The reaction of vinyl grignard reagents with 2-substituted nitroarenes: A new approach to the synthesis of 7-substituted indoles

Bartoli, Giuseppe; Palmieri, Gianni; Bosco, Marcella; Dalpozzo, Renato

doi:10.1016/s0040-4039(01)93730-x

Cited by 305 publications

(137 citation statements)

References 28 publications

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“…7-Chloro-2,3-dimethyl-1H-pyrrolo[2,3-c] pyridine (4) was prepared by the Bartoli reaction using 2-chloro-3-nitropyridine 3 and 3 eq of 1-methyl-1-propenylmagnesium bromide. 10) Condensation with various benzyl amines gave the desired compounds 5a and 5c-g. Introduction of the benzoylamino group (5b) was achieved using a palladium-catalyzed reaction in a similar manner as that reported previously. 11,12) The synthesis of 1-substituted derivative 7 is described in Chart 2.…”

Section: Resultsmentioning

confidence: 99%

Molecular Modeling, Design, Synthesis, and Biological Activity of 1H-Pyrrolo[2,3-c]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

Arikawa

Hasuoka

Hirase

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.Key words potassium-competitive acid blocker (P-CAB); peptic ulcer; acid-related disease; 1H-pyrrolo [2,3-c]pyridine-7-amine; gastric acid secretion; gastroesophageal reflux disease (GERD) Current therapies for gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases either prevent the stimulation of parietal cells (e.g., H 2 receptor antagonists, H 2 RAs) or inhibit gastric H + /K + -ATPase (e.g., proton pump inhibitors, PPIs).1) Despite their potent inhibitory activities against acid secretion and their worldwide clinical application, it is suggested that the current treatment could be improved in several aspects.2) Potassium-competitive acid blockers (P-CABs), a new class of acid suppressants with a different mode of action from the existing therapies, are expected to offer some therapeutic benefits such as better symptom control and faster healing of GERD as well as other acid-related diseases.Over the past 30 years, various companies have focused on developing P-CABs as alternative acid suppressants.3)From our efforts to develop new P-CABs, we found a 1H-pyrrolo[2,3-c] pyridine-7-amine derivative 1 (Fig. 1, Left) has potent H + /K + -ATPase inhibitory activity (IC 50 27 nM). Recently, Panchal et al. also reported this compound and its derivatives as P-CABs.4) The acid secretion inhibitory activity in rats of this compound was 62% at the dose of 1 mg/kg on intravenous (i.v.) administration. This result encouraged us to explore more potent compounds in this derivative. In order to design potent inhibitors, we created the homology model of the luminal region of H + /K + -ATPase from the crystal structure of Ca 2+ -ATPase (PDB ID, 1IWO) 5) using SCWRL ver. 2.9. 6) We identified two lipophilic cavities (LP-1 and LP-2 sites) and two polar residues (Tyr925 and Tyr928) in the enzyme that could be used to improve inhibitory activity. 7,8) Figure 1 displays the docking model of compound 1 and also the target LP-1, LP-2 sites and two Tyr residues. This model suggested that this compound binds to the enzyme mainly via the LP-1 site (mode A).In order to improve the in vitro inhibitory activity, we used the following two strategies. First, the 7-position of PCABs has been considered as a possible target for improving inhibitory activity because the orthogonal conformation of benzyl substituents has a major impact on inhibitory activity in a series of imidazo[1,2-a] pyridine compounds.9) Next, we anticipated that the inhibitory activity could be improved via additional lipophilic and po...

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Section: Resultsmentioning

confidence: 99%

Molecular Modeling, Design, Synthesis, and Biological Activity of 1H-Pyrrolo[2,3-c]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

Arikawa

Hasuoka

Hirase

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…This synthesis detailed the reaction of vinyl Grignard reagents with aryl nitro compounds, demonstrating the reactivity of the aryl nitro group towards Grignard reagents. 15 It is possible that attack on the deactivated ketone group of the xanthone was slower than on the nitro group demonstrating the incompatibility of nitro arenes with Grignard reagents, aiding explanation of the observed results.…”

Section: Grignardmentioning

confidence: 95%

Synthetic scale-up of a novel fluorescent probe and its biological evaluation for surface detection of Staphylococcus aureus

Bywaters

Mulcahy-Ryan

Fielder

et al. 2017

Molecular and Cellular Probes

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“…Gathergood and Scamel (2003), and Bartoli et al (1989) reported the synthesis of 4-hydroxy-tryptamine scaffold and 7-hydroxy-tryptamine, respectively. However, this method is not amenable for the direct preparation of the desired indole moiety present in tryptamine.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of Indole Derivatives by Mycelial Cultures

Alarcón

Cid²,

Lillo³

et al. 2008

Zeitschrift Für Naturforschung C

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The reaction of vinyl grignard reagents with 2-substituted nitroarenes: A new approach to the synthesis of 7-substituted indoles

Cited by 305 publications

References 28 publications

Molecular Modeling, Design, Synthesis, and Biological Activity of 1<i>H</i>-Pyrrolo[2,3-<i>c</i>]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

Molecular Modeling, Design, Synthesis, and Biological Activity of 1<i>H</i>-Pyrrolo[2,3-<i>c</i>]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers

Synthetic scale-up of a novel fluorescent probe and its biological evaluation for surface detection of Staphylococcus aureus

Biotransformation of Indole Derivatives by Mycelial Cultures

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