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    • A general synthesis of the tetrazole is shown in First

    2022-07-11

    A general synthesis of the tetrazole is shown in . First, a magnesium-halogen exchange reaction quenched with DMF afforded benzo[]thiophene-5-carbaldehyde , which was further decorated with a bromine at the 3-position (). A Suzuki reaction with -tolylboronic UNC1999 followed by reduction of the aldehyde gave the alcohol intermediate , which was coupled with the right-side phenolic ester through the chloride . Following ester hydrolysis, the carboxylic acid can be converted to the tetrazole through two routes. The first route utilizes a 1,3-dipolar cycloaddition on the nitrile (obtained from the amide ) with TMS-azide. However this route often gave low yields of tetrazoles. A second more consistent yielding route was developed. The acid was converted to the cyanoethyl amide , which reacted with TMS-azide via the imidoyl chloride intermediate to provide the cyanoethyl-protected tetrazole . Deprotection with aqueous hydroxide under mild conditions led to the tetrazole (experimental details and characterization of can be found in ). Since was found metabolically unstable due to oxidation of the benzo[]thiophene sulfur, we synthesized the benzofuran analog of . The compound showed similar GPR40 activity against both species as , and much more stable in rat microsomes (T = 49 min). However, it was still unstable in human microsomes (T = 6 min). So, we decided to focus on the optimization of the benzo[]thiophene scaffold. The first strategy was to incorporate substation groups at the 2-position of benzo[]thiophene to reduce formation of the sulfoxide. 2-Methyl substituted compound was synthesized utilizing the commercially available methyl 3-bromo-2-methylbenzo[]thiophene-5-carboxylate according to the methods outlined in , first route. The synthesis of other 2-substituted benzo[]thiophenes is described in . The GPR40 activity and intrinsic clearance data of these 2-substituted benzo[]thiophenes are shown in . The methyl group () had minimal effect on either potency or intrinsic clearance. For electron-withdrawing substituents, size of the group affects the potency. For small groups, there was a 2- to 3-fold potency loss as compared to . A significant potency drop occurred when the substituent was as large as the methylsulfonyl group (). There is no major change with the intrinsic clearance, especially in human microsomes. However, there is a trend for improvement in rat microsomal stability with substituents like Cl (), Br (), and CF (). Another modification that may be useful in blocking the phase 1 oxidation on sulfur is the 7-position of the benzo[]thiophene. Analogs with methyl and small halogens (F- and Cl-) substituted at the 7-position were prepared (), and their data are shown in . The methyl compound () was much less active and equally unstable metabolically as compared to . The 7-F compounds (, ) were more potent than the methyl () and the Cl compounds (, ), probably due to their smaller size. The compounds (, ) with a methoxy substituent on the distal -methylphenyl group were designed to reduce the lipophilicity of the molecule. They were generally more active against the GPR40 receptors and more stable in microsomes, especially human microsomes, than the unsubstituted ones (, ). Because methoxy substitution on the distal phenyl group improved the human microsomal stability, a variety of different substituents were explored at the 3-position of the benzo[]thiophene (). Polar groups were introduced on the -methylphenyl ring through alkylation of the corresponding phenols. Many of them maintained good GPR40 activity, and were beneficial for both human and rat microsomal stability (–). Compound was equally potent as , but much more stable in human microsomes, although its intrinsic clearance in rat microsomes was still quite rapid. Compounds and are close analogs of with a 2-methoxyethoxyl group substituted at the 3- and 5-position of the -methylphenyl ring, respectively. They were 9- to 14-fold less potent than in human GPR40 receptors. The sulfone-containing compounds, and had reasonable GPR40 activity, with improved stability in human and rat microsomes. The replacement of the -methyl group with -trifluoromethyl group () had little effect on either activity or stability. When the -methylphenyl ring was replaced with heteroaryls (–) or saturated rings (–), the compounds are generally substantially less potent, yet not stable, especially in human microsomes. These compounds (–) were synthesized in the same manner as described in , and the 3-substitutions were added by Suzuki coupling (–, ), Buchwald reaction (27) or Negishi coupling ().