Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-14
1998-01-27
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514304, 546112, 546124, A61K 31435, C07D45104
Patent
active
057122849
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP 94/02299, filed on Jul. 11, 1994.
The invention relates to certain novel compounds, to pharmaceutical compositions containing such compounds, to a process for the preparation of such compounds and to the use of such compounds as active therapeutic agents, particularly in the treatment of atrial or ventricular cardiac arrhythmias.
European Patent Application Number 0416521 discloses certain N-benzyltropaneamides which are stated to have activity as Class III antiarrhythmic agents, acting by prolonging cardiac action potential duration.
Chemical Abstracts 117:778 discloses
The Journal of Heterocyclic Chemistry (1978), 15, 273-280 discloses stated to analgesics.
The Journal of Heterocyclic Chemistry 31, 313-318, 1994 discloses a series of N-phenylethyl-8-.beta.-amidocamphidines and the use of such compounds to study the influence of certain stereochemical factors on analgesia in this class of compounds.
The Journal of Medicinal Chemistry 1993, Vol. 36, No. 23, 3707-3720, their affinity for dopamine D.sub.2, dopamine D.sub.3, serotonin 5-HT.sub.3 and .alpha..sub.2 adrenergic receptors.
Anti-arrhythmic agents are classified according to their electrophysiological effects on the cardiac cell (Vaugham-Williams, 1970, 1989): class I agents block the fast sodium cent, class II agents are beta-adrenergic blockers, class III agents block potassium currents, class IV agents block the calcium current, and class V agents are specific sinus node inhibitors.
A majority of ventricular and atrial arrhythmias are related to reentrant circuit. The prolongation of myocardial refractoriness within or surrounding such a reentrant circuit is a potential mechanism for the management of cardiac arrhythmias.
Because class III antiarrhythmic agents block cardiac potassium currents, they prolong the repolarisation process and increase refractoriness. Consequently class III agents represent the most specific class to treat reentrant arrhythmias.
However, due to their mechanism of action, i.e. a concentration dependent increase in the cardiac action potential duration, higher doses of class III antiarrhythmic agents may trigger arrhythmias. Such arrhythmias, called Torsade de Pointe represent the main adverse effect for all pure class III compounds currently in development.
It has been discovered that certain novel substituted azabicyclooctane derivatives induce a self-limiting increase of the cardiac action potential duration, related to a dual blockade of cardiac potassium and calcium channels. Consequently, they have an improved pharmacological profile over pure class III anti-arrhythmic agents, in particular they are indicated to have a low proarrhythmic potential and to restore the contractile function of the ischaemic myocardium.
Accordingly, the present invention provides a compound of formula (I): ##STR2## or a salt thereof, or a solvate thereof, wherein B represents a C.sub.1-4 n-alkylene group wherein each carbon is optionally substituted by a C.sub.1-6 alkyl group; wherein X represents O or S; U represents a bond; may be unsubstituted or substituted with 1 to 5 substituents selected from the list consisting of nitro, halogen, alkylsulfonamido, acylamido, 1H-imidazoyl, alkyl or haloalkyl, or Q represents substituted or unsubstituted: furanyl, pyranyl, thienyl, thiazolyl, imidazolyl, triazolyl or the benzo fused equivalents of furanyl, pyranyl, thienyl, thiazolyl, 1H-imidazolyl or triazolyl, indolyl, oxoindolyl, indenyl, isoindenyl, indazolyl, indolizinyl or pyridinyl or cycloalkyl optionally fused to an aryl group; alkoxy or, if attached to adjacent carbon atoms, any two of R.sub.1, R.sub.2 or R.sub.3 together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five or six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; substituents are the above defined R.sub.1, R.sub.2 and R.sub.3 or Ar represents a substituted or unsubstituted heteroaryl group..
Suitably, one or two of R.sub.1, R.sub.2 and R.sub.3 represents alkoxy,
REFERENCES:
patent: 5070094 (1991-12-01), Fowler
patent: 5084572 (1992-01-01), Berlin
Nadler Guy Marguerite Marie Gerard
Souchet Michel Louis
Huang Evelyn
Ivy C. Warren
Lentz Edward T.
McCarthy Mary E.
SmithKline Beecham Laboratoires Pharmaceutiques
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