Practical asymmetric synthesis of alpha-branched 2-piperazinylbenzylamines by 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines.

[reaction: see text] 2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.

Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines.

The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.