Conformationally restricted polysubstituted biphenyl derivatives with angiotensin II receptors antagonist properties

Abstract

The synthesis and in vitro activity of new nonpeptide angiotensin II antagonists is presented. Compared to previously reported biphenyl compounds, the new analogues 8 and 9 have reduced conformational freedom derived from steric hindrance. Methyl 4'-methyl-2',6'-dimethoxy[1,1'-biphenyl]-2-carboxylate 4 has been synthesized by a Von Pechmann condensation of orcinol with oxocyclohexane-2-carboxylate followed by dehydrogenation. This scheme provided the carbon skeleton of the biphenyl potentially substituted on the 2-, 2'-, 4'-, and 6'-positions. Elaboration of the subsituents led to a biphenyl derivative used to alkylate a 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazole. After coupling with the imidazole two regioisomers were separated and identified by 1H NMR. NOESY experiments were useful to establish regiochemistry of the final products that have angiotensin II blocking activity. Their affinity for angiotensin II receptors was established in a binding assay experiment and in an isolated organ test. The presence of 2',6'-dimethoxy substituent on the biphenyl moiety of the antagonist was found to significantly decrease affinity for the receptor.

Nonpeptide angiotensin II antagonists derived from 4H-1,2,4-triazoles and 3H-imidazo[1,2-b][1,2,4]triazoles

“…Precipitation began within a few minutes. After 2.5 h the mixture was taken up in 25 mL of EtOAc and washed with 3 X 25 mL of saturated aqueous Na2C03. The organic phase was dried over MgS04, filtered, and concentrated in vacuo to give 48 mg (96%) of a gum: TLC in 95:5 CHgClg/MeOH; *H NMR (CDClg, 300 MHz) 0.87 (t, J = 7 Hz, 3 ), 1.32 (m, 2 ), 1.66 (m, 2 ), 2.60 (t, J = 8 Hz, 2 H), 4.78 (s, 2 H), 5.25 (s, 2 H), 6.94 (d,«/=7 Hz, 2 H), 7.2-7.S (m, 8 H), 7.63 (m, 1 H), 7.74 (d, J = 8 Hz, 1 H); FAB-MS m/e 505 ( + H)+.…”

Polymer-Assisted Solution-Phase (PASP) Suzuki Couplings Employing an Anthracene-Tagged Palladium Catalyst

“…The Suzuki reaction has proved extremely versatile and has found extensive use in the formation of carbon−carbon bonds, especially the formation of aryl−aryl bonds. In particular, the biaryl unit is represented in many biologically active compounds and novel organic materials …”

Nonpeptide angiotensin II antagonists: N-phenyl-1H-pyrrole derivatives are angiotensin II receptor antagonists

“…The presence of 2',6'-dimethoxy substituents on the biphenyl moiety was found to significantly (10-fold) decrease affinity for the receptor with respect to the unsubstituted analogue. 15 A recent report revealed that naphthalene and tetrahydronaphthalene are mediocre substitutes for the biphenyl spacer. 16 We became interested in the hypothesis that N-phenylpyrrole could be a suitable replacement for the biphenyl group.…”