Synthesis of Indolo[2,1-<i>a</i>][2]benzazepine
and Indolo[2,1-<i>a</i>][2]-benzazocine

Ponzi, Simona; Habermann, J.; Ferreira, Marı́a del Rosario Rico; Narjes, Frank

doi:10.1055/s-0029-1217168

Cited by 9 publications

(1 citation statement)

References 7 publications

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“…Since we were unable to improve potency of this series further, we turned our attention to the modification of the tether moiety in the indole series, which was more successful. SAR around 2 and related series had shown that 7- as well as 8-membered rings were equally well tolerated. , Starting from the tetracyclic benzoazepine 4 , novel pentacyclic compounds such as 5 with superior potency in the cell-based assay with respect to our previous compounds were discovered . However, different from 2 , pentacycle 5 and related compounds lacked oral bioavailability in rodents.…”

Section: Introductionmentioning

confidence: 94%

Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

Narjes¹,

Crescenzi²,

Ferrara³

et al. 2010

J. Med. Chem.

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Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

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Section: Introductionmentioning

confidence: 94%

Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

Narjes¹,

Crescenzi²,

Ferrara³

et al. 2010

J. Med. Chem.

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Olefin Ring‐Closing Metathesis

Yet

2016

Organic Reactions

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The olefin ring‐closing metathesis reaction catalyzed by ruthenium and molybdenum complexes has been employed in the syntheses of carbocycles, heterocycles, supramolecular compounds, and in tandem metathesis reactions. Chiral ruthenium and molybdenum catalysts have provided high enantiomeric and diastereomeric excesses in ring‐closing metathesis reactions. Many of the unsuccessful medium‐ and large‐sized ring formations which were unsuccessful by traditional methods, such as the intramolecular Wittig, Horner–Wadsworth–Emmons, and Julia–Kocienski reactions, can now be formed by olefin ring‐closing metathesis reactions. Ring‐closing metathesis has been a key step and sometimes the only successful method for the synthesis of numerous natural products and drug discovery targets. The objective of this chapter is to provide an updated, comprehensive coverage of the literature of the olefin ring‐closing metathesis reaction and related processes. Key mechanistic points are summarized.

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ChemInform Abstract: Synthesis of Indolo[2,1‐a][2]benzazepine and Indolo[2,1‐a][2]‐benzazocine.

Ponzi¹,

Habermann²,

Ferreira³

et al. 2009

ChemInform

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Multi-membered N-heterocycles R 0690 Synthesis of Indolo[2,1-a][2]benzazepine and Indolo[2,1-a][2]-benzazocine. -In connection with a research on novel RNA-dependent RNA polymerase inhibitors of hepatitis C virus, different strategies for the synthesis of the title compounds are described. They involve ring-closing metathesis as the key step to generate the tetracyclic core structures. -(PONZI*, S.; HABERMANN, J.; DEL ROSARIO RICO FERREIRA, M.; NARJES, F.; Synlett 2009, 9, 1395-1400; Dep. Med. Chem., Ist. Ric. Biol. Mol., I-00040 Pomezia, Italy; Eng.) -Mais 43-173

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Synthesis of Indolo[2,1-a][2]benzazepine and Indolo[2,1-a][2]-benzazocine

Cited by 9 publications

References 7 publications

Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

Olefin Ring‐Closing Metathesis

ChemInform Abstract: Synthesis of Indolo[2,1‐a][2]benzazepine and Indolo[2,1‐a][2]‐benzazocine.

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