Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines

Abstract

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.

Chiral 1,1-diaryl compounds as important pharmacophores

“…Nomifensine is a chiral 1,1-diarylmethane based on a tetrahydroisoquinoline motif. It was withdrawn worldwide in 1986 due to the risk of it causing acute haemolytic anaemia with intravascular haemolysis, however, up to that time, many biologically active analogues had been prepared, [44][45][46][47] including those incorporating a heterocyclic aromatic thiophene ring (Fig. 9).…”

Stereoselective and Regioselective Intramolecular Friedel–Crafts Reaction of Aziridinium Ions for Synthesis of 4-Substituted Tetrahydroisoquinolines

“…THIQ derivatives were reported to possess biological functions including anticancer, antibiotic, and dopamine inhibitory or stimulating activities. 15–17 In particular, 4-substituted THIQs such as nomifensine and dichlofensine are known to display dopamine inhibitory or anti-depressant action. 16–17 However, straightforward and general synthetic methods for optically active 4-substituted THIQs are rarely reported.…”

“…15–17 In particular, 4-substituted THIQs such as nomifensine and dichlofensine are known to display dopamine inhibitory or anti-depressant action. 16–17 However, straightforward and general synthetic methods for optically active 4-substituted THIQs are rarely reported. 18–19 Herein we report a new synthetic method for enantiomerically enriched 4-substituted THIQs based on the intramolecular FC reaction of aziridinium ions.Enantiomerically enriched β-haloamines 1 - 3 (Table 1) were prepared from β-amino alcohols with various functionalities and substituents and used as precursor molecules to generate aziridinium ions in situ for intramolecular FC reactions.…”

“…FC reaction is a useful synthetic method for C–C bond formation in organic synthesis. , We hypothesized that aziridinuim ions containing an aromatic N -substituent will undergo intramolecular FC reactions to provide 4-substituted tetrahydroisoquinolines (THIQ) in high regio- and stereoselectivity. THIQ derivatives were reported to possess biological functions including anticancer, antibiotic, and dopamine inhibitory or stimulating activities. − In particular, 4-substituted THIQs such as nomifensine and dichlofensine are known to display dopamine inhibitory or antidepressant action., However, straightforward and general synthetic methods for optically active 4-substituted THIQs are rarely reported. , Herein we report a new synthetic method for enantiomerically enriched 4-substituted THIQs based on the intramolecular FC reaction of aziridinium ions. Enantiomerically enriched β-haloamines 1 – 3 (Table ) were prepared from β-amino alcohols with various functionalities and substituents and used as precursor molecules to generate aziridinium ions in situ for intramolecular FC reactions.…”

Azepines and Piperidines with Dual Norepinephrine Dopamine Uptake Inhibition and Antidepressant Activity

“…A notable observation in these results is a pronounced difference between the nomifensine stereoisomers [e.g., 3-(S) ≫ 3-(R)], which was confirmed to be consistent with the literature. 21 All activity for nomifensine resides in the (S) stereoisomer, although the nomifensine racemate was used clinically. This large dependence on stereochemistry was not observed with the 3,4-dichlorophenyl 2,3,4,7-tetrahydro-1H-azepines such as 7b versus 7c or 8b versus 8c, where only a minor difference was observed.…”