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2016 | Buch

Synthesis of Heterocycles in Contemporary Medicinal Chemistry

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Über dieses Buch

The series Topics in Heterocyclic Chemistry presents critical reviews on present and future trends in the research of heterocyclic compounds. Overall the scope is to cover topics dealing with all areas within heterocyclic chemistry, both experimental and theoretical, of interest to the general heterocyclic chemistry community. The series consists of topic related volumes edited by renowned editors with contributions of experts in the field. All chapters from Topics in Heterocyclic Chemistry are published Online First with an individual DOI. In references, Topics in Heterocyclic Chemistry is abbreviated as Top Heterocycl Chem and cited as a journal.

Inhaltsverzeichnis

Frontmatter
Development of a Manufacturing Process for the Formation of a Nucleoside Drug Candidate
Abstract
The original synthesis of our oral prodrug of isatoribine, a nucleoside analogue potentially useful for the treatment of patients with chronic hepatitis C and other viral infections, suffered from various limitations. Herein we would like to report a practical and robust process identified for the synthesis of an isatoribine prodrug therefore in the course of our process R&D activities. Our efforts relied on the practical manufacture of the base in a straightforward sequence in a streamlined glycosylation process, followed by an effective and regioselective enzymatic hydrolysis, both with a much improved environmental impact. The catalytic activity of the immobilized lipase was demonstrated to be very robust as the enzyme displayed an excellent behavior as catalyst with high levels of activity, selectivity, and excellent operational stability. This process was further developed in a semicontinuous mode and demonstrated to proceed in an even more efficient manner from a throughput standpoint.
Fabrice Gallou
Development of Efficient Routes to Access C-Glycosides as SGLT-2 Inhibitors for the Treatment of Type 2 Diabetes
Abstract
C-Glycosides represent an attractive class of compounds for the medicinal chemist because they are more resistant to enzymatic hydrolysis than O-glycosides and therefore are considered as potential drug candidates. The potential was confirmed by the emergence of a new family of C-glycosides known as the SGLT-2 inhibitors leading to the development of new drugs for the treatment of type 2 diabetes. In this chapter, chemical processes to access new active pharmaceutical ingredients (API) will be described focusing on the key C-glycosylation step.
Sébastien Lemaire, Didier Schils
Synthetic Routes to Sofosbuvir
Abstract
Due to its global pervasiveness and chronicity, the hepatitis C virus (HCV) is a major health problem that claims around half a million lives annually. In recent years, the pharmaceutical industry has witnessed a surge in the development of new therapies for the treatment of hepatitis C. One such drug, sofosbuvir, marketed by Gilead Sciences, was recently approved for clinical use in several countries. In combination with other antiviral agents, sofosbuvir has shown remarkable efficacy for a broad range of viral genotypes, along with high tolerability. The clinical success of sofosbuvir demands efficient approaches for the synthesis of this pharmaceutical. Marketed as a single isomer, sofosbuvir presents several interesting synthetic challenges, including fluorination chemistry, nucleotide synthesis, and regio- and stereoselective phosphoramidation. This review provides a brief pharmacological background of sofosbuvir including its mode of action, followed by an in-depth analysis of the current synthetic approaches to sofosbuvir and its close analogues.
Roland Barth, Christopher A. Rose, Olga Schöne
Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs
Abstract
The virally encoded serine protease NS3/NS4A is essential for the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The quest for the discovery of antiviral agents targeting the NS3/NS4A was initiated with a substrate-based hexapeptide as the lead structure. Evaluation of the conformational pre-organization of this ligand to the bioactive conformation led to the design of macrocyclic peptides, typified by the antiviral agents BILN 2061. Today, closely related analogs of BILN 2061 represent an important class of human therapeutics for the treatment of HCV infection. The critical steps in the synthesis of these compounds involves the cyclization of a tripeptide diene, containing a (1R,2S)-vinyl aminocyclopropylcarboxylate residue, via ring-closing metathesis (RCM). Conformational factors, ligand effects, and reaction conditions were evaluated, and a protocol was developed for the efficient production of these peptidomimetics in high yield and diastereomeric purity. The assembly of these challenging molecules and the key optimization studies are described.
Youla S. Tsantrizos
Recent Progress in the Synthesis of Super-Statins
Abstract
Super-statins now represent a mature class of marketed drugs that faces the patent cliff, as has already occurred for fluvastatin and atorvastatin and is approaching for rosuvastatin and pitavastatin. However, they continue to trigger huge scientific interest in terms of their efficient preparation. This is not surprising, as easier accessibility of super-statins will promote even bigger demand in the market and consequently the need for higher rates of the production and productivity. Therefore, the stimulus for the development of even more efficient synthetic approaches to the heterocyclic moieties of super-statins and their chiral lateral-chain precursors is at a peak, as also for the assembly of the these two parts into super-statins. The present report summarizes recent developments in the field of the synthesis of super-statins published from 2010 to 2015. Emphasis is given to the analysis of novel approaches to the formation of the chiral statin lateral chain, with detailed discussion of the development of new routes to respective heterocyclic cores and the assembly of these key units into the final super-statin structure.
Zdenko Časar
Development of Synthetic Routes to Dolutegravir
Abstract
Within the last decade, a new class of anti-HIV drugs, the so-called integrase inhibitors featuring a novel mode of action, became available as an additional treatment option. The design and discovery of integrase inhibitors were first focusing on targeting the catalytic site of HIV-1 integrase with a specific effect on strand transfer. This approach led to a first generation of 3′-processing and strand transfer inhibitors (INSTIs), from which raltegravir and elvitegravir have been promoted to market. These first-generation integrase inhibitors proved remarkably efficient at reducing viral load in treatment of naive patients’ viral strains. However, subsequent discovery of a low genetic barrier of resistance demonstrated the pressing need for the development of second-generation INSTIs that should be active against raltegravir-resistant and elvitegravir-resistant viral strains. Very recently, dolutegravir sodium, a molecule with a significantly improved resistance profile, received approval in major markets. Dolutegravir features a tricyclic carbamoyl pyridone core comprising two chiral carbon centres. This paper will summarise several synthetic routes disclosed for the preparation of dolutegravir as well as discuss their applicability at multi-ton scale.
Erwin Schreiner, Frank Richter, Sven Nerdinger
Story of Eribulin Mesylate: Development of the Longest Drug Synthesis
Abstract
Eribulin mesylate (Halaven™), approved in 2010 as an anticancer agent, represents a simplified analogue of the marine natural product halichondrin B, which was isolated in 1986 from the sea sponge Halichondria okadai. The story of the discovery, development, and launch of this drug impressively demonstrates how far the limits of total synthesis of natural products have been pushed today on an industrial scale since it can be considered the most complex synthetic drug today.
Armin Bauer
Backmatter
Metadaten
Titel
Synthesis of Heterocycles in Contemporary Medicinal Chemistry
herausgegeben von
Zdenko Časar
Copyright-Jahr
2016
Electronic ISBN
978-3-319-39917-1
Print ISBN
978-3-319-39915-7
DOI
https://doi.org/10.1007/978-3-319-39917-1

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