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Bioactive Heterocyclic Compound Classes: Pharmaceuticals

Clemens Lamberth (Editor), Jurgen Dinges (Editor)
ISBN: 978-3-527-33395-0
372 pages
October 2012
Bioactive Heterocyclic Compound Classes: Pharmaceuticals (3527333959) cover image
The chemistry of heterocycles is an important branch of organic chemistry. This is due to the fact that a large number of natural products, e. g.
hormones, antibiotics, vitamins, etc. are composed of heterocyclic structures. Often, these compounds show beneficial properties and are therefore applied as pharmaceuticals to treat diseases or as insecticides, herbicides or fungicides in crop protection.
This volume presents important pharmaceuticals. Each of the 20 chapters covers in a concise manner one class of heterocycles, clearly structuredas follows:

* Structural formulas of most important examples (market products)
* Short background of history or discovery
* Typical syntheses of important examples
* Mode of action
* Characteristic biological activity
* Structure-activity relationship
* Additional chemistry information (e.g. further transformations, alternative syntheses, metabolic pathways, etc.)
* References.

A valuable one-stop reference source for researchers in academia and industry as well as for graduate students with career aspirations in the
pharmaceutical chemistry.
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Preface XI

List of Contributors XIII

Introduction 1

1 The Significance of Heterocycles for Pharmaceuticals and Agrochemicals 3
Clemens Lamberth and Jürgen Dinges

1.1 Introduction 3

1.2 Heterocycles as Framework of Biologically Active Compounds 4

1.3 Fine-Tuning the Physicochemical Properties with Heterocycles 6

1.4 Heterocycles as Prodrugs 6

1.5 Heterocycles as Peptidomimetics 7

1.6 Heterocycles as Isosteric Replacement of Functional Groups 8

1.7 Heterocycles as Isosteric Replacement of Alicyclic Rings 11

1.8 Heterocycles as Isosteric Replacement of other Heterocyclic Rings 13

References 16

Part I Neurological Disorders 21

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

2.1 Introduction 23

2.2 History 23

2.3 Synthesis 25

2.4 Mode of Action 29

2.5 Structure–Activity Relationships 32

References 34

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

3.1 Introduction 37

3.2 History 37

3.3 Synthesis 40

3.4 Mode of Action 43

3.5 Structure–Activity Relationship 44

References 48

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

4.1 Introduction 51

4.2 History 52

4.3 Synthesis 57

4.4 Mode of Action 60

4.5 Structure–Activity Relationship 62

References 63

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

5.1 Introduction 65

5.2 History 65

5.3 Synthesis 70

5.4 Mode of Action 72

5.5 Structure–Activity Relationships 76

References 77

6 Arylpiperazine-Based 5-HT1A Receptor Partial Agonists and 5-HT2A Antagonists for the Treatment of Autism, Depression, Anxiety, Psychosis, and Schizophrenia 81
Irini Akritopoulou-Zanze

6.1 Introduction 81

6.2 History 81

6.3 Synthesis 85

6.4 Mode of Action 88

6.5 Structure–Activity Relationship 89

References 96

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

7.1 Introduction 99

7.2 History 99

7.3 Synthesis 106

7.4 Mode of Action 109

7.5 Structure–Activity Relationship 111

References 113

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

8.1 Introduction 115

8.2 History 115

8.3 Synthesis 119

8.4 Mode of Action 124

8.5 Structure–Activity Relationships 128

References 130

Part II Cardiovascular Diseases 135

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

9.1 Introduction 137

9.2 History 139

9.3 Synthesis 141

9.4 Mode of Action 144

9.5 Structure–Activity Relationship 148

References 149

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

10.1 Introduction 153

10.2 History 154

10.3 Synthesis 157

10.4 Mode of Action 159

10.5 Structure–Activity Relationship 161

References 163

11 Thiazide-Based Diuretics for the Treatment of Hypertension and Genitourinary Disorders 169
Jürgen Dinges

11.1 Introduction 169

11.2 History 169

11.3 Synthesis 174

11.4 Mode of Action 177

11.5 Structure–Activity Relationship 179

References 180

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

12.1 Introduction 183

12.2 History 183

12.3 Synthesis 188

12.4 Mode of Action 191

12.5 Structure–Activity Relationship 192

References 198

Part III Infectious Diseases 201

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

13.1 Introduction 203

13.2 History 203

13.3 Synthesis 209

13.4 Mode of Action 212

13.5 Structure–Activity Relationship 212

References 214

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

14.1 Introduction 217

14.2 History 219

14.3 Synthesis 221

14.4 Mode of Action 227

14.5 Structure–Activity Relationship 229

References 232

15 Penicillin and Cephalosporin Antibiotics 237
Michael Z. Hoemann

15.1 Introduction 237

15.2 History 237

15.3 Synthesis 239

15.4 Mode of Action 248

15.5 Structure–Activity Relationships 250

References 251

Part IV Oncology 255

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

16.1 Introduction 257

16.2 History 257

16.3 Synthesis 261

16.4 Mode of Action 264

16.5 Structure–Activity Relationship 266

References 269

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

17.1 Introduction 275

17.2 History 275

17.3 Synthesis 277

17.4 Mode of Action 281

17.5 Structure–Activity Relationship 282

References 286

Part V Inflammation and Gastrointestinal Diseases 289

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

18.1 Introduction 291

18.2 History 293

18.3 Synthesis 297

18.4 Mode of Action 304

18.5 Structure–Activity Relationship 308

References 311

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

19.1 Introduction 313

19.2 History 313

19.3 Synthesis 316

19.4 Mode of Action 319

19.5 Structure–Activity Relationships 320

References 324

Part VI Metabolic Diseases 327

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

20.1 Introduction 329

20.2 History 329

20.3 Synthesis 337

20.4 Mode of Action 343

20.5 Structure–Activity Relationship 344

References 345

Index 349

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Jürgen Dinges obtained his M.S. degree in organic chemistry at the Technical University in Darmstadt, Germany in 1988. He then joined the group of Prof. Frieder W. Lichtenthaler at the same University, where he received his Ph.D. degree in organic chemistry and chemical engineering in 1991. After being awarded a Feodor-Lynen scholarship from the Humboldt foundation, he spent 18 months as a postdoctoral fellow in the group of Prof. William G. Dauben at the University of California at Berkeley, U.S.A. In 1993, Jurgen Dinges joined the department for biochemistry at Syntex, U.S.A. and since 1995 he is working in the pharmaceutical research department at Abbott Laboratories, U.S.A. In 2009, he was a guest editor for Current Topics in Medicinal Chemistry for a special issue on Parkinson's disease. He is an author of 17 publications and 23 patents and a co-inventor of more than 10 clinical drug development candidates.

Clemens Lamberth is a senior team leader in the crop protection research department of Syngenta AG, Switzerland. He studied chemistry at the Technical University of Darmstadt, Germany, where he obtained his Ph.D. under the supervision of Prof. Bernd Giese in 1990. Subsequently, he spent one and a half years as a postdoctoral fellow in the group of Prof. Mark Bednarski at the University of California at Berkeley, U.S.A. In 1992 Clemens Lamberth joined the agrochemical research department of Sandoz Agro AG, Switzerland, which is today, after two mergers, part of Syngenta Crop Protection AG. Since 20 years he is specialized in fungicide discovery. He was the organizer of the two-day session 'New Trends for Agrochemicals' at the 2nd EUCHEMS congress in Torino 2008. He is the author of 46 publications and 56 patents and the inventor of Syngenta's fungicide mandipropamid (Revus, Pergado).
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