Optical isomers of rocastine and close analogs: synthesis and H1 antihistaminic activity of its enantiomers and their structural relationship to the classical antihistamines

Abstract

The enantiomers of 2-[2-(dimethylamino)ethyl]-3,4-dihydro-4-methylpyrido[3,2-f]-1,4- oxazapine-5(2H)-thione (rocastine) and two of its more potent analogues were prepared with an enantiomeric purity of greater than 99.9%. The antihistaminic activity of these compounds was assessed by their ability to block histamine-induced lethality in guinea pigs and to inhibit [3H]mepyramine binding to guinea pig cortex. In this series, compounds having the R configuration at the 2-position are at least 300 times more potent than the S isomers. Conformational analysis and molecular modeling suggest that rocastine can adopt a conformation in which the pyridine ring, ether oxygen, and protonated amine functions are positioned similarly to the corresponding elements of the probable binding conformers of some of the more classical antihistamines. This conformation, boatlike in the oxazepine ring with the side chain quasi-equatorial and folded back toward the ring, is the likely binding conformer at the histamine H1 receptor, and the available structure-activity relationship data is consistent with this interpretation.

A One-Pot Synthesis of Oxazepine-Quinazolinone bis-Heterocyclic Scaffolds via Isocyanide-Based Three-Component Reactions

“…Oxazepines, a privileged scaffold in medicinal chemistry, are a well-known class of seven-membered heterocycles with two heteroatoms and have been receiving continuing attention due to the wide range of biological activities. Among these activities, it is worth mentioning anti-inflammatory (Chakrabarti and Hicks, 1987; Verma et al, 2008), antifungal (Serrano-Wu et al, 2002), antithrombotic (Mishra et al, 2010; Agirbas et al, 2011), anti-epileptic (Pekcec et al, 2009), anti-convulsant (Sharma et al, 2008), progesterone agonist (Dols et al, 2008), antagonist and analgesic (Hallinan et al, 1994), anti-histaminic (Sleevi et al, 1991), anti-psychotic (Liegeois et al, 1994; Liao et al, 1999), anxiolytics (Effland et al, 1982), anti-aggregating (Aono et al, 1991), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory (Smith et al, 2006) activities. Compounds containing oxazepine motif, sintamil (Nagarajan et al, 1986) and loxapine (Liao et al, 1999) were reported, due to their antidepressant and potential clozapine-like properties, respectively (Figure 1) (Samet et al, 2005; Liu et al, 2011) Considering the structural characteristics of the benzoxazepine-3-ones, the existence of seven-membered heterocyclic ring system, fused aromatic group and the group –N–C(= O)–, similar to protein amide bond, it is reasonable to expect inherent physiological activities (Agirbas et al, 2011).…”

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

“…The 1,4-benzoxazepine structural unit and its analogues are found in several pharmacologically active derivatives such as the selective 5-HT 1A agonist SUN 8399 ( 1 ) [ 1 ], the neuroprotective piclozotan ( 2 ) [ 2 – 3 ], the antihistaminic rocastine ( 3 ) [ 4 – 5 ], and the antihelmintic 4 [ 6 ] ( Fig. 1 ).…”

Triethylamine‐Catalyzed Synthesis of Oxazepine from Maleamic Acids

“…Seven‐membered ring systems containing two heteroatoms oxazepines (N and O) and their aryl‐annelated (benzoxazepines) and structural analogues diazepines (N and N) and thiazepines (N and S) occupy an important place in the realm of synthetic organic chemistry, as they account for a significant portion of widely prescribed azepine‐based drugs possessing/showing manifold biological activities like antidepressant , anticonvulsant , antiviral , antimicrobial , antifungal , anticancer , antithrombotic , antihistamines , nonnarcotic analgesic , sedatives, and hypnotics . They are also active in the treatment of Alzheimer's disease and type 2 diabetes .…”