Bioactive Heterocyclic Compound Classes E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
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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Seitenzahl: 551
Veröffentlichungsjahr: 2012
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Table of Contents
Related Titles
Title Page
Copyright
Preface
List of Contributors
Introduction
Chapter 1: The Significance of Heterocycles for Pharmaceuticalsand Agrochemicals
1.1 Introduction
1.2 Heterocycles as Framework of Biologically Active Compounds
1.3 Fine-Tuning the Physicochemical Properties with Heterocycles
1.4 Heterocycles as Prodrugs
1.5 Heterocycles as Peptidomimetics
1.6 Heterocycles as Isosteric Replacement of Functional Groups
1.7 Heterocycles as Isosteric Replacement of Alicyclic Rings
1.8 Heterocycles as Isosteric Replacement of other Heterocyclic Rings
References
Part I: Neurological Disorders
Chapter 2: Tropane-Based Alkaloids as Muscarinic Antagonists for the Treatment of Asthma, Obstructive Pulmonary Disease, and Motion Sickness
2.1 Introduction
2.2 History
2.3 Synthesis
2.4 Mode of Action
2.5 Structure–Activity Relationships
References
Chapter 3: Morphinone-Based Opioid Receptor Agonist Analgesics
3.1 Introduction
3.2 History
3.3 Synthesis
3.4 Mode of Action
3.5 Structure–Activity Relationship
References
Chapter 4: Barbituric Acid-Based GABA(A) Receptor Modulators for the Treatment of Sleep Disorder and Epilepsy and as Anesthetics
4.1 Introduction
4.2 History
4.3 Synthesis
4.4 Mode of Action
4.5 Structure–Activity Relationship
References
Chapter 5: Phenothiazine-Based Dopamine D2 Antagonists for the Treatment of Schizophrenia
5.1 Introduction
5.2 History
5.3 Synthesis
5.4 Mode of Action
5.5 Structure–Activity Relationships
References
Chapter 6: Arylpiperazine-Based 5-HT1A Receptor Partial Agonists and 5-HT2A Antagonists for the Treatment of Autism, Depression, Anxiety, Psychosis, and Schizophrenia
6.1 Introduction
6.2 History
6.3 Synthesis
6.4 Mode of Action
6.5 Structure–Activity Relationship
References
Chapter 7: Arylpiperidine-Based Dopamine D2 Antagonists/5-HT2A Antagonists for the Treatment of Autism, Depression, Schizophrenia, and Bipolar Disorder
7.1 Introduction
7.2 History
7.3 Synthesis
7.4 Mode of Action
7.5 Structure–Activity Relationship
References
Chapter 8: Dibenzazepine-Based Sodium Channel Blockers for the Treatment of Neuropathic Pain
8.1 Introduction
8.2 History
8.3 Synthesis
8.4 Mode of Action
8.5 Structure–Activity Relationships
References
Part II: Cardiovascular Diseases
Chapter 9: Dihydropyridine-Based Calcium Channel Blockers for the Treatment of Angina Pectoris and Hypertension
9.1 Introduction
9.2 History
9.3 Synthesis
9.4 Mode of Action
9.5 Structure–Activity Relationship
References
Chapter 10: Tetrazole-Based Angiotensin II Type 1 (AT1) Antagonists for the Treatment of Heart Failure and Congestive Hypertension
10.1 Introduction
10.2 History
10.3 Synthesis
10.4 Mode of Action
10.5 Structure–Activity Relationship
References
Chapter 11: Thiazide-Based Diuretics for the Treatment of Hypertension and Genitourinary Disorders
11.1 Introduction
11.2 History
11.3 Synthesis
11.4 Mode of Action
11.5 Structure–Activity Relationship
References
Chapter 12: Tetrahydropyranone-Based HMG-CoA Reductase Inhibitors for the Treatment of Arterial Hypercholesterolemia
12.1 Introduction
12.2 History
12.3 Synthesis
12.4 Mode of Action
12.5 Structure–Activity Relationship
References
Part III: Infectious Diseases
Chapter 13: Adenine-Based Reverse Transcriptase Inhibitors as Anti-HIV Agents
13.1 Introduction
13.2 History
13.3 Synthesis
13.4 Mode of Action
13.5 Structure–Activity Relationship
References
Chapter 14: Guanine-Based Nucleoside Analogs as Antiviral Agents
14.1 Introduction
14.2 History
14.3 Synthesis
14.4 Mode of Action
14.5 Structure–Activity Relationship
References
Chapter 15: Penicillin and Cephalosporin Antibiotics
15.1 Introduction
15.2 History
15.3 Synthesis
15.4 Mode of Action
15.5 Structure-Activity Relationships
References
Part IV: Oncology
Chapter 16: Pyrimidine-Based Kinase Inhibitors in Cancer Chemotherapy
16.1 Introduction
16.2 History
16.3 Synthesis
16.4 Mode of Action
16.5 Structure–Activity Relationship
References
Chapter 17: Benzyl Triazole-Based Aromatase Inhibitors for the Treatment of Breast Cancer
17.1 Introduction
17.2 History
17.3 Synthesis
17.4 Mode of Action
17.5 Structure–Activity Relationship
References
Part V: Inflammation and Gastrointestinal Diseases
Chapter 18: Acetonide-Based Glucocorticoids for the Treatment of Asthma, Skin Inflammation, and Diseases of the Eye
18.1 Introduction
18.2 History
18.3 Synthesis
18.4 Mode of Action
18.5 Structure–Activity Relationship
References
Chapter 19: Benzimidazole-Based H+/K+-ATPase Inhibitors for the Treatment of Gastroesophageal Reflux Disease
19.1 Introduction
19.2 History
19.3 Synthesis
19.4 Mode of Action
19.5 Structure–Activity Relationships
References
Part VI: Metabolic Diseases
Chapter 20: Thiazolidinedione-Based Insulin Sensitizers:PPAR-γ Agonists for the Treatment of Type 2 Diabetes
20.1 Introduction
20.2 History
20.3 Synthesis
20.4 Mode of Action
20.5 Structure–Activity Relationship
References
Index
Related Titles
Lamberth, C., Dinges, J. (eds.)
Bioactive Heterocyclic
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2012
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The Editors
Dr. Jürgen Dinges
Abbott Laboratories
Global Pharmaceutical R&D
200, Abbott Park Road
Abbott Park, IL 60064-6217
USA
Dr. Clemens Lamberth
Syngenta Crop Protection AG
Research Chemistry
Schaffhauserstr. 101
4332 Stein
Schweiz
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© 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany
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Bioactive Heterocyclic Compound Classes (Pharmaceuticals and Agrochemicals, 2 Volume Set)
ISBN: 978-3-527-32993-9
Print ISBN: 978-3-527-33395-0
ePDF ISBN: 978-3-527-66448-1
ePub ISBN: 978-3-527-66447-4
mobi ISBN: 978-3-527-66446-7
oBook ISBN: 978-3-527-66445-0
Preface
Approximately 70% of all the 2400 pharmaceuticals listed in the online version of “Pharmaceutical Substances” (A. Kleemann et al., Thieme) bear at least one heterocyclic ring; the latest edition of the “Pesticide Manual” (C. D. S. Tomlin, BCPC) contains a similar percentage of heterocyclic agrochemicals among its about 900 entries. This vast number of known pharmaceuticals and agrochemicals makes 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 the relationship of those heterocyclic active ingredients, which belong together, forming a biologically active heterocylic chemistry class. According to our definition, such a heterocyclic family is built from at least three compounds that fulfill the following conditions: (i) same heterocyclic scaffold, (ii) same mode of action, and (iii) similar substitution pattern.
Although the strength of this concept is that for the first time the members of the most important heterocyclic active ingredient families, their historical background, chemical syntheses, biochemical modes of action, and biological activities are discussed in detail, there are also some limitations. For instance, there are some heterocyclic families of drugs or crop protection agents, such as the analgesic COX-2 inhibitors celecoxib, valdecoxib, and rofecoxib or the dicarboxamide fungicides vinclozolin, iprodione, and procymidone, which are closely related by structure and possess the same mode of action, but bear different heterocyclic scaffolds and therefore could not be considered.
We would like to thank the authors of the 40 chapters of this book, all of them experts in their field, for spending their scarce time summarizing their area of interest. They all agreed to write the chapters according to the same outline: (i) introduction, (ii) history, (iii) synthesis, (iv) mode of action, and (v) structure–activity relationship. Only the agrochemical chapters possess an additional section “biological activity,” mainly describing the target spectrum of the active ingredients. This book would definitely not exist without your engagement!
Furthermore, we also would like to thank Anne Brennführer and Stefanie Volk of Wiley-VCH, who from the beginning guided us very efficiently through all different phases of this exciting project.
The introductory chapter about “The significance of heterocycles for pharmaceuticals and agrochemicals” tries to explain the different roles of heterocyclic scaffolds in active ingredients, e.g. as framework of biologically active substances, as prodrugs, as tool for fine-tuning the physicochemical properties, as isosteric replacements of functional groups, alicyclic rings or other heterocyclic rings. As this is demonstrated at the hand of many prominent and characteristical examples of pharmaceuticals as well as of agrochemicals, also pointing out the many similarities, 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 exactly the same excellent education, a Ph.D. in organic chemistry from the Technical University at Darmstadt, Germany, and a subsequent postdoctoral fellowship at the chemistry department of the University of California at Berkeley. We are very grateful to our teachers, mentors, and research advisors at both universities, who built the foundation for our successful work in the research departments of the agrochemical and pharmaceutical industry.
Finally, we are deeply indebted to our wives Annette and Petra, who continuously supported 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 made this possible!
Clemens Lamberth
Switzerland
Jürgen Dinges
USA
List of Contributors
Introduction
1
The Significance of Heterocycles for Pharmaceuticalsand Agrochemicals*
Clemens Lamberth and Jürgen Dinges
1.1 Introduction
Heterocycles, their preparation, transformation, and properties, are undoubtedly a cornerstone 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 at least one heterocyclic ring. In addition, some of the biggest commercial products to date, such as the blockbuster blood cholesterol reducer atorvastatin (Lipitor®, 1) [11] for the treatment of dyslipidemia and the prevention of cardiovascular diseases and the broad-spectrum fungicide azoxystrobin (Amistar®, 2) [12], currently applied against diseases of more than 100 different crops in more than 100 different countries, belong to this huge heterocyclic group of active ingredients (Figure 1.1).
Figure 1.1 Atorvastatin (1) and azoxystrobin (2), two of the currently most successful pharmaceuticals and agrochemicals.
There are two major reasons for the tremendous value of heterocycles for the lead optimization of pharmaceuticals and agrochemicals. The heterocyclic scaffold of a drug often has a positive impact on its synthetic accessibility and its physicochemical properties, driving these values of lipophilicity and solubility toward the optimal balanced range regarding uptake and bioavailability. Furthermore, heterocycles seem to be perfect bioisosteres of other iso- or heterocyclic rings as well as of several different functional groups, in most cases, delivering through their similarity in structural shape and electronic distribution equal or even better biological efficacy [13].
1.2 Heterocycles as Framework of Biologically Active Compounds
Several heterocycles possess excellent biological activity almost without bearing any substituents, which means that their heterocyclic core is definitely part of the pharmacophore. Examples of such scarcely substituted and highly active heterocycles are the two bipyridyl derivatives such as amrinone (3) [14], which is used in the treatment of congestive heart failure, and paraquat (4) [15], which is applied as a total herbicide (Figure 1.2).
Figure 1.2 The highly active bipyridyl derivatives amrinone (3) and paraquat (4), each carrying only two small substituents.
Another important role of the heterocyclic core of several pharmaceuticals and agrochemicals is that of an easily accessible scaffold, which carries the substituents that are responsible for the biological activity in the right orientation. There are several highly active per-substituted heterocycles, as demonstrated by the pyrazole derivatives propyphenazone () [16] and fipronil () [17], which are widely applied as efficient analgesic and insecticide, respectively, and synthetically available in only few steps ().
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