Resolution, absolute configuration, and antiarrhythmic properties of the enantiomers of disopyramide, 4-(diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide

Abstract

Disopyramide was resolved by fractional crystallization of its diastereomeric bitartrate salts from methanol-acetone. Diastereomeric sulfonamides prepared from (+)-camphor-10-sulfonyl chloride and the primary amines obtained by LiA1H4 reduction of the resolved bases were separable by high-performance LC [liquid chromatography] and were used to show that within experimental error resolution of disopyramide was complete. The absolute configuration was determined by X-ray crystallography. (+)-[(2R-(.sbd.)-4-(Diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide (+)-(2R,3R)-bitartrate] crystallizes in space group P212121: a = 14.789 (4), b = 18.151 (4), c = 9.878 (2) .ANG.; Z = 4; Dx = 1.225, Dm (flotation C6H6/CC14) = 1.226 g cm-3. The structure was solved by direct methods. The enantiomeric bitartrates were tested for antiarrhythmic properties. The enantiomeric bitartrate salts were equally effective in prolonging the effective refractory period (ERP) of rabbit ventricle. At 3 .times. 10-6 M, the (.sbd.)-bitartrate [from (2S)-(+)-disopyramide] increased the ERP 21.8 .+-. 6.3 ms and the (+)-bitartrate [from (2R)-(.sbd.)-disopyramide] increased the ERP 25.8 .+-. 3.6 ms. At 1.5 .times. 10-5 M no significant difference was noted, as the increases in the ERP were 41.2 .+-. 8.9 and 50.5 .+-. 6.3 ms for the (.sbd.)- and (+) bitartrate, respectively.