Enables researchers to fully realize the potential to discover new pharmaceuticals among heterocyclic compounds
Integrating heterocyclic chemistry and drug discovery, this innovative text enables readers to understand how and why these two fields go hand in hand in the effective practice of medicinal chemistry. Contributions from international leaders in the field review more than 100 years of findings, explaining their relevance to contemporary drug discovery practice. Moreover, these authors have provided plenty of practical guidance and tips based on their own academic and industrial laboratory experience, helping readers avoid common pitfalls.
Heterocyclic Chemistry in Drug Discovery is ideal for readers who want to fully realize the almost limitless potential to discover new and effective pharmaceuticals among heterocyclic compounds, the largest and most varied family of organic compounds. The book features:
Several case studies illustrating the role and application of 3, 4, 5, and 6+ heterocyclic ring systems in drug discoveryStep-by-step descriptions of synthetic methods and practical techniquesExamination of the physical properties for each heterocycle, including NMR data and quantum calculationsDetailed explanations of the complexity and intricacies of reactivity and stability for each class of heterocycles
Heterocyclic Chemistry in Drug Discovery is recommended as a textbook for organic and medicinal chemistry courses, particularly those emphasizing heterocyclic chemistry. The text also serves as a guide for medicinal and process chemists in the pharmaceutical industry, offering them new insights and new paths to explore for effective drug discovery.
Chapter 1 Introduction 1
1.1 Nomenclature of Heterocycles 1
1.2 Aromatic Heterocycles 4
1.3 Importance of Heterocycles in Life 5
1.4 Importance of Heterocycles in Drug Discovery 8
PART I FIVE-MEMBERED HETEROCYCLES WITH ONE HETEROATOM 17
Chapter 2 Pyrroles 18
2.1 Introduction 18
2.2 Reactivity 22
2.3 Construction of the Pyrrole Rings 34
2.4 Palladium Chemistry of Pyrroles 44
2.5 Possible Liabilities of Pyrrole-Containing Drugs 46
2.6 Problems 49
2.7 References 51
Chapter 3 Indoles 54
3.1 Introduction 54
3.2 Reactivity of the Indole Ring 58
3.3 Construction of the Indole Rings 64
3.4 Oxindole-Containing Drug Synthesis 88
3.5 Cross-coupling Reactions for Indoles 91
3.6 Azaindole 104
3.7 Possible Liabilities of Drugs Containing 3-Methylindole 109
3.8 Problems 111
3.9 References 113
Chapter 4 Furans, Benzofurans, Thiophenes, and Benzothiophenes 119
4.1 Introduction 119
4.2 Furans and Benzofuran 126
4.3 Thiophenes and Benzothiophenes 158
4.4 Possible Liabilities of Furan and Thiophene-Containing Drugs 185
4.5 Problems 187
4.6 References 191
PART II FIVE-MEMBERED HETEROCYCLES WITH TWO OR MORE HETEROATOMS 197
Chapter 5 Pyrazoles, Pyrazolones, and Indazoles 198
5.1 Introduction 198 viii
5.2 Reactivity of the Pyrazoles and Indazoles 202
5.3 Construction of the Pyrazole and Indazole Rings 206
5.4 Pyrazolone-containing Drugs 217
5.5 Indazole-containing Drugs 220
5.6 Problems 223
5.7 References 226
Chapter 6 Oxazoles, Benzoxazoles, and Isoxazoles 231
6.1 Introduction 231
6.2 Construction of the Heterocyclic Ring 235
6.3 Reactivity 244
6.4 Cross-Coupling Reactions 250
6.5 Selected Reactions of Isoxazoles 269
6.6 Possible Liabilities of Oxazole-Containing Drugs 270
6.6 Problems 271
6.7 References 278
Chapter 7 Thiazoles and Benzothiazoles 283
7.1 Introduction 283
7.2 Reactions of the Thiazole Ring 290 ix
7.3 Palladium Chemistry Undergone by Thiazoles and Benzothiazoles 300
7.4 Construction of the Thiazole Ring 307
7.5 Construction of the Benzothiazole Ring 315
7.6 Possible Liabilities of Drugs Containing Thiazoles and Benzothiazoles 321
7.7 Thiazoles and Benzothiazoles as Bioisosteres 323
7.8 Problems 325
7.9 References 328
Chapter 8 Imidazoles and Benzimidazoles 333
8.1 Introduction to Imidazole 333
8.2 Reactivity of the Imidazole Ring 335
8.3 Construction of the Imidazole Ring 341
8.3.1 Debus 342
8.4 Conversion of Imidazolines to Imidazoles 353
8.5 Possible Liabilities of Imidazole-Containing Drugs 353
8.6 Introduction to Benzimidazole 354
8.7 Synthesis of Benzimidazoles: Classical Approaches 357
8.8 Construction of the Benzimidazole Core Using Transition Metal- Mediated Approaches 361
8.9 Alternative Cyclization Approach toward Benzimidazoles: Process Route toward BYK405879 367
8.10 Problems 368
8.11 References 370
Chapter 9 Triazoles and Tetrazoles 373
9.1 Introduction 373
9.2 Reactivity of the Triazole and Tetrazole Ring 375
9.3 Construction of the Triazole Ring 384
9.4 Possible Liabilities of Triazole-Containing Drugs 392
9.5 Problems 393
9.6 References 394
PART III SIX-MEMBERED HETEROCYCLES WITH ONE HETEROATOM 397
Chapter 10 Pyridines 398
10.1 Introduction 398
10.2 Reactivity of the Pyridine Ring 404
10.3 Construction of the Pyridine Ring 425
10.4. Problems 457
10.5 References 459
Chapter 11 Quinolines and Isoquinolines 471
11.1 Introduction 471
11.2 Reactivity of the Quinoline and Isoquinoline Ring 474
11.3 Construction of Quinoline Core 492
11.4 Construction of Isoquinoline Core 513
11.5 Possible Liabilities of Drugs Containing Quinoline and Isoquinoline Ring 526
11.6 Problems 527
11.7 References 528
PART IV SIX-MEMBERED HETEROCYCLES WITH TWO HETEROATOMS 535
Chapter 12 Pyrazines and Quinoxalines 536
12.1 Introduction 536
12.2 Formation of Diazines 539
12.3 Reactivity of the Molecules 545
12.4 Coupling Reactions 553
12.5 Problems 562
12.6 References 565
Chapter 13 Pyrimidines 569
13.1 Introduction 569
13.2 Construction of the Pyrimidine Ring 573
13.3 Synthesis of Pyrimidine-Containing Drugs 590
13.4 Problems 608
13.5 References 611
Chapter 14 Quinazolines and Quinazolones 615
14.1 Introduction 615
14.2 Reactions of Quinazolines and Quinazolinones 618
14.3 Quinazoline and Quinazolinone Synthesis 625
14.4 Synthesis of Quinazoline- and Quinazolinone-Containing Drugs 636
14.5 Problems 641
14.6 References 644
Subject Index 647
