cis- & trans-6-Amino-6, 7, 8, 9-tetrahydro-5 H-benzocyclohepten-5-ols, IO-Amino-IO, II-dihydro-5H-dibenzo(a, d) cyclohepten-II-ols and 4-Amino-2, 3, 4, 5-tetrahydro-I-benzoxepin-5-ols

Central Drug Research Institute, Lucknow

With a view to increasing our understanding of the conformation of catecholamines representing an 'ideal' fit of the molecules at the adrenergic receptor site, \(cis\)- and trans-2-hydroxy-, 3-hydroxy and 2, 3-dihydroxy-6- amino-(and isopropylamino)-6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-ols and some related compounds, which incorporate a phenyl-ethanolamine residue, a common denominator of many adrenergic compounds, in a rigid framework, have been synthesised and their biological activity studied. Some significant differences between the properties of 6-amino-6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-ols and the corresponding aminotetralols, indanols and acyclic compounds are : (i) very facile acid catalysed epimerisation of both cis and \(trans-isomers\) (3N HC1 for 30 at 100°), and (ii) N←O-acetyl migration taking place in both cis and trans-isomers with retention of configuration. Only in the case of 6, 7 \(-trans-7 -pheny1-6-amino\)\(-\)6, 7, 8, 9-tetrahydro-5H-benzocyclohepten­5-ols and 4-amino-2, 3, 4, 5-tetrahydro-1-benzoxepin-5-ols it has been found that only the trans-isomer under­goes epimerisation and gradually an increasing proportion of the \(cis-isomer\) accumulates in the reaction mixture. Stereochemical assignments and proposals for probable conformations are based on nmr studies. A twist chair conformation has been proposed for cis- and trans-6-amino-6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-ols, while for 6, 7\(-trans-\)5, 6-cis- and\( t r ans-7 -phenyl\)-6, 7, 8, 9-tetrahydro-5H-benzocycloheptenols the nmr data can be best fitted for boat conformations. A characteristic feature of the nmr spectra of these compounds was the marked downfield shift of H-4, which is purl to the 5-OH group, in one of the isomers ; the OH group in this isomer has been assigned equatorial geometry. In a further study of the nature of this deshielding effect 5, 7-cis- and \(trans\)-7-\(phenyl\)-6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-5-ols and their corresponding O-methyl and O-acetyl derivatives have been synthesised and their nmr studied ; it has been found that the extent of deshielding is related to the availability of the lone pair of electrons on the oxygen. The formation of hydrogen bond between H-4 as donor and OR (R=H, Me, Ac) as acceptor may be involved. Both\( cis\)- and \(trans\)-2, 3-dihydroxy-6-amino-6, 7, 8, 9-tetrahydro-benzocycloheptenols show typical α -sympathomimetic activity. These findings have been discussed in terms of the probable structural profile of α-adrenergic receptor.