Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-07-02
1999-11-02
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564166, A61K 31165, C07C23365
Patent
active
059771798
DESCRIPTION:
BRIEF SUMMARY
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.
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 current, 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 antiarrhydimic agents may trigger arrhythmias. Such arrhythmias, called Torsade de Pointe represent the main adverse effect for all pure class III compounds currently in development.
European Patent Application, Publication Number 0 245 997 discloses certain aminoethylsulphoanilides which are stated to have pure class III antiarrhythmic properties.
It has now been discovered that certain novel substituted 4-nitrobenzamide 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 are considered to be useful anti-arrhythmic agents having an improved pharmacological profile over pure class III anti-arrhythmic agents, in particular they are considered to show a low proarrhythmic potential and readily restore the contractile function of the ischaemic myocardium. They are considered to be particularly useful for the treatment of atrial or ventricular cardiac arrhythmias.
Accordingly, the invention relates to a compound of formula (I): ##STR1## or a salt thereof, or a solvate thereof, wherein Ar represents substituted or unsubstituted aryl, wherein the optional substituents are selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon atoms any two substituents together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five to six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; substituted by 1 or 2 C.sub.1-6 alkyl groups; the remaining members of the group of R.sub.2, R.sub.3 and R.sub.4 represent hydrogen; substituted by 1 or 2 C.sub.1-6 alkyl groups.
Suitable substituents for Ar are 1, or favourably, 2 alkoxy groups, especially methoxy groups, the substituents favourably being attached at the 3- and 4-positions relative to the point of attachment of Ar to variable A.
Preferably, Ar represents 3,4-dimethoxyphenyl Suitably, A represents an unsubstituted C.sub.1-4 n-alkylene group. alkyl, C.sub.3 alkyl, C.sub.4 alkyl C.sub.5 alkyl or C.sub.6 alkyl.
Preferably, R.sub.1 is hydrogen. remaining members of the group of R.sub.2, R.sub.3 and R.sub.4 represent hydrogen.
A particularly preferred compound of formula is N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4nitro benzamide or a salt thereof, such as a hydrochloride salt, or a solvate thereof.
As used herein unless otherewise stated, the term "alkyl" includes straight or branched chain alkyl groups having from 1 to 12, favourably 1 to 6 carbon atoms and shall include such alkyl groups when forming part of other groups such as alkoxy or arylalkyl groups.
As used herein, the term "alkylene" includes straight or branched chain alkylene groups having from 2 to 12, favourably 2 to 6 carbon atoms.
As used herein, the term "cycloalkyl" includes C.sub.3-8 cycloalkyl groups,
REFERENCES:
patent: 5208252 (1993-05-01), Russell et al.
Biochem J., Sim, et al. "Metabolics of procainamide and practolol inhibit complement components C3 and C4". p. 324, 1988.
Martin Michel Jean Roger
Nadler Guy Marguerite Marie Gerard
Kinzig Charles M.
Kumar Shailendra
McCarthy Mary E.
SmithKline Beecham p.l.c.
Venetianer Stepehn
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