Various 1-and 2-substituted and 1,2-fused 1,4-dihydropyridine-5-phosphonate derivatives were designed and synthesized as analogues of 1,4-dihydropyridine-3,5-dicarboxylate, and their antihypertensive activities were examined. Several compounds proved to be equal or superior to nifedipine in lowering blood pressure in normotensive and spontaneously hypertensive rats. Among these compounds, 1-substituted 1,4-dihydropyridine derivatives showed potent antihypertensive activities. The structure-activity relationships are discussed.In the previous paper,21 the authors reported the synthesis of 1,4-dihydropyridine-5-phosphonates (I) and the antihypertensive activities of these compounds, which were expected to have more prolonged calcium antagonistic activity and better bioavailability than nifedipine. Among them, methyl 2,6-dimethy1-4-(2-nitropheny1)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-y1)-1,4-dihydropyridine-3-carboxylate (DHP-218), which is approximately 7 times more active than nifedipine and has long-lasting antihypertensive activity,3) was chosen for clinical evaluation.Recently, various new 1-and 2-substituted 1,4-dihydropyridines have been reported. Flordipine is a first development dihydropyridine compound with a substituent on the nitrogen atom (1-position). It exhibits antihypertensive activity in rats and dogs when given by the oral route. FR-75345) and nilvadipine5a.6) are dihydropyridine-related compounds which are substituted in the 2-position with a hydroxymethyl and a cyano group, respectively, in place of the methyl group of nifedipine. Among them, nilvadipine, which shows longlasting antihypertensive activity, has been reported to be clinically effective. 2-Amino7) and 1,2-fused derivatives8) have also been synthesized and their antihypertensive activity examined. The former was active, but the latter was not.In this paper, the synthesis and the antihypertensive activities of 1-and 2-substituted and 1,2-fused 1,4-dihydropyridine-5-phosphonate derivatives (II-IV) are described, and the structure-activity relationships of these compounds are discussed.
Chemistry1-Substituted-1,4-dihydropyridine-5-phosphonates (II) The 1-substituted-1,4-dihydropyridines (II) listed in Table I were synthesized by the two routes shown in Chart 2. As described in the previous paper,2) the 1-arylideneacetonylphosphonates 42) were allowed to react with the appropriate N-substituted 3-aminocrotonates 3 in 2-propanol under reflux to afford II in 13-59% yields, except for compound 9 (R1: NMe2, 3%; method A). In this case, the reaction of 4 with N-isopropyl (3d) and N-methoxy 3-aminocrotonates (3q) did not afford