Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-03
2003-06-03
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S308000, C514S309000
Reexamination Certificate
active
06573279
ABSTRACT:
TECHNICAL FIELD
The present invention relates to drugs, particularly to novel isoquinoline derivatives or salts having a I
f
current inhibitory effect without serious side effects such as convulsion and also to drugs, particularly cardiac rate lowering agents containing these compounds as the active ingredient.
BACKGROUND OF THE INVENTION
With regard to drugs having a cardiac rate lowering effect, there have been known neurotransmitter receptors and drugs acting on ion channels, and representative examples of the former are adenosine receptor agonists, M
2
muscarinic receptor agonists and &bgr;-adrenergic receptor antagonists, while those of the latter are calcium channel blockers. Such drugs which lower the cardiac rate have been confirmed to be useful as preventive and therapeutic agents for various clinical symptoms caused by imbalance between supply and demand of oxygen in cardiac muscles, for example, ischemic heart diseases such as angina and cardiac infarction and circulatory diseases such as arrhythmia and cardiac insufficiency. However, these drugs have not only a cardiac rate lowering effect but also an excessive suppressing effect to atrioventricular conduction and systolic function or a hypotensive effect. In some cases, they may express an action which results in a complete cardiac arrest and, therefore, their use especially to patients whose cardiac function lowers has been worried about.
On the other hand, it has been known that electrical excitation spontaneously takes place in sinoatrial node having a physiological cardiac pacemaker action, atrioventricular node constituting conduction system and cells such as His bundle and Purkinje fiber. In the cells having a cardiac pacemaker action, there has been confirmed the presence of an ionic current having no selectivity in permeation to cations such as sodium ion and potassium ion, being activated by hyperpolarization of membrane potential and being activated by stimulation with a &bgr; receptor, which is named a I
f
current (Difrancesco, D., et al.,
J. Physiol.,
377:61-88, 1986; Irisawa, H., et al.,
Physiol. Rev.,
73:197-227, 1993; and Difracesco, D.,
Annu. Rev. Physiol.,
55:455-472, 1993). It is believed that, in heart, the I
f
current is a current which contributes in the formation of diastolic depolarization of the cells having a pacemaker effect and carries out cardiac rate adjustment.
Accordingly, there has been expected an effect of lowering the cardiac rate by inhibiting the I
f
current regulating the inclination of the diastolic depolarization. In fact, pharmaceuticals of a new type which express the cardiac rate lowering effect by inhibiting the I
f
current have been reported recently. Such I
f
current inhibitors are able to selectively lower the cardiac rate without excessive suppression of atrioventricular conduction and systolic function and also able to reduce the oxygen consumption of cardiac muscle. Accordingly, the current I
f
inhibitors are discriminated from the activity of the conventional various receptor agonists and calcium channel blockers due to the absence of an excessive suppressive effect to atrioventricular conduction and systolic function or of a cardiac arrest effect. Therefore, the I
f
current inhibitors are expected to be able to be preventive and therapeutic agents for ischemic diseases (such as angina and cardiac infarction) and circulatory diseases (such as arrhythmia and cardiac insufficiency) with little side effects. They are also useful to suppress an excessively increased cardiac rate so as to control the cardiac rate to a predetermined state in operations under anesthesia, etc.
It has been further reported that an ionic current having a similar property to the I
f
current (having no selectivity in permeation to cations, being activated by hyperpolarization and being activated by stimulation with a &bgr; receptor) is present not only in the cells having a pacemaker effect but also in inherent cardiac muscle cells usually having no pacemaker effect such as atrial muscle and ventricular muscle cells (Hangang Yu,
Circ. Res.,
72:232-236, 1993). In some types of symptoms of cardiac insufficiency, hypertension or the like, electrical excitation is spontaneously resulted even in the intrinsic cardiac muscle cells and, when effect potential is recorded from those cells, there is observed diastolic depolarization where membrane potential is gradually depolarized during the electrical diastole after the effect potential is repolarized. In such symptom, an increase in the I
f
current is confirmed, and it is presumed that the I
f
current contributes in the formation of this diastolic depolarization causing acceleration of ectopic automatism or triggered activity (Elizabetta, C., et al.,
Circulation,
94:1674-1681, 1996; and Elizabetta, C., et al.,
Circulation,
95:568-571, 1997). Accordingly, it has been believed that the I
f
current inhibitors are useful for the suppression of the acceleration of ectopic automatism or triggered activity in those symptoms.
It has been known that the effect of zatebradine which is known as a compound having a cardiac rate lowering effect is based on the I
f
current inhibitory effect. However, it has been reported that zatebradine expresses a cardiac rate lowering effect and a visual disorder (William H. Frishman,
J. Am. Coll. Cardiol.,
26:305-312, 1995; and Stephen P. Glasser, et al.,
The American Journal of Cardiology,
79:1401-1405, 1997). It has been known that another current (I
h
current) having a similar property to the I
f
current is present in visual cells (Shaul Hestrin,
J. Physiol.,
390:319-333, 1987). But, since zatebradine inhibits the I
h
current together with the I
f
current, such visual disorder is presumed to be expressed thereby. In the study of the I
f
current inhibitors, separation from the I
h
current inhibitory effect is one of the propositions.
With regard to the compound having an anti-tachycardiac effect or a vasodilating effect, &bgr;-amino acid amide derivatives represented by the following general formula have been reported (Japanese Patent Laid-Open No. 138172/1990). However, there is no description for the I
f
current inhibitory effect.
(As to the symbols in the formula, refer to the above-mentioned patent.)
In addition, the present inventors have reported that 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives represented by the following general formula as the compounds having a cardiac rate lowering effect (WO 98/13364).
(As to the symbols in the formula, refer to the above-mentioned patent.)
DISCLOSURE OF THE INVENTION
The present inventors have carried out intensive investigations for the drugs which inhibit the I
f
current. As a result, it has been found that isoquinoline derivatives represented by the following general formula (I) inhibit the I
f
current and have a cardiac rate lowering effect in the heart and confirmed that the derivatives are not accompanied by serious side effects such as convulsion, leading to completion of the present invention.
Specifically, the present invention relates to an isoquinoline derivative represented by the following general formula (I) or a salt thereof and also to drugs, particularly a I
f
current inhibitor or, more particularly, a cardiac rate lowering agent, a therapeutic agent for cardiac insufficiency and a therapeutic agent for arrhythmia, containing the derivative or its salt as an effective ingredient.
(The symbols in the above formula have the following meanings:
A: lower alkylene;
B: —C(═O)—NR
5
— or —NR
5
—C(═O)—;
R
1
and R
2
: hydrogen atom, lower alkyl or —O-lower alkyl, which may be the same or different;
R
3
, R
4
and R
5
: hydrogen atom or lower alkyl, which may be the same or different;
ring D: optionally substituted hydrocarbon ring or optionally substituted hetero ring;
m: 1, 2 or 3;
n: 0 or 1; and
q: 1 or 2.)
The compounds of the present invention have a characteristic feature that an amide moiety is always available in the structural formula and have an excellent profile that they exhibit a strong I
f
Kakefuda Akio
Masuda Noriyuki
Okazaki Toshio
Wada Koichi
Watanabe Toshihiro
Fay Zohreh
Kwon Brian-Yong S.
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