Thiophene analogs of naphthoxazines and 2-aminotetralins:bioisosteres with improved relative oral bioavailability, as compared to 5-OH-DPAT

In the present study, a series of thiophene analogs of 2-aminotetralins and hexahydronaphthoxazines were studied in vivo for their ability to decrease striatal dopamine release, their effects on locomotor activity, and their behavioral characteristics in reserpinized rats, in order to investigate whether a thiophene moiety can act as a bioisostere for the phenol moiety. In general, the new compounds showed lower in vivo activities than 5-hydroxy-2-(N, N,-di-n-propylamino)tetralin (5-OH-DPAT). However, the introduction of the thiophene moiety gave a significant improvement of the relative oral bioavailability, compared to 5-OH-DPAT. Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the thianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[b]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability. (C) 2000 Elsevier Science B.V. All rights reserved

Preparation of (S)-(+)- and (R)-(-)-8-trifluoromethanesulfonyloxymianserin

8-Trifluoromethanesulfonyloxymianserin (3) was synthesized. Its enantiomers were separated by means of HPLC using a chiral stationary phase in the semipreparative mode (100 mg scale) in greater than or equal to 99% optical purity. Reduction of the enantiomers of 3 under catalytic hydrogenation conditions gave the mianserin enantiomers in high purity. The absolute configuration of the enantiomers of 3 were assigned by comparing their respective optical rotations with those of the mianserin enantiomers