A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H4 receptor (H4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (7j), a potent H4R agonist (H4R, pKi = 7.6). Pharmacological data suggests that the series of nonimidazole compounds can be used to describe the orthosteric binding site of the H4R because both 2 and 7j displace [3H]histamine in a competitive manner. Furthermore, it is demonstrated that the effects of 7j are competitively antagonized by the selective H4R antagonist JNJ 7777120 (1), indicating considerable overlap of their binding sites. On the basis of the derived structure-activity relationships and additional pharmacological results, a pharmacophore model was constructed, which will be the premise for the design of novel H4R ligands.

Abstract:The rhodium-catalyzed asymmetric hydrogenation of readily available a,b-unsaturated esterphosphonates affords the corresponding a-chiral phosphonates in excellent yield and ee. The resulting products are useful multifunctional building blocks applied in the synthesis of physiologically active compounds.

A ruthenium pre-catalyst containing two equivalents of the bulky monodentate phosphoramidite 3,3'-dimethyl-PipPhos and one equivalent of a chiral diamine such as 1,2-diphenylethylenediamine or 1,2-diaminocyclohexane was used for the asymmetric hydrogenation of aromatic ketones. A range of substituted and unsubstituted aryl alkyl ketones was hydrogenated using only 0.1 mol% of this catalyst with full conversions and enantioselectivities up to 97%. The phosphoramidite and diamine ligands matched when both had the same configuration, i.e., S-phosphoramidite with S,S-diamine. In that case the product was obtained with high enantioselectivity and the R-configuration. The mismatched case produced the product in lower ee. The product configuration was determined by the configuration of the diamine ligand. A mechanistic proposal was made.

Organo-phosphorus compounds S 0080Asymmetric Hydrogenation of α,β-Unsaturated Ester-Phosphonates. -Several chiral diphosphine and phosphoramidite ligands are examined in the rhodium-catalyzed title reaction. Best results are achieved with FDP to give α-chiral phosphonate esters, useful building blocks for the synthesis of physiologically active compounds.-(HUANG, Y.; BERTHIOL, F.; STEGINK, B.; POLLARD, M. M.; MINNAARD*, A. J.; Adv. Synth. Catal. 351 (2009) 9, 1423-1430; Stratingh Inst., Univ. Groningen, NL-9747 AG Groningen, Neth.; Eng.) -Klein 44-177