10 – the biology of metamorphosis

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C–H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

Modern advances in heterocyclic chemistry in drug discovery

Photoinduced energy and electron transfer processes in rigidly bridged dinuclear Ru/Os complexes

Heterocyclic mesomeric betaines

Heteroatoms as well as heterocyclic scaffolds are frequently present as the common cores in a plethora of active pharmaceuticals natural products. Statistically, more than 85% of all biologically active compounds are heterocycles or comprise a heterocycle and most frequently, nitrogen heterocycles as a backbone in their complex structures. These facts disclose and emphasize the vital role of heterocycles in modern drug design and drug discovery. In this review, we try to present a comprehensive overview of top prescribed drugs containing nitrogen heterocycles, describing their pharmacological properties, medical applications and their selected synthetic pathways. It is worth mentioning that the reported examples are actually limited to current top selling drugs, being or containing N-heterocycles and their synthetic information has been extracted from both scientific journals and the wider patent literature.

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Prescribed drugs containing nitrogen heterocycles: an overview

Es werden Hydrazinoderivate des Phtalazins und des Pyridazins beschrieben, uber deren pharmakologisches Interesse an anderer Stelle berichtet worden ist. Die am Grundtypus vorgenommenen chemischen Abwandlungen betreffen die Substitutionen am heterocyclischen oder aromatischen Ring, den Ersatz des aromatischen Kerns durch den Pyridinring und schliesslich Veranderungen am Hydrazinrest.



Bei der Einwirkung von Acylierungsmitteln auf 1-Hydrazinophtalazine entstehen unter Ringschluss Triazolophtalazine. Unter den mit Oxoverbindungen erhaltlichen Phtalazinyl-hydrazonen lassen sich einige unter Spaltung einer C-C-Bindung ebenfalls in Triazolo-phtalazine uberfuhren.



Es werden noch einige weitere Reaktionen der Hydrazingruppe beschrieben.

Hydrazinderivate der Phtalazin‐ und Pyridazinreihe

The synthesis of 4- and 6-substituted 1-H- and 1-phenyl-pyrazolo-(3,4-d)-pyrimidines is described. It starts from ethyl ethoxymethylene cyanoacetate from which the 4-hydroxy-pyrazolo-(3,4-d)- pyrimidines can be obtained in two steps through the corresponding 2-substituted 3-amino-4-carbethoxy-pyrazoles.

Heilmittelchemische Untersuchungen in der heterocyclischen Reihe. Mitteilung. Pyrazolo‐(3,4‐d)‐pyrimidine

Several new basic substituted derivatives of phthalazine show a potent depressive action on blood-pressure which is characterized by a gradual beginning and a very long duration. This action is limited to a narrow range of dosages. The substances produce an increase in the renal blood-flow and have “adrenolytic” properties of a special character. This combination effects a mode of action not common to other blood-pressure depressing substances.

Eine neue Gruppe blutdrucksenkender Substanzen von besonderem Wirkungscharakter

A number of pyridazines and 4-methyl-pyridazines substituted in the 3- and 6-position are described for pharmacological investigations. Certain 3,6-dialkoxy-pyridazines have good anticonvulsive properties. The 3,6-dihydrazino-pyridazine resembles the blood pressure lowering drugs “A presoline” and “Nepresol” in its pharmacological properties. The sulfaderivative of 3-amino-6-chloro-pyridazine has excellent anti-bacterial effects.

Heilmittelchemische Studien in der heterocyclischen Reihe. 6. Mitteilung. Pyridazine III. Derivate des cyclischen Maleinsäure‐ und Citraconsäure‐phenylhydrazids

Es wird die Darstellung der 5,6-Chinone der drei isomeren Phenanthrolinen beschrieben. Aus den Chinonen werden durch Ringverengung uber die Diazafluorenone die entsprechenden neuen Grundkorper, das 1,5-, 1,8- und das 4,5-Diazafluoren gewonnen.

Jean Druey

Papers

Hydrazinderivate der Phtalazin‐ und Pyridazinreihe

Heilmittelchemische Untersuchungen in der heterocyclischen Reihe. Mitteilung. Pyrazolo‐(3,4‐d)‐pyrimidine

Eine neue Gruppe blutdrucksenkender Substanzen von besonderem Wirkungscharakter

Heilmittelchemische Studien in der heterocyclischen Reihe. 6. Mitteilung. Pyridazine III. Derivate des cyclischen Maleinsäure‐ und Citraconsäure‐phenylhydrazids

Phenanthrolinchinone und Diazafluorene