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Synthesis of a Novel Series of Benzocycloalkene Derivatives as Melatonin Receptor Agonists

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Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan
Cite this: J. Med. Chem. 2002, 45, 19, 4212–4221
Publication Date (Web):August 15, 2002
https://doi.org/10.1021/jm020114g
Copyright © 2002 American Chemical Society

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    Abstract

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    We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding affinities to melatonin receptors. To control the spatial position of the amide group, one of the important pharmacophores, we incorporated an endo double bond, an exo double bond (E- and Z-configurations), and a chiral center (R- and S-configurations) at position 1. The indan derivatives with the S-configuration at position 1 were the most promising in terms of potency and selectivity for the human melatonin receptor (MT1 site), while compounds with the R-configuration showed little potential. Our next attempt was to investigate the most favorable conformation of the methoxy group, the other important pharmacophore for binding to the MT1 receptor. The introduction of a methyl group at position 5 of the indene ring conserved affinity; however, at position 7, it caused a decrease in affinity. These results suggested that the substitution at position 7 forced the methoxy group to adopt an unfavorable orientation. The optimization of the condensed ring size and substituents led to (S)-8d [(S)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]propionamide], which had high affinity for the human MT1 receptor (Ki = 0.041 nM) but no significant affinity for the hamster MT3 receptor (Ki = 3570 nM). In addition, a practical synthetic method of chiral N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]alkanamides employing asymmetric hydrogenation with (S)-2,2‘-bis(diphenylphosphino)-1,1‘-binaphthyl−Ru has been established.

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    X-ray crystallographic data of (S)-8o; detailed information on the synthesis and characterization of the target compounds listed in Table 2; a list of receptors and enzymes tested for (S)-8d; the inhibitory effect of (S)-8d on forskolin-induced cAMP production in CHO cells expressing the human MT1 receptor. This material is available free of charge via the Internet at http://pubs.acs.org.

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