1H-Indole-4-boronic acid → 5-hydroxy-2-[2-(1H-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3H)-one

Participants

Reaction Conditions

Reaction Steps

A mixture of 2-(2-bromopyridin-4-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one (30 mg, 0.106 mmol), 1H-indol-4-ylboronic acid (32 mg, 0.2 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichchloromethane complex (4 mg) in THF (2 mL) and 1 M aq Cs2CO3 (1 mL) was heated in a microwave at 160° C. for 10 min. After cooling to rt, the THF layer was separated and the aq. solution was extracted with THF (2 mL). The combined THF solution was treated with QuadraPure TU resin (Aldrich), filtered, and concentrated. The concentrated residue was purified by LCMS to give 5-hydroxy-2-[2-(1H-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3H)-one (26.5 mg, TPA salt). 1H-NMR (499 MHz, d6-DMSO): δ 11.31 (s, 1H); 9.77 (s, 1H); 8.85 (d, J=5.0 Hz, 1H); 8.08 (s, 1H); 7.61-7.56 (m, 2H); 7.56-7.50 (m, 2H); 7.46 (t, H=2.7 Hz, 1H); 7.22 (t, J=7.7 Hz, 1H); 6.99-6.96 (m, 1H); 3.44 (s, 3H); HRMS calculated for (C18H14N4O2+H)+ 319.1190 found 319.1188. Assays The activity of the compounds in accordance with the present invention as COMT inhibitors may be readily determined without undue experimentation using a fluorescence or fluorescence polarization (FP) methodology that is well known in the art (Kurkela M et al., Anal Biochem (331) 2004, 198-200 and Graves, T L et al., Anal Biochem (373) 2008, 296-306). Assays utilized purified human COMT enzyme of the Val158 variant (membrane-bound MB-COMT or soluble S-COMT) containing a C-terminal 6 or 10-histidine tag. Compounds of the following examples had activity in reference assays by exhibiting the ability to inhibit the methylation of esculetin and/or inhibit the production of S-adenosyl-homocysteine (SAH). Any compound exhibiting an IC50 below 1 μM would be considered a COMT inhibitor as defined herein.

Provenance & Evidence