Synthesis of 11‐(Piperazin‐1‐yl)‐5<i>H</i>‐dibenzo[b,e] [1,4]diazepine on Kilo Scale

Kalhapure, Rahul S.; Patil, Bhushan; Jadhav, Mahantesh; Kawle, Laxmikant A.; Wagh, Sanjay B

doi:10.1155/2011/212014

Cited by 9 publications

(4 citation statements)

References 7 publications

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“…To determine whether the 8-Cl group on the tricyclic core is required to activate hM3Dq, we prepared compounds 21 – 23 according to the synthetic route outlined in Scheme . The commercially available 2-aminobenzoic acid ( 15 ) and 2-nitrophenyl iodide ( 16 ) were subjected to Ullmann coupling conditions to afford the aniline 17 .…”

Section: Resultsmentioning

confidence: 99%

The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

Chen

Choo

Huang

et al. 2015

ACS Chem. Neurosci.

138

131

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Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand–receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure–activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.

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Section: Resultsmentioning

confidence: 99%

The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

Chen

Choo

Huang

et al. 2015

ACS Chem. Neurosci.

138

131

View full text Add to dashboard Cite

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“…All of the compounds have been described in patent applications, although the synthesis of compound 21 has never been reported. Surprisingly, no peer-reviewed biological data have been reported with compounds 5, 13, 15, 21, or 23 (Burki et al, 1977(Burki et al, , 1978Grimm et al, 2006;Kalhapure et al, 2011;Schmutz, 1975;Smits et al, 2006;Warawa et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

et al. 2014

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Many neuropsychiatric drugs interact with more than one molecular target, and therapeutic indices might be improved by prospectively designing compounds with profiles optimized against a combination of targets. The dibenzo-epine scaffold is considered a privileged structure, and this scaffold has been explored rigorously in the search for potential novel neuropharmacologic treatments. Members of this chemical class are known to interact with many receptors and transporters, particularly those of the biogenic amine class. In this study, four points of diversity within a dibenzo-epine scaffold were varied systematically and the pharmacologic profiles of the compounds were assessed across 14 receptors and transporters thought to be important to clinical profiles of efficacy and safety. The resulting data were analyzed using a modified forward selection linear regression procedure, thus revealing potential pharmacophoric relationships of the assessed targets within this chemical class. The results highlight a strong covariance across numerous targets. Moreover, the outcome quantifies the innately problematic issue of prospectively designing compounds with defined affinities across multiple targets. Finally, an exploration of the correspondence of binding affinities to in vitro functional activity reveals an additional layer of complexity central to prospectively designing compounds to engage multiple targets. The apparent relatedness of the 5-HT(2a) and D₂ activities suggests that the structural pharmacophores of these receptors overlap more closely with each other than with members of their respective families.

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“…The synthesis started with a copper-powder-catalyzed reaction of fluorobenzene 3 with anthranilic acid to yield diphenyl amine 4 , followed by catalytic hydrogenation to give phenylenediamine 5 in a nearly quantitative yield (Scheme ). The final cyclization in refluxing concentrated trifluoroacetic acid gave a complex mixture containing the desired product.…”

Section: Results and Discussionmentioning

confidence: 99%

Axially Chiral Trifluoromethylbenzimidazolylbenzoic Acid: A Chiral Derivatizing Agent for α-Chiral Primary Amines and Secondary Alcohols To Determine the Absolute Configuration

et al. 2019

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Synthesis of 11‐(Piperazin‐1‐yl)‐5H‐dibenzo[b,e] [1,4]diazepine on Kilo Scale

Abstract: A synthesis of 11-(piperazin-1yl)-5 H-dibenzo[b,e][1,4]diazepine on kilo scale without any chromatographic purification step is reported. Key steps involved are Ullmann condensation, catalytic hydrogenation, and catalyzed cyclization.

Cited by 9 publications

References 7 publications

The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

The First Structure–Activity Relationship Studies for Designer Receptors Exclusively Activated by Designer Drugs

Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection

Axially Chiral Trifluoromethylbenzimidazolylbenzoic Acid: A Chiral Derivatizing Agent for α-Chiral Primary Amines and Secondary Alcohols To Determine the Absolute Configuration

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