Werner Mederski

(6-oxo-3-pyridazinyl)-benzimidazoles as potent angiotensin II receptor antagonists

The syntheses and angiotensin II antagonistic activities of novel (6-oxo-3-pyridazinyl)-benzimidazole derivatives are reported. Evaluation of the structure-activity relationships led to the discovery of potent orally active antihypertensive compounds.

Pyrido[3,4-b]pyrazines. A New Application of 2-Chloro-3,4-diaminopyridine

5-Chloropyrido[3,4-b]pyrazines were prepared from 1,2-dicarbonyl compounds and 2-chloro-3,4-diaminopyridine. Condensation of unsymmetrical glyoxals provided a mixture of two regiosiomers with 2-substituted pyrido[3,4-b]-pyrazines as the major product. The regiochemistry was unambiguously assigned by 2D-NMR experiments. C-C- and C-N coupling reactions of 5-chloro or 5-oxo intermediates afforded the corresponding C-5 or N-6 substituted derivatives.

On the regiochemistry of the alkylation of tert-butyl N-[6-butyl-1,2-dihydro-2-oxo-3-pyridylmethyl]carbamate: Precursor of a series of potent angiotensin II receptor antagonists

Abstract The key intermediate 5 of a large number of potent AT 1 selective angiotensin II antagonists e.g. the potent cyclopropylmethyl derivative 1 (EMD 69943) was synthesized by regioselective alkylation of carbamate 3 with the well-known 4′-(bromomethyl)biphenyl-2-carbonitrile ( 4 ) and n-butyllithium as the preferred base.

URACIL-BASED ANGIOTENSIN II RECEPTOR ANTAGONISTS

1,2,3,4-Tetrahydro-2,4-pyrimidinedione (uracil) is a valuable nucleus for the construction of potent antagonists of the AT1 angiotensin II receptor. Various synthetic routes were applied in order to introduce a wide range of different groups at the N3-nitrogen and to obtain condensed uracil derivatives as well. 121 with a N,N-dimethylacetamide residue at N3 was the most potent compound with an IC50 of 0.65 nM.