The synthesis of various diastereoisomeric H4a,H5-cis,H4a,H9b-cis- and H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro -1H-indeno[1,2-b]pyridines is described, as well as the evaluation of their antidepressant potency. Elucidation of structure-activity relationships revealed the H4a,H5-trans compounds as being by far the more active of the two series of diastereoisomers. Pharmacological and biochemical data suggest that these compounds are potential antidepressants with central stimulating properties, which are characterized by strong norepinephrine and dopamine reuptake inhibition.

Biological tests indicate hexahydro-1H-indeno[1,2-b]pyridines to be potential human antidepressants with additional stimulating properties. Two diastereomeric series with H4a,H5-trans,H4a,H9b-cis and H4a,H5-cis,H4a,H9b-cis configurations have been tested biologically. The results revealed that the H4a,H5-cis,H4a,H9b-cis series and the ortho-substituted 5-phenyl H4a,H5-trans,H4a,H9b-cis compounds lack activity. Neither the conformation with lowest potential energy nor any other electron-derived parameter correlate with these data. The only relevant difference between the active and the inactive compounds detected thus far is the rotational barrier of the phenyl in the 5-position. The conclusion was reached that certain conformations, which do not resemble those of lowest potential energy, cannot be adopted by the inactive compounds. Therefore, the interaction of the drug with the binding site, responsible for its biological activity, appears to be governed by a dynamic process. This process is characterized by a transformation of the conformation of lowest potential energy to one with an energy content above the minimum.

Nomifensine and three selected compounds from the series of H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro-1H-in deno[1,2-b]pyridines have been resolved into their enantiomers. All compounds exhibit pronounced enantioselective activity with respect to their inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity. Nomifensine exhibits the same preference for one enantiomer with respect to dopamine and norepinephrine reuptake, whereas in the indeno[1,2-b]pyridine series in vitro experiments do not discriminate between the optical antipodes. The absolute stereochemistry of the pharmacologically active enantiomers in both series was determined by X-ray analyses and comparative CD spectra. For biological activity the diphenylmethane is an essential structure feature in both series. Its absolute configuration proved to be 4S for nomifensine and 5S for indenopyridines. The similar pharmacological profile of the two chemical entities is therefore reflected in an identical configuration of this pharmacologically important molecular part.

Reaktionen mit Phosphinalkylenen, XXIII2)Reaktionen von Phosphinalkylenen mit Nitriloxiden. Eine neue Synthesemoglichkeit fiir Azirine, Ketenimine und a . P-ungesattigte Oxime3,4) Aus dem Institut fur Organische Chemie der Universitat Erlangen-Nurnberg (Eingegangen am 11. November 1968) IPhosphinalkylene 1 und Nitriloxide 2 setzen sich zu 4.5-Dihydro-1.2.5Pv-oxazaphospholen (3) urn, die thermisch zerfallen. Die Stabilitat der Verbindungen 3 sowie der Verlauf ihrer Zersetzung ist abhangig von den Substituenten R, R1 und R2. Gruppen R1 und R2 mil ~ Iund -M-Effekt bewirken die Bildung von Keteniminen 10, wahrend die gleichen Gruppen mit elektronendriickender Wirkung die Entstehung von Azirinen 9 zur Folge haben. In beiden FHllen wird gleichzeitig Triphenylphosphinoxid abgespalten. u b e n R einen ~I -und gleichzeitig R1 und R2 einen +-I-Effekt aus, so isoliert man als Endprodukt des Zerfalls von 3 Triphenylphosphin und cc.P-ungesattigte Oxime 8.Im Verlauf unserer systematischen Untersuchungen iiber Phosphina!kylene 1 als nucleophile Reaktionspartner 5,6) haben wir deren Reaktionen rnit Nitriloxiden 2 7 ) studiert. Der Gesamtreaktionsablauf, der in seiner zweiten Phase entscheidend von den Substituenten R1 und R2 (aus 1) und R (aus 2) beeinflufit wird, laBt sich folgendermafien zusammenfassen :Phosphinalkylene 1 und Nitriloxide 2 vereinigen sich zunachst zu 1 : I-Addukten, die man unter gewissen strukturellen Voraussetzungen, auf die weiter unten einge-1) Aus der Dissertat. R. Kunstmann, Univ. Erlangen-Nurnberg 1968.

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