SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF NEW ESTERS OF 2-ALKYLAMINO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC AND 4-ALKYLAMINO-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS ENDOWED WITH POSITIVE INOTROPIC PROPERTIES

In order to gain insight into structure-activity relationships concern ing the positive inotropic effect of N-heterocycles, a series of 1,8-n aphthyridines was synthesized by two different methods. First, 4-hydro xy substituted derivatives were accessible by cyclization of 2-vinylam ino-1,8-naphthyridines using diphenylether followed by chlorination an d nucleophilic reactions with various amino compounds. Second, 2-amino nicotinic acid was transformed to 2-alkylamino-1,8-naphthyridines invo lving a variation of the Friedlander synthesis as well as many subsequ ent steps. The effect of the compounds on myocardial contractility was assessed in guinea pig left atria paced at 3 Hz. In general, the conc entrations for positive inotropism ranged in between 10(-6)-10(-4) mol /l. The compounds differed considerably with respect to the efficacy o f the increase in contractile force. The pharmacological investigation s appear to demonstrate the following requirements for the pharmacopho ric structure. In connection with a lipophilic ester function in 3-pos ition the target compounds have to contain an alkylamino side chain at C-4 bearing a pi-electron-rich center in a definite distance to the N H-function.