Starting from the recently reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents in position 6 of benzimidazole showed receptor activities in the low nanomolar range but were only weakly active when given orally to rats. In contrast, analogous substitution of the benzimidazole moiety with basic heterocycles resulted in potent AII antagonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a candidate for clinical development. On the basis of molecular modeling studies a binding model of this new class of AII antagonists to the AT1 receptor is proposed.

The pharmacological profile of BIBR 277, 4′‐[(1,4′‐dimethyl‐2′‐propyl[2,6′‐bi‐1H‐benzimidazol]‐1′‐yl)methyl]‐[1,1′‐biphenyl]‐2‐carboxylic acid, a novel, nonpeptide angiotensin II receptor antagonist has been investigated by use of receptor binding studies, enzymatic assays, functional in vitro assays in rabbit aorta as well as in vivo experiments in pithed, anaesthetized and conscious rats. BIBR 277 potently interacted with rat AT1 receptors (Ki 3.7 nm). Competitive receptor interaction was shown by radioligand saturation experiments performed in the presence of BIBR 277. The failure to inhibit radioligand binding to AT2 sites demonstrates the selectivity of BIBR 277 for AT1 receptors. This is further substantiated by the findings that BIBR 277 neither interacted with other receptor systems investigated nor affected the activity of components of the human renin‐angiotensin system, such as plasma renin or serum converting enzyme. In rabbit aorta, BIBR 277 had no agonistic properties and was shown to be an insurmountable antagonist of angiotensin II‐induced contractions (KB 0.33 nm). The antagonistic effect persisted even after several wash‐out procedures. However, this interaction was not irreversible since the insurmountable antagonism was concentration‐dependently reversed when BIBR 277 (0.1 μm) and the surmountable antagonist, losartan (0.1 and 1.0 μm) were incubated simultaneously. The specificity of BIBR 277 for the AT1 receptor was further substantiated in this preparation since micromolar concentrations of BIBR 277 neither affected potassium chloride and noradrenaline‐induced contractions nor acetylcholine‐mediated tissue relaxation. In pithed rats, i.v. administration of BIBR 277 (0.1, 0.3 and 1.0 mg kg−1) shifted the dose‐pressor response curve to angiotensin II dose‐dependently to the right with ED50 values of 0.23 μg kg−1 (control) and 1.4 μg kg−1, 4.7 μg kg−1 and 20 μg kg−1, respectively. As observed in the in vitro experiments no agonistic effect was detected and the maximum of the blood pressure response to angiotensin II at the highest dose of BIBR 277 was decreased by 29%. In anaesthetized rats, bolus i.v. administration of 0.1, 0.3 and 1.0 mg kg−1 BIBR 277 attenuated the blood pressure response to bolus i.v. injections of angiotensin II (0.1 μg kg−1). At the highest dose an almost complete blockade was observed even after 2 h. Single oral administration of BIBR 277 (0.3 and 1.0 mg kg−1) to conscious, chronically instrumented renovascular hypertensive rats dose‐dependently decreased the mean arterial blood pressure by 15 and 30 mmHg, respectively. At the higher dose a significant antihypertensive effect was maintained for more than 24 h. Moreover, consecutive daily dosing of 1 mg kg−1 orally resulted in a sustained reduction in blood pressure over the 4 day observation period. It is concluded that BIBR 277 is an effective and selective angiotensin II antagonist with antihypertensive activity after oral administration.

Es werden die Dehydrierung sterisch gehinderter p-Hydroxy-benzaldoxim-0-ather zu Aroxylen unterschiedlicher Stabilitat sowie deren chemische Eigenschaften beschrieben. Aus der Analyse der EPR-Spektren schlieI3en wir auf eine weitgehende Delokalisierung der x-Elektronen in solchen Radikalen.Unterwirft man den in der voranstehenden Mitteilung 1) beschriebenen p-Hydroxybenzaldoxim-chinolather einer nochmaligen monovalenten Dehydrierung, so wird auch die sterisch behinderte Hydroxylgruppe dehydriert. Dabei bildet sich ein neues, stabiles Aroxyl, das die Struktur eines 0-Oximchinolathers besitzt. Auch andere sterisch behinderte p-Hydroxy-benzaldoxiather lassen sich zu tieffarbigen Aroxylen dehydrieren. Diese Aroxyle ergeben EPR-Spektren, die auf einen besonders weitgehend delokalisierten Bindungszustand schliekn lassen. I. DARSTELLUNG DER NEUEN AROXYLEWir untersuchten zunachst die Dehydrierung des Oximathers I1 aus 2.4.6-Tritert.-butyl-phenoxyl und 3.5-Di-tert.-butyl-4-hydroxy-benzaldoxim mit alkalischem Kaliumcyanoferrat(1II) bzw.

Es wird iiber Reaktionen von Aroxylen mit Oximen, Hydroxylaminen, Hydroxamsauren, aliphatischen mi-Nitroverbindungen und Hydroperoxyden berichtet. In fast allen Fallen entstehen chinolide Ather mit z. T. auffallenden Eigenschaften. Die Ergebnisse werden im Hinblick auf eine mechanistische Erklarung der monovalenten, radikalischen Dehydrierung erortert.Im reaktiven Verhalten der Aroxyle spielt die monovalente Dehydrierung geeigneter Verbindungen eine dominierende Rolle. Vielfach, z. B. bei Phenolen, Naphtholen und Thiophenolen, verlaufen diese Reaktionen so glatt wie eine Titration. Da andererseits einfache Enole, Alkohole oder Carbonsauren unter vergleichbaren Bedingungen nicht in Reaktion treten, suchten wir nach anderen dehydrierbaren Stoffklassen. Uberraschenderweise reagieren viele Oxime, aber auch Hydroxylamine, Hydroxamsauren, sogar aliphatische mi-Nitroverbindungen sowie Hydroperoxyde glatt mit Aroxylen, wobei Chinolather mit z. T. besonderen und interessanten Eigenschaften entstehen. Diese neuen Reaktionen werfen auch ein Licht auf den Reaktionsmechanismus der monovalenten Dehydrierungen. I. DEHYDRIERUNGEN VON OXIMEN MIT AROXYLEN Darstellung der DehydrierungsprodukteDehydrierbar sind Mono-und Dioxime von Aldehyden und Ketonen, wobei die Art der Substituenten (aliphatisch oder aromatisch) nicht wesentlich zu sein scheint.Die Umsetzung verlauft bei 40--60" sehr glatt und stochiomstrisch im Molverhaltnis 2 Aroxyl : 1 Oxim. Man erhalt zum Teil hervorragend kristallisierende Verbindungen.

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