KVI.5 BLOCKER FOR THE SELECTIVE INCREASE OF ATRIAL CONTRACTILITY AND TREATMENT OF CARDIAC INSUFFICIENCY

摘要

Use of specific 2-sulfonylamino-benzamides (Ia) or 2-aminophenyl-benzamides (Ib), or their salts, for preparing a composition for treatment or prevention of cardiac insufficiency, is new. Use of the 2-sulfonylamino-benzamides of formula (Ia) or 2-aminophenyl-benzamides of formula (Ib), or their salts, for preparing a composition for treatment or prevention of cardiac insufficiency R 1 = 3-5C alkyl or quinolyl; R 2 = 1-4C alkyl or cyclopropyl; R 3 = phenyl or pyridyl, both optionally substituted by 1 or 2 of fluoro, chloro, trifluoromethyl, trifluoromethoxy, 1-3C alkyl or alkoxy; A = bond, CH 2 or CH 2CH 2; R 4-R 7 = hydrogen, fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, or 1-3C alkyl or alkoxy; B = CH 2 or CH 2CH 2; R 8 = 2-3C alkyl, phenyl or pyridyl (both optionally substituted as above); R 9 = COOR 10 or COR 10; R 10 = -C xH 2x-R 11; x = 0-2; R 11 = phenyl, optionally substituted as above . [Image] ACTIVITY : Cardiant; Antiarrhythmic. Air (about 30 ml) was instilled into the pericardium of pigs, to inhibit ventricular filling, thus reducing the heart-minute volume (HMV) and mimicking diastolic cardiac insufficiency. The mean (n = 11) HMV fell from 2.14 l/minute initially to 1.49 l/minute 30 minutes after instillation. N-(2-(pyridin-3-yl)ethyl) 2'-{[2-(4-methoxyphenyl)acetylamino]methyl}-biphenyl-2-carboxamide was then infused at 3 mg/kg over 30 minutes, at the end of which time HMV had recovered to 1.9 l/minute, and was still 1.65 l/minute 40 minutes after the end of infusion. MECHANISM OF ACTION : (I) block the Kv1.5 potassium channel, so selectively increase contractility of the atrium. The compound N-(2-(pyridin-3-yl)ethyl) 2'-{[2-(4-methoxyphenyl)acetylamino]methyl}-biphenyl-2-carboxamide had IC50 against Kv1.5 of 4.7 mu M when tested in Xenopus laevis oocytes that expressed the human channel.