Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-28
2001-10-09
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S471000, C514S617000, C549S425000, C549S487000, C564S099000, C564S176000
Reexamination Certificate
active
06300368
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel anilide derivatives and antiarrhythmic agents containing them as an active ingredient.
DESCRIPTION OF THE RELATED ART
Cardiac arrhythmia can be divided into two large groups; ventricular and supraventricular arrhythmia. There are many antiarrhythmic agents already in market in order to suppress and prevent these arrhythmia. According to the classification system by Vaughan Williams, these agents can be classified into Class I suppressing the sodium channel in cardiac muscle, Class II being the &bgr;-blocker, Class III suppressing the potassium channel and Class IV suppressing calcium channel.
Ventricular arrhythmia sometimes causes severe blood circulation failure due to the function of ventricle to deliver blood to arteria and thus arrhythmia such as severe ventricular flutter and fibrillation is fatal. Therefore, a large scale clinical trials such as CAST (Cardiac Arrhythmia Suppression Trial) with Class I drugs such as Flecainide and Encainide and SWORD (Survival With Oral d-Sotalol Trial) with Class III drugs such as d-Sotalol in order to prove that prevention of ventricular arrhythmia results in decrease in mortality of patients.
However, results obtained indicated that treatment with these drugs make worse vital prognosis rather than placebo group and gave a warning for use of antiarrhythmic agents at random. Suppression of cardiac function by antiarrhythmic agents when they acted on ventricle and occurrence of new arrhythmia by effect of drugs so called proarrhythmia have been considered as a cause of such aggravation of vital prognosis. According to mode-of-action of existing antiarrhythmic agents, those belong to Classes I, II and IV essentially act on cardiac function as suppresser and those belong to Classes I and III pose a risk of proarrhythmia, therefore a new type of antiarrhythmic agent has been required.
On the other hand, supraventricular arrhythmia is very rare to become directly lethal, but in particular, atrial arrhythmia such as atrial flutter and fibrillation is very high in incidence, causes poor QOL (Quality of Life) problem because of giving strong subjective symptoms such as palpitation, gasping and heart pains, and could move to ventricular arrhythmia which endangers to one's life if it leaves without medical care. For chronic atrial fibrillation, it is well known that blood aggregate as a risk factor of cerebral thrombosis is readily formed due to intra-atrial congestion. Class I drugs are mainly used for atrial arrhythmia, and Class III drugs and Class II drugs may be used for atrial fibrillation associated with hypertrophic cardiomyopathy and sympathicotonic atrial fibrillation, respectively. However, antiarrhythmic agent which selectively acts on atria is not available, so that the same antiarrhythmic agents being used for ventricular arrhythmia are used for atrial arrhythmia.
Therefore, they also act on ventricle and have potential risks such as suppression of cardiac function, proarrhythmia and moreover aggravation of vital prognosis by chronic administration. These potential risks are serious problems because atrial arrhythmia itself is not lethal arrhythmia. Moreover, due to dose limitation to avoid side effect, suppression and prevention effects of atrial arrhythmia is not satisfactory for existing antiarrhythmic agents (Medicine and Drug Journal, Vol. 30, No. 9, 24-81, 1994).
Japanese Patent Laid-Open (Kokai) No. 125032/76 describes 4′-[2-(isopropylamino) ethoxy] acetanilide and 4′-[2-(cyclohexylamino) ethoxy] acetanilide as an example compound which are similar to the anilide derivatives having antiarrhythmic effect in the present invention. This document describes that these compounds act suppressively on ventricular function. In addition, these compounds differ from the anilide derivatives represented by Formula (1) in the present invention in the point that their R
1
is alkyl group.
SUMMARY OF THE INVENTION
An object to be solved according to the present invention is to provide a new type of antiarrhythmic agent free from ventricular function suppression and proarrhythmia and being highly safe.
As the results of active investigation conducted by the present inventors to achieve the above object, the present inventors have found that novel anilide derivatives having specific structure possess following pharmacological characteristics:
(1) Exhibit suppression and prevention effects of arrhythmia at dose levels from 0.3 to 10 mg/kg in aconitin-induced atrial fibrillation model and vagal atrial fibrillation model in anaesthetized dogs as well as in sterile pericarditis atrial flutter model in conscious dogs.
(2) Many compounds extend the effective refractory period of atria, but do not obviously affect on these of ventricle.
(3) Do not obviously affect on action potential in Purkinje's fiber in dogs.
(4) Do not obviously affect on cardiac blood circulation behavior and electrocardiogram in both anaesthetized and conscious dogs.
(5) Very weak side effect in acute toxicity and in central nervous system except for cardiac system.
Based on above findings, the present invention providing new type of antiarrhythmic agents free from effects on ventricular function and having superior effectiveness particularly to atrial arrhythmia has been completed.
Thus, the present invention relates to anilide derivatives expressed by formula (1):
wherein:
R
1
represents a phenyl group (except for monoalkoxy phenyl group) having one or two substituents selected from C
1-3
alkoxy, C
1-3
alkyl, C
1-3
alkanesulfonamido and C
1-3
alkanesulfonyl groups, a furyl group, a 2,3,4,5-tetrahydrofuryl group, a 3,4,5,6-tetrahydro-2H-pyranyl group or —(HC
2
)
n
OR
6
(wherein, n represents an integral number 2 or 3, R
6
represents a C
1-4
alkyl group), R
2
and R
3
represent independently a hydrogen atom, a C
1-3
alkoxy group, a C
1-3
alkyl group, or a C
1-3
alkanesulfonamido group, R
4
and R
5
represent independently a hydrogen atom, a C
1-4
alkyl group, a C
3-6
cycloalkyl group, or —(CH
2
)
n
OR
6
(wherein, n represents an integral number 2 or 3, R
6
represents a C
1-4
alkyl group), or R
4
and R
5
together form —(CH
2
)
2
W(CH
2
)
2
— (wherein, W represents a direct bond, a methylene bridge or an oxygen atom); or their pharmacologically acceptable salts. The present invention relates also to antiarrhythmic agents containing one or more of the above anilide derivatives and their pharmacologically acceptable salts.
The present invention provides antiarrhythmic agents free from any effects on ventricular function. These antiarrhythmic agents are free from any risks such as cardiac function suppression and proarrhythmia, highly safe and particularly useful as therapeutic agent for atrial arrhythmia.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The present invention will be fully described below.
Compounds of the present invention represented by formula (1) are characterized in having anilide structure in the molecule with an amine side chain represented by —OCH
2
CH
2
NR
4
R
5
attached to para-position thereof.
Regarding the substituents of the phenyl group as R
1
in formula (1), C
1-3
alkoxy groups include methoxy, ethoxy, propoxy and isopropoxy groups, C
1-3
alkyl groups include methyl, ethyl, propyl, isopropyl groups, C
1-3
alkanesulfonamido groups include methanesulfonamido, ethanesulfulfonamido, propanesulfonamido, and isopropanesulfonamido groups, C
1-3
alkanesulfonyl groups include methanesulfonyl, ethanesulfonyl, propane/sulfonyl, and isopropanesulfonyl groups. These substitutions can take place arbitrarily at one or two positions in phenyl group. However, the monoalkoxyphenyl group is excluded from the substituted phenyl group having only one alkoxy group, because its effect on the central nervous system is strong. Preferably, at least one of these substituents may substitute at the 2-position of the phenyl group, more preferably 2,6-dimethoxyphenyl, 2,6-diethoxylphenyl, 2,6-dimethylphenyl, substituted phenyl with C
1-
Kai Akiyoshi
Kawai Kohichi
Mohri Junichi
Mori Haruki
Oyabe Akihiro
Burns Doane Swecker & Mathis L.L.P.
Mitsui Chemicals Inc.
Powers Fiona T.
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