Synthesis and Evaluation of Dibenzothiazepines: A Novel Class of Selective Cannabinoid-1 Receptor Inverse Agonists

Abstract

A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).

Iron‐Catalyzed Cross‐Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability

“…One of the most didactic examples showcasing advantages and limitations of iron-catalyzed cross-couplings was reported by Olsson and co-workers at Acadia Pharmaceuticals in the synthesis of CB1 inverse agonists (Scheme 9). [51,52] In 2006, they reported am odel study on the cross-coupling of alkyl and aryl Grignard reagents with imidoyl chlorides catalyzed by Fe(acac) 3 (5 mol %) in THF/NMP (10:1 v/v,N MP: 20 equiv) to give benzodiazepine derivatives in moderate to high yields (not shown). [51] An otable feature was broad functional group compatibility as simple,s terically hindered (secondary and tertiary), and functionalized alkyl, aryl, and even methyl Grignard reagents could be used.…”

“…[12a] In 2009, the authors reported the application of the developed process to the synthesis of selective cannabinoid-1 receptor inverse agonists (Scheme 9). [52] In this study,t he iron-catalyzed strategy developed earlier performed well in the crosscoupling of alkyl nucleophiles;h owever, attempts to install aryl Grignard reagents were fruitless owing to extensive homocoupling to the biaryls.T he inability to efficiently couple aryl nucleophiles is the major limitation of the vast majority of iron catalytic systems developed to date. [9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]…”

Eisenkatalysierte Kreuzkupplungen in der Synthese von Pharmazeutika: Streben nach Nachhaltigkeit

“…Eines der didaktisch besten Beispiele,d as die Vorteile und Einschränkungen der eisenkatalysierten Kreuzkupplungen zeigt, wurde von Olsson und Mitarbeitern bei Acadia Pharmaceutical im Rahmen der Synthese von CB1-inversen Agonisten beschrieben (Schema 9). [51,52] 2006 berichteten sie von einer Modellstudie der Kreuzkupplung von Alkyl-und Aryl-Grignard-Reagenzien mit Imidoylchloriden, die durch Fe(acac) 3 (5 Mol-%) in THF/NMP (10:1 v/v,N MP: 20 ¾quiv.) katalysiert wurde und die entsprechenden Benzodiazepine in mäßigen bis hohen Ausbeuten (nicht gezeigt) lieferte.…”

“…[12a] 2009 beschrieben die Autoren die Anwendung des entwickelten Prozesses auf die Synthese eines selektiven Cannabinoid-1-inversenR ezeptoragonisten (Schema 9). [52] In dieser Studie erwies sich die zuvor entwickelte,eisenkatalysierte Methode in der Kreuzkupplung von Alkyl-Nukleophilen als äußerst leistungsfähig.Die Versuche, Aryl-Grignard-Reagenzien einzubauen, waren jedoch aufgrund der beträchtlichen Homokupplung zu den entsprechenden Biarylen erfolglos.Dieses fehlende Vermçgen, Aryl-Nukleophile effizient zu kuppeln, ist das wesentliche Problem der meisten der bis heute entwickelten Eisenkatalysesysteme. [9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Das wiederkehrende Thema von eisenkatalysierten Kreuzkupplungen in der medizinischen Chemie ist die Verwendung des Fe(acac) 3 /NMP-Katalysesystems fürdie C(sp 2 )-C(sp 3 )-Kreuzkupplung von Alkyl-Grignard-Reagenzien als effektive Alternative zu Alkyl-Negishi- [53] und B-Alkyl-Suzuki-Kreuzkupplungen.…”

Benzothiazepines: chemistry of a privileged scaffold

“…Subsequent diversification of lactam yielded the amide 159 and its further Negishi cross-coupling reaction afforded the final benzo[1,4]thiazepine-8-carboximide 160 54. Detailed description of the mechanism revealed an initial nucleophilic substitution of methyl 2-mercaptobenzoate with ethyl 4fluoro-3-nitrobenzoate to generate bisphenylmonothio product 155.…”