Synthesis and pharmacological evaluation of new esters of 2- and 4-alkylamino-1,8-naphthyridine-3-carboxylic acids endowed with positive inotropic properties.
In order to gain insight into structure-activity relationships concerning the positive inotropic effect of N-heterocycles, a series of 1,8-naphthyridines was synthesized by two different methods. First, 4-hydroxy substituted derivatives were accessible by cyclization of 2-vinylamino-1,8-naphthyridines using diphenyl-ether followed by chlorination and nucleophilic reactions with various amino compounds. Second, 2-amino-nicotinic acid was transformed to 2-alkylamino-1,8-naphthyridines involving a variation of the Friedländer synthesis as well as many subsequent steps. The effect of the compounds on myocardial contractility was assessed in guinea pig left atria paced at 3 Hz. In general, the concentrations for positive inotropism ranged in between 10(-6)-10(-4) mol/l. The compounds differed considerably with respect to the efficacy of the increase in contractile force. The pharmacological investigations appear to demonstrate the following requirements for the pharmacophoric structure. In connection with a lipophilic ester function in 3-position 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 NH-function.
Heber
D
D
Department of Pharmaceutical Chemistry, University of Kiel, Fed. Rep. of Germany.
Verborg
M
M
Mohr
K
K
D000818:Animals; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D009287:Naphthyridines; D007545:Isoproterenol