The modulation of pharmacologically relevant properties of N-alkyl-piperidine-2-carboxamides was studied by selective introduction of 1-3 fluorine atoms into the n-propyl and n-butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non-fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine-2-carboxamide core is chiral, pairs with enantiomeric N-alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation.
The synthesis and X-ray crystal structures of syn and anti 4-N-Boc-aminobicyclo[3.2.0]heptane-1-carboxylic acids are described. The placement of the N-Boc-amino groups in the two stereoisomers in either pseudo-equatorial or pseudo-axial positions renders the molecules conformationally locked, with N-Boc-protected γ-aminobutyric acid (GABA) embedded within the bicyclic core. Despite the different conformations of the urethane and distinct crystal packing, the bicyclic core units of the two stereoisomers adopt virtually identical structures. They correspond to in silico models of the parent bicyclic core and a systematic array of disubstituted derivatives. The study documents an intrinsic property of the bicyclo[3.2.0]heptane core to favor adoption of a boat-like conformation, which is largely unaffected by various substitution patterns. The structural concepts are useful in the design of molecules with spatial and directional fixation of pharmacophoric groups.
In a series of partially fluorinated N-propyl- and N-butylpiperidine derivatives, three compounds were found to exhibit unexpected instability under mild biophysical assay conditions. These compounds carry a single terminal fluorine in the δ-position of an N-butyl group as a common structural feature. An adjacent fluorine substituent at the γ-position significantly slows down the reactivity. All other compounds, having either no or more than one fluorine substituent at the δ-position are chemically inert under all assay conditions. The reactivity of the labile compounds is traced to an intramolecular ring-closing fluorine substitution reaction by the moderately basic piperidine unit, leading to a spiro-pyrrolidinium salt. The chemical lability of δ-monofluorinated or γ,δ-difluorinated N-butylpiperidine derivatives even under very mild biophysical assay conditions constitutes a caveat to the molecular design of partially fluorinated alkylamines.
The molecular and crystal structures of 19 N‐alkyl‐substituted pipecolamide derivatives with partial fluorination of N‐propyl and N‐butyl groups are presented. Fluorination patterns include one F‐atom at internal or terminal locations, two F‐atoms in geminal or vicinal arrangements at various positions, as well as terminal trifluoromethylation. Due to the presence of the carboxamide side chain in pipecolamide derivatives, enantiomeric fluorination patterns in the N‐alkyl group result in diastereomeric compounds, which exhibit dramatically different crystal and molecular structures. An extraordinary conformational diversity is diagnosed for the various N‐alkylpiperidine units. Structural comparisons and theoretical assessments based on extensive force field calculations provide insight into consistent conformational patterns that point to intramolecular factors as well as intermolecular modulations due to crystal packing effects.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.