Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2- c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to sigma 1 affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma 1 affinity. The most potent sigma 1 ligands display high selectivity against sigma 2, 5-HT 1A, 5-HT 6, 5-HT 7, alpha 1A, alpha 2, and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma 1 antagonistic activity.

On the basis of the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 σ ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased σ(2) affinity and therefore to decreased σ(1)/σ(2) selectivity. Small substituents (e.g., OH, OCH(3), CN, CH(2)OH) in 6'-position adjacent to the O-atom were well tolerated by the σ(1) receptor. Removal of the substituent in 6'-position resulted in very potent but unselective σ ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of σ(1) affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the σ(1) affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the σ(1) affinity.

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Alcohols Q 0230 Novel, One-Pot Procedure for the Synthesis of 2-Arylethanol Derivatives. -It is demonstrated that non-toxic ethylene sulfate represents an interesting C-2 building block for the synthesis of hydroxyethyl derivatives. -(SCHLAEGER, T.; OBERDORF, C.; TEWES, B.; WUENSCH*, B.; Synthesis 2008, 11, 1793-1797; Inst. Pharm. Med. Chem.,

An efficient one-pot synthesis of 2-arylethanol derivatives using ethylene sulfate as a C 2 building block is described. High yields are obtained upon trapping of aryllithium intermediates generated by halogen-metal exchange or directed metalation with ethylene sulfate. The resulting heteroaryl or phenylethanol derivatives represent versatile building blocks for the synthesis of annulated pyran derivatives by oxa-Pictet-Spengler reaction.