Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-07-28
2001-07-24
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S605000, C514S630000, C514S654000, C514S821000, C564S027000, C564S099000, C564S220000, C564S353000, C564S354000
Reexamination Certificate
active
06265445
ABSTRACT:
The present invention relates to novel, antiarrhythmically active phenoxyalkylamine derivatives possessing a double point of attack. More particularly, the present invention relates to new phenoxyalkylamine derivatives of the formula (I)
and their salts as well as pharmaceutical compositions containing these compounds.
It is known that cardiac arrhythmias represent one of the most severe fields of cardiovascular disorders. Out of these, the most serious one is cardiac ventricular fibrillation, which is the most frequent immediate cause of the sudden cardiac death and leads to about 400,000 deceases in one year in the United States alone. Atrial fibrillation also accompanied by serious complications occurs at nearly one million persons. The most widely used method of treatment of arrhythmias is drug therapy. Nevertheless, the agents available at present cannot by far be considered to be the best solutions: their use may significantly be limited by their serious side effects. From this point of view, the negative results of two series of comprehensive clinical investigations [CAST I and CAST II. The CAST Investigators, N. Engl. J. Med. 321, 406 (1989) and ibidem 327, 227 (1992)] bringing to light that some so-called class IC antiarrhythmic agents with slow-recovery kinetics, which inhibit the maximal rate of repolarization of the action potential of heart, i.e. the sodium channel, deteriorated the chances of survival of patients recovering from myocardial infarction [an up-to-date classification of antiarrhythmics is presented e.g. by A. O. Grant., Jr. and N. C. Durham: Am. Heart J. 123, 1130,(1992)]. These unfavourable results can be brought into relation to the proarrhythmic (i.e. arrhythmia-provoking) effect and negative inotropic [i.e. cardiac performance (output)-weakening] effect of IC class antiarrhythmic agents. Later, it turned out that similarly, antiarrhythmic agents of class III, calling an increasing attention in the early 90's [which prolong the duration of action potential and therefore, the effective refractory period (abbreviated ERP)], are not free of dangerous side effects; and the clinical trials of d-sotalol (chemically d-N-[4-[1-hydroxy-2-(1-methylethylamino)ethyl]phenyl]methanesulfonamide hydrochloride) as a prototype of class III were even interrupted in the treatment group because of the increase in mortality ascribable to the proarrhythmic effect [see e.g. P. Mátyus, A. Varró, J. Gy. Papp et al.: Med. Res. Rev. 17, 427 (1997)].
There exist the dangers or limits, respectively, of the use of two additional antiarrhythmic drug classes (II and IV) as well as of two other subgroups (IA and IB) of the sodium channel blocking class I (especially in the case of classes IV and IA).
Even on the basis of those said above it is obvious that a high demand exists on a new type, safe but simultaneously suitably active antiarrhythmic agent. The aim of the invention is to develop an active agent and composition, respectively, meeting these requirements.
A number of phenoxyalkylamine derivatives are known in the literature. However, both their chemical structures and biological effects are different from the compounds of formula (I) of the present invention.
Hereinbelow, only the references describing the substances with structures most related to those according to the present invention are summarized.
The EP 245,997 relates to antiarrhythmically effective bis(arlkyl)amines and phenoxyalkylamine derivatives, from which some compounds exert a positive inotropic action, too. According to the authors, these compounds are selective antiarrhythmics of class III. The derivative of formula (VI)
containing methanesulfonamido group in 4-positions of both phenyl rings was found to be most active.
The published Japanese patent application No. 06,107,614 discloses compounds not falling within the scope of the present invention, which can be characterized by formula (I), wherein R
1
, R
2
and R
3
mean hydrogen, both n and m are 0, or one of them is 1; R
6
means hydrogen, alkyl, formyl or alkylthiocarbamoyl group and R
7
stands for amino group substituted by p-chlorobenzenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl, 8-quinolinesulfonyl, 1-naphthoyl or 2-pyridinecarbonyl group. According to the description these compounds are endowed of antiulcer effects.
In U.S. Pat. No. 4,044,150 4′-[1-hydroxy-2-[(1-phenoxyethyl)amino]ethyl]-methanesulfonanilide of formula (VII)
and the salts thereof are disclosed, which have a chemical structure standing near to a part of compounds of the present invention. According to the authors of this patent these substances are &bgr;-adrenerg receptor-blocking agents and as such they may be useful as antihypertensives.
Phenoxyalkylamine derivatives possessing chemical structures standing near to the compounds of the invention are known from GBP 2,088,873, wherein the phenoxy group can be mono- or disubstituted by hydrogen, halogen, hydroxyl or alkoxy group, while the phenyl group(s) on the other end of the alkylaminoalkyl chain can be di- or trisubstituted by a para-hydroxyl or amino group and/or meta-halogen(s) as well as trifluoromethyl, cyano or nitro group(s). According to the authors, these compounds act on the heart and circulation, more particularly they exert antihypertensive, antiarrhythmic and/or cardiotonic effects. However, the biological data given in the description confirm only the positive inotropic efficiency of the compounds.
Finally, it is mentioned as a point of interest that compounds analogous to substances of formula (I) of the invention, the phenoxy group of which is substituted by an acylamino group, and the phenyl group on the other end of the alkylaminoalkyl chain is substituted by a C
1-4
alkyl or alkoxy group and/or halogen (which, consequently, contain a substitution inverse to the compounds of the invention), possess an antitumour effect (EP 494,623).
It has surprisingly been found during our investigations that the compounds of formula (I) possess a strong antiarrhythmic action and do not exhibit adverse side effects. In their mode of action, IB and III type effects are associated to result in a very favourable antiarrhythmic action of broader spectrum than those characterizing the individual components of action; this is a consequence of the combined mechanism. Simultaneously, it has been stated that the compounds of formula (I) are free from serious adverse effects, which are characteristic of the classes I and III.
These favourable pharmacological properties of the compounds of formula (I) are particularly surprising in view of the literature data. Namely, concerning the chemical structural requirements of antiarrhythmics of classes IB and III, there exists a standpoint that the antiarrhythmic action of class IB is characteristic of ortho-disubstituted phenoxyalkylamino (or isosteric) systems containing a short alkyl chain and an amino substituent with small steric demand (cf. e.g. tocainide, lidocaine); whereas compounds exerting a strong effect of class III are characterized by a structure containing two phenyl groups connected by a relatively long chain, wherein both of the phenyl groups have typically para-positioned, i.e. symmetrically situated, electron-attracting substituents [for the detailed analysis of structure-effect relations, see e.g.: P. Mátyus, A. Varró, J. Gy. Papp et al: Med. Res. Rev. 17, 427 (1997)].
Consequently, it is surprising even to one skilled in the art that compounds of formula (I) according to the invention, which have a structure fundamentally different from the typical representatives of antiarrhythmics of both classes IB and III, possess a significant antiarrhythmic effect associating the effects of both types IB and III while they are free from proarrhythmic or negative inotropic effects.
From the literature it is well known that compounds with a double point of attack are very important for the pharmaceutical chemistry [see e.g.: “The Practice of Medicinal Chemistry”
Barlocco Daniella
Berzsenyi Pal
Cignarella Giorgio
Druga Alice
Matyus Peter
Gyogyszerkutato Intezet KFT
Keil & Weinkauf
O'Sullivan Peter
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