Oxocyclohexa compounds of urea, pharmaceutical composition, method of treatment

 

The invention relates to 4-oxocyclohexyl the urea compounds of General formula (I), where X, Y, R, R1, R2, R3, R4, R5And L, such as defined in the claims. Also described pharmaceutical composition on the basis of these compounds and a method of treating arrhythmia and cardiac fibrillation. The technical result obtained new compounds possess valuable biological properties. The invention can be used in medicine as a therapeutic agent for the treatment of arrhythmias and cardiac fibrillation. 3 S. and 11 C.p. f-crystals, 1 PL.

Description text in facsimile form (see graphic part)and

Claims

1. Oxocyclohexa connection urea of General formula

in which X represents a saturated or unsaturated 5-, 6 - or 7-membered, carbocycle;

R is chosen from the group consisting of a covalent bond, oxygen atom, carbonyl group, preferably a covalent bond; or R is absent;

Y is substituted or unsubstituted, saturated or unsaturated 5 - or 6-membered, preferably 5-membered, gay condensed ring systems; and when R represents a covalent bond, X and Y represent a ring system, connected through a covalent bond; and when Y is absent, R is covalent bond and X is connected to L through R;

R1, R2and R3independently selected from the group consisting of chlorine, fluorine, bromine, HE, and alkyl groups, or any of R1, R2and R3no, preferably chlorine, fluorine, bromine, CH3and HE;

L is chosen from the group consisting of alkylamino, alkylamino, where the nitrogen atom of the group linked to the nitrogen atom, which is 1 position 4-oxocyclohexa ring parts urea;

R4selected from the group consisting of alkyl and alkenylphenol groups;

A represents a substituted saturated straight chain or branched (C1-C8)heteroalkyl group, or a substituted or unsubstituted, saturated 5 - or 6-membered heterocycle, preferably a 6-membered heterocycle, and most preferably a heterocycle containing two nitrogen atom; and

R5represents unsubstituted (C1) or (C2) alkyl group, preferably (C1) alkyl group,

or their pharmaceutically acceptable salts or esters.

2. Oxocyclohexa connected which allows carbonyl group.

4. Oxocyclohexa connection urea under item 1, where R is missing.

5. Oxocyclohexa connection urea under item 1, where a represents C1-C8heteroalkyl group.

6. Connection on p. 1, where R is a covalent bond and is attached to X in position 1 of the groups X and Y in position 5 of group Y.

7. Connection on p. 1, where Y represents a 5-membered heterocycle, preferably oxygen-containing heterocycle, where Y is linked to the carbon end of the L in position 2 group Y.

8. The compound according to any one of paragraphs.1-7, where the heteroatom Y is oxygen, which is 1 position specified heterocycle.

9. The compound according to any one of paragraphs.1-8, where one of R1, R2or R3represents chlorine, fluorine or bromine, and two of R1, R2or R3no.

10. The compound according to any one of paragraphs.1-9, selected from the group including

1-[[(5-chloro-2-hydroxyphenyl)methylene]amino]-3-[2-(1-piperidinyl)ethyl]-2,4-imidazolidinedione hydrochloride;

3-[[(5-chloro-2-hydroxyphenyl)methylene]amino]-3-[3-(4-methylpiperidino)propyl]-2,4-imidazolidinedione hydrochloride;

3-[3-(dimethylamino)propyl]-1-[[(2-hydroxy-1-naphthalenyl)methylene]amino]-2,4-imidazolidinedione hydrochloride;

3-[3-(dimethylamino)propyl]-1-[[(2-kenolio]-2,4-imidazolidinedione hydrochloride:

1-[[[5-(4-bromophenyl)2-oxazolyl]methylene]amino]-3-[3-(dimethylamino)propyl]-2,4-imidazolidinedione hydrochloride;

1-[[(2,4-dichlorophenyl)methylene]amino]-3-[3-(4-methyl-1-piperazinil)propyl]-2,4-imidazolidinedione dhirajlal;

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

3-(3-dimethylaminopropyl)-1-[[(2-fluorenyl)methylene]amino]-2,4-imidazolidinedione hydrochloride;

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

1-[[[5-(1-cyclohexen-1-yl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinil)butyl]-2,4-imidazolidinedione the dihydrochloride;

3-[2-(dimethylamino)ethyl]-1-[[(2-naphthalene)methylene]amino]-2,4-imidazolidinedione hydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[2-(dimethylamino)ethyl]-2,4-imidazolidinedione hydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[3-(N,N-dimethylamino)propyl]-2,4-imidazolidinedione hydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-(4-dimethylaminomethyl)-2,4-imidazolidinedione hydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[2-(4-methyl-1-piperazinil)ethyl]-2,4-imidazolidinedione the dihydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[2-(1-piperidinyl)ethyl]-2,4-imidazolidinedione what she dihydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[6-(4-methyl-1-piperazinil)hexyl]-2,4-imidazolidinedione the dihydrochloride;

1-[[[3-(4-chlorophenoxy)phenyl]methylene]amino]-3-[3-(4-methylpiperazine)propyl]-2,4-imidazolidinedione the dihydrochloride;

1-[[(3-benzoyl-2,4-dichlorophenyl)methylene]amino]-3-[3-(dimethylamino)propyl]-2,4-imidazolidinedione hydrochloride;

1-[[(3-benzoyl-2,4-dichlorophenyl)methylene]amino-3-[3-[(4-methylpiperazine)propyl]-2,4-imidazolidinedione the dihydrochloride;

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

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

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

3-(3-(dimethylamino)propyl)-1-[[(5-phenylphenyl)methylene]amino]-2,4-imidazolidinedione hydrochloride;

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

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

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

ID;

(E,e)-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[4-(4-methyl-1-piperazinil)-2-butene]-2, 4-imidazolidinedione the dihydrochloride;

1,1-dimethylethylene ether (L)-N-[1-[4-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-2,4-dioxo-3-imidazolidinyl]butyl]Proline.

11. The compound according to any one of paragraphs.1-9, where the nitrogen atom And that is not associated with the R4is substituted, and the substituents selected from the group consisting of methyl, hydroxyethylene, alkyl, aryl, heterocyclic, arylalkyl, mercaptoethanol and methanesulfonyl groups.

12. Pharmaceutical composition for the treatment of arrhythmia and fibrillation, characterized in that it includes a safe and effective amount of from 15 to 90% oxocyclohexa connection urea under item 1 or a mixture of such compounds and from 10 to 85% of pharmaceutically acceptable excipients selected from the group consisting of 0-2% corrigentov, 0-50% co-solvents, 0-5% buffer, 0-2% of surface-active agents, 0-2% preservatives; 0-5% sweeteners agents, 0-5% thickeners, 0-75% fillers, 0.5 to 2% of a lubricating agent, 1-5% of glidants, 4-15% baking powder and 1-10% of binders.

13. The pharmaceutical composition according to p. 12, wherein the pharmaceutically acceptable excipients are selected from the group consisting of the lei, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, corrigentov, pharmaceutical dyes or pigments and substances substances.

14. The method of treatment of a human or other mammal suffering from cardiac arrhythmia and/or cardiac fibrillation, characterized in that it includes the introduction of the aforementioned person or other mammal a safe and effective amount of a compound according to any one of paragraphs.1-11 or pharmaceutical compositions by p. 12.

 

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< / BR>
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< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

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< / BR>
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< / BR>
in which X denotes O or S;

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< / BR>
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