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Thiophene derivativesThiophene derivatives R 0090 Duloxetine (Cymbalta™), a Dual Inhibitor of Serotonin and Norepinephrine Reuptake. -The serotonin and norepinephrine uptake affinity of initially prepared naphthyl ethers is improved by incorporation of a phenyl ring into the amino-ether chain. Since substitution of the phenyl ring does not improve the inhibition of NE uptake while maintaining inhibition of 5-HT uptake, an isosteric replacement of the phenyl ring with furanyl and thienyl analogues is carried out with the result of better 5-HT uptake inhibition. These heterocyclic alternatives are prepared analogously to the thiazole derivative (VI). Two chiral routes to the enantiomers of the thienyl derived amino ether, starting from the common intermediate (VII), are developed. (S)-Enantiomer (XI) (Cymbalta™) is shown to be effective in the treatment of depression. -(BYMASTER*, F. P.; BEEDLE, E. E.; FINDLAY, J.; GALLAGHER*, P. T.; KRUSHINSKI, J. H.; MITCHELL, S.; ROBERTSON, D. W.; THOMPSON, D. C.; WALLACE, L.; WONG, D. T.; Bioorg. Med. Chem. Lett. 13 (2003) 24,