Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-23
2001-04-24
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S310000, C514S319000, C514S603000, C544S159000, C546S153000, C546S205000, C564S085000, C564S086000, C564S087000
Reexamination Certificate
active
06221866
ABSTRACT:
The invention relates to compounds of formula I
in which R(8) is either a 1-indanyl radical of formula II or a 2-indanyl radical of formula III
and in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(9), R(10), R(11), R(12), R(13), R(14), and R(15) have the meanings stated below, their preparation, and their use, in particular in medicaments.
Compounds according to the invention act on the so-called Kv1.5 potassium channel and inhibit a potassium current, referred to as “ultra-rapidly activating delayed rectifier,” in the human atrium. The compounds are therefore very particularly suitable as novel antiarrhythmic active substances, in particular for the treatment and prophylaxis of atrial arrhythmias, e.g., atrial fibrillation or atrial flutter.
Atrial fibrillation (AF) and atrial flutter are the most frequent persistent cardiac arrhythmias. They occur increasingly with increasing age and frequently lead to fatal consequences, such as, for example, a cerebrovascular accident. AF affects about 1 million Americans annually and leads to more than 80,000 strokes every year in the USA. The class I and III antiarrhythmic drugs commonly used at present reduce the rate of recurrence of AF but, owing to their potential proarrhythmic side effects, are used only to a limited extent. There is therefore a considerable medical necessity for the development of better medicaments for the treatment of atrial arrhythmias (S. Nattel, “Newer developments in the management of atrial fibrillation,”
Am. Heart J.
130 (1995;) 1094-1106).
It was found that most supraventricular arrhythmias are based on so-called “re-entry” excitation thresholds. Such re-entries occur when the heart tissue has slow conductivity and at the same time very short refractory periods. Increasing the myocardial refractory time by lengthening the action potential is a recognized mechanism for terminating arrhythmias and for preventing their occurrence (T. J. Colatsky et al., “Potassium channels as targets for antiarrhythmic drug action,”
Drug Dev. Res.
19 (1990) 129-140). The length of the action potential is essentially determined by the extent of repolarizing K
+
currents that flow out of the cell via various.; K
+
channels. Particularly great importance here is attributed to the so-called “delayed rectifier” I
K
, which consists of three different components: IK
r
, IK
s
, and IK
ur
.
Most known class III antiarrhythmic drugs (e.g., Dofetilide, E4031, and d-Sotalol) predominantly or exclusively block the fast-activating potassium channel IK
r
, which is detectable both in the cells of the human ventricle and in the atrium. However, it has been found that these compounds give rise to a high proarrhythmic risk at low or normal heart rates, in particular arrhythmias referred to as “Torsades de pointes” having been observed (D. M. Roden, “Current status of class III antiarrhythmic drug therapy,”
Am. J. Cardiol.
72 (1993) 44B-49B). In addition to this high, sometimes fatal risk at low rate, the IK
r
blockers were found to decline in activity under the conditions of tachycardia, precisely where the activity is required (“negative use-dependence”).
While some of these disadvantages can possibly be overcome by blockers of the slowly activating component (IK
s
), their activity has not been demonstrated to date, since no clinical studies with IK
s
channel blockers are known.
The “particularly rapidly” activating and very slowly inactivating component of tile delayed rectifier IK
ur
(=ultra-rapidly activating delayed rectifier), which corresponds to the Kv1.5 channel, plays a particularly major role for the repolarization time in the human atrium. Compared with the inhibition of IK
r
or IK
s
, inhibition of the Ik
ur
potassium outward current is thus a particularly effective method for lengthening the atrial action potential and hence for terminating or preventing atrial arrhythmias.
In contrast to IK
r
and IK
s
, which also occur in the human ventricle, the IK
ur
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 blockage of IK
r
or IK
s
, the risk of a proarrythmic effect on the ventricle is ruled out from the outset. (Z. Wang et al., “Sustained Depolarisation-Induced Outward Current in Human Atrial Myocytes,”
Circ. Res.
73 (1993) 1061-1076; G. -R. Li et al., “Evidence for Two Components of Delayed Rectifier K
+
-Current in Human Ventricular Myocytes,”
Circ. Res.
78 (1996) 689-696; G. J. Amos et al., “Differences between outward currents of human atrial and subepicardial ventricular myocytes,”
J. Physiol.
491 (1996) 31-50).
Selective blockers of the IK
ur
or Kv1.5 channel have not been described to date in the literature. Although a blocking effect on the Kv1.5 channel has been described for numerous pharmaceutical active substances (e.g., Tedisamil, Bupivacaine, or Sertindole), the Kv1.5 blockage in each case constitutes only a side effect here, alongside other principal effects of the substances. WO 98 04 521 claims, as potassium channel blockers, aminoindanes which block the Kv1.5 channel. However, an equipotent action on the Kv1.3 channel is also described for these compounds. Blockage of the Kv1.3 channel, which plays a role in human T-lymphocytes, has an immunosuppressive effect, which is undesirable as a side effect of an antiarrhythmic drug to be administered for a chronic condition. Applications WO 98 18 475 and WO 98 18 476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmic drugs, which are said to act by blocking the IK
ur
. However, these compounds were originally (WO 96 25 936) also described as immunosuppressive drugs, so that their medical usability for the treatment of atrial arrhythmias appears doubtful.
It has now been found that compounds according to the invention are potent blockers of the human Kv1.5 channel. They can therefore be used as novel antiarrhythmic drugs having a particularly advantageous safety profile. In particular, the compounds are suitable for the treatment of supraventricular arrhythmias, e.g., AF or atrial flutter.
Compounds according to the invention, of formula I, were not previously known. Some structurally related indane derivatives are described in the applications EP 258 096 and EP 374 054. However, the compounds claimed there differ from the compounds according to the invention in this application in that, in said applications, R(9) is a basic amino substituent. Moreover, only unsubstituted sulfonamides (R(1) and R(2)=H) are described there, whereas it has been found here that it is precisely substituted sulfonamides that are particularly effective blockers of the Kv1.5 channel.
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patent: 5348971 (1994-09-01), Clemence et al.
patent: 5877221 (1999-03-01), Cohen et al.
patent: 6015822 (2000-01-01), Brendel et al.
patent: 0 258 096 A2 (1988-03-01), None
patent: 0 374 054 A1 (1990-06-01), None
patent: 0 915 087 A2 (1999-05-01), None
patent: 95/18617 (1995-07-01), None
Brendel Joachim
Gerlach Uwe
Lang Hans-Jochen
Stilz Hans Ulrich
Aventis Pharma Deutschland GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
O'Sullivan Peter
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