Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals

Following the successful and proven concept used in "Bioactive Heterocyclic Compound Classes" by the same editors, this book is the first to present approved pharmaceutical and agrochemical compounds classified by their carboxylic acid functionality in one handy volume. Each of the around 40 chapters describes one or two typical syntheses of a specific compound class and provides concise information on the history of development, mode of action, biological activity and field of application, as well as structure-activity relationships. In addition, similarities and differences between pharmaceuticals and agrochemicals are discussed in the introduction. Written by a team of experts in the field, this is a useful reference for researchers in academia and chemical or pharmaceutical companies working in the field of total synthesis and natural product chemistry, drug development, and crop protection research.

Table of Contents:
List of Contributors XV Preface XXI 1 Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals 1 Clemens Lamberth and Jürgen Dinges 1.1 Introduction 1 1.2 Solubilizer 1 1.3 Pharmacophore 3 1.4 Prodrug 4 1.5 Bioisosteric Replacement 6 1.6 Scaffold 8 1.7 Conclusion 9 Part I Neurology 13 2 Carboxylic Ester Containing Norepinephrine–Dopamine Reuptake Inhibitors (NDRIs) 15 David J. O'Neill 2.1 Introduction 15 2.2 History 15 2.3 Synthesis 17 2.4 Mode of Action 21 2.5 Structure–Activity Relationships 22 3 Analgesic and Anesthetic Amides 27 Thomas Erhard 3.1 Introduction 27 3.2 History 27 3.3 Synthesis 30 3.4 Mode of Action 33 3.5 Structure–Activity Relationships 34 Part II Cardiovascular Diseases 39 4 Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPARα Activators) 41 Gavin O'Mahony 4.1 Introduction 41 4.2 History 42 4.3 Synthesis 45 4.4 Mode of Action 48 4.5 Structure–Activity Relationships 50 5 Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events 57 Modesto de Candia, Nunzio Denora, and Cosimo D. Altomare 5.1 Introduction 57 5.2 History 57 5.3 Synthesis 60 5.4 Mode of Action 62 5.5 Structure–Activity Relationships 67 6 Carboxylic Acids and Lactones as HMG-CoA Reductase Inhibitors 71 Xiang-Yang Ye and Pratik Devasthale 6.1 Introduction 71 6.2 History 72 6.3 Synthesis 73 6.4 Mode of Action 80 6.5 Structure–Activity Relationship 81 7 Angiotensin II Receptor Antagonists with Carboxylic Functionalities in Cardiovascular Disease 87 Steve Swann and Simone Bigi 7.1 Introduction 87 7.2 History 89 7.3 Synthesis 90 7.4 Mode of Action 95 7.5 Structure–Activity Relationships 96 8 Carboxylic Acid Containing Direct Thrombin Inhibitors for the Treatment of Thromboembolic Diseases 103 Harry R. Chobanian and Mathew M. Yanik 8.1 Introduction 103 8.2 History 104 8.3 Synthesis 106 8.4 Mode of Action 108 8.5 Structure–Activity Relationship 109 Part III Infectious Diseases 115 9 Tetracycline Amide Antibiotics 117 Ingo Janser 9.1 Introduction 117 9.2 History 120 9.2.1 First-Generation Tetracyclines – The Discovery 120 9.2.2 Second-Generation Semisynthetic Tetracyclines 121 9.2.3 Tetracycline Resistance 122 9.2.4 Third-Generation Tetracyclines 123 9.3 Synthesis 123 9.4 Mode of Action 127 9.5 Structure–Activity Relationships 128 10 Carboxylic-Acid-Based Neuraminidase Inhibitors 133 Stacy Van Epps 10.1 Introduction 133 10.2 History 133 10.3 Synthesis 136 10.4 Mode of Action 142 10.5 Structure–Activity Relationships 143 11 Oxazolidinone Amide Antibiotics 149 Cristiana A. Zaharia, Saverio Cellamare, and Cosimo D. Altomare 11.1 Introduction 149 11.2 History 150 11.3 Synthesis 153 11.4 Mechanism of Action 156 11.5 Structure–Activity Relationships 162 12 Sovaldi, an NS5B RNA Polymerase-Inhibiting Carboxylic Acid Ester Used for the Treatment of Hepatitis C Infection 167 Alastair Donald 12.1 Introduction 167 12.2 History 168 12.3 Synthesis 170 12.4 Mode of Action 172 12.5 Structure–Activity Relationships 173 Part IV Metabolic Diseases 177 13 Dipeptidyl Peptidase-4 (DPP-4)-Inhibiting Amides for the Treatment of Diabetes 179 Naomi S. Rajapaksa and Xiaodong Lin 13.1 Introduction 179 13.2 History 179 13.3 Synthesis 184 13.4 Mode of Action 187 13.5 Structure–Activity Relationships 188 Part V Oncology 197 14 Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton's Tyrosine Kinase 199 Timothy D. Owens 14.1 Introduction 199 14.2 History 199 14.3 Synthesis 201 14.4 Mechanism of Action 202 14.5 Structure–Activity Relationships 203 Part VI Anti-Inflammatory Drugs 209 15 Fumaric Acid Esters 211 Tony S. Gibson 15.1 Introduction 211 15.2 History 211 15.3 Synthesis 213 15.4 Mode of Action 213 15.5 Structure–Activity Relationships 215 16 Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 221 Yan Lou and Jiang Zhu 16.1 Introduction 221 16.2 History 222 16.3 Synthesis 224 16.4 Mode of Action 228 16.5 Structure–Activity Relationships 230 17 Carboxylic-Acid-Containing Antihistamines 237 Irini Akritopoulou-Zanze 17.1 Introduction 237 17.2 History 237 17.3 Synthesis 239 17.4 Mode of Action 241 17.5 Structure–Activity Relationship 241 18 Corticosteroid Carboxylic Acid Esters 245 Maurizio Franzini 18.1 Introduction 245 18.2 History 249 18.3 Synthesis 252 18.4 Mode of Action 258 18.5 Structure–Activity Relationships 261 Part VII Ophthalmology 269 19 Prostaglandins with Carboxylic Functionalities for the Treatment of Glaucoma 271 Fabrizio Carta and Claudiu T. Supuran 19.1 Introduction 271 19.2 History 271 19.3 Synthesis 272 19.4 Mode of Action 276 19.5 Structure–Activity–Relationship (SAR) 278 Part VIII Weed Control 281 20 Herbicidal Carboxylic Acids as Synthetic Auxins 283 Paul Schmitzer, Jeffrey Epp, Roger Gast,William Lo, and Jeff Nelson 20.1 Introduction 283 20.2 History 283 20.3 Synthesis 286 20.4 Mode of Action 289 20.5 Biological Activity 289 21 Chloroacetamide Herbicides 293 Clemens Lamberth 21.1 Introduction 293 21.2 History 293 21.3 Synthesis 296 21.4 Mode of Action 297 21.5 Biological Activity 299 21.6 Structure–Activity Relationship 300 22 Carboxylic-Acid-Containing Sulfonylurea Herbicides 303 Atul Puri and Paul H. Liang 22.1 Introduction 303 22.2 History 303 22.3 Synthesis 305 22.4 Mode of Action 306 22.5 Biological Activity 308 22.6 Structure–Activity Relationship 309 23 Amino Acids as Nonselective Herbicides 315 Stephane Jeanmart 23.1 Introduction 315 23.2 History 316 23.3 Synthesis 317 23.4 Mode of Action 319 23.5 Biological Activity 320 23.6 Structure–Activity Relationships 321 24 Herbicidal Aryloxyphenoxypropionate Inhibitors of Acetyl-CoA Carboxylase 325 William G.Whittingham 24.1 Introduction 325 24.2 History 325 24.3 Synthesis 327 24.4 Mode of Action 329 24.5 Biological Activity 330 24.6 Structure–Activity Relationships 331 25 Pyridines Substituted by an Imidazolinone and a Carboxylic Acid as Acetohydroxyacid-Synthase-Inhibiting Herbicides 339 Dale Shaner 25.1 Introduction 339 25.2 History 339 25.3 Synthesis 341 25.4 Mode of Action 342 25.5 Biological Activity 342 25.6 Structure–Activity Relationship 344 26 Carboxylic-Acid-Containing Protoporphyrinogen-IX-Oxidase-Inhibiting Herbicides 347 George Theodoridis 26.1 Introduction 347 26.2 History 347 26.3 Synthesis 350 26.4 Mode of Action 351 26.5 Biological Activity 352 26.6 Structure–Activity Relationship 352 Part IX Disease Control 357 27 Phenylamide Fungicides 359 Laura Quaranta 27.1 Introduction 359 27.2 History 359 27.3 Synthesis 362 27.4 Mode of Action 364 27.5 Biological Activity 365 27.6 Structure–Activity Relationship 365 28 Complex III Inhibiting Strobilurin Esters, Amides, and Carbamates as Broad-Spectrum Fungicides 371 Clemens Lamberth 28.1 Introduction 371 28.2 History 371 28.3 Synthesis 375 28.4 Mode of Action 379 28.5 Biological Activity 380 28.6 Structure–Activity Relationship 381 29 Scytalone-Dehydratase-Inhibiting Carboxamides for the Control of Rice Blast 385 Andrew E. Taggi 29.1 Introduction 385 29.2 History 385 29.3 Synthesis 389 29.4 Mode of Action 390 29.5 Biological Activity 391 29.6 Structure–Activity Relationships 392 30 Carboxylic Acid Amide Fungicides for the Control of Downy Mildew Diseases 395 Clemens Lamberth 30.1 Introduction 395 30.2 History 395 30.3 Synthesis 397 30.4 Mode of Action 399 30.5 Biological Activity 400 30.6 Structure–Activity Relationship 400 31 Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides 405 Harald Walter 31.1 Introduction 405 31.2 History 406 31.3 Synthesis 409 31.4 Mode of Action and Importance of Respiration Inhibitors 415 31.5 Biological Activity and Market Impact 416 31.6 Structure–Activity Relationships 418 Part X Insect Control 427 32 Esters and Carbamates as Insecticidal Juvenile Hormone Mimics 429 Sebastian Rendler 32.1 Introduction 429 32.2 History 429 32.3 Synthesis 431 32.4 Mode of Action 433 32.5 Biological Activity 434 32.6 Structure–Activity Relationship 434 33 N-Benzoyl-N′-Phenyl Ureas as Insecticides, Acaricides, and Termiticides 439 Peter Jeschke 33.1 Introduction 439 33.2 History 439 33.3 Synthesis 442 33.4 Mode of Action 445 33.5 Biological Activity 446 33.6 Structure–Activity Relationship 448 34 Pyrethroid Esters for the Control of Insect Pests 453 Régis Mondière and Fides Benfatti 34.1 Introduction 453 34.2 History 454 34.3 Synthesis 457 34.4 Mode of Action 459 34.5 Biological Activity 461 34.6 Structure–Activity Relationship 462 35 Ecdysone Receptor Agonistic Dibenzoyl Hydrazine Insecticides 467 Ottmar F. Hüter 35.1 Introduction 467 35.2 History 467 35.3 Synthesis 468 35.4 Mode of Action 471 35.5 Biological Activity 473 35.6 Structure–Activity Relationship 473 36 Diamide Insecticides as Ryanodine Receptor Activators 479 André Jeanguenat 36.1 Introduction 479 36.2 History 479 36.3 Synthesis 481 36.4 Mode of Action 485 36.5 Biological Activity 485 36.6 Structure–Activity Relationship 486 Index 491

About the Author :
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, USA. In 1992 he joined the agrochemical research department of Sandoz Agro AG, Switzerland, which is today, after two mergers, part of Syngenta Crop Protection AG. Since 22 years he is specialized in fungicide discovery. He is the author of more than 130 publications and patents and inventor of Syngenta's fungicide mandipropamid (Revus?, Pergado?). Jurgen Dinges is a senior principal research scientist in the pharmaceutical research department at Abbvie, USA. He studied chemistry at the Technical University of Darmstadt, Germany, where he obtained his Ph.D. degree in organic chemistry and chemical engineering under the supervision of Prof. Frieder W. Lichtenthaler 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, USA. In 1993 he joined the Department for Biochemistry at Syntex, USA, which today is part of Hoffmann-La Roche Ltd., Switzerland. In 1995 he joined the pharmaceutical research department at Abbott Laboratories, USA, which became part of Abbvie in 2013. Since 19 years he is specialized in drug discovery. He is an author on 57 publications and patents and a co-inventor of more than 10 clinical drug development candidates.