Piperidine derivatives, conformational studies

With the above-mentioned nomenclature the 2,6-diaryl-substituted piperidine derivatives under study were characterized and are presented in Table 2. The analysis shows that the piperidine ring adopts a chair conformation if the hf-position is free or substituted by methyl groups irrespective of the substituents at the other positions. If the N-position contains a - X = Y group bearing tt electrons it invariably adopts either a boat or twist boat conformation. In the N-substituted group if relatively more electronegative atoms are present the piperidine ring prefers a twist-boat conformation. This is in line with the reported studies [62-66]. 

A similar series of reactions was performed on a 6-azido-6-deoxy-2-ketose.246,252 In most of the foregoing syntheses, the piperidine formed is accompanied by the tautomeric furanose. The tautomers can, however, be separated without occurrence of equilibration (which can be induced by changing the pH of the medium). For the ketose derivative 183, the equilibrium mixture includes246 compound 184 and a dehydration product (182). The conformation and anomeric effect in these piperidines have been studied by n.m.r. spectroscopy,253 and their fragmentation pathways have been determined by mass spectrometry.254... 

A hypothesis has been advanced to explain the different pharmacological response to opioid agonists and antagonists in terms of conformational differences about the basic center, as discussed in Chapter 13. However, a study by 13C-nmr of two such pairs (morphine-nalorphine, oxymorphone-naloxone) revealed little difference between agonist and antagonist molecules in either piperidine ring conformation (chairs only) or ratio of N- R axial to equatorial forms (83 17 for morphine, virtually 100% eq JV-R for 14-OH derivatives).035 ... 

The H-NMR spectra of salts of morphine and its congeners are complicated by the existence of protonated epimers, evident from signal duplication and first reported in a 600 MHz study carried out at low pH to slow the interconversion rate Figure 5.10 and [44]). The usual pronounced preference of N-methyl for the equatorial conformation in piperidine derivatives is reduced in the fused-ring system of morphine by non-bonded interactions with the fi-lO-... 

The importance of these piperidine derivatives hes in the clinical use of suitably substituted groups and the different ways available for making modifications in the anticipated structure of the pharmacologically active compoimd. Therefore, a series of piperidine derivatives with bulky aryl substitutions at the 2,6 positions and different substituents in different possible positions, especially the N-substitution, have been crystallized and their conformational features have been studied by crystallographic methods (Table 1) so as to correlate the biological activity with stereochemistry. 

The importance of the stereochemical, intermolecular, and polymorphic analysis of the various heterocyclic drugs were studied. The stereochemical analysis were carried out for piperidine and azepine derivatives, weak TT-interaction studies were pursued for isoxazole, imidazole, indole, quino-Une, and triazole and the polymorphic analyses were done for two commercially available drugs, valdecoxib and sildenafil citrate. These analyses were correlated with the crystal structures of their respective drugs that were foimd in complex with the receptor. The influence of these parameters over the drug s activity were explained. Even though these analyses were based on solid-state conformations, it can provide a wealth of information for the drug design community. 

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