Aminoethylthiophene derivatives

#This invention relates to aminoethylthiophene derivatives and more particularly 2- and 3-aminoethylthiophene derivatives which are useful as antiarrhythmic agents.

#It has been estimated that in persons between the ages of 35 and 64 years of age, nearly 1 death in three is due to coronary heart disease [Gordon, T.; Kannel, W. B. J. Amer. Med. Assoc., 1971, 215, 1617] and there are approximately 400,000 sudden cardiac deaths annually in the United States alone [Green, H. L.; et al., Amer. J. Cardiology, 1989, 63, 1]. During the last few years, development of drugs to treat cardiac arrhythmias (sudden cardiac death) has received much attention [Steinberg, M. I.; Lacefield, W. B.; Robertson, D. W. Class I and III Antiarrhythmic Drugs. In Ann. Reports in Med. Chem., Bailey, D. M., Ed.; Academic Press, Inc.: Orlando, 1986; 21, pp 95-108; Arrowshmith, J. E.; Cross, P. E. Antiarrhythmic Agents. In Ann. Reports in Med. Chem., Bristol, J. A., Ed.; Academic Press, Inc.: San Diego, 1990; 25, pp 79-88]. A classification scheme of antiarrhythmic drugs has been presented by Vaughan Williams [Vaughan Williams, E. M. J. Clin. Pharmacol ., 1984, 24, 129] which is based on their electrophysiological effects on cardiac tissue.

#Class I agents and subclasses (Ia, Ib, Ic) are defined as antiarrhythmic agents which have inhibitory effects on the sodium channel which result in a reduction of conduction velocity in the cardiac tissue. The class I agents are currently the most widely used for antiarrhythmic therapy. Recent results of the Cardiac Arrhythmia Suppression Trial (CAST) [N. Engl. J. Med., 1989, 321, 406] have raised concerns about the Class IC subtype (e.g. flecainide) and suggest that antiarrhythmic drugs having other mechanisms of action should be considered.

#The invention will now be illustrated by examples. The examples are not intended to be limiting of the present invention. In conjunction with the detailed and general description above, the examples provide further understanding of the present invention and outline a process for producing the compounds of the invention.

#The following examples represent preferred embodiments of the compounds, compositions, processes and methods of the invention for satisfying the stated objects of the invention.

#The following processes and procedures for preparing the compounds of the present invention correspond to those reaction schemes illustrated above. The procedures below describe with particularity the various chemical reactions and procedures utilized. Any methods, starting materials or reagents which are not particularly described are those which are known or would be generally known and available to those skilled in the art. Procedures from the following references, as described in the examples below were utilized to produce certain intermediate compounds utilized in the synthesis of the compounds of the invention: J. Med. Chem., 1978, 21, 978; J. Amer. Chem. Soc., 1954, 76,4466; J. Org. Chem., 1950, 15, 807; and Tetrahedron, 1968, 24, 5721. The entire disclosure of these references are hereby incorporated herein by reference. The compounds of the invention (10-16) produced in accordance with the example schemes are identified below and designated by Example Numbers 1-31. The titled compounds may be produced as hydrochloride and dihdrochloride salts which is apparent from the description thereof and is not indicated in the title.