title: Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties.
abstract: 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.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland.
authors.forename: Raffael
authors.initials: R
authors.lastname: Vorberg
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland.
authors.forename: Nils
authors.initials: N
authors.lastname: Trapp
authors.affiliation: F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zimmerli
authors.affiliation: F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.affiliation: F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.affiliation: F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Kratochwil
authors.affiliation: F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland. erickm.carreira@org.chem.ethz.ch.
authors.forename: Erick M
authors.identifier: 0000-0003-1472-490X
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland. klaus.mueller@org.chem.ethz.ch.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
mesh_terms: D004305:Dose-Response Relationship, Drug; D054879:Halogenation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D010880:Piperidines; C000620896:piperidine-2-carboxamide
keywords: fluorine; levobupivacaine; partial fluorination patterns; pharmacological properties; ropivacaine