Edited by Jurgen Dinges and¨download.e-bookshelf.de/download/0000/6577/70/L-G...and Sanjay R. Chemburkar 18.1 Introduction 291 18.2 History 293 18.3 Synthesis 297 18.4 Mode of Action

Edited by Jurgen Dinges and

Clemens Lamberth

Bioactive Heterocyclic Compound Classes

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Edited by Jurgen Dinges and Clemens Lamberth

Bioactive Heterocyclic Compound Classes

Pharmaceuticals

The Editors

Dr. Jurgen DingesAbbott LaboratoriesGlobal Pharmaceutical R&D200, Abbott Park RoadAbbott Park, IL 60064-6217USA

Dr. Clemens LamberthSyngenta Crop Protection AGResearch ChemistrySchaffhauserstr. 1014332 SteinSchweiz

All books published by Wiley-VCH arecarefully produced. Nevertheless, authors,editors, and publisher do not warrant theinformation contained in these books,including this book, to be free of errors.Readers are advised to keep in mind thatstatements, data, illustrations, proceduraldetails or other items may inadvertently beinaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-PublicationDataA catalogue record for this book is availablefrom the British Library.

Bibliographic information published bythe Deutsche NationalbibliothekThe Deutsche Nationalbibliotheklists this publication in the DeutscheNationalbibliografie; detailed bibliographicdata are available on the Internet at<http://dnb.d-nb.de>.

© 2012 Wiley-VCH Verlag & Co.KGaA, Boschstr. 12, 69469 Weinheim,Germany

All rights reserved (including those oftranslation into other languages). No partof this book may be reproduced in anyform – by photoprinting, microfilm, or anyother means – nor transmitted or translatedinto a machine language without writtenpermission from the publishers. Registerednames, trademarks, etc. used in this book,even when not specifically marked as such,are not to be considered unprotected by law.

Bioactive Heterocyclic Compound Classes(Pharmaceuticals and Agrochemicals,2 Volume Set) ISBN: 978-3-527-32993-9

Print ISBN: 978-3-527-33395-0ePDF ISBN: 978-3-527-66448-1ePub ISBN: 978-3-527-66447-4mobi ISBN: 978-3-527-66446-7oBook ISBN: 978-3-527-66445-0

Cover Design Adam-Design, WeinheimTypesetting Laserwords Private Limited,Chennai, IndiaPrinting and Binding Markono PrintMedia Pte Ltd, Singapore

Printed in SingaporePrinted on acid-free paper

V

Contents

Preface XIList of Contributors XIII

Introduction 1

1 The Significance of Heterocycles for Pharmaceuticalsand Agrochemicals 3Clemens Lamberth and Jurgen Dinges

1.1 Introduction 31.2 Heterocycles as Framework of Biologically Active Compounds 41.3 Fine-Tuning the Physicochemical Properties with Heterocycles 61.4 Heterocycles as Prodrugs 61.5 Heterocycles as Peptidomimetics 71.6 Heterocycles as Isosteric Replacement of Functional Groups 81.7 Heterocycles as Isosteric Replacement of Alicyclic Rings 111.8 Heterocycles as Isosteric Replacement of other Heterocyclic Rings 13

References 16

Part I Neurological Disorders 21

2 Tropane-Based Alkaloids as Muscarinic Antagonistsfor the Treatment of Asthma, Obstructive Pulmonary Disease,and Motion Sickness 23Michael L. Schulte and Craig W. Lindsley

2.1 Introduction 232.2 History 232.3 Synthesis 252.4 Mode of Action 292.5 Structure–Activity Relationships 32

References 34

VI Contents

3 Morphinone-Based Opioid Receptor Agonist Analgesics 37Stephanie M. Ng

3.1 Introduction 373.2 History 373.3 Synthesis 403.4 Mode of Action 433.5 Structure–Activity Relationship 44

References 48

4 Barbituric Acid-Based GABA(A) Receptor Modulators for the Treatmentof Sleep Disorder and Epilepsy and as Anesthetics 51Ingo Janser and Romy Janser

4.1 Introduction 514.2 History 524.2.1 Barbiturates in the Treatment of Sleep Disorders 554.2.2 Barbiturates in the Treatment of Epilepsy 554.2.3 Barbiturates as Anesthetics 564.3 Synthesis 574.4 Mode of Action 604.5 Structure–Activity Relationship 624.5.1 5,5-Disubstitution 624.5.2 Substitution at the Nitrogens 63

References 63

5 Phenothiazine-Based Dopamine D2 Antagonists for the Treatmentof Schizophrenia 65Cristiana A. Zaharia


References 77

6 Arylpiperazine-Based 5-HT1A Receptor Partial Agonists and 5-HT2AAntagonists for the Treatment of Autism, Depression, Anxiety, Psychosis,and Schizophrenia 81Irini Akritopoulou-Zanze


References 96

Contents VII

7 Arylpiperidine-Based Dopamine D2 Antagonists/5-HT2A Antagonistsfor the Treatment of Autism, Depression, Schizophrenia, andBipolar Disorder 99Ying Wang


References 113

8 Dibenzazepine-Based Sodium Channel Blockersfor the Treatment of Neuropathic Pain 115Derek W. Nelson


References 130

Part II Cardiovascular Diseases 135

9 Dihydropyridine-Based Calcium Channel Blockersfor the Treatment of Angina Pectoris and Hypertension 137Milan Bruncko


References 149

10 Tetrazole-Based Angiotensin II Type 1 (AT1) Antagonistsfor the Treatment of Heart Failure and CongestiveHypertension 153Edward C. Lawson, Brian C. Shook, and James C. Lanter


References 163

VIII Contents

11 Thiazide-Based Diuretics for the Treatment of Hypertensionand Genitourinary Disorders 169Jurgen Dinges


References 180

12 Tetrahydropyranone-Based HMG-CoA Reductase Inhibitorsfor the Treatment of Arterial Hypercholesterolemia 183Hongyu Zhao

12.1 Introduction 18312.2 History 18312.3 Synthesis 18812.4 Mode of Action 19112.5 Structure–Activity Relationship 19212.5.1 The Hydrophilic Dihydroxypentanoic Acid Portion 19212.5.2 The SAR of Natural Statins 19212.5.3 SAR of Synthetic Statins 19512.5.4 Liver-Selective HMGCoA Inhibitors 19712.5.5 X-Ray Crystal Structures 197

References 198

Part III Infectious Diseases 201

13 Adenine-Based Reverse Transcriptase Inhibitors as Anti-HIVAgents 203Alastair Donald


References 214

14 Guanine-Based Nucleoside Analogs as Antiviral Agents 217Maurizio Franzini


References 232

Contents IX

15 Penicillin and Cephalosporin Antibiotics 237Michael Z. Hoemann

15.1 Introduction 23715.2 History 23715.3 Synthesis 23915.3.1 Total Syntheses 23915.3.2 Core Modifications 24315.4 Mode of Action 24815.5 Structure–Activity Relationships 250

References 251

Part IV Oncology 255

16 Pyrimidine-Based Kinase Inhibitors in Cancer Chemotherapy 257Robert Mah


References 269

17 Benzyl Triazole-Based Aromatase Inhibitors for the Treatmentof Breast Cancer 275Dawn George and Stacy Van Epps


References 286

Part V Inflammation and Gastrointestinal Diseases 289

18 Acetonide-Based Glucocorticoids for the Treatment of Asthma, SkinInflammation, and Diseases of the Eye 291Kevin P. Cusack, Vikram G. Kalthod, Rajarathnam E. Reddy,and Sanjay R. Chemburkar

18.1 Introduction 29118.2 History 29318.3 Synthesis 29718.4 Mode of Action 30418.4.1 Asthma 30618.4.2 Skin Inflammation 30718.4.3 Eye Disease 307

X Contents

18.5 Structure–Activity Relationship 308References 311

19 Benzimidazole-Based H+/K+-ATPase Inhibitors for the Treatmentof Gastroesophageal Reflux Disease 313Steve Swann


References 324

Part VI Metabolic Diseases 327

20 Thiazolidinedione-Based Insulin Sensitizers:PPAR-γ Agonists for theTreatment of Type 2 Diabetes 329Steven Richards


References 345

Index 349

XI

Preface

Approximately 70% of all the 2400 pharmaceuticals listed in the online versionof ‘‘Pharmaceutical Substances’’ (A. Kleemann et al., Thieme) bear at least oneheterocyclic ring; the latest edition of the ‘‘Pesticide Manual’’ (C. D. S. Tomlin,BCPC) contains a similar percentage of heterocyclic agrochemicals among itsabout 900 entries. This vast number of known pharmaceuticals and agrochemicalsmakes the field of commercialized active ingredients an unmanageable jungle.Only specialists are able to understand the connectivities of these active ingredients,many of which are heterocycles.

Therefore, we decided to put this book together, which tries to show therelationship of those heterocyclic active ingredients, which belong together, forminga biologically active heterocylic chemistry class. According to our definition, such aheterocyclic family is built from at least three compounds that fulfill the followingconditions: (i) same heterocyclic scaffold, (ii) same mode of action, and (iii) similarsubstitution pattern.

Although the strength of this concept is that for the first time the members of themost important heterocyclic active ingredient families, their historical background,chemical syntheses, biochemical modes of action, and biological activities arediscussed in detail, there are also some limitations. For instance, there are someheterocyclic families of drugs or crop protection agents, such as the analgesic COX-2inhibitors celecoxib, valdecoxib, and rofecoxib or the dicarboxamide fungicidesvinclozolin, iprodione, and procymidone, which are closely related by structureand possess the same mode of action, but bear different heterocyclic scaffolds andtherefore could not be considered.

We would like to thank the authors of the 40 chapters of this book, all ofthem experts in their field, for spending their scarce time summarizing theirarea of interest. They all agreed to write the chapters according to the sameoutline: (i) introduction, (ii) history, (iii) synthesis, (iv) mode of action, and(v) structure–activity relationship. Only the agrochemical chapters possess anadditional section ‘‘biological activity,’’ mainly describing the target spectrum of theactive ingredients. This book would definitely not exist without your engagement!

Furthermore, we also would like to thank Anne Brennfuhrer and Stefanie Volk ofWiley-VCH, who from the beginning guided us very efficiently through all differentphases of this exciting project.

XII Preface

The introductory chapter about ‘‘The significance of heterocycles for pharma-ceuticals and agrochemicals’’ tries to explain the different roles of heterocyclicscaffolds in active ingredients, e.g. as framework of biologically active substances,as prodrugs, as tool for fine-tuning the physicochemical properties, as isostericreplacements of functional groups, alicyclic rings or other heterocyclic rings. Asthis is demonstrated at the hand of many prominent and characteristical examplesof pharmaceuticals as well as of agrochemicals, also pointing out the many similar-ities, but also some differences between the two big classes of active ingredients,we decided to put this chapter in front of both volumes.

Although currently living in two different continents, both of us enjoyed exactlythe same excellent education, a Ph.D. in organic chemistry from the TechnicalUniversity at Darmstadt, Germany, and a subsequent postdoctoral fellowship atthe chemistry department of the University of California at Berkeley. We are verygrateful to our teachers, mentors, and research advisors at both universities, whobuilt the foundation for our successful work in the research departments of theagrochemical and pharmaceutical industry.

Finally, we are deeply indebted to our wives Annette and Petra, who continuouslysupported us, as always, and tolerated that we spent many hours of our spare time,which should have belonged to our families, working on this book. You really madethis possible!

Clemens LamberthSwitzerland

Jurgen DingesUSA

XIII

List of Contributors

Irini Akritopoulou-ZanzeAbbott LaboratoriesGlobal Pharmaceutical R&DR4CP, AP10-1100 Abbott Park RoadAbbott ParkIL 60064-6099USA

Milan BrunckoAbbott LaboratoriesGlobal Pharmaceutical R&DDepartment R4N6, AP10100 Abbott Park RoadIL 60064-6101USA

Sanjay R. ChemburkarAbbott LaboratoriesGPODepartment 045B NCR13-21401 Sheridan RoadNorth ChicagoIL 60064USA

Kevin P. CusackAbbott LaboratoriesGlobal Pharmaceutical R&DImmunology381 Plantation StreetWorcesterMA 01605USA

Jurgen DingesAbbott LaboratoriesGlobal Pharmaceutical R&DDepartment R4CP200 Abbott Park RoadIL 60064-6217USA

Alastair DonaldHarlowUnited Kingdom

Maurizio FranziniExelixis Pharmaceuticals210 East Grand AvenueSouth San FranciscoCA 94080USA

XIV List of Contributors

Dawn GeorgeAbbott LaboratoriesGlobal Pharmaceutical R&D381 Plantation StreetWorcesterMA 01605USA

Michael Z. HoemannAbbott Laboratories381 Plantation StreetWorcesterMA 01605USA

Ingo JanserEastern Michigan UniversityDepartment of ChemistryYpsilantiMI 48197USA

Romy JanserYpsilantiMI 48197USA

Vikram G. KalthodAbbott LaboratoriesGPODepartment 045B NCR13-21401 Sheridan RoadNorth ChicagoIL 60064USA

Clemens LamberthSyngenta Crop Protection AGResearch ChemistrySchaffhauserstrasse 1014332 SteinSwitzerland

James C. LanterJohnson and Johnson R&DDrug DiscoveryWelsh and McKean RoadsSpring HousePA 19477USA

Edward C. LawsonJohnson and Johnson R&DDrug DiscoveryWelsh and McKean RoadsSpring HousePA 19477USA

Craig W. LindsleyVanderbilt University MedicalCenterDepartment of Chemistry andPharmacology2213 Garland AvenueNashvilleTN 37232-6600USA

Robert MahGlobal Discovery Chemistry -OncologyNovartis Institutes for BioMedicalResearchNovartis Pharma AGBaselSwitzerladn

Derek W. NelsonAbbottGlobal Pharmaceutical Researchand DevelopmentAbbott ParkIL 60064USA

List of Contributors XV

Stephanie M. NgExelixis210 East Grand AvenueSouth San FranciscoCA 94080USA

Rajarathnam E. ReddyAbbott LaboratoriesGPODepartment 045B NCR13-21401 Sheridan RoadNorth ChicagoIL 60064USA

Steven RichardsExelixis210 East Grand AvenueSouth San FranciscoCA 94080USA

Michael L. SchulteVanderbilt University MedicalCenterDepartment of Chemistry2213 Garland AvenueNashvilleTN 37232-6600USA

Brian C. ShookJohnson and Johnson R&DDrug DiscoveryWelsh and McKean RoadsSpring HousePA 19477USA

Steve SwannFragment Based Drug DiscoveryTranslational Sciences andTechnologyEli LillySan Diego, CAUSA

Stacy Van EppsAbbott LaboratoriesGlobal Pharmaceutical R&D381 Plantation StreetWorcesterMA 01605USA

Ying WangAbbottDepartment R4CPBLDG. AP10100 Abbott Park RoadNorth ChicagoIL 60064USA

Cristiana A. Zaharia644 Topaz StreetRedwood CityCA 94061USA

and

Exelixis Inc.210 East Grand AvenueSouth San FranciscoCA 94083USA

Hongyu ZhaoAbbott LaboratoriesR4CP, 100 Abbott Park RoadAbbott ParkIL 60064USA

1

Introduction

Bioactive Heterocyclic Compound Classes: Pharmaceuticals,First Edition. Edited by Jurgen Dinges and Clemens Lamberth.© 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

3

1The Significance of Heterocycles for Pharmaceuticalsand Agrochemicals∗

Clemens Lamberth and Jurgen Dinges

1.1Introduction

Heterocycles, their preparation, transformation, and properties, are undoubtedly acornerstone of organic chemistry. Several books not only on heterocyclic chemistry[1–6] but also on some special aspects, such as heterocyclic name reactions [7],heterocyclic palladium-catalyzed reactions [8], heterocyclic carbene complexes [9],and fluorinated heterocycles [10], have been published recently.

Approximately more than 70% of all pharmaceuticals and agrochemicals bear atleast one heterocyclic ring. In addition, some of the biggest commercial products todate, such as the blockbuster blood cholesterol reducer atorvastatin (Lipitor®, 1) [11]for the treatment of dyslipidemia and the prevention of cardiovascular diseases andthe broad-spectrum fungicide azoxystrobin (Amistar®, 2) [12], currently appliedagainst diseases of more than 100 different crops in more than 100 differentcountries, belong to this huge heterocyclic group of active ingredients (Figure 1.1).

There are two major reasons for the tremendous value of heterocycles for the leadoptimization of pharmaceuticals and agrochemicals. The heterocyclic scaffold of adrug often has a positive impact on its synthetic accessibility and its physicochemicalproperties, driving these values of lipophilicity and solubility toward the optimalbalanced range regarding uptake and bioavailability. Furthermore, heterocyclesseem to be perfect bioisosteres of other iso- or heterocyclic rings as well asof several different functional groups, in most cases, delivering through theirsimilarity in structural shape and electronic distribution equal or even betterbiological efficacy [13].

∗ Identically published in both volumes of ‘‘Bioactive Heterocyclic Compound Classes’’, asdifferent roles of heterocycles in pharmaceuticals and agrochemicals are explained in thisintroductory chapter.

Bioactive Heterocyclic Compound Classes: Pharmaceuticals,First Edition. Edited by Jurgen Dinges and Clemens Lamberth.© 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

4 1 The Significance of Heterocycles for Pharmaceuticals and Agrochemicals

O

NN

O

NO

O

O

N

O

NH

OH OH

OH

O

F

Azoxystrobinfungicidal

2

Atorvastatinantilipemic

1

Figure 1.1 Atorvastatin (1) and azoxystrobin (2), two of the currently most successfulpharmaceuticals and agrochemicals.

1.2Heterocycles as Framework of Biologically Active Compounds

Several heterocycles possess excellent biological activity almost without bearingany substituents, which means that their heterocyclic core is definitely part ofthe pharmacophore. Examples of such scarcely substituted and highly activeheterocycles are the two bipyridyl derivatives such as amrinone (3) [14], which isused in the treatment of congestive heart failure, and paraquat (4) [15], which isapplied as a total herbicide (Figure 1.2).

Another important role of the heterocyclic core of several pharmaceuticals andagrochemicals is that of an easily accessible scaffold, which carries the substituentsthat are responsible for the biological activity in the right orientation. There areseveral highly active per-substituted heterocycles, as demonstrated by the pyrazolederivatives propyphenazone (5) [16] and fipronil (6) [17], which are widely appliedas efficient analgesic and insecticide, respectively, and synthetically available inonly few steps (Figure 1.3).

Even simple aliphatic heterocycles display astonishing biological activities. Thegem-diethyl-substituted barbituric acid derivative barbital (7) has been widely appliedas a sleeping aid [18]. The pentamethylated piperidine pempidine (8) is used as aganglionic blocker [19]. The trithiane thiocyclam (9), in comparison to the marinenatural product nereistoxin enlarged by one additional ring sulfur atom, has been

NH

N

H2N

ON

N

+

+

Cl−

Cl−

Amrinonecardiotonic

3Paraquatherbicidal

4

Figure 1.2 The highly active bipyridyl derivatives amrinone (3) and paraquat (4), eachcarrying only two small substituents.

1.2 Heterocycles as Framework of Biologically Active Compounds 5

NN

Cl Cl

S

NH2

F FF

NO

F

FF

NN O

Propyphenazoneanalgesic

5Fipronil

insecticidal

6

Figure 1.3 The persubstituted pyrazole derivatives propyphenazone (5) and fipronil (6).

SS

S

N

N N

S SNHN

NH

O

O O

Thiocyclaminsecticidal

Barbitalsedative

Pempidineantihypertensive

7

Dazometnematicidal

8 9 10

Figure 1.4 The saturated bioactive heterocycles barbital (7), pempidine (8), thiocyclam (9),and dazomet (10) [18–21].

developed as a broad-spectrum insecticide [20]. The cyclic dithiocarbamate dazomet(10) is a soil fumigant, which readily decomposes, yielding methyl isothiocyanateas principal toxicant against nematodes (Figure 1.4) [21].

Not only monocyclic heterocycles but also annelated bicyclic ring systems areapplied as pharmaceuticals and crop protection agents, regardless of whether thebiheterocyclic core consists of aliphatic, aliphatic and aromatic, or purely aromaticrings. The tetrahydroimidazothiazole levamisole (11) has been used as anthelminticand immunomodulator [22]. The dopamine agonist talipexole (12) combines a five-and seven-membered ring and has been proposed as an antiparkinsonian agent[23]. The triazolopyrimidine sulfonanilide flumetsulam (13) is used for the controlof broadleaf weeds in corn and soybean (Figure 1.5) [24].

Finally, there are also several examples of active ingredients, which bear twoor more heterocycles in completely different positions of the molecule. For in-stance, the nonsteroidal anti-inflammatory drug meloxicam (14) consists of anamide with a benzothiazine-dione acid moiety and a thiazole amine component[25]. In addition, the agrochemical fungicide ethaboxam (15) contains an amidefunctionality, combining a thiazole carboxylic acid with a thiophene-containingamine (Figure 1.6) [26].


N

S

N

NH2

NN

S

HN

N

N

N SNH

F

FO O

Talipexoleantiparkinsonian

Levamisoleanthelmintic

Flumetsulamherbicidal

11 12 13

Figure 1.5 The highly active annelated bicyclic heterocycles levamisole (11), talipexole (12),and flumetsulam (13) [22–24].

N

S

SN

NH

OOH

O OS

N

SO

NH

N

NH

Meloxicamanti-inflammatory

14

Ethaboxamfungicidal

15

Figure 1.6 Meloxicam (14) and ethaboxam (15), two active ingredients carrying heterocy-cles in different parts of the molecule [25, 26].

1.3Fine-Tuning the Physicochemical Properties with Heterocycles

The fact that in most cases aromatic heterocycles are more polar than theirisocyclic analogs is often used for the lead optimization of pharmaceuticals andagrochemicals. For example, the replacement of the 4-trifluoromethylphenyl moietyof the herbicidal lead structure 16 by a 5-CF3-pyrid-2-yl group resulting in thepostemergence herbicide fluazifop-butyl (17) did not lead to any considerableenhancement of the herbicidal activity but significantly improved the ability ofthe target grass weeds to translocate into the plant tissue because of an optimumpartition coefficient [27]. Furthermore, the replacement of the furane scaffold of theantiulcer histamine H2-receptor antagonist ranitidine (18) by a thiazole resultedin nizatidine (19), which possesses not only a considerably lower log P value thanranitidine but also a much higher human oral bioavailability (Figure 1.7) [28].

1.4Heterocycles as Prodrugs

The efficacy of several heterocyclic active ingredients is based on the fact thatthe heterocycle is acting as a prodrug, itself being not efficacious against thetarget enzyme or organism but delivering the intrinsically active compound by

1.5 Heterocycles as Peptidomimetics 7

O

OO

OF

FF

ON

OO

OF

FF

OS

NH

NH

NO2

N

S

NS

NH

NH

NO2

N

Fluazifop-butylherbicidal

16 17

Nizatidineantiulcer

19

Ranitidineantiulcer

18

Herbicidal

Figure 1.7 Fluazifop-butyl (17) and nizatidine (19) possess optimum physicochemicalproperties to transport their high intrinsic activity to the target [27, 28].

UV light, heat, moisture, or a metabolic transformation. Leflunomide (20), forexample, is a prodrug against transplant rejection, which ring-opens quantita-tively in the cellular system to the hydroxypropenamide (21), which is responsiblefor the immunosuppressive efficacy [29]. In addition, the isoxazole ring of theherbicide isoxaflutole (22) is metabolically converted in plants and soil to the2-cyano-1,3-diketone (23), which is a potent inhibitor of p-hydroxyphenylpyruvatedioxygenase (HPPD), one of the most important molecular targets for herbi-cides [30]. The fungicidal activity of the benzothiadiazine derivative 24 originatesfrom its ability to be converted by sulfur extrusion in aqueous solutions andin plants into the benzimidazole fungicide carbendazim (25) [31]. The in vivoisomerization of fluthiacet-methyl (26) by glutathione-S-transferase leads to theurazole derivative 27, which is entirely responsible for the strong herbicidalactivity (Figure 1.8) [32].

1.5Heterocycles as Peptidomimetics

Several different heterocyclic rings have a proven record as perfect isostericreplacement of the amide function in peptides [33]. The highly active HIV-1protease inhibitors saquinavir (29) [34] and (30) [35] are close analogs of telinavir(28) [36], in which part of its urea function have been replaced by either adecahydroisoquinoline or a tetrazole (Figure 1.9).

Also, other five-membered heterocycles have been applied as amide isosteres inHIV-1 protease inhibitors for the treatment of AIDS. Examples are the imidazolederivative 32 [37] and the pyrrolinone (34) [38], in which the heterocyclic ringreplaces the amide function of the corresponding di- or tripeptides 31 and 33(Figure 1.10). All four HIV-1 protease inhibitors, the peptidic drugs, as well as


NO

SO

OO

F

FF

SO

OO

F

FF

O

N

N

SNH

NH

O

O

NH

N

NH

O

O

SSO

O

Cl F

N

NN

O NSO

O

Cl F

NN

O

S

NO N

H

O F

FF

NH

O F

FF

N

OH

Leflunomide

20

Immunomodulatory

21

Isoxaflutole

22

Herbicidal

23

Carbendazim fungicidal

2524

Fluthiacet-methyl

26

Herbicidal

27

Figure 1.8 The heterocyclic prodrugs leflunomide (20), isoxaflutole (22), andfluthiacet-methyl (26) and (24).

their heterocyclic isosteres are active in the nanomolar range. The pyrrolidinonepeptidomimetic 36 is 100 times more potent than the open-chain thrombininhibitor NAPAP (35) [39]. The pyridine-based peptidomimetic 38 is a potentanalog of PLG (37) (Pro-Leu-Gly-NH2), an endogenous tripeptide found in thecentral nervous system, which is known to exert its pharmacological effectsthrough the modulation of dopamine D2 receptors [40].

Further heterocycles, which have been successfully applied as amide isosteres,are pyrroles [41], thiazolidines [42], isoxazolines [43], imidazolines [44], oxazoles[45], triazoles [46], oxadiazoles [47], and benzimidazoles [48].

1.6Heterocycles as Isosteric Replacement of Functional Groups

Heterocycles are also capable of mimicking other functional groups, besides theabove-mentioned amide group. The most prominent examples are 5-substituted1H-tetrazole as carboxylic acid replacements [49]. One of the success stories of

1.6 Heterocycles as Isosteric Replacement of Functional Groups 9

NN

NN

NO

NH

NH

O

NH2 OH

O

NH

O

NO

NH

NH

O

NH2

O

OH

N NH

O

NO

NH

NH

O

NH2

O

OHN

NH

O

H

H

30

Telinaviranti-HIV

28

Saquinaviranti-HIV

29

Anti-HIV

Figure 1.9 Telinavir (28) and its peptidomimetics saquinavir (29) and (30).

the tetrazole-carboxylate isosterism is the angiotension II receptor antagonistlosartan (40). This drug for the treatment of hypertension and its carboxylic acidlead structure 39 possess similar acidity (pKa of 39: 4.5, losartan: 5.0) but differsignificantly in lipophilicity (log P of 39: 1.2, losartan: 4.5). The higher lipophilicityof losartan results in considerably improved oral bioavailability [49]. Also, the twogamma-aminobutyric acid (GABA) agonists isoguvacine (41) and gaboxadol (THIP,42) possess similar pharmacological properties due to comparable acidity (pKa ≈ 4)(Figure 1.11) [50].

Moreover, triazoles [51], hydroxythiadiazoles [13a], hydroxychromones [52], oxa-diazolones [53], and thiazolidinediones [54] have been reported as heterocycliccarboxylic acid bioisosteres.

If tetrazole is an excellent carboxylic acid replacement, then alkylated tetrazolesshould be able to mimick esters. This is demonstrated by azimsulfuron (44),which shows longer persistence in rice paddy fields than its ethyl ester analogpyrazosulfuron-ethyl (43) [55]. Also, oxazoles [56] and oxadiazoles [57] have beensuccessfully applied as bioisosteres of esters (Figure 1.12).

In search for more potent and selective dopamine D2 agonists for the treatmentof psychiatric and neurological diseases such as schizophrenia and Parkinson’sdisease, the indole moiety in 46 turned out to be an excellent bioisosteric re-placement of the metabolically labile phenol function of the lead structure 45[58].


O

O

O

NH OH

O

NH

OH NH

O

O

O

NH OH OH

O

O

NH OH

O

NH

NH

O

O

NH2

O

N

NH

O

NH OH

NH

O

O O

SNH

NH

O

N

NH

NH2

O O

O

N O

N

NH

NH2

ONH

SO O

NH O

NH

NH

NH2

O

O

NH O

ONH2

O

N

33

31 32

34

NAPAPanticoagulant

35 36

PLG

37 38

Anti-HIV Anti-HIV

Anti-HIVAnti-HIV

Anticoagulant

Figure 1.10 The heterocyclic peptidomimetics 32, 34, 36, and 38.

A widely used trick in lead optimization makes use of the fact that a carbonatom bearing a cyano function is often isosteric with an azomethine, oftenthe ring nitrogen of an aromatic heterocycle. The potassium channel open-ers BMS182264 (47) and pinacidil (48), only differing by the replacement ofa cyanophenyl ring by pyridine are both highly potent aortic smooth musclerelaxants [59].

The replacement of the highly basic benzamidine group in the thrombin inhibitorNAPAP (35) by a moderately basic 1-aminoisoquinoline moiety provides 49, whichdisplays potent enzyme inhibition and significant improvements in membranetransport and oral bioavailability [60].

1.7 Heterocycles as Isosteric Replacement of Alicyclic Rings 11

N

N

OHO

OH

Cl

NNN NH

N

NOH

Cl

NH

OHONO

NH

HO

losartanantihypertensive

4039

Isoguvacine

41

Gaboxadol (THIP)sedative

42

Antihypertensive

Figure 1.11 The tetrazole derivative losartan (40) and the hydroxyisoxazole derivativegaboxadol (42) as carboxylic acid bioisosteres.

1.7Heterocycles as Isosteric Replacement of Alicyclic Rings

A phenyl ring in biologically active compounds can often be replaced by a thiophenewithout any loss of activity because the sulfur atom is equivalent to an ethylenicgroup with respect to size, mass, and capacity to provide an aromatic lone pair [61].For instance, a phenyl ring of the biologically active compound piroxicam (50) can beexchanged by thiophene, leading to tenoxicam (51) with similar anti-inflammatoryactivity (Figure 1.13) [62]. The thiophene derivative sufentanil (53) is at least fivetimes more potent than its phenyl-analog fentanyl (52) [63]. The replacementof the o,o′-dialkylated phenyl ring of the chloroacetamide herbicide metolachlor(54) by a 2,4-dimethylthiophene results in dimethenamid (55) with comparablebiological activity [64]. Also, in the area of acetolactate-synthase-inhibiting sulfony-lurea herbicides, the ester-substituted phenyl ring could be successfully replacedby thiophene, leading from metsulfuron-methyl (56) to thifensulfuron-methyl(57) [65].

In addition, other heterocycles are able to mimic the phenyl ring of biologicallyactive compounds. The substitution of one of the benzene rings of promazine’sphenothiazine scaffold by pyridine led to prothipendyl (59) with improved neurolep-tic activity and reduced undesired sedative and extrapyramidal effects (Figure 1.14)


N N

SNH

NH

O

N

N

O

O

O OOO

N N

SNH

NH

O

N

N

O

O

O ON

NN

N

O

HN

HO HN O

HN

NH

NH

N

NN

N

NH

NH

N

N

SNH

NH

O

N

NH2

NH

O O

O

SNH

NH

O

NO O

O

N

NH2

Pyrazosulfuron-ethylherbicidal

43

Azimsulfuronherbicidal

44

Dopaminergic

45

Dopaminergic

46

BMS182264vasodilatory

47

Pinacidilvasodilatory

48

NAPAPanticoagulant

35 49

anticoagulant

Figure 1.12 Ring nitrogen atoms of heterocycles 44, 46, 48, and 49 are able to mimicfunctional groups such as ester, phenol, nitrile, and amidine, respectively.

[66]. Both compounds are structurally related to the antidepressants maproti-line (60) and imipramine (61), the latter also a heterocyclic isostere of thetetracarbocyclic maprotiline (60) [67]. Interestingly, molecular geometry is de-termining the direction of pharmacological activity of these four psychotropicdrugs [13b]. A dihedral angle between both planes of the two annelated phenylrings higher than 50◦, as is the case for the dibenzobicyclo[2.2.2]octane 60 andthe dibenzazepine 61, results in the preponderance of antidepressive activity [68].If the same angle is only around 25◦, as in the phenothiazines 58 and 59, thenneuroleptic efficacy prevails.

Documents

Edited by Jurgen Dinges and¨download.e-bookshelf.de/download/0000/6577/70/L-G...and Sanjay R. Chemburkar 18.1 Introduction 291 18.2 History 293 18.3 Synthesis 297 18.4 Mode of Action