Nitro-benzamides useful as anti-arrhythmic agents

Details Nitro-benzamides useful as anti-arrhythmic agents Nitro-benzamides useful as anti-arrhythmic agents

2002-01-30

2003-05-27

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S142000, C514S619000

Reexamination Certificate

active

06570037

ABSTRACT:

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 antiarrhytmic 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.
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):
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;
A represents a C
1-4
n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C
1-6
alkyl groups;
R
1
represents hydrogen, alkyl, alkenyl or cycloalkyl; one or two of the group of R
2
, R
3
and R
4
represents nitro the remaining members of the group of R
2
, R
3
and R
4
represent hydrogen;
X represents a —CO—NH— moiety; and
Z represents C
2-4
n-alkylene group wherein each carbon is optionally substituted by 1 or 2 C
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
1-4
n-alkylene group.
Preferably, A represents —CH
2
—CH
2
.
When R
1
is alkyl it is preferably C
2-6
alkyl such as C
2-
alkyl, C
3
alkyl, C
4
alkyl, C
5
alkyl or C
6
alkyl.
In one aspect, R
1
is alkylene or cycloalkyl.
Preferably, R
1
is hydrogen.
Suitably, any one of R
2
, R
3
and R
4
represents nitro and the remaining members of the group of R
2
, R
3
and R
4
represent hydrogen.
Preferably, R
2
represents 4-nitro.
Preferably, R
3
and R
4
each represents hydrogen.
Suitably, Z represents an unsubstituted C
2-4
n-alkylene group.
Suitably, Z represents CH
2
CH
2
CH
2
.
A particularly preferred compound of formula is N-[3-[[2-(3,4 -dimethoxyphenyl)ethyl]amino]propyl]-4-nitro 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
3-8
cycloalkyl groups, favourably C
5-6
carbon groups.
As used herein, unless otherwise stated, the term “aryl” includes phenyl and naphthyl, preferably phenyl.
As used herein, unless otherwise stated, “halogen” includes fluorine, chlorine or bromine.
As used herein, the term “cardiac arrhythmia” relates to any variation from the normal rhythm of heart beat, including, without limitation, sinus arrhythmia, premature heartbeat, heartblock, fibrillation, flutter, tachycardia, paroxysmal tachycardia and premature ventricular contractions.
The compounds of formula (I) may possess a chiral carbon atom (for example when Z represents a branched alkylene group and may therefore exist in more than one stereoisomeric form. The invention extends to any of the stereoisomeric forms, including enantiomers of the compounds of formula (I) and to mixtures thereof, including racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.
The pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable mineral acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, &agr;-keto-glutaric, &agr;-glycerophosphoric, and glucose-1-phosphoric acids. Preferably the acid addition salt is a hydrochloride.
Pharmaceutically acceptable salts include pharmaceutically acceptable N-oxides, and the invention extends to these.
The compounds of the formula (I) and their salts may also form solvates, especially pharmaceutically acceptable solvates, such as hydrates, and the invention extends to these, and especially to the pharmaceutically acceptable solvates.
The salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form an aspect of the present invention.
A compound of formula (I), or a salt thereof, or a solvate thereof, may be prepared by reacting a compound of formula (II):
wherein A, Ar, R
1
and Z are as defined in relation to formula (I), with a compound of formula (III):
wherein R
2
, R
3
and R4 are as defined in relation to formula (I) and L
1
represents a leaving group; and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into a further compound of formula (I);
(ii) preparing a salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
Compounds of formula (III) are known, commercially available compounds.
The reaction between the compounds of formulae (II) and (III) may be carried out in any suitable inert solvent, such as dichloromethane, in the presence of a base, usually an organic base, for example triethylamine, at a temperature which provides a suitable rate of formation of the required product, generally at a low to ambient temperature, preferably ambient
A preferred leaving group L
1
is a halogen atom, such as a chlorine atom.
The compounds of formula (II) are kno

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