Heterocyclic Chemistry in the 21st Century A Tribute to Alan Katritzky PDF
Preview Heterocyclic Chemistry in the 21st Century A Tribute to Alan Katritzky
VOLUMEONEHUNDREDANDTWENTYONE A DVANCES IN HETEROCYCLIC CHEMISTRY Heterocyclic Chemistry in the 21st Century: A Tribute to Alan Katritzky EDITORIAL ADVISORY BOARD A. T. Balaban Galveston, Texas, United States of America A. J. Boulton Norwich, United Kingdom M. Brimble Auckland, New Zealand D. L. Comins Raleigh, North Carolina, United States of America J. Cossy Paris, France J. A. Joule Manchester, United Kingdom V. I. Minkin Rostov-on-Don, Russia B. U. W. Maes Antwerp, Belgium A. Padwa Atlanta, Georgia, United States of America V. Snieckus Kingston, Ontario, Canada B. Stanovnik Ljubljana, Slovenia C. V. Stevens Ghent, Belgium J. A. Zoltewicz Gainesville, Florida, United States of America VOLUME ONEHUNDREDAND TWENTY ONE A DVANCES IN HETEROCYCLIC CHEMISTRY Heterocyclic Chemistry in the 21st Century: A Tribute to Alan Katritzky Editors ERIC F. V. SCRIVEN Department of Chemistry, University of Florida, Gainesville, FL, USA CHRISTOPHER A. RAMSDEN Lennard-Jones Laboratories, Keele University, Staffordshire, United Kingdom AcademicPressisanimprintofElsevier 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates 525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates 125LondonWall,LondonEC2Y5AS,UnitedKingdom TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Firstedition2017 Copyright©2017ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicor mechanical,includingphotocopying,recording,oranyinformationstorageandretrievalsystem,without permissioninwritingfromthepublisher.Detailsonhowtoseekpermission,furtherinformationabout thePublisher’spermissionspoliciesandourarrangementswithorganizationssuchastheCopyright ClearanceCenterandtheCopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/ permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher (otherthanasmaybenotedherein). 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ISBN:978-0-12-811174-1 ISSN:0065-2725 ForinformationonallAcademicPresspublicationsvisitour websiteathttps://www.elsevier.com/ Publisher:ZoeKruze AcquisitionEditor:PoppyGarraway EditorialProjectManager:ShellieBryant ProductionProjectManager:SuryaNarayananJayachandran Designer:GregHarris TypesetbyTNQBooksandJournals CONTRIBUTORS Saadia T. Chaudhry Department of Chemistry, PurdueUniversity, WestLafayette, IN, USA Johannes G.de Vries Leibniz-Institut für Katalyse e.V.an derUniversität Rostock, Rostock, Germany Andrew J.F.Edmunds Syngenta Crop Protection AG,Basel, Switzerland Jian-Bo Feng Leibniz-Institut für Katalyse e.V.an derUniversität Rostock, Rostock, Germany Peter Maienfisch Syngenta Crop Protection AG,Basel, Switzerland Charles M.Marson Department of Chemistry, University College London,Christopher IngoldLaboratories, London,UK Colin H.McAteer Vertellus Specialties Inc., Indianapolis,IN, USA Jianguo Mei Department of Chemistry, PurdueUniversity, WestLafayette, IN, USA Ramiah Murugan Vertellus Specialties Inc., Indianapolis,IN, USA Jean’neM.Shreeve Department of Chemistry, University of Idaho,Moscow, ID, USA Yarlagadda V. SubbaRao Vertellus Specialties Inc., Indianapolis,IN, USA Xiao-Feng Wu Leibniz-Institut für Katalyse e.V.an derUniversität Rostock, Rostock, Germany Ping Yin Department of Chemistry, University of Idaho,Moscow, ID, USA Tony Y. Zhang Small Molecule Design andDevelopment, Lilly Research Laboratories, EliLilly and Company, Indianapolis,IN, USA Xikang Zhao Department of Chemistry, PurdueUniversity, WestLafayette, IN, USA j ix PREFACE AshorttributetoAlanKatritzkyhighlightingtheaspectsofhismajorwork in heterocyclic chemistry (structure, mechanism, theory, QSAR, synthetic methods, applications, and the review literature) appeared in Volume 113 ofAdvancesinHeterocyclicChemistry.Forover50years,Alanwasatthefore- frontofadvancesinandapplicationsofheterocyclicchemistry.Heinitiated the publication of Advances in Heterocyclic Chemistry in 1963 and personally commissioned and edited 112 volumes. When we considered what would be a fitting tribute to his contribution, we posed the question, as we felt Alan would have, “What is happening now, and what next?” In response to this question, we have been fortunate to receive chapters from leaders currently involved in heterocyclic chemistry and its applications. These coverthelatestadvancesintheareasmentionedabovetogetherwithabroad scope of new developments. This, the third and final volume of the tribute, contains eight chapters which focus on synthetic approaches and applications of heterocycles with current or prospective commercial importance. The first chapter by Tony Zhang(Eli LillyandCo.) containsan analysisof thestructuresof heterocy- clicdrugsanddrugcandidates,whichillustratestheneedforrobustreactions thatleadtomorediversestructures.InChapter2,CharlesMarson(Univer- sityCollegeLondon)reviewssaturatedheterocycles(withoneheteroatom, spiroheterocyclic,andheterobicyclosystems)withapplicationsinmedicinal chemistry covering the period 2013–2015. Peter Maienfisch and Andrew Edmunds(SyngentaCropProtectionAG)presentanaccountofthecontri- butionofthiazolesandisothiazolestocropprotectioninChapter3.Jean’ne Shreeve and Ping Yin (University of Idaho) (Chapter 4) review nitrogen- rich azoles as high-density energy materials. In Chapter 5, Jianguo Mei, Xikang Zhao, and Saadia Chaudhry (Purdue University) describe the use of five-membered ring heterocycles used as building blocks for production of organic semiconductors. InChapter6,ColinMcAteer,RamiahMurugan,andYarlagaddaSubba Rao (Vertellus Specialties, Inc.) give a broad treatment of heterogeneously catalyzedsynthesisofthree-toseven-memberedheterocyclesincludingdis- cussion of catalyst choice, process, and economic considerations. The main advances(2013–2015)inpalladium-catalyzedcarbonylativesynthesis,espe- cially of five- and six-membered heterocycles, is given by Xiao-Feng Wu and Jian-Bo Feng (Leibnitz Institute for Catalysis, University of Rostock) j xi xii Preface in Chapter 7. In the final chapter, Johannes de Vries (Leibnitz Institute for Catalysis, University of Rostock) discusses powerful new catalytic methods available and in development that allow the utilization of renewable resources, particularly 5-hydroxymethylfurfural as a platform chemical. Chris Ramsden and Eric Scriven September, 2016. CHAPTERONE The Evolving Landscape of Heterocycles in Drugs and Drug Candidates Tony Y. Zhanga SmallMoleculeDesignandDevelopment,LillyResearchLaboratories,EliLillyandCompany, Indianapolis,IN,USA E-mail:[email protected] Contents 1. Introduction 2 2. Method 3 3. ResultsandDiscussion 3 4. Conclusion 9 Acknowledgments 11 References 11 Abstract Substructureanalysisofapproveddrugsanddrugcandidatesinclinicaltrialswasper- formedtoillustratetheevolvingrolesofheterocyclesinpharmaceuticalresearch.The increasingrepresentationofbiarylsandheteroaromaticsisnotedandattributedpre- dominantlytotheirbetteraccessibilitybroughtuponbyadvancesinmetalcatalyzed cross-coupling and hetero-coupling reactions. Possible future focus of academic research is proposed for improving structural diversity and probability of success for drug research, and enhancing the impact of heterocyclic chemistry to the develop- mentofnewmedicines. Keywords: Analysis; Biaryl; Cross-coupling; Drug; Drug candidates; Drug of the future; Heterocycle; Palladium catalysis; Pharmacophore; Pyrazole; Pyridine; Structural diversity; Substructures; Synthetic accessibility; Synthetic feasibility; Synthetic methodology development a ThispaperisdedicatedtothememoryofProfessorAlanR.Katritzky,fromwhomtheauthorlearned thereasonofbeingforheterocycles. AdvancesinHeterocyclicChemistry,Volume121 ISSN0065-2725 ©2017ElsevierInc. j http://dx.doi.org/10.1016/bs.aihch.2016.05.001 Allrightsreserved. 1 2 TonyY.Zhang 1. INTRODUCTION Heterocycleshaveplayedaprominentroleamongpharmaceuticals,as theyhave beenessentialintheperpetuation,propagation,andevolution of lifeinmolecularformssuchasnucleotides,carbohydrates,hemes,andamino acids. While most drugs achieve the desired therapeutic outcomes through interactions with proteins or DNA/RNA, the morphology of successful drugs does not necessarily resemble that of their biological targets. In fact, the shapes of drugs are heavily influenced by three artificial factors, i.e., (a) the structure of the initial hit or lead; (b) the synthetic feasibility for the intended structure; and (c) the availability of starting material for the preparation (Figure 1). The feedback loop connecting compound synthesis and biological testing during structural activity relationship (SAR) studies is still a relatively long and arduous process. It is worth noting that all these three major factors are a culmination of historic synthetic chemistry efforts and natural product explorations in the last200years.Asaresulttheytendtobebiasedtowardcertainchemicallin- eages, such as petroleum, coal tar, naval store chemicals, and existing drugs supplychain.Forexample,hitsareusuallyobtainedfromscreeninganexist- ingcompoundcollection,whichitselfwascollectedthroughtheyearsfrom various sources. We want to note that in recent years more tailor-designed librariesofhitstructures,guidedbyinsightsintoproteinstructureswiththe aidofcomputationalchemistryandNMRtechniques(e.g.,fragment-based drug discovery/design) (2015DDT(20)1104) are matriculating into the De novo design insights Hit/Lead structures In vitro /in vivo activity and selectivity ADME and toxicology Synthetic Availability of properties starting feasibility material Figure1 Majorinfluencersofdrugstructuresduringthediscoveryprocess. TheEvolvingLandscapeofHeterocyclesinDrugs 3 public and industrial collections to compliment compounds of natural and industrial origin. However, composition of these libraries is heavily influ- enced by high efficiency chemistry and separation technology that enabled theirfacilesynthesisandpurification.ForSARinvestigation,mostchemists preferreactionsthatarereliableandhighlyefficient,startingfromcommer- cially available starting materials. In other words, compounds that are easily synthesizedarebiasedtohaveabetterchanceofprogressinginthedrugdis- covery journey. 2. METHOD To have a more quantitative glimpse at the structural trend of drug molecules, we performed a substructure analysis of approved drugs as well as drug candidates currently in clinical and preclinical development using theDrugDataReport(MDDR)database(2016MI1).MDDRisacommer- cial database that retrieves chemical structures from published documents. The database includes the respective therapeutic classes and status of devel- opmentofdrugcandidates.Itisdifficulttocompileahistoricaloverviewof snap shots of the shapes of molecules in development as the numbers are constantly changing. Therefore, we plot the data of all launched drugs (N¼1631), those drugs that have been approved in the last decade (2005e2014, N¼221); the previous decade (1995e2004, N¼331); drug candidates currently in Phase III (N¼351), Phase II (N¼1457), and Phase I (N¼1161); or in preclinical development (N¼17,580), as of Sept 2015. Only compounds with defined structures were included and as a consequence large molecules such as antibodies and large peptides were omitted. The database also has a “Biological testing” category for development stage, which covers a broad range of the compounds that havenotyetenteredintopreclinicaldevelopment.Theywerenotincluded in the analysis due to the lack of commonly accepted criteria for the mile- stone. Compounds with a development stage classified as “registered,” “pre-registered,” “recommended approval,” and those between phases were not included due to the small representation. 3. RESULTS AND DISCUSSION Of the more than 22,000 compounds with defined structures in the selected dataset, a great majority (95%) contain at least one ring (top line,
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