2′-Substituted 1,1′-biphenyl-2-carboxamides,...

Details 2′-Substituted 1,1′-biphenyl-2-carboxamides,... 2′-Substituted 1,1′-biphenyl-2-carboxamides,...

2000-10-30

2003-03-11

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S264000, C546S265000, C546S266000, C546S267000

Reexamination Certificate

active

06531495

ABSTRACT:

This application claims the benefit of foreign priority under 35 U.S.C. §119 to German patent application no. 19947457.5, filed on Oct. 2, 1999, the contents of which are incorporated by reference herein.
The invention relates to compounds of the formula I,
in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30) and R(31) have the meanings indicated below, their preparation and their use, in particular in pharmaceuticals.
The compounds of the formula I according to the invention were hitherto unknown. They act on the so-called Kv1.5 potassium channel and inhibit a potassium current described as “ultra-rapidly activating delayed rectifier” in the human atrium. The compounds are therefore very particularly suitable as novel antiarrhythmic active compounds, in particular for the treatment and prophylaxis of atrial arrhythmias, e.g. atrial fibrillation (AF) or atrial flutter.
The compounds can be used for the termination of existing atrial fibrillation or flufter to restore sinus rhythm (cardioversion). Furthermore the compounds reduce the incidence for the development of new episodes of fibrillation (maintenance of sinus rhythm, prophylaxis).
Atrial fibrillation (AF) and atrial flutter are the most frequent persistent cardiac arrhythmias. The occurrence increases with increasing age and frequently leads to fatal sequelae, such as, for example, cerebral apoplexy. AF affects about 1 million Americans annually and leads to more than 80,000 strokes each year in the USA. The presently customary antiarrhythmics of classes I and III, reduce the reoccurrence rate of AF, but because of their potential proarrhythmic side effects only have restricted use. There is therefore a great medical need for the development of better medicaments for the treatment of atrial arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; “Newer developments in the management of atrial fibrillation”).
It was shown that most supraventricular arrhythmias are subject to so-called “reentry” excitatory waves. Such reentries occur when the cardiac tissue has a slow conductivity and at the same time very short refractory periods. The increasing of the myocardial refractory time by prolongation of the action potential is a recognized mechanism for ending arrhythmias or preventing their formation (T. J. Colatsky et al., Drug Dev. Res. 19, 1990, 129-140; “Potassium channels as targets for antiarrhythmic drug action”). The length of the action potential is essentially determined by the extent of repolarizing K
+
currents which flow out of the cell via various K
+
channels. Particularly great importance is ascribed here to the so-called “delayed rectifier” I
K
, which consists of 3 different components: IK
r
, IK
s
and IK
ur
.
Most known class III antiarrhythmics (e.g. dofetilide, E4031 and d-sotalol) mainly or exclusively block the rapidly activating potassium channel IK
r
, which can be detected both in cells of the human ventricle and in the atrium. However, it has been shown that at low or normal heart rates these compounds have an increased proarrhythmic risk, arrhythmias which are described as “Torsades de pointes” being observed in particular (D. M. Roden, Am. J. Cardiol. 72, 1993, 44B-49B; “Current status of class III antiarrhythmic drug therapy”). In addition to this high, in some cases fatal, risk at low frequency, a decrease in the efficacy under the conditions of tachycardia, in which the action is especially needed, has been found for the I
Kr
blockers (“negative use-dependence”).
While some of these disadvantages can possibly be overcome by blockers of the slowly activating components (IK
s
), their efficacy has hitherto not been confirmed, as no clinical investigations with IK
s
channel blockers are known.
The “particularly rapidly” activating and very slowly inactivating component of the delayed rectifier IK
ur
(=ultra-rapidly activating delayed rectifier), which corresponds to the Kv1.5 channel, plays a particularly large role in the repolarization period in the human atrium. In comparison to the inhibition of IK
r
or IK
s
, inhibition of the Ikur potassium outward current is thus a particularly effective method for the prolongation of the atrial action potential and thus for the ending or prevention of atrial arrhythmias. Mathematical models of the human action potential suggest that the positive effect of a blockade of the Ikur, especially under the pathological conditions of chronic atrial fibrillation, should be particularly pronounced (M. Courtemanche, R. J. Ramirez, S. Nattel, Cardiovascular Research 1999, 42, 477-489: “Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model”).
In contrast to IK
r
and IK
s
, which also occur in the human ventricle, the IK
ur
admittedly plays an important role in the human atrium, but not in the ventricle. For this reason, on inhibition of the IK
ur
current in contrast to the blockade of IK
r
or IK
s
, the risk of a proarrhythmic action on the ventricle is excluded from the start (Z. Wang et al., Circ. Res. 73, 1993, 1061-1076: “Sustained Depolarisation-Induced Outward Current in Human Atrial Myocytes”; G.-R. Li et al, Circ. Res. 78,1996, 689-696: “Evidence for Two Components of Delayed Rectifier K
+
Current in Human Ventricular Myocytes”; G. J. Amos et al., J. Physiol. 491, 1996, 31-50: “Differences between outward currents of human atrial and subepicardial ventricular myocytes”).
Antiarrhythmics which act via a selective blockade of the IK
ur
current or Kv1.5 channel were previously not available, however, on the market. For numerous pharmaceutical active compounds (e.g. tedisamil, bupivacaine or sertindole), a blocking action on the Kv1.5 channel was admittedly described, but the Kv1.5 blockade here in each case represents only a side effect next to other principal actions of the substances.
WO 98 04 521 claims aminoindans as potassium channel blockers which block the Kv1.5 channel. The applications WO 98 18 475 and WO 98 18 476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmics, which should act via a blockade of the IK
ur
. However, the same compounds were originally also described as immuno-suppressants (WO 96 25 936). The compounds described in these mentioned applications are structurally completely different to the compounds according to the invention of this application.
It has now surprisingly been found that the 2′-substituted 1,1′-biphenyl-2-carboxamides described here are potent blockers of the human Kv1.5 channel. They can therefore be used as novel antiarrhythmics having a particularly advantageous safety profile. In particular, the compounds are suitable for the treatment of supraventricular arrhythmias, e.g. atrial fibrillation or atrial flutter.
The compounds according to the invention were previously unknown. Some structurally related compounds are described in Helv. Chim. Acta 1994 (70) 70 and references cited there. For the peptide compounds described there (e.g. compound A), however, no potassium channel-blocking activity is known. Moreover, compounds of this type should have too low a metabolic stability for use as antiarrhythmics on account of the numerous peptide bonds.
A further similar compound (compound B) is mentioned in European Patent Application EP 0620216. The compound B and all other compounds of this application carry, in the position of R(3), a specific substituent (e.g. benzoyl-1,2,3,4-tetrahydroisoquinoline), which is not included in the compounds according to the invention of this application. The compounds mentioned in EP 0 620 216 act as vasopressin antagonists and thus have a completely different biological activity to the blockers of the Kv1.5 channel described here.
The present invention relates to compounds of the formula I
in which:
R(1) is C(O)OR(9), SO
2
R(10), COR(11), C(O)NR(12)R(13) or C(S)NR(12)R(13);
R(9) is C
x
H
2x
—R(14);
x is 0, 1, 2, 3 or 4, where x cannot be 0 if R(14) is OR(15) or SO
2
Me;
R(14) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl h

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