Benzodiazepines

Details Benzodiazepines Benzodiazepines

1996-05-14

1997-10-21

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540558, 540559, 540560, 540562, 540563, 540564, 540566, A61K 3155, C07D48704

Patent

active

056796722

DESCRIPTION:

BRIEF SUMMARY
SUMMARY OF THE INVENTION

This invention is concerned with novel compounds of general structural formula I: ##STR2##
The invention is also concerned with pharmaceutical formulations comprising one or more of the compounds as active ingredient, either alone or in combination with one or more of a Class I, Class II or Class IV antiarrhythmic agent.


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 antiarrythmic agents are now available on the market, those, having both satisfactory effects and high safety, have not been obtained. For example, antiarrhythmic 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 drags which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drags 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. Drags 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.


DETAILED DESCRIPTION OF THE INVENTION

The novel compound this invention has structural formula I: ##STR3## or a pharmaceutically acceptable salt thereof, wherein A is a 2 or 3 membered chain which is all carbon or one and only one member can be nitrogen or oxygen, which is unsubstituted or substituted on carbon with more than one heteroatom selected from --NH-- --S-- or --O--; selected from Cl, Br, I, F, CF.sub.3 or C.sub.1-3 alkyl; C.sub.1-3 alkyl or C.sub.5-7 cycloalkyl,
Representative of the novel compounds of this invention are the following:


______________________________________ ##STR4## A R.sup.1 R.sup.2 ______________________________________ ##STR5## cyclohexyl Ph ##STR6## cyclohexyl Ph ##STR7## cyclohexyl Ph ##STR8## 2,4-di Cl Ph Ph ##STR9## 2,4-di Cl Ph Ph ##STR10## 2,4-di Cl Ph Ph ##STR11## 2,4-di Cl Ph Ph ##STR12## 4-CF.sub.3 Ph Ph ##STR13## 2,4-di Cl Ph Ph ##STR14## cyclohexyl Ph ##STR15## 2,4-di Cl Ph Ph ##STR16## 2,4-di Cl Ph i Pr ##STR17## 2,4-di Cl Ph i Pr ##STR18## 2,4-di Cl Ph i Pr ##STR19## 2,4-di Cl Ph i Pr ##STR20## cyclohexyl Ph ##STR21## cyclohexyl Ph ##STR22## 2,4-di Cl Ph Ph ##STR23## cyclohexyl ##STR24## This invention is meant to include the individual diastereomers, where such exist and mixtures thereof and enantiomers and mixtures of the
The pharmaceutically acceptable salts of the compounds of Formulas I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formula I 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 hyd

REFERENCES:
patent: 4663321 (1987-05-01), Bock et al.

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