2‐Chloro‐2‐imidazoline has been synthesized by the reaction of ethylene‐thiourea with chlorine in aqueous solution at 50°. The compound was reacted with aromatic amines, phenols, and thiophenols.
The metabolic fate of a new anti-hypertensive, 1-pyrrolyl pyridazinamine, was studied in male Wistar rats after both p.o. and i.v. administration (1 mg/kg). The compound undergoes rapid metabolism, disappearing from the central compartment with a half-life of about 0.5 h. Plasma concn. of the parent drug and its major metabolite I following i.v. and p.o. administration suggest a route-dependent first-pass metabolism. Ten metabolites were isolated from the urine and identified by u.v., i.r., mass and 1H-n.m.r. spectroscopy. The structure of some was confirmed by 13C-n.m.r. and chemical synthesis. All biotransformations are restricted to the pyrrole ring which undergoes oxidative cleavage followed by a series of chemical rearrangements. A minor pathway leads to the formation of methyl sulphinyl and methyl sulphonyl pyrroles. It is suggested that, as with natural indoles, the pyrrole might be oxidized by a 2,3-dioxygenase. The three major metabolites, I, II and IX, along with two minor ones, VI and VII, were inactive when tested i.v. for antihypertensive activity.
The metabolism of the anti-hypertensive drug, mopidralazine, N-(2',5'-dimethyl-1H-pyrrol-1-yl)-6-(4"-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2'(5')-13CH3]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine. The previously proposed mesonic structure of the major metabolite I, i.e., 5'-hydroxy-3',6'-dimethyl-1'-[6-(4"-morpholinyl)-3-pyridazinyl]pyrida zinium hydroxide inner salt, was confirmed by chemical synthesis, X-ray diffraction analysis and 1H n.m.r. of the [3',6'-13CH3]-labelled metabolite I. Metabolite II, 3-methyl-6-(4-morpholinyl)-triazolo [4,3-6 b]pyridazine and metabolite VII, 3-methyl-7-(4-morpholinyl)-3H-pyridazino[1,6-c]pyridazine, were shown to retain the 13CH3 labelling of mopidralazine, whereas metabolite X, 3-acetyl-hydrazino-6-(4-morpholinyl)-pyridazine, loses the labelling, indicating that their formation involves two different pathways. It is hypothesized that the oxidation of the pyrrole leads to ring opening followed by a chemical rearrangement giving rise directly to metabolites II and VII or, with the intermediacy of the pharmacologically active 3-hydrazino-6-(4-morpholinyl) derivative and an enzymic acetylation or conjugation with pyruvic acid, to metabolites X, II and VII.
Es wird über eine intramolekulare Umamidierung berichtet, welche in guter Ausbeute von den viergliedrigen 3,3‐disubstituierten 1‐(o‐Aminophenyl)‐azetidin‐2‐onen (V) durch Ringerweiterung zu den siebengliedrigen 3,3‐disubstituierten 2,3,4,5‐Tetrahydro‐1H‐(benzo[b]1,4‐diazepin)‐2‐onen (VII) führt. Neben der Synthese wird über die chemischen und physikalisch‐chemischen Eigenschaften dieser neuen Verbindungen, über deren IR.‐ und NMR.‐Spektren sowie über einige ihrer Umsetzungen ausführlich berichtet. Der mutmassliche Mechanismus dieser Umlagerung wird diskutiert. Diese Synthese stellt zugleich den ersten allgemeinen Weg zur einfachen Darstellung der bis heute noch nicht beschriebenen 3,3‐disubstituierten 2,3,4,5‐Tetrahydro‐1H‐(benzo[b]1,4‐diazepin)‐2‐one (VII) dar.
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