Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-05-16
1997-12-09
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514214, 540521, 540522, 540523, A01N 4346
Patent
active
056961111
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Arrthythrmias 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 antiarrythmic 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 IH are drags 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.
SUMMARY OF THE INVENTION
This invention is concerned with novel compounds represented by structural formulae I and II. ##STR2## Where R is a straight or branched alkyl of C.sub.1 to C.sub.6, arylalkyl, aryl, heteroaryl, O-alkyl, O-acyl, carboxylic acid, aldehyde, ketone, ester;, R' is a straight or branched alkyl of C.sub.1 to C.sub.6, arylalkyl, aryl, N-alkyl, N-aryl, O-alkyl, or O-aryl and R" is a straight or branched alkyl or aryl group or pharmaceutically acceptable salts, hydrates and crystal forms thereof, which are useful as antiarrhythmic agents. The invention is also concerned with pharmaceutical formulations comprising one of the novel compounds as an active ingredient.
The invention is also concerned with a method of treating arrhythmia by the administration of one of the novel compounds or formulation thereof to a patient in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention have structural formulae of I or II ##STR3## Where R is a straight or branched alkyl of C.sub.1 to C.sub.6, arylalkyl, aryl, heteroaryl, O-alkyl, O-acyl, carboxylic acid, aldehyde, ketone, ester;, R' is a straight or branched alkyl of C.sub.1 to C.sub.6, arylalkyl, aryl, N-alkyl, N-O-alkyl, O-aryl: and R" is a straight or branched Alkyl.
The pharmaceutically acceptable salts, crystal forms and hydrates of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formulae I and II formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfuric, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glucolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethion
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Baldwin John J.
Claremon David A.
Liverton Nigel
Selnick Harold G.
Bigley Francis P.
Bucknum Michael
Daniel Mark R.
Korsen Elliott
Merck & Co. , Inc.
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