050 mole) dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione.

The example IN

The mixture dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[8-(4-methyl-1 - piperazinil)octyl]-2,4-imidazolidinedione

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The above-mentioned connection receive and synthesize as described below.

1. Synthesis of 1-benzylideneamino-3-(8-hydroxyacyl)-2,4-imidazolidinedione. 1-(Benzylideneamino)as receive according to the method described in literature (J. Gut, A. Noracet, and P. Fiedler, Coll. Czech. Chem. Commun., Vol. 33, pp. 2087-2096 (No. 7), given here as a reference.

To a solution consisting of up to 30.5 grams (0.15 mole) of 1-(benzylideneamino) as in 500 ml of dimethylformamide, add about 15 min and increases from 25 to 35oC, and after about 5 min after the addition was completed the selection of a white solid. Add 700 ml of dimethylformamide, than promote uniform mixing. The mixture is warm at about 80oC (steam bath) for one hour, and then allowed to cool. This multiple cooling the mixture at 50oC, then add to 24.7 grams (0.15 mole) of 8-chloro-1-octanol. The mixture was then heated to 100-110oC, warm for 3 h, and then she was given the opportunity to cool for approximately 16 h White solid disappears after the first hour of heating, and then gradually allocated another solid substance.

The resulting mixture is filtered, and the filtrate is concentrated to reduce the volume at 1/3 of the original volume and then poured into 1.2 l of water. A white precipitate is collected, well washed with water and dried in air. Solid weighs 24 g (48%). By recrystallization 3.5 g of 50 ml of nitromethane obtain 2.86 g of 1-benzylideneamino-3-(8-hydroxyacyl)-2,4-imidazolidinedione, which is a crystalline white solid.

II Synthesis dihydrochloride 1-benzylideneamino-3-[8-(4-methyl-1-piperazinil)-octyl] -2,4-imidazolidinedione. The mixture comprising the fridge for about 4 hours The reaction mixture is filtered while hot and collect some amount of insoluble substances. A small amount of solids separated from the filtrate upon cooling. The mixture is then poured in about 400 ml of hexane, and immediately precipitated white solid, representing the chloride octyl. Dropped the chloride octyl collected, well washed with hexane and dried in air.

A mixture consisting of 4,85 g (of 0.014 mole) of the above-mentioned sludge and 1.5 g (0,015 mol) of N-methylpiperazine in 125 ml of dimethylformamide, is refluxed. After 28 h boiling under reflux, the mixture is concentrated under reduced pressure to obtain a brown residue. Treatment with a saturated solution of sodium bicarbonate NaHCO3get a brown solid. The mixture is filtered, and collected a sticky brown solid is treated further by a simple ether and again filtered. This sticky solid is the dihydrochloride of 1-benzylideneamino-3-[8-(4-methyl-1-piperazinil)octyl]-2,4-imidazolidinedione (1,96 g).

III. Synthesis dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino] -3-[8-(4-methyl-1-piperazinil) octyl]-2,4-imidazolidinedione. A mixture consisting of a 1.96 g Digue is with 1.5 g of 5% palladium-on-charcoal, subjected to hydrogenation in the mixer Parra. Full recovery requires two days, and otoczenie 24 h add 1.5 g of palladium-on-charcoal grill. The supply of hydrogen is stopped when the rotation number was 110% of theoretical value; and the catalyst is filtered off. The filtrate is concentrated under reduced pressure, resulting in a gain dark solution with a small amount of solid substances released when standing.

The above residue is diluted with 10 ml of dimethylformamide, and add a solution consisting of 0,98 g of 5-(4-chlorophenyl)-2-furancarboxaldehyde (obtained as described in U.S. patent N 4882354, issued November 21, 1984 Huang (Huang and others, the right which belongs to the company "Norwich Eaton pharmaceutical, Inc.; see columns 7 and 8; the patent is included here as a reference) in 10 ml of dimethylformamide. Almost immediately falls yellowish solid. After four hours of stirring the mixture is filtered, and the solid is washed thoroughly with substance SDA-32, and then a simple ether, and then air-dried. The weight of the substance is 1.5, the Recrystallization of 2.27 g of this raw from 350 ml of nitromethane obtain 0.9 g of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino-3-[8- (4-me-2-furanyl]methylene]amino]-3-[8 -(4-morpholinyl)octyl]-2,4-imidazolidinedione

< / BR>
The above-mentioned connection receive and synthesize as described below.

A mixture of 5.0 (0,015 mol) of artilharia (synthesized as described in part II of example), in 100 ml of dimethylformamide (DMF) and 1.5 g (of 0.017 mole) of the research, refluxed for 32 hours the Mixture is concentrated under reduced pressure and get dark reddish residue. Treatment with a saturated solution of sodium bicarbonate NaHCO3get a brown solid, which is collected, well washed with water and then dried in air. This is somewhat sticky brown solid is dissolved in acetone, treated with activated charcoal and filtered. The acetone filtrate is diluted with water, which is added until, until it begins to fall solid. The mixture is cooled and then filtered. The solid is collected, well washed with water and then dried in the air, get 3,18 g (0,008 mole) sticky solid.

The above solid is placed in 100 ml of 2 N HCl solution together with 1 g of the catalyst is 5% palladium-on-charcoal, and hydrogenizing in the mixer Parra. The flow of hydrogen going to the hydrogenation was stopped after 6 h (18 lbs (8,16 kg), 110%), and the mixture Phi viscous liquid residue. To this liquid residue in 10 ml of dimethylformamide under stirring at ambient temperature is added a solution consisting of 1.65 g (0,008 mole) of 5-(4-chlorophenyl)-2-furancarboxaldehyde (obtained as described in U.S. patent N 4882354, issued November 21, 1984 Huang (Huang and others, the rights to which belong to the company "Norwich Eaton Pharmaceutical, Inc. "; see columns 7 and 8 (which included saliva as links) in 20 ml of dimethylformamide. The mixture is allowed to mix at ambient temperature for 16 h and then concentrated under reduced pressure to obtain a brown residue. Add a fresh portion of dimethylformamide to dissolve the solid, and also add about 15 ml of ethanolic HCl solution. The solution warm at 40 - 45oC for two hours and then concentrated under reduced pressure. The resulting residue is treated with absolute ethanol, and the ethanol removed under reduced pressure in a rotary evaporator. This process was repeated once more, and a brown semi-solid residue is treated with simple ether and filtered. This sticky functions of the cellular solid is triturated then with isopropanol and filtered. The crude solid weighs 2.38 g, and paracrystal-imidazolidinedione.

Example D

Synthesis of dihydrochloride of 1-[[[3,5-dimethyl-4-hydroxyphenyl] methylene]amino] -3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione

< / BR>
Named above connection receive and synthesize as described below.

A mixture of 3.23 g (0,0075 mole) of the dihydrochloride of 1-phenylethylamine-3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione (obtained as described in parts I, II and III a) in 125 ml of 2 N HCl solution together with 2 g of 5% palladium-on-coal (in the form of a 50% aqueous suspension), hydrogenizing in the mixer Parra. The flow of hydrogen ceased after the introduction of hydrogen in the amount of 125% of theoretical value. The catalyst was removed by filtration, and the filtrate concentrated under reduced pressure in a rotary evaporator to yield a sticky solid residue. The residue is repeatedly treated with substance SDA-32, and the solvent is removed under reduced pressure in a rotary evaporator. Get a white solid.

The above solid is placed in 100 ml of dimethylformamide. After boiling for 10 min dissolution is observed. The mixture cool slightly and it added 1.13 g (0,0075 mole) of 3,5-dimethyl-4-hydroxybenzaldehyde. The mixture is left to mix in techeniya dimethylformamide, solvent SDA-32, a simple ether and air-dried. The output is 3.75 g (it exceeds 100%). By recrystallization from a mixture consisting of 100 ml of solvent SDA-32 and about 30 ml of water, obtain 2.17 g (yield 66%) of the dihydrochloride of 1-[[[3,5-dimethyl-4-hydroxyphenyl] methylene] amino]-3-[4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione.

Example E

Synthesis dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylamino]-3-[3-[4-(2-hydroxyethyl) -1-piperazinil]propyl]-2,4-imidazolidinedione

< / BR>
1. Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-(3-chlorpropyl)-2,4 - imidazolidinedione. A solution containing 1-[5-(4-chlorophenyl)-2-furfuryladenine] as (obtained as described in U.S. patent N 3415821, issued December 10, 1968 to Davis (Davis) and Snyder (Snyder), the right which belongs to the company "Norwich Eaton pharmaceuticals, Inc.; see columns 2 and 3; the patent is mentioned here as a reference (25,0 g, 0,082 mole) in dimethylformamide mark H. D. and. (423 ml), stirred and blown off with nitrogen. The solution is treated with portions of the mixture of sodium hydride (60% in mineral oil (3,29 g, 0,082 mol) for five minutes. The reaction mixture (later became the solution, and then a thick mixture) by warming on the steam bath for 15 minutes the Reaction mixture, the cooling gap-chloropropanol (26,9 g, 0,165 mol), and warm on a steam bath for 4 h, the Reaction mixture is cooled and poured into 1500 ml of water, was obtained oily mixture. When standing for 5 min produced a yellow solid. The yellow solid is filtered off and washed with water, get 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-(3-chlorpropyl)-2,4 - imidazolidinedione (33,0 g).

II. Synthesis dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino] -3-[3-[4-(2-hydroxyethyl) -1-piperazinil]propyl]-2,4-imidazolidinedione. Stir a solution of 4-(2-hydroxyethyl)piperazine (3,83 g 0,03 mole) in dimethylformamide mark H. D. and. (130 ml) is treated 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-(3-chlorpropyl) -2,4-imidazolidinedione (6,92 g 0,015 mol). The reaction solution heat at a temperature close to the boiling temperature under reflux for 1.5 h, and then concentrated under reduced pressure to obtain an oily residue. The above residue is treated with saturated solution of sodium bicarbonate and receives a yellow mixture. The mixture is filtered and washed with water, and get to 3.92 g of crude product in the form of free base. The solid is dissolved in alcohol and treated with a mixture that represents a saturated ethanolic solution H is trevanian and get the crude product. A single recrystallization from 95% alcohol allocate dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] -amino]-3-[3-[4-(2-hydroxyethyl) -1-piperazinil]propyl]-2,4-imidazolidinedione (to 2.57 g).

Example F

Synthesis of hydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-[4-(2-hydroxyethyl) piperidinyl]butyl]-2,4-imidazolidinedione

< / BR>
Hydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3- [4-[4-(2-hydroxyethyl)piperidinyl] butyl] -2,4-imidazolidine receive and synthesize as described below.

1. Synthesis 1-[[[5-(4-chlorophenyl-2-furanyl-2-furanyl]methylene]amino]-3-(4-chlorobutyl( -2,4-imidazolidinedione. To a stirred solution of 5-(4-chlorophenyl)-2-furancarboxaldehyde (obtained as described in U.S. patent N 4882354, issued November 21, 1984 Huang (Huang and others, the rights to which belong to the company "Norwich Eaton pharmaceuticals, Inc.; see columns 7 and 8 (which is included here as a reference)) (26,0 g, 0,0856 mole) in dimethylformamide (500 ml) is added portions of 60% sodium hydride in mineral oil (3.4 g, 0,856 mol) for two minutes. After the addition the mixture is stirred for one hour at ambient temperature and then warm when the temperature of the steam bath for one hour. Received resses stirred at ambient temperature for 30 min and then at 80 - 90oC for two hours. After cooling, the mixture is concentrated under reduced pressure until a volume of 1/3 of the original value. One stripped off the mixture was then poured into water (1500 ml) and then stirred. The solid is collected, air-dried and then dried at 70oC, obtain 35.5 g (0,090 mole; output exceeds 100%) 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-(4-chlorobutyl)-2,4 - imidazolidinedione.

II. Synthesis of hydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino] -3-[4-[4-(2-hydroxyethyl)piperidinyl] butyl] -2,4 - imidazolidinedione. Mix a solution consisting of 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(4-chlorobutyl)- 2,4-imidazolidinedione (5.0 g, 0,0127 mol) (obtained as described above), dimethylformamide (150 ml), sodium iodide (3.8 g, 0,0254 mol), K2CO3(1,76 g, 0,0127 mol) and 4-piperidinemethanol (4.1 g, 0,0318 mol), heat on a steam bath for 1.5 hours, After cooling the mixture is concentrated under reduced pressure to obtain a semi-solid residue. This residue is suspended in water (300 ml) and then extracted with CH2Cl2. The extract was washed with water (3 times 100 ml) and then dried over magnesium sulfate (activated charcoal). The filtered solution is concentrated under ponizhennoe on the air. This solid residue is dissolved in absolute ethanol (300 ml) under heating, cooled and acidified with Et-OH/HCl. After cooling in an ice bath for several hours, the solid is collected, washed with anhydrous simple ether, air-dried and 70oC, get of 4.05 g (0,077 mole) of the hydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-[4-(2- hydroxyethyl)piperidyl] -butyl]-2,4-imidazolidinedione.

Example G

Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-[4- methyl-1-piperazinil)butyl]-2,4-imidazolidinedione

< / BR>
Free base 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino]-3-[4-[4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione receive as described below. Salt, dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene] amino] -3-[4-[4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione (6,56 g, 0,01245 mole), obtained as described in example A was dissolved in water (300 ml) and washed once in 100 ml). The aqueous phase is alkalinized with saturated solution of NaHCO3. The resulting mixture is extracted with CH2Cl2(4 times 100 ml). The extract was washed with a saturated solution of NaCl (twice 50 ml), dried over magnesium sulfate (activated charcoal), filtered and concentrated ether, harvested and dried in the air. A single recrystallization from absolute ethanol, and then from toluene (activated charcoal) with subsequent washing simple anhydrous ether and air drying gain of 2.05 g (0,0045 mole) 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-[4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione.

Example H

Any hydrochloric salt new 4-oxocyclohexa compounds of urea obtained in examples A-F, can be converted to their free base by the method described in example G.

Example 1

Synthesis of salt accession di-2-Z-butandione acid to 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-[4-methyl-1 - piperazinil)butyl]-2,4-imidazolidinedione.

< / BR>
Salt accession di-2-Z-butandione acid to 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-(4-(4-methyl-1 - piperazinil)butyl]-2,4-imidazolidine receive as described below.

Free base [[[5-(4-chlorophenyl)-2-furanyl]methylene]amino] -3-(4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidine (obtained as described in example G), (4.4 g, 0,0096 mole) is dissolved in methylene alcohol (125 ml), treated with activated charcoal and filtered. To this solution add Noi temperature for about 2 h, then cooled and air-dried. This solid is recrystallized from absolute ethyl alcohol OH Et/H20 (activated charcoal), filtered and then cooled. The solid is collected, washed with anhydrous simple ether, air-dried and 70oC, and get 4,99 g (0,0072 mole) salt 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino] -3-(4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidine and di-2-Z-butandione acid.

Example J

Any hydrochloric salt of 4-oxocyclohexa compounds of urea synthesized in examples A-F and converted into the free base as described in example H, can be converted into their salt di-2-Z-butandione acid according to the method described in example 1.

Example TO

Synthesis 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3- [3-[4-(2-hydroxyethyl)-1-piperazinil]propyl]2,4-imidazolidinedione

< / BR>
1-[[[5-(4-Chlorophenyl)-2-furanyl] methylene] amino] -3- [3-[4-(2-hydroxyethyl)-1-piperazinil] propyl] 2,4-imidazolidinedione receive and synthesize as described below.

The dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3- [3-[4-(2-hydroxyethyl)-1-piperazinil]propyl]2,4-imidazolidinedione, obtained as described in example E, dissolved in water (300 ml), polivaut water, get to 5.21 g 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3- [3-[4-(2-hydroxyethyl)-1-piperazinil]propyl]2,4-imidazolidinedione, the form of the free base to the hydrochloride 4-oxocyclohexa compounds of urea synthesized in example E.

Example L

Any compound synthesized in examples A-F, can be converted into a free base by the method described in example K.

Example M

Preparation of tablets oral assignments from dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1 - piperazinil)butyl] 2,4-imidazolidinedione

Tablet containing connection - dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[4-(4-methyl-1 - piperazinil)butyl]-2,4-imidazolidinedione is obtained as described in example A, has the following structure.

The active ingredient

The dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]- 3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione - 350 mg

Fillers

Lactose - 192 mg

Matrikamantra 50 mg

Pre gelatinizing starch 30 mg

Talc - 12 mg

Magnesium stearate 6 mg

Ten thousand tablets of the above composition is prepared as the description of the Nile)-2-furanyl]methylene]amino]- 3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione, 1,92 kg of lactose, 0.50 kg of nachrichtentechnische and 0.30 kg pre gelatinizing starch and then granularit with water, using stimulating knife.

Granular material is then dried on trays in the oven or in a fluidized bed dryer.

Granular material is milled and passed through a sieve 12 mesh (1,68 mm), which use a vibrator or other suitable mill.

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

A mixture consisting of talc, magnesium stearate and granular material, pressed into tablets weighing 640 mg on a suitable tablet press machine.

Tablets prepared as described above, gives the patient suffering from cardiac arrhythmia and/or cardiac fibrillation in a dosage that is acceptable for this particular patient.

Example N

Preparation of tablets oral assignments from dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-[4-(2- hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione.

Oral tablet containing dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-[4-(2- hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazole

The dihydrochloride 1-[[[5-(4-Chlorophenyl)-2-furanyl] methylene]amino]- 3-[3-[4-(2-hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione 300 mg

Fillers

Dibasic calcium phosphate 219 mg

Crosspovidone 60 mg

Povidone - 12 mg

Talc - 6 mg

Magnesium stearate 3 mg

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

In the homogenizer Patterson-Kelly (Patterson-Kelly) mix 3.0 kg dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]- 3-[3-[4-(2-hydroxyethyl)-1-piperazinil] propyl] -2,4-imidazolidinedione, 2,19 kg dibasic calcium phosphate, 0.60 kg of crosspovidone and 0.12 kg of povidone, and then granularit with water, using stimulating knife.

The granulated material is dried on trays in the oven or in a fluidized bed dryer. The granulated material is then ground and passed through a sieve 12 mesh (1,68 mm), which use a vibrator or other suitable mill.

Granular material is mixed with 60 g of talc and 30 g of magnesium stearate. And, finally, a mixture consisting of granular material, talc and magnesium stearate, and compressed into tablets weighing 600 mg on a suitable tablet press machine.

The patient suffering from the improper dosage regimen, acceptable for this particular patient.

Example O

Cooking capsules oral assignments from dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione

Oral capsule containing the dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1 - piperazinil)butyl]-2,4-imidazolidinedione, obtained as described in example A, has the following structure.

The active ingredient

The dihydrochloride 1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]- 3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione 300 mg

Fillers

Lactose - 92 mg

Matrikamantra 40 mg

Pre gelatinizing starch 25 mg

Talc - 12 mg

Magnesium stearate 3 mg

Hard gelatin capsule shell - 1 capsule

Ten thousand capsules of the above composition is prepared as described below.

In the homogenizer Patterson-Kelly (Patterson-Kelly) mixed 3.00 kg dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]- 3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione, 0,92 kg of lactose, 0,40 kg of nachrichtentechnische and 0.25 kg pre gelatinizing starches, and granulates or in a fluidized bed dryer.

Granular material is milled and passed through a sieve 12 mesh (1,68 mm), which use a vibrator or other suitable mill. Granular material is mixed with 120 g of talc and 30 g of magnesium stearate.

And, finally, a mixture consisting of granular material, talc and magnesium stearate and taken in quantities of 472 mg, fill each capsule shell on a suitable machine designed for filling capsules.

The capsule prepared as described above was given to the patient suffering from cardiac arrhythmia and (simultaneously or separately) heart fibrillation that was done in the proper dosage.

Example P

Preparation of tablets oral assignments from dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[3-[4-(2- hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione

Oral capsule containing the dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[3-[4-(2- hydroxymethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione, obtained as described in example E, has the following structure.

The active ingredient

The dihydrochloride 1-[[[5-(4-Chlorophenyl)-2-furanyl] methylene]amino]- 3-[3-[4-(2-hydroxyethyl)-1-piperazinil]p is vidon - 25 mg

Povidone - 5 mg

Talc 5 mg

Magnesium stearate 2 mg

Hard gelatin capsule shell - 1 capsule

Ten thousand capsules of the above composition is prepared as described below.

In the homogenizer Patterson-Kelly (Patterson-Kelly) or in another suitable homogenizer mix of 1.75 kg dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[3-[4-(2- hydroxymethyl)-1-piperazinil] propyl] -2,4-imidazolidinedione, 1,20 kg microcrystalline cellulose, 0.25 kg of crosspovidone and 0.05 kg of povidone, and then granularit with water, using stimulating knife.

The granulated material is dried on trays in the oven or in a fluidized bed dryer. Granular material is milled and passed through a sieve 12 mesh (1,68 mm), which use a vibrator or other suitable mill. Granular material is mixed with 50 g of talc and 20 g of magnesium stearate.

A mixture consisting of granular material, talc and magnesium stearate in the amount of 322 mg injected into each capsule shell, which is used capsulation machine.

Capsules, obtained as described above, give patients suffering from cardiac arrhythmia and/or cardiac fibrils is aktsionnogo comprising dihydrochloride 1-[[[5-(4-chlorophenyl-2-furanyl] -methylene] amino] -3-[4-(4-meteo-1 - piperazinil)butenyl]-2,4-imidazolidinedione

Solution suitable for use as intravenous injection compound has the following structure.

The active ingredient

The dihydrochloride 1-[[[5-(4-chlorophenyl-2-furanyl] -methylene] amino]-3-[4-(4-meteo-1 - piperazinil)butenyl]-2,4-imidazolidine - 400 mg

Fillers

Mannitol 500 mg

Citric acid/sodium citrate in an amount sufficient to establish a pH in the region of 5.5 to 6.5

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

In 10 l of sterile water intended for injection, dissolve 400 g of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione, 500 g of mannitol and the amount of citrate and/or citric acid, which is sufficient to maintain the pH in the region of 5.5 to 6.5.

The resulting solution is aseptically filtering through a 0.2 μm filter and injected into ampoules of 10 ml per ampoule.

Capsules are loaded into lyophilizator, hamper, dry and closed. Liofilizovannye product is diluted with 10 ml of sterile water immediately before injection.

The patient, Strada the ora in the proper dosage.

Example R

Any active ingredient in the form of 4-oxocyclohexa connection urea obtained in any of examples A-L, can be used as the active ingredient in the preparation of various dosage forms in the examples U-Q.

Example S

White male 57 years old was discovered at home without consciousness and without a palpable pulse. Member families organized restore cardiac activity and respiration. The first beating, documented by ambulance, was a ventricular fibrillation. Patient was successfully resuscitated.

Patient three years ago, the transfer of myocardial infarction and since then constantly suffers from angina.

Upon admission revealed that the patient does not have myocardial infarction. Monomorphic persistent ventricular tachyarrhythmia was initiated by programmed electrical stimulation.

The patient's cardiologist has prescribed him dihydrochloride 1-[[[5-(4-chloro-phenyl)-2-furanyl] methylene] amino-3-[4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione in a dose of 350 mg twice a day after meals. After treatment for four days arrhythmia is not stimulated when conducting a follow up survey with programmable electrical stimulus is exceeding two years, and the treatment will last.

Example T

Black man 65 years experienced fainting, which was preceded by a sensation of rapid heart rate. For the past several months, the patient experienced frequent increased heart rate, once with presyncope. In his medical history was recorded hypertension cardiovascular origin, diabetes, old myocardial infarction and obesity.

Stable monomorphic ventricular tachycardia induce programmed electrical stimulation. The patient's cardiologist has prescribed him dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino-3-[4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione during oral dose of 350 mg once daily after a meal. After several days of treatment fibrillation is not induced re-programmed electrical stimulation. Over the next three years of follow-up had no similar episodes of syncope or presyncope state.

Example U

58 year old woman, a resident of East, diabetic cardiomyopathy, have experienced repeated fainting. The ejection fraction was 65%. Programmed electrical stimulation induced the appearance of p. the definition of drugs. The fourth drug, moricizine, reduced speed tachyarrhythmias, and its reception continued: but tachyarrhythmia initiated yet and hypotension. She was implanted automatic implantable cardioverter-defibrillator ((AICD).

The defibrillator is discharged twice a year after implantation of the automatic implantable cardioverter-defibrillator. Monitor registers persistent the ventricular tachyarrhythmia in moments of defibrillation. After the second discharge, the patient was hospitalized. Stable monomorphic ventricular tachyarrhythmia were induced programmed electrical stimulation. Cardiologist patient interrupted the purpose moricizine and prescribed dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-(4-methyl-1 - piperazinil)butyl] -2,4-imidazolidinedione during oral dose of 350 mg twice a day after meals. When you re-induction of programmed electrical stimulation after a few days arrhythmia was not shown and defibrillation threshold was left unchanged. Further one-year observation it was determined that future discharges not perceived.

Example V

Female 35 years experiences for over 15 years who I dizziness and fatigue. These attacks do not allow her to work. The current through the telephone network status monitor showed the presence of paroxysmal supraventricular tachycardia. The doctor the patient has prescribed her dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] -mutilin] amino]-3- [4-(2-hydroxyethyl)-1-piperazinil] propyl]-2,4-imidazolidinedione orally at a dose of 175 mg per day. Subsequent annual monitoring it was found that the frequency of these attacks has fallen to one month if there is a noticeable improvement in her card registration requests for medical aid at work.

Example W

The man is 75 years old, dark-skinned, who for 50 years has smoked a pack a day, suffered defined attacks predserdnuu fibrillation, documented monitoring via the telephone to sit down, with a repetition frequency of three times per month in terms of treatment with digoxin and quinidine. These attacks sometimes lasted for eight hours and prevented the patient to engage in normal daily activities such as work in the garden, because of the weakness. Doctor patient was switched it with quinidine on dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] -mutilin] amino] -3- [4-(2-hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione during oral dose of 175 mg month.

Example X

Male 40 years old, dark-skinned, for several years suffered from frequent bouts of palpitations. Patient experienced anxiety and shortness of breath during rapid heartbeat and was constantly fear death. Extensive surveys have pointed to the absence of organic heart disease. Monitoring Holter (Holter) was found to 2500 ventricular extrasystoles per day, univocally forms, with 50 pairs a day. Neither beliefs nor the subsequent therapy with the use of propranolol has not been effective.

The doctor prescribed dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[4-(4-methyl-1 - piperazinil)butyl]-2,4-imidazolidinedione during oral dose of 350 mg per day after meals.

The frequency of occurrence of acadeny decreased and weakened related anxiety and shortness of breath. Monitoring Holter now, it was determined that 250 ventricular extrasystole per day and found no re-forms. After a few months began to disappear thoughts about death. The patient was under constant surveillance and continued to feel satisfactorily over the next five years.

Example V

Carowner cholesterol, exceeding 300 mg/DL, transfer myocardial infarction. Two weeks after the heart attack he had no symptoms, except that he felt short of breath during physical activity. The share of emissions from him was 29%, and when carrying out within 24 h Holter monitoring (Holter), it was determined that 50 univocally ventricular extrasystoles per hour, sometimes paired form, and one series of five beats of ventricular tachyarrhythmias.

His cardiologist has prescribed him dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] -amino] -3-[4-(4-methyl-1 - piperazinil)butyl]-2,4-imidazolidinedione during oral dose of 350 mg per day after meals. Re Holter's monitoring shows the absence of all re-forms and the presence of an average of 9 ventricular extrasystoles per hour. The patient felt satisfactorily over the next three years.

Example Z

Any patient described in the examples of S-V, may be subjected to any treatment dosage forms, synthesized in examples M-Q, using any of the ingredients described above in examples A-L.

1. 4-Oxocyclohexa connection urea of General formula

< / BR>
in which X represents an unsaturated 6-membered carbocycle;

erotic or 6-membered carbocycle, preferably a heterocycle, or is absent;

when R is absent, X and Y are condensed ring systems; when R is a covalent bond, X and Y represent a ring system, connected through a covalent bond; Y is absent, R is a covalent bond and X is connected to L through R;

R1, R2and R3, independently, selected from the group consisting of chlorine, fluorine, bromine, OH, alkyl; or R1, R2and

R3no;

L represents alkylamino, in which the nitrogen atom of the group linked to the nitrogen atom in 1,4 oxocyclohexa ring component urea;

R4is alkylene;

A represents an alkyl or hydroxyalkyl, substituted or unsubstituted saturated 6-membered heterocycle or heteroalkyl, most preferably a heterocycle containing two nitrogen atom;

R5represents-CH2,

or its pharmaceutically acceptable salts or esters.

2. Connection on p. 1, wherein R is a covalent bond and binds X in position 1 with Y in position 5.

3. The compound according to any one of paragraphs.1 and 2, in which Y before the carbon-based end L.

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

5. The compound according to any one of paragraphs.1 to 4, in which one of R1, R2or R3represents chlorine, fluorine or bromine, and two of R1, R2or R3no.

6. The compound according to any one of paragraphs.1 and 5, selected from the group including

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

1-[[[4-hydroxy-3, 5dimethylphenyl] methylene] amino] -3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[3-[4-(1-methylethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[3-[4-(2-hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[6-(4-methyl-1-piperazinil)hexyl]-2,4-imidazolidinedione;

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

1-[[[5-(4-forfinal)-2-furanyl] -methylene] amino] -3-[4-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[4-[4-(2-hydroxyethyl)-1-piperidinyl the]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-[3-[4-(2-mercaptoethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione;

1-[[[5-(4-bromophenyl)-2-oxazolidinyl] methylene] amino] -3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[3-(dimethylaminopropyl)dihydro]-2,4-(1H, 3H)pyrimidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino] -3-(3-dimethylaminopropyl)-2,4-imidazolidinedione;

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

1-[[[5-(4-forfinal)-2-furanyl] methylene] amino] -3-[3-[4-(2-hydroxyethyl)-1-piperazinil]propyl]-2,4-imidazolidinedione;

1-[[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-3-[8-(4-morpholinyl)octyl] -2,4-imidazolidinedione;

and their pharmaceutically acceptable hydrochloride and maleate.

7. The compound according to any one of paragraphs.1 to 6, in which the nitrogen atom A is not associated with the R4is substituted, and the substituents are selected from the group consisting of methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol and methanesulfonyl groups.

8. Pharmaceutical composition for the treatment of arrhythmia and fibrillation, characterized in that it includes safe and effective on whitesky acceptable excipients, selected from the group comprising up to 2% of corrigentov, up to 50% co-solvents, up to 5% of a buffer system, up to 2% surfactant, up to 2% preservatives, up to 5% sweeteners, up to 5% thickening substances, up to 75% filler, 0.5 to 2% of a lubricating agent, 1 to 5% facilitate sliding of substances, 4 - 15% baking powder and 1 to 10% binding substances.

9. The pharmaceutical composition under item 8, wherein the pharmaceutically acceptable excipients are selected from the group consisting of polymers, resins, plasticizers, fillers, binding agents, lubricants, easy slip agents, leavening agents, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, corrigentov, pharmaceutical dyes or pigments and substances substances.

10. The method of treatment of a human or other mammal suffering from cardiac arrhythmia and/or cardiac fibrillation, characterized in that it includes the introduction of the aforementioned person or mammal a safe and effective amount of a compound or pharmaceutical composition according to any one of paragraphs.1 - 8.

 

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The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

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< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

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or their pharmaceutically acceptable salts

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FIELD: medicine, oncology.

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EFFECT: higher efficiency of therapy.

1 ex

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