J. Med. Chem. 1993,36,3947-3955
3947
Syntheses of 2,5- and 2,6-Difluoronorepinephrine,2,5-Difluoroepinephrine, and 2,6-Difluorophenylephrine: Effect of Disubstitution with Fluorine on Adrenergic Activity' George T. Chen,t Michael King,t Fabian Gusovsky, Cyrus R. Creveling, John W. Daly, BangHua Chen, Jun-ying Nie, and Kenneth L. Kirk' Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Imtitutes of Health, Bethesda, Maryland 20892, and Department of Chemistry, George Wmhington University, Washington, D.C.20052 Received June 30, 19938
Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed. The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes. The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophdes to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive a t both a- and @-adrenergicreceptors. These results are consistent with earlier observations that 2-fluor0 substitution of adrenergic agonists decreases a-adrenergic activity whereas 6-fluor0 substitution decreases 8-adrenergic activity. We have described in several publications the striking definition of the molecular mechanism whereby fluorine effects of fluorine substitution on the agonist properties substitutionalters adrenergicselectivitybae beenobtained. of a series of adrenergic agonists. In all phenolic phenethIt is apparent that fluorinepresent on the 2- or 6-position anolamines examined [the mixed a l p adrenergic agonists of adrenergicagonistsstrongly influencesagonist-receptor norepinephrine (NE)23and epinephrine (EPI);4the seinteractions. In view of this, we felt that substitution of lective a-adrenergic agonist phenylephrine (PE);5and the a second fluorine on the aromatic ring might further alter selective @-adrenergicagonist, isoproterenol (ISO)61, a the adrenergic activity of the 2- or 6-fluoro-substituted fluorine substituted at the 2-position of the aromatic ring analog. For example, effects of intramolecular hydrogen greatly reduces affinity of the agonist for a-adrenergic bonding between fluorineand the benzylicOH group could receptors, while fluorine substituted at the 6-position be canceled in a 2,6-difluoro-substitutedderivative, promarkedly reduces affinitiesat @-adrenergicreceptors. The ducing an active but nonselective analog. In contrast, resulting 2-fluor0 derivatives thus are highly selective for negative effects of binding caused by dipole-dipole re@-adrenergicreceptors, while the 6-fluor0 derivatives are pulsion of the C-F bond and benzylic OH group, or highly selective for a-adrenergic receptors. In certain intermolecularrepulsiveinteractions of the C-F bond with the receptor, should be additive, producing an analogue systems, the 2-fluor0 and 6-fluor0 analogs were not only more selective, but were also more potent than the parent with reduced activity at both a- and @-receptors.Peras @- and a-adrenergicagonists,respectively. Substitution turbations of the electroniccharacter of the aromatic ring of fluorine in the 5-position of NE and IS0 had relatively caused by a single fluorine substituent also should be little effect on adrenergic properties. Similar fluorinealtered by the presence of a second fluorine. Herein we induced adrenergic selectivitieswere found for the potent describethe synthesesof a,&difluoro-NE(l),2,6-difluoro@-adrenergicagonist 3-(N-tert-butylamino)-l-(3,4-dihy- PE (2), 2,B-difluoro-NE(3), and 2,5-difluoro-EPI (4) and droxypheno~y)propanolamine.~ discuss the mechanistic implications of the results. There has been considerable speculation as to the H O e N H 2 H O eF N OH H C H 3 molecular mechanismts)by which the presence of fluorine can cause such marked changes in receptor affinity.' For example, proposals were made that putative interactions HO of the benzylic hydroxyl group with an ortho-situated fluorine-hydrogen bonding or dipole-dipole repulsion1 2 could introduce conformational biases that favored or inhibited binding to either a-or @-adrenergic re~eptors.~l~*~*~ Alternativeproposals not involvingside-chaininteractions H O w N H 2 H O w N H C H 3 invoked electronic perturbations caused by the presence of the highly electronegative fluorine s u b ~ t i t u e n t . ~ J ~ HO HO Examples of such perturbations are reduced electron F F density on the carbon to which fluorineis attached, altered 3 4 frontier orbital characteristics, or the presence of the C-F dipole. These effects could lead to adrenergicselectivities Chemistry by alteringthe interactionsof the aromatic ring with critical The syntheticapproach to the target phenethanolamines sites on the adrenergicreceptor. However, as yet, no clear was based on side-chain elaboration of the appropriately substituted benzaldehyde precursors, as shown retroayn+ George Washington University. Abstract published in Advance ACS Abstracts, October 15, 1993. thetically in Scheme I. 0022-262319311836-3947$04.00/0 0 1993 American Chemical Society
3948 Journal of Medicinal Chemistry, 1993, Vol. 36,No. 24
Chen et al. Scheme 11
Scheme I F
F
F
=-&O.
F
Pt
