Heterocyclic Chemistry in the 21st Century A Tribute to Alan Katritzky

304 Pages·2017·14.49 MB·English

by  Eric F.V. Scriven and Christopher A. Ramsden (Eds.)

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
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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,