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Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties.
Journal article

Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties.

  • Vorberg R Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland.
  • Trapp N Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland.
  • Zimmerli D F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Wagner B F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Fischer H F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Kratochwil NA F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Kansy M F. Hoffmann-La Roche AG, Pharmaceutical Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Carreira EM Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland. erickm.carreira@org.chem.ethz.ch.
  • Müller K Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093, Zürich, Switzerland. klaus.mueller@org.chem.ethz.ch.
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  • 2016-09-16
Published in:
  • ChemMedChem. - 2016
fluorine
levobupivacaine
partial fluorination patterns
pharmacological properties
ropivacaine
Dose-Response Relationship, Drug
Halogenation
Humans
Hydrophobic and Hydrophilic Interactions
Microsomes, Liver
Molecular Structure
Piperidines
Structure-Activity Relationship
Temperature
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/113988
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