Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-04
2004-03-23
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S212000, C546S213000, C546S217000, C514S327000
Reexamination Certificate
active
06710060
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel 4-hydroxypiperidine derivatives, a method for manufacturing thereof, and a pharmaceutical composition comprising at least one of the derivatives as active ingredients, in particular an antiarrythmic agent capable of oral administration.
2. Description of Related Art
The heart can regularly beat when the excitation initiated at the sinus node conducts in a correct order. Arrythmia is generated when abnormal excitation and conduction to the heart are caused. Accordingly, the mechanism of onset of arrythmia is categorized into three groups of (1) abnormal excitation (2) abnormal conduction of excitation and (3) a combination of abnormal excitation and abnormal conduction of excitation.
Vaughan Williams, Singh and Houswirth have categorized antiarrythmic agents into four classes based on their action in the first half of 1970's. Since then, this classification—namely the Vaughan Williams classification—has been utilized as a standard classification of the antiarrythmic agents. This classification method is excellent in that it briefly expresses features of pharmacological action of various antiarrythmic agents, and has been utilized by many physicians. This classification method roughly classifies the antiarrythmic agents into four classes of the class I to class IV.
The antiarrythmic agents classified into the class I are medicines which have mainly a sodium channel blocking activity, and reduce the maximum upstroke velocity of depolarization at the 0-th phase of the action potential, thereby reducing the conduction speed. The class I agents are further classified into sub-classes of Ia, Ib and Ic based on their effects on the action potential duration. The class I agents are featured in reduction of the cardiac contractility as a result of reduced intracellular calcium concentration due to activation of a sodium/calcium exchange mechanism, because the intracellular sodium concentration is reduced by blocking the sodium channel. Reduction of the cardiac contractility is one of crucial adverse effects of the class I antiarrythmic agents comparable to a proarrhythmic activity directly related to suppression of conduction due to the sodium channel blocking activity.
The antiarrythmic agents belonging to the class II are medicines which mainly have a &bgr;-receptor blocking activity. Stimulation of the &bgr; (&bgr;
1
)-receptor in the cardiac muscle cells with catecholamines activates adenylate cyclase, enhances production of cyclic AMP and increases the inward calcium current. As a result, physiological automaticity of the sinus node as well as abnormal automaticity in the morbid cardiac muscle are exacerbated. Action potential duration is also shortened by activating various ion channels related to repolarization. Although the class II antiarrythmic agents are effective against the arrhythimia related to the sympathetic nerve by their antagonistic activity against the action of catecholamines, adverse effects such as suppression of cardiac function due to &bgr;-receptor blocking activity is worried.
The antiarrythmic agents belonging to the class III are defined as the medicines with a primary action to retard repolarization and prolong of the action potential duration. These agents suppress arrythmia by prolonging refractory period as a result of prolongation of the action potential duration. It was made clear from recent studies that blocking action on the potassium channel is mainly responsible for the principal action of such agent, and a term “pottasium channel blocker” is currently synonymous with the class III agent. The class III agents are advantageous over the class I agents in that the former shows no suppression on cardiac contractility. On the other hand, “torsades de pointes” as a result of a prolonged QT interval is a crucial and potentially lethal adverse effect common to the class III agents.
The antiarrythmic agents classified into the class IV is defined as medicines the main action of which is the blocking of the calcium channel. Although the agents are used for treating arrythmia caused by acceleration of automaticity in the sinus node and arrythmia related to the atrioventricular node, an antiarrythmic agent, for example, verapamil may weaken contraction force of the cardiac muscle.
In the Cardiac Arrythmia Suppression Trial (CAST) operated in 1989 in USA, Flecainide and Encainide belonging to the class I antarrythmic agents were used for post-myocardial infarction patients with silent and mild symptoms of ventricular extrasystole, and it was found that incidence of sudden death increases in the group administered with test drugs (Echt, D. A. et al., The new England Journal of Medicine, Vol. 324, pp.781-788, 1991). In other words, it was shown that suppression of ventricular extrasystole by the class I agents does not always suppress severe arrythmia such as ventricular fibrillation that is considered to cause sudden death. This research report aroused the need of paying attention to an appropriate use of the antiarrythmic agents, besides affording novel antiarrythmic agents to be developed. In place of conventional chemicals represented by powerful sodium channel blockers that have been used in the CAST study and suppress depolarization process of the cardiac muscle, potassium channel blockers that prolong the refractory period by prolonging the repolarization process have been expected to be the antiarrythmic agents for preventing sudden death. Clinical trials with amiodarone and sotalol at an early stage have accelerated this trend, and the potassium channel blocker without severe side-effects of amiodarone (for example, interstitial pneumonia and fibrosis of the lung) has been largely expected. However, developments of d-sotalol, E-4031 and sematilide have been suspended since it was proved that the incidence of “torsades de pointes” accompanied by the QT prolongation was unexpectedly high in clinical trials in Japan as well as those in the USA and Europe with large scale in addition to the increase of mortality by these drugs. No antiarrythmic agent that can suppress sudden death of the arrythmia patients with basal diseases such as ischemic heart diseases and heart failure while avoiding the severe side-effects of amiodarone (for example, interstitial pneumonia and fibrosis of the lung) have been discovered in the present time. The large problems involved in drug therapy of arrythmia are (1) the class I and class III agents that affect conduction velocity and action potential duration by acting on the normal cardiac muscle cannot be safe antiarrythmic agents since they have proarrythmic action, and (2) the class II and class IV agents are only effective to limited symptoms of arrythmia. Accordingly, developments of novel type of antiarrythmic agents that are highly safe while avoiding the drawbacks of the antiarrythmic agents belonging to the class I to class IV classification are desired.
The sodium current normally observed in the excitable cells is rapidly inactivated after being promptly activated by a stimulus (depolarization), and thus the observed current is a transient inward current. The class I agent suppresses this transient sodium current, and decreases the maximum upstroke velocity of depolarization at the 0-th phase of the action potential to reduce the conduction velocity. However, some kinds of the sodium current are slowly or seldom inactivated, and these currents are considered to be involved in adjustment of physiological excitability of the neurons and cardiac myocytes. This sort of current is called as a persistent sodium current. This current is suggested to be involved in abnormal excitability of the neurons (for example, epileptic attack and ischemia) and morbidity of the cardiac myocytes (for example, onset of arrythmia), as reported by Segal, M. M. et al. (Journal of Neurophysiology, Vol. 77, pp. 3021-3034, 1997) and Ju, Y-K et al. (Journal of Physiology, Vol. 497, No. 2, pp. 337-347, 1996).
While lidocaine and quinidine are report
Itoh Manabu
Miyazaki Yutaka
Ogawa Shin-ichi
Yamamoto Ichiro
Yamasaki Fumiaki
Chang Ceila
Mochida Pharmaceutical Co. Ltd.
Oliff & Berridg,e PLC
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