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

Abstract

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 (MT(1) 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 MT(1) 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 MT(1) receptor (K(i) = 0.041 nM) but no significant affinity for the hamster MT(3)receptor (K(i) = 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.

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…The relative position of the methoxy group and the N-acetylaminoethyl side chain seems to be an important determinant of affinity (Depreux et al, 1994;Langlois et al, 1995;Garratt et al, 1996). The indole ring is not essential for ligand binding because it can be replaced by various other aromatic systems such as naphthalene, benzofuran, benzothiophene, or benzocycloalkene rings (Depreux et al, 1994;Leclerc et al, 1998;Fukatsu et al, 2002). If methoxy and N-acylaminoethyl groups are positioned appropriately on these aromatic scaffolds, ligands with high affinity can result.…”

Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

“…Indane derivatives, including the marketed drug ramelteon (Fig. (4)) were described as MTr ligands in an extensive SAR report published in 2002 [122,123]. Their scaffold recalls the indole derivatives of Fig.…”

Synthesis of Compounds as Melatonin Agonists and Antagonists

“…Indane and indene derivatives are effective cores for melatonin agonists [71][72][73][74]. 2-Aminoindans are readily available by the method of Cannon et al [75].…”