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.

Tramadol is a centrally acting opioid analgesic structurally related to codeine and morphine. O-Alkyl, N-desmethyl, and non-phenol containing derivatives of tramadol were synthesized to probe their effect on metabolic stability and both in vitro and in vivo potency.

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.

Reaction of Rh-2(S)-PTPA(4) with the (R)-citronellol-derived alpha -diazo-beta -ketoester 1 led to the formation of cyclic beta -ketoester 2 in 95% yield and 48% diastereomeric excess. The purity of 2 was increased to >99% de after one crystallization. To demonstrate its utility in steroid total synthesis, the beta -ketoester 2 was carried on to secosteroid (-)-astrogorgiadiol (3), a naturally occuring vitamin D analogue with antiproliferative properties.

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis, Structure, and Reactivity of the First Enantiomerically Pure Ortho-Metalated Rhodium(II) DimerDouglass F. Taber, Scott C. Malcolm, Klaus Bieger, Pascual Lahuerta, Mercedes Sanaú, Salah-Eddine Stiriba, Julia Pérez-Prieto, and M. Angeles MongeView Author Information Department of Chemistry and Biochemistry University of Delaware, Newark, Delaware 19716 Departamento de Química Inorgánica Universitat de Valencia 46100 Burjassot, Valencia, Spain Departamento de Química Orgánica Universitat de Valencia 46100 Burjassot, Valencia, Spain Instituto de Ciencia de Materiales, CSIC Campus de Cantoblanco 28049 Madrid, Spain Cite this: J. Am. Chem. Soc. 1999, 121, 4, 860–861Publication Date (Web):January 14, 1999Publication History Received4 June 1998Published online14 January 1999Published inissue 1 February 1999https://doi.org/10.1021/ja9819559Copyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views510Altmetric-Citations47LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (114 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Catalysts,Mixtures,Molecular structure,Transition states Get e-Alerts

The unsymmetrical α-diazo ester 1b, derived from the chiral naphthylborneol 5, was cyclized with a set of rhodium carboxylates (L = CF3CO2, CH3CO2, CH3(CH2)6CO2, (CH3)3CCO2). The ratio of the three major products ((R,R)-3b, (S,S)-3b, 4b) was determined. It was found that the rhodium catalyst derived from pivalic acid gave the highest ratio of 3b:4b. Lowering the temperature of the reaction (L = (CH3)3CCO2) increased both the yield and the diastereoselectivity of the cyclization. From these results and from our computational analysis, it is concluded that the ester carbonyl and the rhodium carbenoid are probably syn in the transition state leading to cyclization.

The preparation of the Z-triene 3 is described. Internal Diels-Alder cycloaddition of 3 proceeds smoothly in the presence of BF3. OEt2 to give 2. Ketone 2 is converted by epimerization, carbonyl extrusion, and homologation to the sesquiterpene (+/-)-alpha-oplopenone (1).