The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.

The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.

The present work expands the chemical space known to offer potent inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) and discloses novel bicyclic octahydrocyclopenta[c]pyrrole and octahydro-1H-isoindole scaffolds as potent triple reuptake inhibitors (TRIs) for the potential treatment of depression. Optimized compounds 22a (SERT, NET, DAT, IC(50) = 20, 109, 430 nM), 23a (SERT, NET, DAT, IC(50) = 29, 85, 168 nM), and 26a (SERT, NET, DAT, IC(50) = 53, 150, 140 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 10 and 30 mpk PO, and were not generally motor stimulants at doses ranging from 1 to 30 mpk PO. Moderate in vitro cytochrome P450 (CYP) and potassium ion channel Kv11.1 (hERG) inhibition were uncovered as potential liabilities for the chemical series.

Novel compounds were prepared that united the pharmacologies of the mu-opioid tramadol with the 5-HT4 agonists metoclopramide and norcisapride. The synthesis, chiral separation and in vitro activity of the new compounds is described.

Easily accessible bicyclic lactones were efficiently arylated under modified Hartwig and Buchwald conditions to form quaternary aryl centers with complete cis selectivity. This series is notable in that unreactive substrates, including sterically-demanding ortho-substituted aromatic compounds, enjoyed significant rate acceleration under microwave radiation. Additionally, it was noted that the reactions could be accomplished under standard anaerobic conditions and on multi-gram scale.

Un premier aspect de la presente invention concerne de nouveaux composes heterocycliques. Un deuxieme aspect de cette invention se rapporte a l'utilisation de ces nouveaux composes heterocycliques en tant que ligands destines a divers recepteurs cellulaires, y compris des recepteurs opiaces, d'autres recepteurs couples a la proteine G et des canaux ioniques. Un autre aspect de l'invention concerne l'utilisation de ces nouveaux composes heterocycliques en tant qu'analgesiques.

2-Amidophenol attached to a solid support can be converted to the corresponding benzoxazole by treatment with triphenylphosphine and diethyl azodicarboxylate in THF at room temperature in high yield and purity.

A novel, facile and efficient method for the synthesis of aryl iminophosphorane has been developed by treating a series of ArNH2 (1) attached to a solid support with Ph3P and diethyl azodicarboxylate at room temperature. The resulting solid-supported cinnamyl iminophosphorane (4) was treated with an aryl isocyanate to generate the corresponding solid-supported carbodiimide (5), which upon exposure to a secondary amine underwent 1,2-addition followed by an intramolecular Michael addition to afford the desired 3,4-dihydroquinazoline (7).

The cytotoxic effect of the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) is believed to be associated with a compromise in cellular energy arising as a consequence of its persistent inhibition of mitochondrial respiration. MPP+ is a rather weak inhibitor of electron transport, but it undergoes passive accumulation inside actively respiring mitochondria in response to the transmembrane electrochemical potential gradient. In order to test the prediction that dicationic analogs of MPP+ might be concentrated to a much greater extent and thereby exert especially potent inhibition of respiration on the intact organelle, we synthesized four differently spaced bis-pyridines, each in neutral, monocationic, and dicationic forms, and evaluated their inhibitory activities in intact mitochondria and in electron transport particles (ETP). Compared to the neutrals, the monocations and especially the dications exhibit reduced inhibition in ETP, but the inhibition in mitochondria is enhanced selectively for the cationic inhibitors presumably on account of their accumulation in the mitochondrial matrix. This enhancement is limited by the relatively poor ability of the cationic bis-pyridines to enter mitochondria, as judged from experiments which evaluated the rate of onset of inhibition (without preincubation), in the absence and presence of tetraphenylborate (TPB−). The dications appear to be transported less well than the monocations, and only the most lipophilic dication exhibited a substantially greater accumulation-dependent enhancement of inhibitory activity on mitochondria than did the corresponding monocation. The compounds studied here constitute a novel class of respiratory chain probes which may be useful for a variety of studies on mitochondria.