JP3347691B2 - Novel 4-oxocyclic ureas useful as antiarrhythmic and antifibrillation agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 4-oxocyclic urea compound useful for treating a human or other mammal having cardiac arrhythmia and / or cardiac fibrillation, and a pharmaceutical composition thereof.

[0002]

The novel 4-oxocyclic urea compounds of the present invention are active as anti-fibrillation and anti-arrhythmic agents. The compounds exhibit broad efficacy against cardiac arrhythmias and fibrillation and are satisfactorily applicable in substantially reducing and / or preventing arrhythmias and fibrillation. In addition, the compounds reduce the incidence of some of the undesirable side effects than with many conventional antiarrhythmic therapies. Another advantage of the compounds described herein is that they exhibit both anti-fibrillation and anti-arrhythmia activity; most conventional therapies do not usually show efficacy as anti-fibrillation agents. For example, Coplen, SE et al., 'Effica
cy and Safety of Quinodine Therapy for Maintenance
of Sinus Rhythm after Cardioversion: A meta-anal
ysis' (Efficacy, safety and post-analysis of quinidine therapy for maintenance of sinus rhythm after cardioversion), Circulatio
n, Vol. 82, pp. 1106-1116 (1990); Echt, DS et al., '
Mortality and Morbidity in Patients Receiving Ecai
nide, Flecainide or Placebo; The Cardiac Arrhythm
ia Suppression Trial '(mortality and morbidity in patients receiving ecainide, flecainide or placebo:
Cardiac arrhythmia suppression test), New England Journal of Medic
ine, Vol. 324, pp. 781-788 (1991); both are incorporated herein by reference.

[0003] In a healthy, structurally normal heart, the precise sequential electrical activation and subsequent inactivation of the entire myocardium that occurs precisely with each beat is characterized as a normal cardiac rhythm. Arrhythmias are characterized as the appearance of abnormal electrical activity that interferes with normal cardiac rhythm. Abnormal electrical activity can prevent the onset and / or uniform spread of electrical waves that trigger cardiac contraction (i.e., myocardial depolarization and subsequent repolarization). Disruption of the smooth periodic process of cardiac function associated with normal cardiac rhythm due to the presence of arrhythmias is in some cases life threatening.

[0004] Arrhythmias ranging from relatively benign (comprising asymptomatic rare premature ventricular waveforms [PVC]) to life threatening (comprising ventricular fibrillation and slow ventricular tachyarrhythmia) can be severe. It varies in degrees. For a good overview of arrhythmias and an overview of antiarrhythmic therapies, see, for example, Bigger, Thomas J.,
AnAntiarrhythmic Treatment: An Overview ′, American Journal of Cardiology,
Vol. 53, pp. 8B-16B, February 27, 1984; Goldstein,
S., ′ Toward a New Understanding of the Mechanism a
nd Prevention of Sudden Death in Coronary Heart D
isease '(towards a new understanding of the mechanism and prevention of sudden death in coronary heart disease), Circulation, Vol. 87
(1), pp. 284-88 (1990); Woolsey, RL, 'Antiarrh
ythmicDtugs ′ (antiarrhythmic drug), Annual Review Pharma
cology and Toxicology, Vol. 31: pp. 427-455 (1991)
See; all are incorporated herein by reference.

[0005] Life threatening arrhythmias are noted as the leading cause of death worldwide. For example, sudden cardiac death due to ventricular fibrillation is about 400,000-yearly in the United States.
It is estimated that 600,000 people have been killed. US
Department of Health and Human Services (1985) NCHS
See Monthly Vital Statistics Report, 33: 8-9.

[0006] Arrhythmias are usually classified into two types: 1).
Supraventricular arrhythmias (eg, atrial fibrillation and flutter) and 2) Ventricular arrhythmias (eg, ventricular tachyarrhythmia and ventricular fibrillation and flutter).

[0007] Supraventricular arrhythmias are usually not life threatening. Individuals with these arrhythmias experience a range of symptoms ranging in intensity from mild to severe. These individuals experience a feeling of loss of heartbeat, excessive heartbeat and / or flutter, sometimes with slight headache or dizziness, shortness of breath and / or
Or they may have chest pain. Because this situation is generally not life threatening in nature, more aggressive remedies, such as conventional antiarrhythmic drugs, are sometimes not prescribed because the side effects that are usually associated with them are unacceptable for non-life threatening conditions. Would. However, the novel compounds of the present invention are usually much better tolerated than many of the conventional commercial antiarrhythmic agents; therefore, they are an acceptable therapy for individuals with supraventricular arrhythmias, Substantially reduce individual experience.

On the other hand, ventricular arrhythmias are potentially considerably more severe and are categorized as 3 groups: 1) benign; 2) prognostically significant (potentially fatal); 3) life threatening (lethal). Was done. For example, Morganrot incorporated here for reference
h, J. and Bigger, JT, 'Pharmacological Managem
ent of Ventricular Arrhythmias after the Cardiac A
rrhythmia Suppression Trial '(pharmacological management of ventricular arrhythmia after cardiac arrhythmia suppression test), American Journal
al. Cardiology, Vol. 65. pp. 1497-1503, 1990 (hereinafter Morganroth & Bigger).

[0009] Individuals with benign arrhythmias have a very low risk of death, cardiac scarring and heart disease. Benign ventricular arrhythmias are relatively common, accounting for about 30% of all ventricular arrhythmias. Benign arrhythmias such as premature ventricular waveform (PVC) present only minimal risk to the individual and rarely require antiarrhythmic therapy. However, PVC is associated with frequent or complex or sufficiently alarming symptoms, so that individuals who have experienced them cannot be reassured that the arrhythmia and symptoms are not dangerous. They also do not respond to the most conventional treatments (eg, β-blockers). In these cases, treatment with the novel compounds of the invention appears to be beneficial to these individuals.

[0010] Prognostically significant arrhythmias are usually associated with some other additional clinical manifestations of heart disease such as mild heart failure, ischemic symptoms and / or cardiac scarring. About 6 of total ventricular arrhythmias
5% have been said to be prognostically significant. For example, Mo
See rganroth & Bigger, page 1497.

Patients with life-threatening arrhythmias develop syncope (sudden loss of consciousness-usually stunning-with insufficient cerebral perfusion), cardiac arrest, heart failure and / or myocardial ischemia in the presence of structural heart disease There is. Life threatening arrhythmias are relatively rare; perhaps less than 10% of individuals with arrhythmias take a life threatening form. See Morganroth & Bigger, page 1497. However, due to the life-threatening nature of fatal ventricular arrhythmias and the severity of the symptoms associated therewith, they must be treated aggressively.

The novel compounds of the present invention are effective against cardiac fibrillation and supraventricular and ventricular arrhythmias. In addition, the novel compounds of the present invention usually show less of some of the undesirable effects that have been tolerated by many of the traditional antiarrhythmic drugs due to the lack of acceptable alternative therapies. For example, many current therapies cause pulmonary toxicity, cardiac depression and non-specific neurological effects on cardiac tissue. For a good description of the side effects associated with traditional antiarrhythmic therapy, see Bigger, JT and Hoffman,
BF, 'Antiarrhythmic Drugs' (Go)
odman and Gilman's The Basis of Pharmacological Th
erapeutics, 8th edition, ed. AG Gilman, pp.840-
873, New York; Pergamon and Woolsey, R, L., 'Antiar
rhythmic Agents ′ (antiarrhythmic agent), The Heart, ed.
JW Hurst, pp.1682-1711, New York, McGraw-Hill
(1990); both are hereby incorporated by reference.

[0013] In addition, the novel compounds of the present invention are readily bioavailable. This facilitates treatment by oral administration, and therefore, greatly facilitates patient compliance. In addition, the novel compounds of the present invention are relatively inexpensive to produce and they exhibit a high degree of stability in oral dosage forms.

[0014]

As mentioned above, the present invention provides novel compounds that are potent against cardiac fibrillation and supraventricular and ventricular arrhythmias, and that do not usually show some of the undesirable effects. The purpose is to do. It is a further object of the present invention to provide novel compounds in which such compounds are readily bioavailable and can facilitate treatment.

[0015]

DISCLOSURE OF THE INVENTION The novel 4-oxocyclic ureas, pharmaceutically acceptable salts or biohydrolysable esters thereof of the present invention are useful as antiarrhythmic and antifibrillant agents. Has the general structure:

[0016]

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Wherein (a) X is a saturated or unsaturated 5, 6 or 7 membered heterocycle or carbocycle; (b) R is a covalent bond, no bond, a heteroatom, carbonyl, a heterocyclic ring, Selected from the group consisting of carbocyclic rings, alkyl, alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy and acylamino; (c) Y is substituted or unsubstituted, saturated or unsaturated 5, 6 Or 7
A membered heterocyclic ring or carbocyclic ring or none; when R is absent, X and Y are fused ring systems; when R is a covalent bond, X and Y are shared A ring system connected by a bond; when Y is absent, R is a covalent bond and X is connected to L at R; (d) R ₁ , R ₂ and R ₃ are each independently Te, Cl, F, B
r, NH ₂ , CF ₃ , OH, SO ₃ H, CH ₃ , SO ₂ N
H, COOH, NO ₂ , alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acylalumino and acyloxy; (e) L is alkylamino, alkenylamino, alkylimino, alkenyl It is selected from the group consisting of imino and acylamino; wherein the nitrogen atom is bonded to the nitrogen atom at 1-position of the 4-oxo cyclic urea moiety in the above; (f) R ₄ is alkyl, alkenyl, alkynyl, alkyl acyl And (g) A is substituted or unsubstituted, saturated or unsaturated, linear or branched C ₁ -C ₈ heteroalkyl or substituted or unsubstituted having 5, 6 or 7 members. substituted, it is a saturated or unsaturated heterocyclic ring; a is having a single nitrogen atom adjacent to R ₄ ; And (h) R ₅ is substituted or unsubstituted C ₁ or C ₂ alkyl.

However, when X is an aromatic ring, R is a covalent bond, and Y is a substituted or unsubstituted unsaturated 5, 6, or 7-membered heterocycle, L is alkylamino, alkenylamino. And A is a substituted or unsubstituted unsaturated heterocycle having 5, 6, or 7 members, or substituted or unsubstituted, saturated or unsaturated, linear or branched. Chain C ₁ -C ₈ heteroalkyl.

Ring system (XRY) The novel 4-oxocyclic urea compounds of the present invention comprise a 4-oxocyclic urea moiety joined to the ring system (XRY) at the linking moiety (L). Consists of 4-oxocyclic ureas are 3
Group having a nitrogen atom at the position (R ₄ )
At the 3-position of the 4-oxocyclic urea moiety with an amino-containing moiety (A) consisting of an amino group separated from the nitrogen. The moiety represented by (X—R—Y) is a ring system moiety, and is one or more, preferably one or more, as defined herein.
Or consists of two fused or unfused, saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic rings. Each carbocyclic or heterocyclic ring contains 5, 6 or 7, preferably 5 or 6 members.

The ring system (XRY) is polycyclic and has 2
Preferably, the ring represented by Y adjacent to the connecting portion L is a heterocyclic ring, more preferably a 5-membered ring containing an oxygen heteroatom at the 1-position. preferable. In addition, when there are two rings in the ring system, the heterocycle (Y) is at the 5-position of the heterocycle Y and at the 1
It is also preferred that the heterocycle Y is covalently bonded to the other ring (X) at the position and the heterocycle Y is bonded to the L moiety at the 2-position of Y.

Although not preferred, the ring system (XR-
Y) can also consist of two rings (X and Y) separated by an alkyl, carbonyl or heteroatom, most preferably oxygen (R). In addition, the ring system may be monocyclic; in this case, Y is absent;
R is a covalent bond bonded to L. However, when only one ring is present in the system, the ring is not particularly limited but preferably is at least 2 selected from the group consisting of hydroxy, methyl, Cl, methoxy and benzoyl.
One, most preferably substituted with at least three substituents.

When substituted, any or all of the members of the ring system (whether monocyclic or polycyclic) may have one or more substituents, such as Cl, F, Br,
NH ₂ , CF ₃ , OH, SO ₃ H, CH ₃ SO ₂ NH, CO
Substituted with OH, NO ₂ , alkoxy, alkyl, alkoxycarbonyl, carboxyalkyl, aminoalkyl, acylamino or acyloxy.

Linking moiety (L) L is the linking moiety of the novel 4-oxocyclic urea compounds of the present invention. The carbon-containing terminus of L is Y, but is X when Y is absent, most preferably attached to the ring system at the 2-position of the Y ring or at the 1-position of X when Y is absent. I have. The nitrogen atom of the L moiety is attached to the nitrogen atom at position 1 of the 4-oxocyclic urea moiety. The L moiety is not particularly limited but is selected from the group consisting of alkylamino, alkenylamino, alkylimino, alkenylimino and acylamino; L is preferably alkylimino, most preferably C
₁ alkylimino CH = N.

4-oxocyclic urea moiety The 4-oxocyclic urea moiety of the novel compounds of the present invention gives the novel compounds of the present invention their characteristic name. 4
The -oxocyclic urea moiety is a 5- or 6-membered ring, preferably a 5-membered ring. The 4-oxo cyclic urea moiety is joined to the nitrogen atom of the linking moiety (L) at the nitrogen atom at position 1 of the 4-oxo cyclic urea moiety. The 4-oxocyclic urea moiety has the following structure:

[0025]

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In the above formula, R ₅ is C ₁ or C ₂ alkyl, preferably C ₁ alkyl. A is a heteroalkyl or heterocyclic ring, which must always contain at least one nitrogen atom attached to R ₄ . When A is heteroalkyl, A is straight or branched, saturated or unsaturated, substituted or unsubstituted. When A is a heterocycle,
A is a 5, 6 or 7 membered heterocyclic ring. The rings are substituted or unsubstituted, preferably substituted, and are saturated or unsaturated, preferably saturated. R ₄ is bonded to the nitrogen atom of the nitrogen atom and A at the 3-position of 4-oxo cyclic urea moiety. R ₄ is not particularly limited, and includes alkyl, alkenyl,
It is selected from the group consisting of alkynyl, alkylacyl and heteroalkyl.

When A is a substituted heteroalkyl, the substituent is not particularly limited and is selected from the group consisting of methyl, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethyl and methanesulfonyl.

Heterocycle A has two heteroatoms,
When both are nitrogen, the nitrogen atom not adjacent to R ₄ is not particularly limited and is a substituent selected from the group consisting of methyl, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethyl and methanesulfonyl. It is preferably substituted. Heterocycle A
If There has only one nitrogen atom, the heterocyclic ring is hydroxyethyl without being particularly limited, hydroxy, with a substituent selected from the group consisting of oxo and methyl (in R ₄ if the heterocycle has 6-membered It is preferably substituted (in the para position relative to the bonded nitrogen).

[0029]

DETAILED DESCRIPTION OF THE INVENTION Definitions and Usage of Terms The following is a list of definitions for terms used herein.

"Hetero atoms" are nitrogen, sulfur or oxygen atoms. Groups containing one or more heteroatoms may contain different heteroatoms.

"Alkyl" is an unsubstituted or substituted, straight or branched, saturated hydrocarbon chain having from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms unless otherwise specified. Preferred alkyl groups are not particularly limited and include methyl, ethyl, propyl, isopropyl and butyl.

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

"Alkenyl" refers to unsubstituted or substituted, straight or branched carbon atoms having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one olefinic double bond. It is a hydrogen chain.

"Alkynyl" is an unsubstituted or substituted, straight or branched hydrocarbon chain having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one triple bond. .

As used herein, "ring system" refers to a ring-containing moiety in which a 4-oxocyclic urea moiety is joined at a linking moiety L. It is designated herein as "XRY" and may be a monocyclic moiety or a fused, bridged or spiro-polycyclic moiety and may include carbocycles, heterocycles or both. A monocycle usually contains 3 to 8 atoms, preferably 5 to 7 atoms. Polycyclic systems consisting of two rings usually contain 6 to 16, preferably 10 to 12, atoms. Polycyclic systems consisting of three rings usually contain 13 to 17 atoms, preferably 14 to 15 atoms.

As used herein, the term "carbocyclic ring" or "carbocycle" generally refers to an unsubstituted or substituted, saturated, unsaturated or aromatic carbon atom containing 3 to 8 atoms, preferably 5 to 7 atoms. It is a hydrogen ring.

As used herein, the term "heterocyclic ring" or "heterocycle" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring composed of carbon atoms and one or more heteroatoms in the ring. . Heterocyclic rings usually contain 3 to 8, preferably 5 to 7 atoms. Unless stated otherwise, each heteroatom may be independently selected from nitrogen, sulfur and oxygen.

"Aryl" is an aromatic carbocyclic ring. Preferred aryl groups are not particularly limited and include phenyl, tolyl, xylyl, cumenyl and naphthyl.

"Heteroaryl" is an aromatic heterocyclic ring. Preferred heteroaryl groups are not particularly limited and include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl and tetrazolyl.

"Alkoxy" is an oxygen atom having a hydrocarbon chain substituent wherein the hydrocarbon chain is alkyl or alkenyl (eg, -O-alkyl or -O-alkenyl). Preferred alkoxy groups are not particularly limited,
There are methoxy, ethoxy, propoxy and alkyloxy.

"Hydroxyalkyl" is a substituted hydrocarbon chain having a hydroxy substituent (eg, -OH), which may have other substituents. Preferred hydroxyalkyl groups are not particularly limited, and include hydroxyethyl, hydroxypropyl, and phenylhydroxyalkyl.

"Carboxyalkyl" refers to a substituted hydrocarbon chain having a carboxy substituent (eg, -COOH) and may have other substituents. Preferred carboxyalkyl groups include carboxymethyl, carboxyethyl and their acids and esters.

"Aminoalkyl" is a hydrocarbon chain (eg, alkyl) (eg, NH-alkyl-) substituted with an amine moiety such as dimethylaminoalkyl.

"Alkylamino" is an amino moiety having one or two alkyl substituents (eg, -N-alkyl).

"Alkenylamino" is an amino moiety having one or two alkenyl substituents (eg, -N-alkenyl).

"Alkynylamino" is an amino moiety having one or two alkynyl substituents (eg, -N-alkynyl).

"Alkylimino" is an imino moiety having one or two alkyl substituents (eg, -N-alkyl-).

"Arylalkyl" is an alkyl moiety substituted with an aryl group. Preferred arylalkyl groups include benzyl and phenylethyl.

“Arylamino” is an amino moiety substituted with an aryl group (eg, —NH-aryl).

“Aryloxy” is an oxygen atom having an aryl substituent (eg, —O-aryl).

"Acyl" or "carbonyl" is a moiety formed by the removal of hydroxy from a carboxylic acid (eg, RC (= O)-). Preferred alkylacyl groups are not particularly limited, and include acetyl, propionyl and butanoyl.

“Acyloxy” refers to an oxygen atom having an acyl substituent (eg, —O-acyl), such as —O—C
(＝ O) -alkyl.

"Acylamino" refers to an amino moiety having an acyl substituent (eg, -N-acyl) such as -NH
—C (＝ O) -alkyl.

"Halo", "halogen" or "halide"
Is a chloro, bromo, fluoro or iodo atom.
Chloro, bromo and fluoro are preferred halides.

Further, as mentioned herein, "lower"
A hydrocarbon moiety (eg, a "lower" alkyl) is a hydrocarbon chain composed of 1 to 6, preferably 1 to 4, carbon atoms, unless otherwise stated.

A “pharmaceutically acceptable” salt is a cationic salt formed with any acidic (eg, carboxyl) group or an anionic salt formed with any basic (eg, amino) group. Many such salts are known in the art as described in International Patent Publication No. 87/05297 to Johnston et al., Published September 11, 1987, which is incorporated herein by reference. Be incorporated. Preferred cationic salts include alkali metal salts (such as sodium and potassium) and alkaline earth metal salts (such as magnesium and calcium). Preferred anionic salts include halide salts (such as chloride).

"Biohydrolysable esters" are 4-oxocyclic that do not interfere with the antiarrhythmic activity of the compound or that are readily metabolized by humans or other mammals to produce the antiarrhythmic active 4-oxocyclic urea. It is an ester of a urea compound. Many such esters are described in Johnston et al., International Patent Publication No. 87/05, published September 11, 1987.
It is known in the art as described in US Pat. No. 297, which is incorporated herein by reference. Such esters include lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), (phthalidyl and thiophthalidyl esters) Lactonyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), lower alkoxyacyloxyalkyl esters, alkoxyalkyl esters, choline esters and (such as acetamidomethyl esters) There are acylaminoalkyl esters.

The substituents themselves may be substituted, as defined above and as used herein. Such substitutions may be one or more substituents. Such substituents are not particularly limited and are incorporated herein by reference. C. Hansch and A. Leo, Substituent Constan
ts for Correlation Analysis in Chemistry and Biolo
gy (Substituent constants for correlation analysis in chemistry and organisms) (1979). Preferred substituents are not particularly limited, and include alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (eg, aminomethyl), cyano, halo, carboxy, alkoxyacetyl (eg, carbethoxy), thiol, aryl , Cycloalkyl, heteroaryl, heterocycloalkyl (eg, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, etc.),
There are imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention is certain novel 4-oxocyclic ureas, a process for their preparation, and pharmaceutical compositions thereof. The novel compounds and compositions thereof can be used to treat cardiac arrhythmias and / or fibrillation in humans or other mammals. Therefore, the specific compounds and compositions used in the present invention must be pharmaceutically acceptable. As used herein, such "pharmaceutically acceptable" ingredients are balanced in humans and / or without undue adverse side effects (such as toxicity, irritation and allergic reactions) at a reasonable benefit / risk ratio. It is suitable for use in other mammals.

Novel 4-Oxocyclic Urea Compounds The compounds of the present invention referred to herein as "4-oxocyclic ureas" are various 4-oxocyclic urea compounds having the general structure: Or a biohydrolysable ester:

[0061]

Embedded image

Wherein (a) X is a saturated or unsaturated 5-, 6- or 7-membered heterocycle or carbocycle; (b) R is a covalent bond, no bond, a heteroatom, carboxyl, a heterocyclic ring, Selected from the group consisting of carbocyclic rings, alkyl, alkenyl, alkoxy, alkylamino, arylalkyl, aryloxy, acyl, acyloxy and acylamino; (c) Y is substituted or unsubstituted, saturated or unsaturated 5, A 6- or 7-membered heterocyclic or carbocyclic ring or none; when R is absent, X and Y are fused ring systems; when R is a covalent bond, X and Y are a covalent bond When Y is absent, R is a covalent bond and X is connected to L at R; (d) R ₁ , R ₂ and R ₃ are each independently None, Cl, F, B
r, NH ₂ , CF ₃ , OH, SO ₃ H, CH ₃ SO ₂ NH,
L is selected from the group consisting of COOH, NO ₂ , alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acylalumino and acyloxy; (e) L is alkylamino, alkenylamino, alkylimino, alkenylimino and Selected from the group consisting of acylamino; wherein the nitrogen atom of L is attached to the nitrogen atom at position 1 of the 4-oxocyclic urea moiety; (f) R ₄ is alkyl, alkenyl, alkynyl, alkylacyl and (G) A is substituted or unsubstituted, saturated or unsaturated, straight or branched chain C ₁ -C ₈ heteroalkyl or substituted or unsubstituted having 5, 6 or 7 members. , saturated or unsaturated heterocyclic ring; the a one nitrogen atom least adjacent to R ₄ To; and (h) R ₅ is substituted or unsubstituted C ₁ or C ₂ alkyl.

However, the novel compound of the present invention is characterized in that when X is an aromatic ring, R is a covalent bond and Y is a substituted or unsubstituted unsaturated 5, 6, or 7-membered heterocyclic ring,
Is selected from the group consisting of alkylamino, alkenylamino, and acylamino; A is a substituted or unsubstituted unsaturated heterocycle having 5, 6, or 7 members; Saturated, straight-chain or branched C ₁ -C ₈ heteroalkyl.

Ring system ( XRY ) The novel 4-oxocyclic urea compounds of the present invention are a 4-oxocyclic urea moiety joined to the ring system (XRY) at the linking moiety (L). Consists of 4-oxocyclic ureas are 1
It also has nitrogen atoms at the 3rd and 3rd positions. The nitrogen atom at position 3 is replaced by an amino-containing group (A) which is separated from the nitrogen atom at position 3 by an intermediate group (R ₄ ).

The ring system (XRY) is a ring-containing moiety and is one or more, preferably one or two, fused or unfused, saturated or unsaturated, substituted or unsubstituted as defined herein. Consists of rings. Thus, the ring system may be monocyclic (Y is absent) or polycyclic (X and Y are both rings or X, R and Y are all rings). Each ring may be either a carbocycle or a heterocycle and contains 5, 6 or 7, preferably 5 or 6 members.

The ring system is preferably polycyclic and consists of two non-fused rings. The ring (Y) adjacent to the linking moiety (L) is more preferably a heterocyclic ring, most preferably a 5-membered ring containing an oxygen atom at the 1-position. In addition, when there are two rings in the ring system, the heterocycle (Y)
Is covalently bonded (at R) to the other ring (X) at the 5-position of the heterocycle Y and at the 1-position of the ring X; It is also preferred that they are combined.

Although not preferred, the ring system may be an alkyl, carbonyl or heteroatom, preferably an oxygen (R)
Is also a polycyclic system composed of two rings (X and Y) separated by In addition, suitable ring systems include polycyclic ring systems composed of two fused (X and Y) rings (with no R) or three fused rings (X, R and Y) . When R is a ring, it is preferably a 5- or 6-membered carbocyclic or heterocyclic ring.

Particularly suitable ring systems are monocyclic and thus consist of only one ring (X) covalently linked to the carbon-containing moiety of L (R is a covalent bond and Y is absent). However, if only one ring is present in the ring system, the ring is 6
It is preferably a membered carbocycle, more preferably substituted with at least two and most preferably at least three substituents, which are not particularly limited but include hydroxy, methyl, chloro, methoxy and benzoyl. Are independently selected from the group consisting of

There is.

When substituted, any or all of the members of the ring system, whether monocyclic or polycyclic, may have one or more substituents. The substituents are not particularly limited, but include Cl, F, Br, NH ₂ , CF ₃ , O
H, SO ₃ H, CH ₃ SO ₂ NH, COOH, NO ₂ , alkoxy, alkoxycarbonyl, hydroxyalkyl,
Alkyl, aminoalkyl, acylamino, acyloxy and carboxyalkyl, especially Cl, F, Br, OH
And CH _{3 are} independently selected from each other.

Preferred ring systems of the novel 4-oxocyclic ureas are not particularly limited and include, for example: 2-acetoxy-5
-Chlorophenyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl, 2-thienyl, 4
-Pyrimidinyl, 5-methoxycarbonyl-2-furanyl, cyclohexyl, 5-chloro-2-hydroxyphenyl, 5-chloro-2-methoxyphenyl, 2-methanesulfonylaminophenyl, 3-aminophenyl, 2-
Methoxyphenyl, 5-ethyl-2-furanyl, 3-methoxyphenyl, 2-aminophenyl, 2-furanyl,
There are single rings including, but not limited to, 3,5-dimethyl-4-hydroxyphenyl and 5-acetyloxymethyl-2-furanyl. Suitable polycyclic systems consisting of two non-fused rings covalently linked to each other are not particularly limited and include, for example: 5- (4-carboxyphenyl) -2-furanyl,
5- (4-methanesulfonylphenyl) -2-furanyl, 5- (3,4-dimethoxyphenyl) -2-furanyl, 5- (4-methanesulfonylaminophenyl) -2
-Furanyl, 5- (4-bromophenyl) -2-oxazolyl, 5- (4-methoxyphenyl) -2-furanyl, 5- (1-cyclohexen-1-yl) -2-furanyl, 5-cyclohexyl-2 -Furanyl, 5- (3-
Trifluoromethylphenyl) -2-furanyl, 5-
(4-methylphenyl) -2-furanyl, 2- (4-chlorophenyl) -3-furanyl, 5- (4-chlorophenyl) -2-furanyl, 5- (4-fluorophenyl)
-2-furanyl. Suitable polycyclic systems consisting of two non-fused rings each joined together with a heteroatom, alkyl or other acyclic carbon-containing group are not particularly limited and include, for example, 2-benzyloxy-5-chlorophenyl, -Benzyloxyphenyl, 3- (4-t-butylphenyloxy) phenyl, 3-benzoyl-2,4-dichlorophenyl, 2-chloro-3-benzyloxyphenyl,
There is 3- (4-chlorophenoxy) phenyl. Suitable polycyclic systems containing two or more fused rings are not particularly limited,
For example, 1H-indol-3-yl, 2-fluorenyl, 2-naphthyl, 2-hydroxy-1-naphthyl, 2
-Quinolinyl, 5-chloro-2-benzofuranyl.

Preferred ring systems (XRY) for the novel 4-oxocyclic ureas defined herein are not particularly limited and include:

[0073]

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Linking moiety (L) L is a linking moiety of the novel 4-oxocyclic urea compound of the present invention. The carbon-containing terminus of L is Y, with the proviso that when Y is absent, and most preferably at the 2-position of the Y ring or at the 1-position of X when Y is absent. Bound to the system. The nitrogen atom of the L moiety is attached to the nitrogen atom at position 1 of the 4-oxocyclic urea moiety. The L moiety is selected from the group consisting of alkylamino, alkenylamino, alkylimino, alkenylimino and acylamino, preferably alkylimino, most preferably C ₁ alkyliminoCH ＝ N.

4- Oxocyclic Urea Moieties The 4- oxocyclic urea moieties of the novel compounds of the present invention give the novel compounds of the present invention their characteristic names. 4
The -oxocyclic urea moiety is a 5- or 6-membered ring, preferably a 5-membered ring. The 4-oxocyclic urea moiety has the following structure:

[0076]

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In the above formula, R ₅ is C ₁ or C ₂ alkyl, preferably C ₁ alkyl. 4-oxo cyclic ureas when R ₅ is C ₁ alkyl is a five-membered ring, 4-oxo cyclic ureas when R ₅ is a C ₂ alkyl is 6-membered ring.

A is a linear or branched, substituted or unsubstituted, saturated or unsaturated C ₁ -C ₈ heteroalkyl or substituted or unsubstituted, saturated or unsaturated 5, 6 or 7, preferably 5 or 6 membered heteroatom. It is a cyclic ring. A portion may be a heteroalkyl even or heterocyclic, at least must be coupled to R ₄ should have a single nitrogen atom.

When A is a substituted heteroalkyl, the substituent is not particularly limited and is preferably selected from the group consisting of methyl, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethyl and methanesulfonyl. .

When A has two nitrogen atoms, the nitrogen atom not adjacent to R ₄ (in the case of a 6-membered heterocycle, which is para to the nitrogen atom adjacent to R ₄ ) is not particularly limited. It is preferably substituted with a substituent selected from the group consisting of methyl, hydroxyethyl, alkyl, aryl, mercaptoethyl, methanesulfonyl, heterocycle and arylalkyl. When heterocycle A has only one nitrogen atom and A is a 6-membered ring, the para-position to the nitrogen atom adjacent to R ₄ is not particularly limited, and consists of hydroxyethyl, hydroxy, oxo and methyl. It is preferably substituted with a substituent selected from the group.

Preferred amine-containing (A) moieties of the novel 4-oxocyclic ureas defined herein include, but are not limited to:

[0082]

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Accordingly, suitable A moieties include, but are not limited to, those wherein A is heteroalkyl, are not particularly limited and include dimethylamino, diethylamino, bis-2-hydroxyethylamino, bis [ (1-methyl) ethyl] amino, N-benzyl-N
-Methylamino, N- (2-hydroxyethyl) -N-
There is methylamino. Suitable A moieties wherein A is a heterocycle are not particularly limited and include N- (1-methylethyl)-
N- [2-hydroxy-2-[(4-methanesulfonylamino) phenyl] ethyl] amino, 4-phenylpiperazinyl, 4- (2-hydroxyethyl) piperazinyl, 4- (1-methylethyl) piperazinyl, 4- (2
-Methylpropyl) piperazinyl, 4-hexylpiperazinyl, 4-benzylpiperazinyl, 1-piperazinyl, 4-hydroxy-1-piperidinyl, 4-methyl-
1-piperazinyl, 4-n-butyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 3- (4-methyl-1-piperazinyl) -3-oxopropyl, 4-phenyl-1-piperazinyl, N- ( 2-pyridinyl) -1
-Piperazinyl, N- (2-pyrimidinyl) -1-piperazinyl, 4- (4-methoxyphenyl) -1-piperazinyl, 4-acetyl-1-piperazinyl, N-methyl-N-phenylamino, 1-imidazolyl, − (2-
Methylphenyl) -1-piperazinyl, 4- (4-methanesulfonylaminophenyl) -1-piperazinyl, N
-Morpholinyl, N-thiomorpholinyl, 4-oxo-
1-piperidinyl, 2- (t-butoxycarbonyl)-
1-pyrrolidinyl, pyrrolidinyl, 4- (4-acetylphenyl) -1-piperazinyl, hexahydro-1H-
There is azepin-1-yl.

R ₄ is attached to the nitrogen atom at position 3 of the 4-oxocyclic urea moiety and to the nitrogen atom of A. R ₄ is alkyl, alkenyl, alkynyl, alkyl acyl, and heteroalkyl, especially C ₃ -C ₆ alkyl, i.e. propyl, butyl, is selected from the group consisting of pentyl and hexyl, but are not limited to.

As noted above, the novel 4-oxo cyclic urea compounds of the present invention are comprised of a 4-oxo cyclic urea moiety joined to the ring system at the linking moiety. Accordingly, suitable compounds of the present invention include, but are not limited to, the following compounds and their pharmaceutically acceptable esters and salts, especially the hydrochloride salt thereof: 1-[[(4-hydroxy-3,5-dimethyl Phenyl) methylene] amino] -3- [4- (4-
Methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione; 1-[[[5- (4-bromophenyl) -2-oxazolidinyl] methylene] amino] -3
-[4- (4-methyl-1-piperazinyl] 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.

Further, 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [4-
(4-methyl-1-piperazinyl) butyl] -2,4-
Imidazolidinedione; 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3-
[3- [4- (1-methylethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione; 1-
[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione; 1-[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [6
-(4-methyl-1-piperazinyl) hexyl] -2,
4-imidazolidinedione; 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3
-[5- (4-methyl-1-piperazinyl) pentyl]
-2,4-imidazolidinedione; 1-[[[5- (4
-Fluorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) 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] amino] -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-piperazinyl] propyl] -2,4-imidazolidinedione; 1-[[[5- (4-chlorophenyl) -2
-Furanyl] methylene] amino] -3- [3- (4-methyl-1-piperazinyl) propyl] -2,4-imidazolidinedione; 1-[[[5- (4-fluorophenyl) -2-furanyl ] Methylene] amino] -3- [3-
[4- (2-hydroxyethyl) -1-piperazinyl]
Propyl] -2,4-imidazolidinedione; 1-
[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [8- (4-morpholinyl) octyl] -2,4-imidazolidinedione can also be used.

Examples AL illustrate the preparation of the preferred novel 4-oxocyclic urea compounds described herein.

A new 4- oxocyclic urea compound was contained.
4-Oxocyclic Urea Pharmaceutical Compositions The novel 4-oxocyclic urea compounds of the present invention are not particularly limited, but can be obtained by various routes including oral dosage forms and injection (intravenous, intramuscular, intraperitoneal and subcutaneous). Administered to humans or other mammals. Many other dosage forms containing the novel 4-oxocyclic urea compounds of the present invention can be readily formulated by those skilled in the art using the appropriate pharmaceutical excipients as described below. Oral dosage forms are usually most preferred, given patient compliance.

The term "pharmaceutical composition" as used herein refers to a combination of a safe and effective amount of an active ingredient of a 4-oxocyclic urea compound or a mixture thereof and a pharmaceutically acceptable excipient.

The phrase "safe effective amount" as used herein is sufficient to significantly improve (at a reasonable benefit / risk ratio) the condition and / or condition being treated within sound medical judgment. Means a compound or composition in an amount that is large, but small enough to avoid severe side effects. The safe and effective amount of the active ingredient useful in the pharmaceutical composition used in the method of the present invention will depend on the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the duration of the combination therapy. It depends on the nature, the particular active ingredient used, the particular pharmaceutically acceptable excipient used and the similar factors belonging to the knowledge and skill of the attending physician.

As used herein, the term "pharmaceutically acceptable excipient" is compatible with the physical and chemical characteristics of the particular active 4-oxocyclic urea compound selected for use. And any physiologically inert and pharmacologically inactive substances known to those skilled in the art. Pharmaceutically acceptable excipients are not particularly limited, and include polymers, resins, plasticizers, fillers, binders, lubricants, lubricants, disintegrants, solvents, co-solvents, buffer systems, surfactants, There are preservatives, sweeteners, flavoring agents, pharmaceutical grade dyes or pigments and thickeners.

The term "oral dosage form" as used herein refers to any pharmaceutical composition for systemic administration to an individual by delivering the composition through the individual's mouth into the gastrointestinal tract of the individual. For the purposes of the present invention, the delivery form is in the form of coated or uncoated tablets, solutions, suspensions, coated or uncoated capsules.

As used herein, the term “injection”
To deliver a solution or emulsion to the circulatory system of an individual by either intravenous, intramuscular, intraperitoneal or subcutaneous injection, puncture the individual's skin to deliver a solution or emulsion containing the active ingredient to a human or By any pharmaceutical composition for systemic administration to another mammal.

The rate of systemic delivery can be satisfactorily controlled by one of ordinary skill in the art by manipulating one or more of the following: (a) properly active ingredients; (b) pharmaceutically acceptable excipients. (C) the type of excipient and the desired thickness and permeability (swelling properties) of the excipient associated therewith, as long as the variables do not interfere with the activity of the particular active ingredient selected; ) Time-dependent conditions within the excipient itself and / or within the excipient; (e) particle size of the granulated active ingredient; and (f) pH-dependent conditions of the excipient, especially with acid addition salts and carboxylic acids. The solubility, acidity and susceptibility of different active salts of different 4-oxo cyclic ureas such as, for example, alkali metal salts, alkaline earth metal salts and the like, and esters, for example, alkyl, alkenyl, aryl, arylalkyl, etc. Guidelines for making the right choice May be used. In addition, appropriate pH conditions may be established within the oral dosage form by adding the appropriate buffer to the active ingredient according to the desired release pattern.

As described above, pharmaceutically acceptable excipients are not particularly limited, and include resins, fillers, binders, lubricants, solvents, lubricants, disintegrants, cosolvents, surfactants, There are preservatives, sweeteners, flavoring agents, buffer systems, pharmaceutical grade dyes or pigments and thickeners.

A preferred solvent is water.

[0097] Flavoring agents belonging to those useful herein include Remington's Pharmaceut, incorporated herein by reference.
ical Sciences (Remington's Pharmaceutical Sciences), 18th Editio
n, Mack Publishing Company, 1990, pp. 1288-1300. Pharmaceutical compositions suitable for use herein generally contain from 0 to 2% of a flavoring agent.

[0098] Dyes or pigments belonging to those useful herein include the Handbook of Phar incorporated herein by reference.
maceutical Excipients, Handbook of Pharmaceutical Excipients, pp.81-90, 1986, the American Pharmaceutical
Association & the Pharmaceutical Society of Great
Some are listed in Britain. The pharmaceutical compositions usually contain 0-2% of a dye or pigment.

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

Preferred buffers include acetic acid, boric acid, carbonic acid, phosphoric acid, succinic acid, malic acid, tartaric acid, citric acid,
Acetic acid, benzoic acid, lactic acid, glyceric acid, gluconic acid, glutaric acid and glutamic acid and their sodium, potassium and ammonium salts, but are not limited thereto. Phosphoric acid, tartaric acid, citric acid and acetic acid and salts are particularly preferred. The pharmaceutical composition of the present invention usually contains 0 to 5% of a buffer system.

Preferred surfactants include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters, lanolin esters and ethers, alkyl sulfates, and sodium, potassium and ammonium salts of fatty acids. Not limited. The pharmaceutical composition of the present invention contains 0 to 2% of a surfactant.

Preferred preservatives are phenol and p-
Alkyl esters of hydroxybenzoic acid, o-phenylphenol benzoic acid and its salts, boric acid and its salts, sorbic acid and its salts, chlorobutanol, benzyl alcohol, thimerosal, acetic acid and phenylmercuric nitrate, nitromersol, benzalco chloride , Cetylpyridinium chloride, methyl paraben and propyl paraben, but are not limited thereto. Particular preference is given to salts of benzoic acid, cetylpyridinium chloride, methylparaben and propylparaben. The compositions according to the invention usually contain 0 to 2% of a preservative.

Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, sorbitol, mannitol and aspartame. Sucrose and saccharin are particularly preferred. The pharmaceutical composition of the present invention contains 0-5% of a sweetener.

Preferred viscosifiers include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, gum arabic, guar gum, xantham gum and tragacanth. Particularly preferred are methylcellulose, carbomer, xan gum, guar gum, povidone, sodium carboxymethylcellulose and magnesium aluminum silicate. The compositions of the present invention contain 0-5% of a viscosity agent.

Preferred fillers include lactose, mannitol, sorbitol, tricalcium phosphate, dicalcium phosphate, compressible sugar, starch, calcium sulfate,
Include, but are not limited to, dextro and microcrystalline cellulose. The compositions of the present invention contain from 0 to 75% filler.

Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid and talc. The pharmaceutical compositions of the present invention contain 0.5-2% of a lubricant.

[0107] Preferred lubricants include, but are not limited to, talc and colloidal silicon dioxide. The composition according to the invention contains 1 to 5% of a lubricant.

Preferred disintegrants include starch, sodium starch glycolate, crospovidone, croscarmellose sodium and microcrystalline cellulose,
Not limited to them. The pharmaceutical composition of the present invention comprises 4 to 15
% Disintegrant.

Preferred binders are gum arabic, tragacanth, hydroxypropylcellulose, pregelatinized starch, gelatin, povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Sugar solutions such as methylcellulose, sucrose and sorbitol and ethylcellulose, but are not limited thereto. The composition according to the invention contains 1 to 10% of a binder.

Therefore, the pharmaceutical composition of the present invention comprises 15 to
95% 4-oxocyclic urea compound active ingredient or a mixture thereof; 0-2% flavoring agent; 0-50% co-solvent;
% Buffer system; 0-2% surfactant; 0-2% preservative; 0-5% sweetener; 0-5% viscosity agent;
Filler; 0.5-2% lubricant; 1-5% lubricant;
Contains 4-15% disintegrant; 1-10% binder.

Suitable pharmaceutical compounds are described in Examples MQ. Modifying the non-limiting examples described herein to obtain a wide range of pharmaceutical compositions is well within the ability of those skilled in the art.

Imperfection due to novel 4-oxocyclic urea compounds
Methods of Treating Pulses The novel compounds of the present invention are efficacious in treating humans or other mammals with supraventricular and ventricular arrhythmias and / or cardiac fibrillation. As mentioned above, except in rare cases,
Supraventric arrhythmias do not appear to be life threatening and are usually not aggressively treated with conventional antiarrhythmic drugs due to their undesirable side effects. Therefore, this type of arrhythmia is not usually treated aggressively simply to relieve symptoms characterized as mild to severe. However, the novel compounds of the present invention are usually well tolerated and do not usually show as many undesirable side effects as many of the more conventional antiarrhythmic drugs, and thus actually discomfort if not a life threatening situation May be a well-tolerated therapy to reduce the symptoms exhibited by individuals with supraventricular arrhythmias.

As noted above, the novel 4-oxocyclic urea compounds of the present invention are also effective in treating ventricular arrhythmias, which are usually much more severe than supraventricular arrhythmias, and thus require aggressive therapy. Many patient typings have been performed, in part because of the potential severity of ventricular arrhythmias.

An individual with a benign ventricular arrhythmia is similar to an individual who has experienced a supraventricular arrhythmia from a philosophical point of view of whether to treat. These individuals do not have heart disease,
Experience dizziness and palpitations and often feel some emotional distress based on the instability caused by their physical symptoms.
These individuals usually suffer from PVC, which is usually physically harmless, but clearly produces some anxiety.
The novel 4-oxocyclic urea compounds of the present invention have the undesirable side effects that have previously deferred the use of many conventional antiarrhythmic drugs due to undesirable more severe and / or life threatening medical conditions in these individuals. Is usually not shown much. However, these individuals will usually benefit from better tolerated therapies.

Another class of individuals who would benefit from therapy utilizing the novel 4-oxocyclic urea compounds of the present invention are those individuals who are characterized as having "prognostically significant" arrhythmias. These individuals usually have myocardial infarction and may develop PVC and / or any of the symptomatic and / or non-symptomatic non-ventricular tachyarrhythmias. They do not show the same degree of immediate urgency life threatening symptoms as the individuals described below, and are not at risk for immediate or near-term death according to conventional characterization. However, they have a significantly greater risk of heart failure than the general population, and thus will have a lower risk of sudden death with therapy with the novel compounds of the present invention. See Morganroth & Bigger, page 1498.

There are other individuals who exhibit continually life threatening arrhythmias and are at risk of immediate or near-term death. In these individuals, ventricular tachyarrhythmias or ventricular fibrillation are usually exhibited. Ventricular arrhythmias in these individuals usually show hemodynamically important cues or signs such as syncope, heart failure, myocardial ischemia or hypotension. These patients have the greatest risk of sudden cardiac death and usually the most severe form of underlying heart disease. See Morganroth & Bigger, p. 1498. The novel compounds of the present invention are effective aggressive antiarrhythmic therapies suitable for use in this class of individuals, due to the need and unavailability of alternatives suitable for treating life threatening arrhythmias, provided that Some of the undesirable side effects that have been conventionally tolerated with conventional antiarrhythmic agents are small.

As noted above, the novel antiarrhythmic agents of the present invention do not exhibit many of the undesirable side effects associated with many conventional antiarrhythmic therapies. These side effects include, but are not limited to, pulmonary toxicity, cardiac depression and non-specific neurological effects on heart tissue.

In addition, the novel compounds of the present invention are not only antiarrhythmic, but also antifibrillatory; they prevent sudden cardiac death by uniformly extending the period of non-excitation of the heart with each beat.
Conventional therapies exhibit anesthetic and / or cardiosuppressive properties that render the heart unresponsive, rather than defibrillating.

Accordingly, the novel 4-oxocyclic urea compounds of the present invention are useful in treating cardiac arrhythmias and / or fibrillation in humans or other mammals. Accordingly, the present invention relates to a method for preparing an active ingredient of 4-oxocyclic urea compound or a mixture thereof comprising 15 to 90% and a pharmaceutically acceptable excipient 10%.
A method for treating a human or other mammal with cardiac arrhythmia and / or fibrillation, comprising administering to said human or other mammal a safe and effective amount of a pharmaceutical composition comprising -85%.

Examples S-Z illustrate this patient situation and describe how pharmaceutical compositions containing the novel 4-oxocyclic urea compounds of the present invention may be used to treat cardiac arrhythmias and fibrillation. Explain. Modifying the non-limiting examples described herein to treat a broad class of individuals with cardiac arrhythmias and fibrillation is well within the ability of those skilled in the art.

The following examples serve to further illustrate the invention.

[0122]Example A 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- (4-methyl-1
-Piperazinyl) butyl] -2,4-imidazolidinedi
Synthesis of ondihydrochloride

[0123]

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The above compounds are prepared and synthesized as follows.

I.1-phenylmethyleneamino-3-
(4-chlorobutyl) -2,4-imidazolidinedione
Synthesis of dihydrochloride 1-phenylmethyleneamino-3- (4-chlorobutyi
2) -2,4-Imidazolidinedione dihydrochloride is dimethyl
1- (benzylidenea) in ruformamide (1000 ml)
Mino) hydantoin [I.
Gut, A Novacet and P. Fieldler, Coll.Czech.Chem.Commu
n., Vol. 33, pp. 2087-2096 (No. 7), 1968
(39.5 g, 0.1944 mol)
The solution was added to 60% sodium hydride in mineral oil (7.8 g, 0.1 g).
(1944 mol) over 1 hour.
You. After the addition is completed, the solution is heated to the steam bath temperature (about 100 ° C)
For 1.5 hours. The obtained mixture was heated to ambient temperature (3
0 ° C). While stirring at ambient temperature,
Bromo-4-chlorobutane (100 g, 0.5832 mol
l, 3 eq) all at once. The mixture began to generate heat, and about 3
It reaches about 35 ° C. in 0 minutes. Steam near solution
Heat at about 80 ° C for 4 hours in a bath, cool, and cool to ambient temperature.
Stir at (30 ° C.) for about 8 hours. Filter turbid mixture
To remove small amounts of insoluble solids. The filtrate is halved under reduced pressure.
Concentrate to a solid residue. This residue is H_TwoO (400ml)
Milled, collected, recrystallized from acetonitrile,
After air-drying, 1-phenylmethyleneamineno-3- (4
-Chlorobutyl) -2,4-imidazolidinedione 4
3.1 g (0.1467 mol) are obtained.

II.1-phenylmethyleneamino-3-
(4-Iodobutyl) -2,4-imidazolidinedione
Synthesis of 1-phenylmethyleneamino-3- (4-chlorobutyi
L) -2,4-Imidazolidinedione (as described in Part I above)
(43.1 g, 0.1467)
mol), acetone (1200 ml) and sodium iodide
(48.4 g, 0.3227 mol) by heating to reflux
You. Reflux is maintained for 5 hours. Filter the mixture to remove insolubles
Collect. Re-add sodium iodide (10g) to the filtrate
Then reflux is resumed and maintained for 15 hours. Cool to ambient temperature
After recirculation, the mixture is filtered to remove insoluble NaCl (total
(9.5 g, 110% recovery). H while stirring the filtrate_Two
Pour into O (2000 ml). After stirring for 30 minutes, collect the solid
And air-dried to give 1-phenylmethyleneamino-3- (4-
Iodobutyl) -2,4-imidazolidinedione 51.
5 g (0.1337 mol) are obtained.

III.1-phenylmethyleneamino-3-
[4- (4-methyl-1-piperazinyl) butyl]-
Synthesis of 2,4-imidazolidinedione dihydrochloride 1-phenylmethyleneamino-3- (4-iodobutyi
Ru) -2,4-imidazolidinedione (10.0 g,
0.0260 mol) (prepared as described above in Part II)
Dimethylformamide (150 ml) and 1-
Tilpiperazine (11.5 ml, 10.4 g, 0.104
(0 mol) is heated to reflux. Reflux is maintained for 3 hours.
After cooling to about 40 ° C, the solution was rotary evaporated under reduced pressure.
Concentrate to an oily solid residue with a rotator. This residue is H
_TwoO (200 ml) and then saturated NaHCO
_Three(200 ml). About 2
Stir for hours. Collect the solids and air-dry, then dry
Dissolve in ethanol (150 ml), then filter,
After acidification against litmus wet with EtOH / HCl
Let After cooling for several hours, the solid was collected and air-dried.
Nylmethyleneamino-3- [4- (4-methyl-1-pi
Perazinyl) butyl] -2,4-imidazolidinedione
8.04 g (0.0187 mol) of the dihydrochloride are obtained.

IV. 1-amino-3- [4- (4-methyl
-1-piperazinyl) butyl] -2,4-imidazolidi
Synthesis of on hydrochloride 1-phenylmethyleneamino-3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride (8.04 g, 0.0187 mol), 2
NHCl (125 ml) and 5% Pd / C: 50% H ₂
A mixture of O (1.5 g) is contacted with hydrogen at 40 psi (about 2.8 kg / cm ² ) at ambient temperature in a Parr apparatus. After 2 hours, the catalyst is filtered off. The filtrate is divided into two equal parts. Each is concentrated under reduced pressure on a rotary evaporator to an oily residue of 1-amino-3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidione hydrochloride.

V.1-[[[5- (4-chlorophenyl
Ru) -2-furanyl] methylene] amino] -3- [4-
(4-methyl-1-piperazinyl) butyl] -2,4-
Synthesis of imidazolidinedione dihydrochloride 1-amino-3- [4- (4-methyl-1-piperazini)
Ru) butyl] -2,4-imidazolidinedione hydrochloride
(0.0094 mol), dimethylformamide (75 ml)
And 5- (4-chlorophenyl) -2-furancarboxy
Sardide (Norwich Eaton Pharmacue
Transferred to Tikals, Inc. on November 21, 1984
U.S. Pat. No. 4,882,354 issued to Huang et al.
Manufactured as described in US Pat.
, Incorporated herein for reference] (1.94 g,
(0.0094 mol) at ambient temperature for 72 hours.
You. Filter the mixture and collect the solid. Absolute ethanol
/ H_TwoBy recrystallization from O and air drying, 1-[[[5-
(4-chlorophenyl) -2-furanyl] methylene] a
Mino] -3- [4-methyl-1-piperazinyl) buty
2.6-2. 4-imidazolidinedione dihydrochloride
g (0.0050 mol) are obtained.

[0130]Example B 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [8- (4-methyl-1
-Piperazinyl) octyl] -2,4-imidazolidine
Synthesis of dione dihydrochloride

[0131]

Embedded image

The above compounds are prepared and synthesized as follows.

I. 1-benzylideneamino-3- (8-
(Hydroxyoctyl) -2,4-imidazolidinedione
J.Gut the synthesis of 1- (benzylidene-amino) hydantoin incorporated herein by reference, A Noracet and P.Fieldler, C
oll.Czech.Chem.Commun., Vol.33, pp.2087-2096 (No.7), 1
Prepared according to the method described in 968.

500 ml of dimethylformamide (DMF)
Medium 1- (benzylideneamino) hydantoin 30.5 g
(0.15 mol) in sodium hydride (60 in mineral oil)
% Suspension) are added in about 15 minutes with stirring. The temperature of the reaction mixture rises from 25 ° C. to 35 ° C., while a white solid separates in about 5 minutes after the addition is complete. An additional 700 ml of dimethylformamide promotes smooth stirring. The mixture is warmed to about 80 ° C. (steam bath) for 1 hour and then cooled. Then 50
24.7 g (0.15 mol) of 8-chloro-1-octanol are added to this slightly cooled mixture at C. The mixture is then heated to 100-110 ° C. for 3 hours, then
Cool for 6 hours. The white solid disappears after the first hour of heating, after which another solid gradually separates.

The mixture obtained is filtered, the filtrate is concentrated to about one third of its original volume and then poured into 1.2 l of H ₂ O. The white precipitate is collected, washed thoroughly with water and air-dried. The solid is 24 g (48%). Recrystallization of 3.5 g of nitromethane from 50 ml gave 1- as a crystalline white solid.
Benzylideneamino-3- (8-hydroxyoctyl)
2.86 g of -2,4-imidazolidinedione are obtained.

II. 1-benzylideneamino-3- [8-
(4-methyl-1-piperazinyl) octyl] -2,4
Synthesis of imidazolidinedione dihydrochloride 9.95 g of the above crude alcohol in 125 ml of benzene
(0.03 mol) and thionyl chloride (3.0 ml, 0.04 mol)
The mixture of l) is heated under reflux for about 4 hours. The reaction mixture is filtered while hot to collect some insoluble material. A small amount of solids separates from the filtrate on cooling. Mix hexane with approx. 40
When poured into 0 ml, a white solid, octyl chloride, immediately precipitates. Collect the precipitated octyl chloride, wash well with hexane and air dry.

A mixture of 4.85 g (0.014 mol) of the above precipitate and 1.5 g (0.015 mol) of N-methylpiperazine in 125 ml of dimethylformamide is heated under reflux. After heating at reflux for 28 hours, the mixture is concentrated under reduced pressure to give a brown residue. Trituration with a saturated NaHCO ₃ solution gives a brown solid. The mixture is filtered and the collected sticky brown solid is further triturated with ether and filtered again. This sticky solid was 1-benzylideneamino-3- [8-
(4-methyl-1-piperazinyl) octyl] -2,4
-Imidazolidinedione dihydrochloride (1.96 g).

III.1-[[[5- (4-chlorophenyl
Ru) -2-furanyl] methylene] amino] -3- [8-
(4-methyl-1-piperazinyl) octyl] -2,4
-Synthesis of imidazolidinedione dihydrochloride 2N HC combined with 1.5 g of 5% palladium on carbon
1-benzylideneamino-3- [8-
(4-methyl-1-piperazinyl) octyl] -2,4
A mixture of 1.96 g of imidazolidinedione dihydrochloride
Hydrogenate in a Parr shaker. 2 days for reduction
During which time 1.5 g of palladium on carbon was added after 24 hours
to add. Stop hydrogen uptake after 110% of theory
Is filtered off. The filtrate was concentrated under reduced pressure to give a dark solution
However, a small amount of solids separates out on standing.

The above residue was treated with dimethylformamide (DM
F) Dilute with 10 ml and add 5 ml of dimethylformamide in 10 ml
-(4-Chlorophenyl) -2-furancarboxaldehyde [U.S. Pat. No. 4,882,354 to Huang et al., Assigned to Norwich Eaton Pharmaceuticals, Inc. and issued on Nov. 21, 1984. Manufactured as described in the specification; see columns 7 & 8, incorporated herein by reference]. A yellowish solid separates almost immediately. 4
After stirring for a period of time, the mixture was filtered, and the solid matter was removed from SDA-3.
2. After that, wash well with ether and air dry. Wt =
1.5 g. This crude product is obtained from 350 ml of nitromethane.
After recrystallization of 27 g, 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3- [8-
(4-methyl-1-piperazinyl) octyl] -2,4
0.9 g of imidazolidinedione dihydrochloride are obtained.

[0140]Example C 1-[[[5- (4-chlorophenyl) -2-furani
Methylene] amino] -3- [8- (4-morpholini
Ru) octyl] -2,4-imidazolidinedione hydrochloride
Synthesis of

[0141]

Embedded image

The above compounds are prepared and synthesized as follows.

100 ml of dimethylformamide (DMF)
Octyl medium chloride (synthesized in Part B of Example B) 5.0
g (0.015 mol) and 15 g of morpholine (0.017
(mol) is heated under reflux for 32 hours. The mixture is concentrated under reduced pressure to give a dark reddish residue. Saturated NaH
Trituration with CO ₃ solution gave a brown solid which was collected,
Rinse well and then air dry. This slightly sticky brown solid is dissolved in acetone, treated with activated carbon and filtered. The acetone filtrate is diluted with water until solids begin to separate. The mixture is cooled and then filtered. The solid was collected, washed well with water, and then air-dried to give a sticky solid 3.1.
8 g (0.008 mol) are obtained.

The above solid substance was added to 1 g of a 5% palladium on carbon catalyst.
In 100 ml of 2N HCl and hydrogenated in a Parr shaker. The hydrogenation uptake is stopped after 6 hours [18 lb, 110%] and the mixture is filtered. The yellow filtrate is concentrated on a rotary evaporator under reduced pressure to give a brown viscous liquid residue. This liquid residue in 10 ml of dimethylformamide is added with stirring at ambient temperature,
5- (4-chlorophenyl) -2-furancarboxaldehyde in 20 ml of dimethylformamide [Norwich
Transferred to Eaton Pharmaceuticals, Inc. 1
Manufactured as described in Huang et al., U.S. Pat. No. 4,882,354, issued Nov. 21, 984; see columns 7 & 8 (incorporated herein by reference)]. 65 g (0.008 mol) of solution are added.
The mixture is stirred at ambient temperature for 16 hours, then concentrated under reduced pressure to give a brown residue. Dissolve the solid by adding fresh dimethylformamide and add about 15 ml of ethanolic HCl solution. Heating the solution at 40-45 ° C. for 2 hours,
Thereafter, the mixture is concentrated under reduced pressure. The residue obtained is triturated with absolute ethanol and the ethanol is removed on a rotary evaporator under reduced pressure. This process is repeated once more, the brown semi-solid residue is triturated with ether and filtered.
The sticky muddy solid is further triturated with isopropanol and filtered. The crude solid weighed 2.38 g, which was recrystallized from SDA-32 to give 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino]-.
3- [8- (4-morpholinyl) octyl] -2,4-
This gives imidazolidinedione hydrochloride.

[0145]Example D 1-[[(3,5-dimethyl-4-hydroxyphenyl
L) methylene] amino] -3- [4- (4-methyl-1
-Piperazinyl) butyl] -2,4-imidazolidinedi
Synthesis of ondihydrochloride

[0146]

Embedded image

The above compounds are prepared and synthesized as follows.

A solution of 2N HCl combined with 2 g of 5% palladium on carbon (50% wet) was added to 125 ml of 1-phenylmethyleneamino-3- [4- (4-methyl-1-piperazinyl) butyl] -2,4- A mixture of 3.23 g (0.0075 mol) of imidazolidinedione dihydrochloride (prepared as described in Part I, II and III of Example A) is hydrogenated in a Parr shaker. Hydrogen uptake is one of the theory
Stop at 25%. The catalyst is filtered off and the filtrate is concentrated on a rotary evaporator under reduced pressure to give a sticky solid residue. The residue is triturated several times with SDA-32 and the solvent is removed on a rotary evaporator under reduced pressure. A white solid is obtained.

The above solid substance was treated with dimethylformamide 100
Add to ml. No solution forms after boiling for 10 minutes. The mixture is cooled slightly and 1.13 g (0.0075 mol) of 3,5-dimethyl-4-hydroxybenzaldehyde are added.
The mixture is stirred overnight and then warmed for 45 minutes in a steam bath. After cooling, the mixture is filtered and the solid is washed with dimethylformamide, SDA-32, ether and air-dried. The yield is 3.75 g (100% or more). SDA
Recrystallization from a mixture of about 30 ml of H ₂ O with 100 ml of -32 gave 1-[[(3,5-dimethyl-4-hydroxyphenyl) methylene] amino] -3- [4- (4-methyl-1- This gives 2.17 g (66%) of (piperazinyl) butyl-2,4-imidazolidinedione dihydrochloride.

[0150]Example E 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [3- [4- (2-hydr
Roxyethyl) -1-piperazinyl] propyl] -2,
Synthesis of 4-imidazolidinedione dihydrochloride

[0151]

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I.1-[[[5- (4-chlorophenyl
Ru) -2-furanyl] methylene] amino] -3- [3-
(Chloropropyl) -2,4-imidazolidinedione
Synthesis AR Grade 1 in dimethylformamide (423 ml)
[5- (4-chlorophenyl) -2-furfurylidenea
Mino] Hydantoin [Norwich Eaton Fur
Transferred to Macuticals, Inc., December 1, 1968
US Patent No. of Davis and Suyder, issued on date 0
Manufactured as described in US Pat. No. 3,415,821.
See columns 2 & 3, incorporated herein by reference)
(25.0 g, 0.082 mol) with stirring and stirring with nitrogen
clean. The solution was made up of sodium hydride (60%) in mineral oil.
Mix with the mixture (3.29 g, 0.082 mol) over 5 minutes.
Process one by one. Reaction mixture (later solution, then concentrated
The mixture is heated in a steam bath for 15 minutes. Reaction mixture
Is cooled to ambient temperature, and then nitrogen cleaning is stopped.
The reaction solution was treated with 1-bromo-3-chloropropane (26.9).
g, 0.165 mol) and heated in a steam bath for 4 hours
I do. Cool the reaction mixture and pour it into 1500 ml of water to make it oily.
Obtain a mixture. On standing for 5 minutes a yellow solid is formed
It is. The yellow solid was filtered, washed with water and 1-[[[5-
(4-chlorophenyl) -2-furanyl] methylene] a
Mino] -3- (3-chloropropyl) -2,4-imida
Zolidinedione (33.0 g) is obtained.

II.1-[[[5- (4-chlorophenyl
Ru) -2-furanyl] methylene] amino] -3- [3-
[4- (2-hydroxyethyl) -1-piperazinyl]
Propyl] -2,4-imidazolidinedione dihydrochloride
Synthesis 4- in AR grade dimethylformamide (130 ml)
(2-hydroxyethyl) piperazine (3.83 g,
0.03 mol) of a stirred solution of 1-[[[5- (4-chloro
Phenyl) -2-furanyl] methylene] amino] -3-
(3-chloropropyl) -2,4-imidazolidinedio
(6.92 g, 0.015 mol). Reaction solution
Is heated under reflux for 1.5 hours, and then concentrated under reduced pressure.
Shrink to give an oily residue. The residue is washed with saturated sodium bicarbonate
And a yellow mixture is obtained. Filter the mixture
And washed with water to obtain 3.92 g of a crude product as a free base.
You. Dissolve the solid in alcohol and add saturated ethanol / H
Treat with a mixture of Cl. Solution is crystalline solid after 5 minutes
To form The solid is collected by filtration to give a crude product. 1-
[[[5- (4-chlorophenyl) -2-furanyl] me
[Tylene] amino] -3- [3- [4- (2-hydroxy
Ethyl) -1-piperazinyl] propyl] -2,4-a
Midazolidinedione dihydrochloride from 95% alcohol to 1
Isolated in two recrystallizations (2.57 g).

[0154]Example F 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- [4- (2-hydr
Roxyethyl) piperidinyl] butyl] -2,4-imi
Synthesis of dazolidinedione hydrochloride

[0155]

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1-[[[[5- (4-chlorophenyl)-
2-furanyl] methylene] amino] -3- [4- [4-
(2-hydroxyethyl) piperidinyl] butyl]-
2,4-Imidazolidinedione hydrochloride is prepared and synthesized as follows.

I.1-[[[5- (4-chlorophenyl
Ru) -2-furanyl] methylene] amino] -3- [4-
Synthesis of [chlorobutyl] -2,4-imidazolidinedione 5- (4-chloro) in dimethylformamide (500 ml)
Phenyl) -2-furancarboxaldehyde [nowy
Transferred to Touch Eaton Pharmaceuticals, Inc.
Huang et al., Issued November 21, 1984
U.S. Pat. No. 4,882,354.
Manufactured as; see columns 7 & 8 (set here for reference)
Stirring)] (26.0 g, 0.0856 mol)
To the solution was added 60% NaH in mineral oil (3.4 g, 0.0856 mol
l) is added in small portions over 2 minutes. After addition, mix
Stir at ambient temperature for 1 hour, then at steam bath temperature for 1 hour
Heat for a while. Cool the resulting concentrated mixture to ambient temperature
You. 1-Bromo-3-chlorobutane (22.0 g, 0.
1284 mol) and the mixture is left at ambient temperature for 30 minutes.
Thereafter, the mixture is stirred at 80 to 90 ° C. for 2 hours. After cooling, the mixture
Is concentrated under reduced pressure to 1/3 of its volume. Then reduction
Mixture is H_TwoPour into O (1500ml), then stir
You. Collect the solids, air dry and then dry at 70 ° C
And 1-[[[5- (4-chlorophenyl) -2-fura
Nyl] methylene] amino] -3- (4-chlorobutyl)
35.5 g of 2,4-imidazolidinedione (0.09
0 mol, yield 100% or more).

II.1-[[[5- (4-chlorophenyl
Ru) -2-furanyl] methylene] amino] -3- [4-
[4- (2-hydroxyethyl) piperazinyl] butyl
Synthesis of hydrochloride of 2,4-imidazolidinedione 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- (4-chlorobutyl)-
2,4-Imidazolidinedione (5.0 g, 0.012
7 mol) (prepared as above), dimethylforma
Mid (150 ml), sodium iodide (3.8 g, 0.1 g).
0254 mol), K_TwoCO_Three(1.76g, 0.0127mo
l) and 4-piperazine ethanol (4.1 g, 0.03
(18 mol) is heated in a steam bath for 1.5 hours
You. After cooling, the mixture is concentrated under reduced pressure to a semi-solid residue.
This residue is H_TwoO (300 ml) and then CH_Two
Cl_TwoExtract with Extract to H_TwoWash with O (3x100ml)
Clean, then MgSO_Four(Activated carbon) and dry. Filtration
Concentrate the filtered solution to a solid residue under reduced pressure. Without this
Triturate with water ether, collect and air dry. Add this solid
Dissolve in anhydrous EtOH (300 ml) while warming and cool
And acidify with EtOH / HCl. Cool on ice for several hours
Afterwards, the solid was collected, washed with anhydrous ether, air-dried and dried.
After drying at 0 ° C., 1-[[[5- (4-chlorophenyl)
Ru) -2-furanyl] methylene] amino] -3- [4-
[4-hydroxyethyl) piperidinyl] butyl] 2-
4.05 g of 4-imidazolidinedione hydrochloride, (0.0
77 mol).

[0159]Example G 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- (4-methyl-1
-Piperazinyl) butyl] -2,4-imidazolidinedi
On synthesis

[0160]

Embedded image

1-[[[[5- (4-chlorophenyl)-
2-furanyl] methylene] amino] -3- [4- (4-
Methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione and free base are prepared as follows. The dihydrochloride prepared as described in Example A, 1-
[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride (6. 56 g, 0.0124 mol) in H ₂ O (30
0 ml) and wash with (1 x 100 ml). The aqueous phase is basified with a saturated NaHCO ₃ solution. The resulting mixture is extracted with CH ₂ Cl ₂ (4 × 100 ml). The extract is washed with saturated NaCl (2 × 50 ml), dried over MgSO ₄ (activated charcoal), filtered and concentrated under reduced pressure to a solid residue.
The solid is triturated with anhydrous ether, collected and air dried.
Recrystallize once from anhydrous EtOH and then from toluene (activated carbon), then wash with anhydrous ether, air dry and
-[[[5- (4-chlorophenyl) -2-furanyl]
There are obtained 2.05 g (0.0045 mol) of [methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione.

EXAMPLE H Any of the novel 4-oxocyclic urea hydrochloride compounds prepared in Examples AF can be converted to their free base form utilizing the procedure set forth in Example G.

[0163]Example I 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- (4-methyl-1
-Piperazinyl) butyl] -2,4-imidazolidinedi
Synthesis of on-2-Z-butenedionate

[0164]

Embedded image

1-[[[5- (4-chlorophenyl)-
2-furanyl] methylene] amino] -3- [4- (4-
Methyl-1-piperazinyl) butyl] -2-Z-butenedioate of 2,4-imidazolidinedione is prepared as follows.

Free base compound, 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino]-
3- [4- (4-methyl-1-piperazinyl) butyl]
2,4-Imidazolidinedione (prepared as described in Example G) (4.4 g, 0.0096 mol) was added to Me.
Dissolve in OH (125 ml), treat with activated charcoal and filter. Maleic acid (2.23 g, 0.0192) was added to this solution.
mol) in one portion. The resulting mixture is stirred at room temperature for about 2 hours, then collected and air-dried. This solid is recrystallized from anhydrous EtOH / H ₂ O (activated carbon) and then cooled. Collect the solid, wash with anhydrous ether,
Air-dried, dried at 70 ° C. and 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3
-[4- (4-methyl-1-piperazinyl) butyl]-
4.99 g (0.0072 mol) of 2,4-imidazolidinedione-2-Z-butenedioate are obtained.

Example J Any compound 4-oxocyclic urea hydrochloride prepared in Examples AF and converted to their free base as described in Example H utilizes the procedure set forth in Example I. May be converted to their 2--2-Z-butenedioate form.

[0168]Example K 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [3- [4- (2-hydr
Roxyethyl) -1-piperazinyl] propyl] -2,
Synthesis of 4-imidazolidinediones

[0169]

Embedded image

1-[[[5- (4-chlorophenyl)-
2-furanyl] methylene] amino] -3- [3- [4-
(2-Hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione is produced and synthesized as follows.

1-prepared as described in Example E
[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione The hydrochloride is dissolved in water (300 ml), then a solution of saturated sodium bicarbonate is added.
The white solid precipitate was collected by filtration, washed with water, and the free base form of the 4-oxocyclic urea hydrochloride compound synthesized in Example E 1-
[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione 5 0.21 g are obtained.

Example L Any of the compounds synthesized in Examples AF can be converted to the free base form using the procedure set forth in Example K.

[0173]Example M 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- (4-methyl-1
-Piperazinyl) butyl] -2,4-imidazolidinedi
Manufacture of oral dihydrochloride tablets Compound 1-[[[5 prepared as described in Example A
-(4-chlorophenyl) -2-furanyl] methylene]
Amino] -3- [4- (4-methyl-1-piperazini)
Butyl) -2,4-imidazolidinedione dihydrochloride
The tablet containing has the following composition:Active ingredient 1-[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl] butyl] -2,4-imidazolidinedione dihydrochloride 350 mgExcipient Lactose 192 mg Sodium starch glycolate 50 mg Pregelatinized starch 30 mg Talc 12 mg Magnesium stearate 6 mg 10,000 tablets having the above composition are produced as follows.
1-[[[5- (4-chlorophenyl) -2-fura
Nil] methylene] amino] -3- [4- (4-methyl-
1-piperazinyl) butyl] -2,4-imidazolidine
3.55 kg of dione dihydrochloride, 1.92 kg of lactose,
0.50 kg of sodium starch glycolate and pre-gelatin
0.30 kg of starch modified with Patterson-Kelly
on-Kelly) Blend in a blender and then strengthen bar
Granulate with water using

The granules are then dried on trays in an oven or fluid bed dryer.

The granules are milled through a 12 mesh screen using a vibrator or other suitable mill.

The granules are blended with 120 g of talc and 60 g of magnesium stearate.

The talc, magnesium stearate and granule mixture are compressed into 640 mg tablets on a suitable tablet machine.

Tablets prepared as described above are given to individuals with cardiac arrhythmia and / or fibrillation utilizing dosage regimens appropriate for the particular patient.

[0179]Example N 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [3- [4- (2-hydr
Roxyethyl) -1-piperazinyl] propyl] -2,
Production of 4-Imidazolidinedione Dihydrochloride Oral Tablet 1-[[[5- (4 (4) prepared as described in Example E
-Chlorophenyl) -2-furanyl] methylene] amido
No] -3- [3- [4- (2-hydroxyethyl) -1
-Piperazinyl] propyl] -2,4-imidazolidine
Oral tablets containing dione dihydrochloride have the following composition
You.

Active ingredient 1-[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl] -2 , 4-Imidazolidinedione dihydrochloride 300 mg Excipient dicalcium phosphate 219 mg Crospovidone 60 mg Povidone 12 mg Talc 6 mg Magnesium stearate 3 mg 10,000 tablets having the above composition are prepared as follows: 1- [ [[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl]-
2,4-imidazolidinedione dihydrochloride 3.00 kg, dicalcium phosphate 2.19 kg, crospovidone 0.60
kg and 0.12 kg of povidone are blended in a Patterson-Kelly blender and then granulated with water using a strengthening bar.

Dry the granules on trays in an oven or fluid bed dryer. The granules are then ground through a 12 mesh screen using a vibrator or other suitable mill.

The granules are blended with 60 g of talc and 30 g of magnesium stearate. Finally, the granules, talc and magnesium stearate mixture are compressed into 600 mg tablets on a suitable tablet press.

Tablets prepared as described above are provided to patients with cardiac arrhythmia and / or fibrillation utilizing dosage regimens appropriate for the particular patient.

[0184]Example O 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- (4-methyl-1
-Piperazinyl] butyl] -2,4-imidazolidinedi
Manufacture of oral dihydrochloride capsules Compound 1-[[[5 prepared as described in Example A
-(4-chlorophenyl) -2-furanyl] methylene]
Amino-3- [4- (4-methyl-1piperazinyl) butane
Chill] -2,4-imidazolidinedione dihydrochloride
The oral capsule has the following composition:Active ingredient 1-[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride 300 mgExcipient Lactose 92mg Starch sodium glycolate 40mg Pregelatinized starch 25mg Talc 12mg Magnesium stearate 3mg Hard gelatin capsule shell 1 / capsule 10,000 oral capsules having the above composition are as follows
Producing: 1-[[[5- (4-chlorophenyl) -2
-Furanyl] methylene] amino] -3- [4- (4-me
Tyl-1-piperazinyl] butyl-2,4-imidazoli
Zindione dihydrochloride 3.00 kg, lactose 0.92 k
g, 0.40 kg of sodium starch glycolate and before
0.25 kg of gelatinized starch Patterson-Kerive
Blend in render and granulate with water using a strengthening bar
You.

The granules are dried on trays in an oven or fluid bed dryer.

The granules are milled through a 12 mesh screen using a vibrator or other suitable mill. Granules with talc 120
g and 30 g of magnesium stearate.

Finally, 472 mg of the granule, talc and magnesium stearate mixture are filled into each capsule shell with a suitable capsule filling machine.

The oral capsules prepared as described above are given to patients with cardiac arrhythmia and / or fibrillation in an appropriate dosage regimen.

[0189]Example P 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [3- [4- (2-hydr
Roxyethyl) -1-piperazinyl] propyl] -2,
Production of 4-imidazolidinedione dihydrochloride oral capsule 1-[[[5- (4 (4) prepared as described in Example E
-Chlorophenyl) -2-furanyl] methylene] amido
No] -3- [3- [4- (2-hydroxyethyl) -1
-Piperazinyl] propyl] -2,4-imidazolidine
Oral capsules containing dione dihydrochloride have the following composition:
Do:Active ingredient 1-[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidin Dione dihydrochloride 175mgExcipient Microcrystalline cellulose 120mg Crospovidone 25mg Povidone 5mg Talc 5mg Magnesium stearate 2mg Hard gelatin capsule shell 1 / capsule 10,000 capsules having the above composition are manufactured as follows
1-[[[5- (4-chlorophenyl) -2-f
Ranyl] methylene] amino] -3- [3- [4- (2-
(Hydroxyethyl) -1-piperazinyl] propyl]-
1.75 kg of 2,4-imidazolidinedione dihydrochloride, fine
1.20 kg crystalline cellulose, 0.25 kg crospovidone
And 0.05 kg of povidone in Patterson-Kelly or other
Blend in a suitable blender and then use a strengthening bar
And granulate with water.

The granules are dried on trays in an oven or fluid bed dryer. The granules are milled through a 12 mesh screen using a vibrator or other suitable mill. Granules 50 g of talc and 20 g of magnesium stearate
Blend with.

322 mg of the granule, talc and magnesium stearate mixture are filled into each capsule shell with a suitable capsule filling machine.

The oral capsules prepared as described above are given to patients with cardiac arrhythmia and / or fibrillation in a suitable dosage regimen.

[0193]Example Q 1-[[[5- (4-chlorophenyl) -2-furani
L] methylene] amino] -3- [4- (4-methyl)-
1-piperazinyl] butyl] -2,4-imidazolidine
Production of lyophilized injection of dione dihydrochloride Solutions suitable for use as intravenous (IV) injections include:
Having the composition:Active ingredient 1-[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride 400 mgExcipient Mannitol 500 mg Citric acid / sodium citrate Sufficient amount to adjust pH to 5.5 to 6.5 V. Make 1000 vials of the above solution for injection
The method is described below.

1-[[[5- (4-chlorophenyl)-
2-furanyl] methylene] amino] -3- [4- (4-
Methyl-1-piperazinyl] butyl] -2,4-imidazolidinedione dihydrochloride 400 g, mannitol 500
9. Sufficient sodium citrate and / or citric acid to obtain a solution of pH 5.5-6.5 in sterile water for injection.
Dissolve in 0 l.

The resulting solution is sterile filtered through a 0.2 micron filter and filled into vials in a volume of 10 ml per vial.

The vial is placed in a freeze dryer, frozen, dried and stoppered. Immediately before injecting the lyophilized product with sterile water 10
Dilute with ml.

For patients with cardiac arrhythmia and / or heart fibrillation, the I.S. V. Make an injection.

Example R Any of the 4-oxocyclic urea compounds prepared in Examples AL can be used in place of the active ingredients utilized in the preparation of the various dosage forms of Examples MQ.

Example S A 57 year old Caucasian man becomes unconscious and has no palpable pulse at home. Family members begin cardiopulmonary resuscitation. The first rhythm recorded by the rescue squad is ventricular fibrillation. The patient resurrected successfully.

The patient had a myocardial infarction three years ago and has had stable angina since.

During subsequent hospitalizations, it is known that the patient has not had a myocardial infarction. Monomorphic ventricular tachyarrhythmias are induced by programmed electrical stimulation.

[0202] The patient's cardiologist should give 350 doses twice daily after meals.
1-[[[5- (4-chlorophenyl) -2
-Furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl] butyl] -2,4-imidazolidinedione dihydrochloride After 4 days of treatment, the arrhythmia is repeatedly programmed Not induced by electrical stimulation test.
The patient has developed no further cardiac arrest for the next two years and treatment is continuing.

Example T A 65 year old black man has a syncope attack prior to palpitations. Over the past few months, the patient had frequent palpitations, and had a near-stunning attack once. He has a history of hypertensive cardiovascular disease, diabetes, minor myocardial infarction and obesity.

[0204] Slow single ventricular tachyarrhythmias are induced by programmed electrical stimulation. The patient's cardiologist may give 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino]-at a 350 mg oral dose once daily after meals.
3- [4- (4-methyl-1-piperazinyl] butyl]
Prescribe -2,4-imidazolidinedione dihydrochloride.
After several days of treatment, the arrhythmia is not induced by repeated programmed electrical stimulation. During the following three years of observation, there is no further occurrence of syncope or previous syncope.

EXAMPLE A 58-year-old Oriental female patient with U cardiomyopathy exhibits recurrent syncope. She has an ejection fraction of 35%. Programmed electrical stimulation (PE
S) induces almost unacceptable slow ventricular tachyarrhythmias that do not respond to three different antiarrhythmic drugs. The fourth drug, moricidin, reduces the rate of tachyarrhythmias and is ongoing, although tachyarrhythmias still induce hypotension. She has been implanted with an automatic implantable cardioverter defibrillator (AICD).

The defibrillator is available two years after the AICD implantation.
Has been discharged several times. The monitor of the device records the ventricular tachyarrhythmia during defibrillation. After the second discharge, the patient was hospitalized. Brady-single ventricular tachyarrhythmias are induced by PES. Moricidin was discontinued and 1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3
-[4- (4-methyl-1-piperazinyl] butyl]-
2,4-imidazolidinedione dihydrochloride 2 times a day after meal
Initiated by the patient's cardiologist at an oral dose of 350 mg each time. After several days with repeated PES, no arrhythmia is induced and the defibrillation threshold is not reached. In subsequent years, no further discharge was experienced.

Example V A 35 year old woman has a 15 year history of frequent (twice / month) seizures of rapid heartbeat lasting several hours with dizziness and fatigue. These seizures are taking her time to work. A telephone course monitor shows spastic supraventricular tachyarrhythmia. The patient's physician stated that 1-
[[[5- (4-Chlorophenyl) -2-furanyl] methylene] amino] -3- [4- (2-hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione dihydrochloride To prescribe. In subsequent years, the frequency of these attacks decreased to once every other month, indicating a marked improvement in her attendance record.

EXAMPLE W A 75 year old Caucasian male with a history of smoking 50 packs per year shows onset of atrial fibrillation recorded by telephone monitor three times a month and is on digoxin and quinidine therapy. These seizures sometimes last for eight hours and, due to their weakness, prevent their daily activities, such as gardening, from being carried out by the patient. The patient's doctor will give 175 mg of quinidine to the patient
1-[[[5- (4-chlorophenyl) -2-furanyl] methylene] amino] -3-
[3- [4- (2-Hydroxyethyl) -1-piperazinyl] propyl] -2,4-imidazolidinedione dihydrochloride. The frequency of seizures then decreases to monthly over the course of four months of observation.

Example X A 40 year old Caucasian male has a history of frequent palpitations of several years.
The patient developed anxiety and shortness of breath on palpitations, and his heart became dominated by fear of death. Detailed evaluation indicated the absence of structural heart disease. Holter monitoring showed a single lesion at 2500 caplets / day at 50 caplets / day. Successful propranolol therapy as well as cheer up was ineffective.

The physician was advised to give an oral dose of 350 mg / day after meals.
-[[[5- (4-chlorophenyl) -2-furanyl]
Methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride is formulated.

The frequency of palpitations was reduced, and the associated anxiety and shortness of breath were reduced. 250 PV for holter monitoring
Shows C / day and does not show repetitive forms. Dedicated to death has disappeared for several months. The patient has been closely monitored and has remained healthy for the next five years.

Example Y A 58-year-old black man with a 10-year history of non-insulin-dependent diabetes mellitus and cholesterol levels above 300 mg / dl has a myocardial infarction. Two weeks after the infarction, he is asymptomatic except for dyspnea during work. His ejection fraction was 29%, and 50 hours of Holter monitoring was 50 hours.
Single lesion PVC / hr, showing ventricular tachyarrhythmia with occasional caplets and 1-5 beating runs.

His cardiologist suggested an oral dose of 350 mg / day after meals at 1-[[[5- (4-chlorophenyl) -2-).
Furanyl] methylene] amino] -3- [4- (4-methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione dihydrochloride is formulated. Repeat holter monitoring shows disappearance of all repeats and an average of 9 PVC / hr. The patient has been in good health for three years of ongoing care.

Example Z Any of the patients described in Examples SY may utilize any of the ingredients described in Examples AL to receive any of the dosage forms obtained in Examples MQ. Can be treated.

[0215]

The novel compounds of the present invention are effective against cardiac fibrillation and supraventricular and ventricular arrhythmias. Also, the novel compounds of the present invention do not show some of the undesirable effects that have been tolerated by many of the conventional antiarrhythmic drugs. In addition, the compounds are readily bioavailable and facilitate treatment by oral administration. Furthermore, the compounds are relatively inexpensive to produce,
Shows high stability in oral dosage form.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/535 A61K 31/535 A61P 9/06 A61P 9/06 C07D 405/12 C07D 405/12 405/14 405/14 413 / 12 413/12 413/14 413/14 (72) Inventor Carcanho, Mark Arthur Oxford, New York, USA, Box, 163 A, Aal, Dee, Number, 2 (56) References 48665 (JP, A) Journal of Medicinal Chemistry; vol. 16 (No. 8) p953-9 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 233/80 C07D 405/12 C07D 405 / 14 C07D 413/12 C07D 413/14 CA (STN) REGISTRY (STN)

Claims (17)

(57) [Claims] 1. A novel 4-oxocyclic urea compound having the following general structure, a pharmaceutically acceptable salt thereof, or a biohydrolyzable ester: Wherein a) X is a saturated or unsaturated 5, 6 or 7 membered heterocycle or carbocycle; b) R is a covalent bond, no heteroatom, carbonyl, heterocycle, carbocycle, Alkyl, alkenyl, alkoxy,
Alkylamino, arylalkyl, aryloxy,
Selected from the group consisting of acyl, acyloxy, and acylamino; c) Y is substituted or unsubstituted, saturated or unsaturated, 5,
In the above, when R is absent, X and Y are fused ring systems, and when R is a covalent bond, X and Y are through a covalent bond. R is a covalent bond and X is connected to L via R; d) R ₁ , R ₂ , and R ₃ are null, Cl, F, Br,
NH ₂ , CF ₃ , OH, SO ₃ H, CH ₃ SO ₂ NH,
E) L is independently selected from the group consisting of COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy, and acylamino; e) L is alkylamino, alkenylamino, alkenylimino, alkylimino, And wherein the nitrogen atom of L is attached to the nitrogen atom at position 1 of the 4-oxocyclic urea ring moiety; f) R ₄ is alkyl, alkenyl, alkynyl, alkyl G) A is substituted or unsubstituted, saturated or unsaturated, linear or branched C ₁ -C ₈ heteroalkyl, or 5,
A substituted or unsubstituted, saturated or unsaturated heterocycle having 6 or 7 members, wherein A has at least one nitrogen atom adjacent to R ₄ ; h) R ₅ is a substituted or unsubstituted C is ₁ or C ₂ alkyl; provided, X is an aromatic ring, R is a covalent bond, Y
Is a substituted or unsubstituted unsaturated 5, 6, or 7 membered heterocyclic ring; L is selected from the group consisting of alkylamino, alkenylamino, and acylamino; or A is 5, 6, or 7 membered Or a substituted or unsubstituted, saturated or unsaturated, linear or branched C ₁ -C ₈ heteroalkyl. ]. 2. The compound according to claim 1, wherein R is adjacent to X at position 1 of X and to Y at position 5 of Y. 3. The compound according to claim 2, wherein Y is conjugated to the carbon-containing end of L at the 2-position of Y. 4. The compound according to claim 1, wherein the heteroatom of Y is oxygen at the 1-position of the heterocycle. 5. _One of R ₁ , R ₂ or R ₃ is:
Cl, F, or Br; R ₁ , R ₂ , or R ₃
5. The compound according to claim 4, wherein two of them are absent. 6. 1-[[[4-hydroxy-3,5-dimethylphenyl] methylene] amino] -3- [4- (4
-Methyl-1-piperazinyl) butyl] -2,4-imidazolidinedione; 1-[[[5- (4-bromophenyl) -2-oxazolidinyl] methylene] amino] -3
-[4- (4-methyl-1-piperazinyl) 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; and their pharmaceutically acceptable hydrochlorides and maleic acid The compound of claim 1, wherein the compound is selected from the group consisting of acid salts. 7. The compound according to claim 1, wherein R ₄ is C ₃ -C ₆ alkyl. 8. The compound according to claim 1, wherein R ₄ is substituted alkyl. 9. The compound according to claim 1, wherein the nitrogen atom of the heteroalkyl A has a substituent. 10. The compound according to claim 1, wherein A has two nitrogen atoms. 11. The compound according to claim 10, wherein the nitrogen atom of A not bonded to R ₄ has a substituent. 12. The compound according to claim 1, wherein the heterocycle A has 6 members and is substituted at the 4-position. 13. The method according to claim 9, wherein the substituent is selected from the group consisting of methyl, hydroxyethyl, alkyl, aryl, heterocycle, arylalkyl, mercaptoethyl, and methanesulfonyl.
2. The compound according to 1. 14. The compound of claim 12, wherein said substituent is selected from the group consisting of hydroxyethyl, hydroxy, oxo, and methyl. 15. A stable effective amount of from 15 to 90% of the 4-oxocyclic urea compound or a mixture thereof according to claim 1,
A pharmaceutical composition for use as at least one of an antiarrhythmic agent and an antifibrillation agent, comprising 10 to 85% of a pharmaceutically acceptable excipient. 16. The pharmaceutically acceptable excipient may be a polymer, resin, plasticizer, filler, binder, lubricant, lubricant, disintegrant, solvent, co-solvent, buffer system, surfactant. A preservative, a sweetener, a flavoring agent, a pharmaceutical grade dye or pigment, and a viscosity agent, wherein at least one of the antiarrhythmic agent and the anti-fibrillation agent according to claim 15, characterized in that it is selected from the group consisting of: Pharmaceutical composition used. 17. 4-oxocyclic urea active ingredient (or mixture thereof) 15-95%, flavoring agent 0-2%, cosolvent 0
-50%, buffer system 0-5%, surfactant 0-2%, preservative 0-2%, sweetener 0-5%, viscosity agent 0-5%, filler 0-75%, lubricant The antiarrhythmic and antifibrillation agent according to claim 16, characterized in that it contains 0.5 to 2%, a lubricant 1 to 5%, a disintegrant 4 to 15% and a binder 1 to 10%. A pharmaceutical composition used as at least one.