[Benzo[c][2,7]naphthyridine-5-yl-arylamines-phenol Mannich bases of the amodiaquine-, cycloquine- and pyronaridine-type]. / Benzo[c][2,7]naphthyridin-5-yl-arylamine-Phenol-Mannich-Basen vom Amodiaquin-, Cycloquin- und Pyronaridin-Typ.

2,5-Dichloro-4-methyl-benzo[c][2,7]naphthyridine (1) reacted with aromatic amines selectively by substitution at the 5-position to yield the amidines 2. The 4-aminophenol 2c could also be synthesized by cleavage of the ether 2b. The structure of 2c was proved by X-ray crystal analysis. Aminomethylation of 2c yielded the amodiaquine analogue 3. The mono- and bisaminomethylated derivatives 4 and 5 were obtained by reaction of compound 1 with phenol Mannich base hydrochlorides. Compounds 3-5 were tested in vitro for antimalarial activity using chloroquine-sensitive and resistant Plasmodium-falciparum strains. The highest activities were shown by the pyronaridine-type compounds 5a and 5b with IC50 values of approximately 200 nM.

[Annulated heterocycles from methyl 6-chloro-5-formyl-2-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate]. / Anellierte Heterocyclen aus 6-chlor-5-formyl-2-methyl-4-(2-nitrophenyl)-1,4- dihydropyridin-3-carbonsäuremethylester.

The pyridone 1a reacts with POCl3/DMF to yield the title compound 2a. After irradiation of 2a the enolether 3 is isolated, as shown by an X-ray structure determination. The pyridine 4 obtained by dehydrogenation of 2a leads under reductive conditions to the benzo[c][2,7]naphthyridines 5-7. The reaction of 4 with o-phenylenediamine gives the benzimidazole 8, while using 2-aminophenol or 2-aminothiophene respectively the pyrido[2,3-b[1,5]benzoxazepine 11 and the corresponding benzothiazepine 12 are obtained.

[Benzo[c][2,7]naphthyridine-2-yl-, 5-yl- and 2,5-diyl novaldiamines--synthesis and investigation of anti-malarial activity]. / Benzo[c][2,7]naphthyridin-2-yl-, 5-yl- und 2,5-diyl-novaldiamine--synthese und prüfung auf wirksamkeit gegen Malaria.

The 2,5-dichlorobenzo[c][2,7]naphthyridine 6 was synthesized starting from the 2-pyridone 1 in four or five steps, respectively. The 5-yl amine 7 and the 2,5-diyl amines 8 and 9 were isolated by the reaction of compound 6 with the novaldiamine base. Starting with the reaction of the 6-chloropyridine 3 with the novaldiamine base to yield the 6-aminopyridine 11, the 2-yl amine 13, isomeric to 7, was obtained. Compounds 7-13 were tested for in vitro antimalarial activity using a chloroquine sensitive and resistant Plasmodium falciparum strain. The highest activity was shown by 8 with IC50 values of 90 nM and 190 nM, respectively.