- Design of fluorinated cyclopropane derivatives of 2-phenylcyclopropylmethylamine leading to identification of a selective serotonin 2C (5-HT2C) receptor agonist without 5-HT2B agonism
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A new series of fluorinated 5-HT2C agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclop
- Cheng, Jianjun,Kozikowski, Alan P.,McCorvy, John D.,Roth, Bryan L.,Shen, Sida,Zhang, Guiping
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- Fluorinated Phenylcyclopropylamines. 1. Synthesis and Effect of Fluorine Substitution at the Cyclopropane Ring on Inhibition of Microbial Tyramine Oxidase
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Two series of diastereopure phenylcyclopropylamine analogues, 2-fluoro-2-phenylcyclopropylamines and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2-fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines, were synthesized in order to study the effects of fluorine substitution on monoamine oxidase inhibition. Inhibitory activity was assayed using commercially available microbial tyramine oxidase. Characterization of tyramine oxidase, carried out prior to the inhibition experiments, confirmed earlier suggestions that this enzyme is a semicarbazide-sensitive copper-containing monoamine oxidase. The most potent competitive inhibitor was trans-2-fluoro-2-phenylcyclopropylamine, which had an IC50 value 10 times lower than that of the nonfluorinated compound, tranylcypromine. 2-Fluoro-1-phenylcyclopropylmethylamine was found to be a weak noncompetitive inhibitor of tyramine oxidase. The presence of a free amino group, directly bonded to the cyclopropane ring, and a fluorine atom in a relationship cis to the amino group were structural features that increased tyramine oxidase inhibition.
- Yoshida, Shinichi,Meyer, Oliver G. J.,Rosen, Thomas C.,Haufe, Günter,Ye, Song,Sloan, Milton J.,Kirk, Kenneth L.
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p. 1796 - 1806
(2007/10/03)
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- Synthesis, reactions and structural features of monofluorinated cyclopropanecarboxylates
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Monofluorinated cyclopropanecarboxylates are available in racemic or optically active form by transition metal-catalyzed reactions of vinylfluorides with diazoacetates. From α-fluorostyrene and tert-butyl diazoacetate in the presence of 2mol% of an enantiopure bis(oxazoline) copper complex, a 81:19 mixture of tert-butyl trans- and cis-2-fluoro-2-phenylcyclopropanecarboxylates was obtained with high enantiomeric excess (ee) of 93 or 89%, respectively. The corresponding racemic ethylesters were used as starting materials for the synthesis of carboxamides, of the cis- and trans-isomers of analogues of tranylcypromine, an anti-depressive drug and several of its homologous fluorinated cyclopropylmethyl and cyclopropylethyl amines. Corresponding enantiopure cyclopropylmethanols and several of their derivatives were synthesized also. Solid state structures of a selection of these compounds were examined by X-ray crystallography. Particularly, the cis-configurated fluorinated phenylcyclopropane derivatives showed extremely close intermolecular C-H···F-C contacts. The shortest of such distances (2.17A) was found in the N-(4-bromophenyl)carbamate of (1S,2R)-(2-fluoro-2-phenylcyclopropyl)methanol.
- Haufe, Guenter,Rosen, Thomas C.,Meyer, Oliver G.J.,Froehlich,Rissanen, Kari
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p. 189 - 198
(2007/10/03)
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