2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT 2A antagonists Brock T. Shireman, * Curt A. Dvorak, Dale A. Rudolph, Pascal Bonaventure, Diane Nepomuceno, Lisa Dvorak, Kirsten L. Miller, Timothy W. Lovenberg and Nicholas I. Carruthers Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA Received 11 December 2007; revised 17 January 2008; accepted 23 January 2008 Available online 30 January 2008 Abstract—The synthesis and SAR for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro- pyrimido-azepines is described. Representative compounds were shown to be subtype selective 5-HT 2A antagonists. Optimal place- ment of a basic nitrogen relative to the pyrimidine and the presence of a 4-fluorophenyl group in the pyrimidine 4-position was found to have a profound effect on affinity and selectivity. Ó 2008 Elsevier Ltd. All rights reserved. Known for almost 50 years, the neurotransmitter sero- tonin was first isolated and identified in as 5-hydroxy- tryptamine (5-HT). 1,2 Perceptive operational studies have shown that the monoamine elicits a complex array of pharmacological and physiological responses by act- ing at a diversity of 5-HT receptors. Molecular cloning studies 1 confirmed the existence of at least 14 different subtypes of 5-HT receptors, each encoded by distinct genes. These receptors have been divided into seven fam- ilies, designated as 5-HT, 1–7 based on pharmacology, amino acid sequences, gene organization, and second messenger coupling pathways. 3 With the exception of the 5-HT 3 receptor, 4 a ligand gated ion-channel, all of the 5-HT receptor subtypes are coupled to G-proteins. The therapeutic value of many widely prescribed CNS drugs may be attributed to their action on at least one of the 5-HT receptor subtypes. 5 For example, the 5- HT 2A receptor has been implicated in a variety of behav- ioral processes and neuropsychiatric disorders. 6,7 In addition, the 5-HT 2A receptor appears to be the site of action of many hallucinogenic compounds. Specifically LSD, mescaline, and bufotenin are 5-HT 2A agonists. However, as part of their pharmacological profile the atypical antipsychotics risperdal, olanzapine, and cloza- pine act as high affinity antagonists of the 5-HT 2A recep- tor. 5 In addition to affinity for presynaptic a 2 receptors, the antidepressant mirtazepine possesses pharmacology that includes but is not limited to antagonism of the 5- HT 2 receptor subtypes. 5 Consequently, the undesirable side effects of these and other medicines may be a result of their lack of selectivity. Therefore, the ability to de- sign selective 5-HT receptor agonists or antagonists rep- resents an opportunity to discover better tolerated medicines. Early pharmacological studies also suggested a role for 5-HT 2A antagonists in the treatment of certain sleep dis- orders. 8 In fact, both selective and non-selective 5-HT 2A antagonists have been shown to increase the amount of time humans spend in slow wave sleep, the most restor- ative stage of the sleep cycle. 9 Shown in Figure 1 are rep- resentative 5-HT 2A antagonists that have been reported. Introduced in the mid-1980s, ritanserin (1) 7–9 is a high affinity 5-HT 2A antagonist that has been shown to in- crease the amount of time humans spend in slow wave sleep. 7 Eplivanserin (2), 10 a highly selective 5-HT 2A antagonist has been shown to improve sleep mainte- nance, by reducing wake after sleep onset, decreasing the number of awakenings, increasing the total sleep time, and improving the quality of sleep. One of the more highly studied selective 5-HT 2A antagonists is MDL-100907 (3). 11 A recent proof of concept study demonstrated that MDL-100907 increases deep slow wave sleep in wild-type but not in 5-HT 2A knockout mice. 9 Although 3 is selective for the 5-HT 2A receptor, 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.01.090 Keywords: Serotonin; 5-HT2A; 5-HT2B; 5-HT2C; 5-HT. * Corresponding author. Tel.: +1 858 320 3434; fax: +1 858 450 2089; e-mail: BShirema@prdus.jnj.com Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 2103–2108