Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-11-02
1997-12-16
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 16, 546 17, A61K 3144, C07D22100
Patent
active
056985665
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
This invention is concerned with novel spirocycles of general structural formula: ##STR3## or a pharmaceutically acceptable salt, hydrate or crystal form thereof, wherein alkylCONH--, NO.sub.2 --; is OH; ; ##STR4## which are Class III antiarrhythmic agents and positive inotropic or cardiotonic agents,
The invention is also concerned with pharmaceutical formulations comprising one or more of the novel compounds as active ingredient, either alone or in combination with one or more of a Class I, Class II or Class IV antiarrhythmic agent.
The invention is also concerned with a method of treatment of arrhythmia and impaired cardiac pump functions with the above-described novel compounds and formulations thereof.
The invention is further concerned with processes for preparing the novel compounds.
BACKGROUND OF THE INVENTION
Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation and can cause sudden death.
Though various antiarrhythmic agents are now available on the market, those, having both satisfactory effects and high safety, have not been obtained. For example, antiarrythmic agents of Class I according to the classification of Vaughan-Williams which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
A number of antiarrhythmic agents have been reported in the literature, such as those disclosed in:
Compounds of similar structure are found in Japanese patent publication 88-63533-B of Daiichi Pharmaceutical Co.; J. Med. Chem., 19, 1315 (1976) by Bauer et al; Iorio et al in Il. Farmaco-Ed Sci., 32, 212-219 (1977): Houlihan et al, U.S. Pat. No. 3,686,186; Davis et al, U.S. Pat. No. 4,420,485; Kealey, U.S. Pat. No. 4,810,792; Parham et al, J. Org. Chem., 41, 2629 (1976). None of the compounds disclosed in the foregoing references are alleged to have antiarrhythmic activity.
Now with the present invention, there is provided as antiarrhythmic agent new compounds with an increased degree of activity.
DETAILED DESCRIPTION OF THE INVENTION
The novel compound of this invention has structural formula: ##STR5## or a pharmaceutically acceptable salt, hydrate or crystal form thereof; wherein: alkylCONH--, NO.sub.2 --; =OH; ; ##STR6##
In a preferred embodiment of the novel compound, --, ##STR7##
In particular it is preferred that R.sup.7 is ##STR8##
It is also preferred that ##STR9##
It is also preferred that ##STR10##
It is even more preferred that ##STR11## or the hydrochloride, maleate, methanesulfonate, tri-citrate or
REFERENCES:
patent: 5206240 (1993-04-01), Baldwin et al.
patent: 5382587 (1995-01-01), Baldwin et al.
patent: 5439914 (1995-08-01), Claremon et al.
patent: 5484923 (1996-01-01), Cai et al.
Antiarrhythmic Agents", Journal of Medicinal Chemistry, vol. 35, pp. 3973-3976, 1992.
Baldwin John J.
Claremon David A.
Elliott Jason M.
Ponticello Gerald S.
Remy David C.
Bigley Francis P.
Coleman Brenda
Daniel Mark R.
Korsen Elliott
Merck & Co. , Inc.
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