Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-06-20
1999-02-23
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514821, 564 99, A61K 3118, C07C31108
Patent
active
058744754
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed toward selected (S)-enantiomeric methanesulfonamides characterized by a hydroxy-alkyl linkage between a tertiary amine group having a substituted side chain and a methanesulfonamide substituted phenyl, useful as Class III antiarrhythmics. These novel enantiomeric methanesulfonamides prolong the effective refractory period of the myocardium and are very potent and stable against metabolism. More importantly, these Class III antiarrhythmic compounds do not have the undesirable side effect of producing polymorphic ventricular tachycardia ("PVT").
Antiarrhythmic drugs act upon the electrophysiological properties of the myocardium and conductive tissues. Typically the rhythmic contractions of the heart are dependent upon the ability of the myocardium and conductive tissues to respond to electrical impulses. When the conductivity of the heart's muscle and conductive tissue is altered by an occlusion of an artery or disease, a life threatening cardiovascular deterioration is likely. It is therefore desirable to treat the electrophysiological properties of the myocardium and conductive tissue to restore rhythmic contractions.
One means for restoring rhythmic contraction is with an antiarrhythmic agent that selectively prolongs the action potential duration and concomitantly increases the refractory period of heart cells without significant effect on cardiac conduction. Such drugs are classified as Class III antiarrhythmic agents. Class III antiarrhythmics which have good bioavailability and which do not affect other circulatory parameters such as blood pressure and heart rate are continually being sought. The subject compounds are Class III antiarrhythmics which are suitable for the treatment of mammals suffering from arrhythmic disorders or disease.
Unfortunately, Class III antiarrhythmic agents are known to produce PVT or torsades de pointes, which is a drug-induced arrhythmia, in a percentage of patients treated with these agents. This potentially lethal arrhythmia represents a liability for this class of antiarrhythmic agents. Surprisingly, it has been discovered that the instant compounds, although potent Class III antiarrhythmics, do not cause PVT in an animal model for this arrhythmia. This is a breakthrough in preparing a Class III antiarrhythmic without the serious PVT side effect.
Bioavailability is an important characteristic of any drug. Unfortunately, with compounds similar to the subject compounds such as those disclosed in U.S. Pat. No. 5,155,268, bioavailability is hampered by a rapid metabolism of the amine side chain. The subject invention solves this problem, as previously disclosed in PCT WO 91/01299, by substituting the side chain with at least one fluorine atom to prevent rapid metabolism and thereby increase bioavailability.
INFORMATION DISCLOSURE STATEMENT
The subject compounds are generally related to those compounds described in European Patent No. 0164865, which can be used as intermediates for the preparation of the subject compounds; and PCT WO 91/01299 which does not disclose the advantageous S-enantiomeric form of the subject compounds.
European Patent Application EP 0134424 discloses quaternary ammonium salts of compounds which are isomers of the subject alkanesulfonamides.
T. K. Morgan, Jr. et al., J. Med Chem., 29, 1398 (1986) reports tertiary amine alkanesulfonamides compounds.
U.S. Pat. Nos. 3,341,584 and 3,478,149 disclose sulfonamide compounds some of which can be used as intermediates for the preparation of the subject compounds.
Other U.S. Patents having examples of sulfonamide containing compounds and antiarrhythmic activity are DeMarinis et al. U.S. Pat. No. 4,507,320, Molloy et al. U.S. Pat. Nos. 4,569,801 and 4,596,827, and Gould et al. U.S. Pat. No. 3,574,741.
SUMMARY OF THE INVENTION
In one aspect the subject invention is directed toward a compound of Formula I, where the asymmetric alcohol carbon has the (S) absolute configuration, its enantiomers at other asymmetric carbons or pharmacologically acce
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Morgan, TK; Wohl, RA; Lumma, WC; Wan, CN; Davey, DD; Gomez, RP; Marisca, AJ; Briggs, M; Sullivan, ME; Wong, SS; Synthesis and Class III antiarrhythic Activity of (Phenylbut-2-enyl)ammonium Salts. Effect of Conformation of Activity, J. Med. Chem., vol. 29, No. 8, 1398-1405 (1986).
Cimini, MG; Brunden, MN; Gibson, JK; Effects of ibutiide fumarate, a novel antiarrhythmic agent, and its enantiomers on isolated rabbit myocardium, European Journal of Pharmacology, 222 (1992) 93-98.
Stolle, WT; Stelzer, LS; Hester, JB; Perricone, SC; Hsi, RSP; Synthesis of radiolabeled racemic and enantiomeric antiarrhythmic agents, Chemical Abstracts, vol. 122, 1995, pp. 1156, 55666.
Gibson J. Kenneth
Hester, Jr. Jackson B.
Corneglio Donald L.
O'Sullivan Peter
Pharmacia & Upjohn Company
Yang Lucy X.
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