Bioactive Carboxylic Compound Classes E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
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.
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Veröffentlichungsjahr: 2016
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Table of Contents
Title Page
Copyright
List of Contributors
Preface
Chapter 1: Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals
1.1 Introduction
1.2 Solubilizer
1.3 Pharmacophore
1.4 Prodrug
1.5 Bioisosteric Replacement
1.6 Scaffold
1.7 Conclusion
References
Part I: Neurology
Chapter 2: Carboxylic Ester Containing Norepinephrine–Dopamine Reuptake Inhibitors (NDRIs)
2.1 Introduction
2.2 History
2.3 Synthesis
2.4 Mode of Action
2.5 Structure–Activity Relationships
References
Chapter 3: Analgesic and Anesthetic Amides
3.1 Introduction
3.2 History
3.3 Synthesis
3.4 Mode of Action
3.5 Structure–Activity Relationships
References
Part II: Cardiovascular Diseases
Chapter 4: Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPARα Activators)
4.1 Introduction
4.2 History
4.3 Synthesis
4.4 Mode of Action
4.5 Structure–Activity Relationships
References
Chapter 5: Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events
5.1 Introduction
5.2 History
5.3 Synthesis
5.4 Mode of Action
5.5 Structure–Activity Relationships
References
Chapter 6: Carboxylic Acids and Lactones as HMG-CoA Reductase Inhibitors
6.1 Introduction
6.2 History
6.3 Synthesis
6.4 Mode of Action
6.5 Structure–Activity Relationship
References
Chapter 7: Angiotensin II Receptor Antagonists with Carboxylic Functionalities in Cardiovascular Disease
7.1 Introduction
7.2 History
7.3 Synthesis
7.4 Mode of Action
7.5 Structure–Activity Relationships
References
Chapter 8: Carboxylic Acid Containing Direct Thrombin Inhibitors for the Treatment of Thromboembolic Diseases
8.1 Introduction
8.2 History
8.3 Synthesis
8.4 Mode of Action
8.5 Structure–Activity Relationship
References
Part III: Infectious Diseases
Chapter 9: Tetracycline Amide Antibiotics
9.1 Introduction
9.2 History
9.3 Synthesis
9.4 Mode of Action
9.5 Structure–Activity Relationships
References
Chapter 10: Carboxylic-Acid-Based Neuraminidase Inhibitors
10.1 Introduction
10.2 History
10.3 Synthesis
10.4 Mode of Action
10.5 Structure–Activity Relationships
References
Chapter 11: Oxazolidinone Amide Antibiotics
11.1 Introduction
11.2 History
11.3 Synthesis
11.4 Mechanism of Action
11.5 Structure–Activity Relationships
References
Chapter 12: Sovaldi, an NS5B RNA Polymerase-Inhibiting Carboxylic Acid Ester Used for the Treatment of Hepatitis C Infection
12.1 Introduction
12.2 History
12.3 Synthesis
12.4 Mode of Action
12.5 Structure–Activity Relationships
References
Part IV: Metabolic Diseases
Chapter 13: Dipeptidyl Peptidase-4 (DPP-4)-Inhibiting Amides for the Treatment of Diabetes
13.1 Introduction
13.2 History
13.3 Synthesis
13.4 Mode of Action
13.5 Structure–Activity Relationships
References
Part V: Oncology
Chapter 14: Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton's Tyrosine Kinase
14.1 Introduction
14.2 History
14.3 Synthesis
14.4 Mechanism of Action
14.5 Structure–Activity Relationships
References
Part VI: Anti-Inflammatory Drugs
Chapter 15: Fumaric Acid Esters
15.1 Introduction
15.2 History
15.3 Synthesis
15.4 Mode of Action
15.5 Structure–Activity Relationships
References
Chapter 16: Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
16.1 Introduction
16.2 History
16.3 Synthesis
16.4 Mode of Action
16.5 Structure–Activity Relationships
References
Chapter 17: Carboxylic-Acid-Containing Antihistamines*
17.1 Introduction
17.2 History
17.3 Synthesis
17.4 Mode of Action
17.5 Structure–Activity Relationship
References
Chapter 18: Corticosteroid Carboxylic Acid Esters
18.1 Introduction
18.2 History
18.3 Synthesis
18.4 Mode of Action
18.5 Structure–Activity Relationships
References
Part VII: Ophthalmology
Chapter 19: Prostaglandins with Carboxylic Functionalities for the Treatment of Glaucoma
19.1 Introduction
19.2 History
19.3 Synthesis
19.4 Mode of Action
19.5 Structure–Activity–Relationship (SAR)
References
Part VIII: Weed Control
Chapter 20: Herbicidal Carboxylic Acids as Synthetic Auxins
20.1 Introduction
20.2 History
20.3 Synthesis
20.4 Mode of Action
20.5 Biological Activity
References
Chapter 21: Chloroacetamide Herbicides
21.1 Introduction
21.2 History
21.3 Synthesis
21.4 Mode of Action
21.5 Biological Activity
21.6 Structure–Activity Relationship
References
Chapter 22: Carboxylic-Acid-Containing Sulfonylurea Herbicides
22.1 Introduction
22.2 History
22.3 Synthesis
22.4 Mode of Action
22.5 Biological Activity
22.6 Structure–Activity Relationship
References
Chapter 23: Amino Acids as Nonselective Herbicides
23.1 Introduction
23.2 History
23.3 Synthesis
23.4 Mode of Action
23.5 Biological Activity
23.6 Structure–Activity Relationships
References
Chapter 24: Herbicidal Aryloxyphenoxypropionate Inhibitors of Acetyl-CoA Carboxylase
24.1 Introduction
24.2 History
24.3 Synthesis
24.4 Mode of Action
24.5 Biological Activity
24.6 Structure–Activity Relationships
References
Chapter 25: Pyridines Substituted by an Imidazolinone and a Carboxylic Acid as Acetohydroxyacid-Synthase-Inhibiting Herbicides
25.1 Introduction
25.2 History
25.3 Synthesis
25.4 Mode of Action
25.5 Biological Activity
25.6 Structure–Activity Relationship
References
Chapter 26: Carboxylic-Acid-Containing Protoporphyrinogen-IX-Oxidase-Inhibiting Herbicides
26.1 Introduction
26.2 History
26.3 Synthesis
26.4 Mode of Action
26.5 Biological Activity
26.6 Structure–Activity Relationship
References
Part IX: Disease Control
Chapter 27: Phenylamide Fungicides
27.1 Introduction
27.2 History
27.3 Synthesis
27.4 Mode of Action
27.5 Biological Activity
27.6 Structure–Activity Relationship
References
Chapter 28: Complex III Inhibiting Strobilurin Esters, Amides, and Carbamates as Broad-Spectrum Fungicides
28.1 Introduction
28.2 History
28.3 Synthesis
28.4 Mode of Action
28.5 Biological Activity
28.6 Structure–Activity Relationship
References
Chapter 29: Scytalone-Dehydratase-Inhibiting Carboxamides for the Control of Rice Blast
29.1 Introduction
29.2 History
29.3 Synthesis
29.4 Mode of Action
29.5 Biological Activity
29.6 Structure–Activity Relationships
References
Chapter 30: Carboxylic Acid Amide Fungicides for the Control of Downy Mildew Diseases
30.1 Introduction
30.2 History
30.3 Synthesis
30.4 Mode of Action
30.5 Biological Activity
30.6 Structure–Activity Relationship
References
Chapter 31: Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides
31.1 Introduction
31.2 History
31.3 Synthesis
31.4 Mode of Action and Importance of Respiration Inhibitors
31.5 Biological Activity and Market Impact
31.6 Structure–Activity Relationships
Acknowledgments
References
Part X: Insect Control
Chapter 32: Esters and Carbamates as Insecticidal Juvenile Hormone Mimics
32.1 Introduction
32.2 History
32.3 Synthesis
32.4 Mode of Action
32.5 Biological Activity
32.6 Structure–Activity Relationship
References
Chapter 33: N-Benzoyl-N′-Phenyl Ureas as Insecticides, Acaricides, and Termiticides
33.1 Introduction
33.2 History
33.3 Synthesis
33.4 Mode of Action
33.5 Biological Activity
33.6 Structure–Activity Relationship
References
Chapter 34: Pyrethroid Esters for the Control of Insect Pests
34.1 Introduction
34.2 History
34.3 Synthesis
34.4 Mode of Action
34.5 Biological Activity
34.6 Structure–Activity Relationship
References
Chapter 35: Ecdysone Receptor Agonistic Dibenzoyl Hydrazine Insecticides
35.1 Introduction
35.2 History
35.3 Synthesis
35.4 Mode of Action
35.5 Biological Activity
35.6 Structure–Activity Relationship
References
Chapter 36: Diamide Insecticides as Ryanodine Receptor Activators
36.1 Introduction
36.2 History
36.3 Synthesis
36.4 Mode of Action
36.5 Biological Activity
36.6 Structure–Activity Relationship
References
Index
End User License Agreement
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Guide
Table of Contents
Preface
Part I
Begin Reading
List of Illustrations
Chapter 1: Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals
Figure 1.1 Ionization state of ciprofloxacin in the gastrointestinal tract [1].
Figure 1.2 Increasing solubility of antihistaminic compounds by carboxylic acids.
Figure 1.3 Examples for pharmacophores of active ingredients based on carboxylic acids, esters, and amides.
Scheme 1.1 Some examples of ester, carbonate, and carbothioic
S
-ester prodrugs.
Scheme 1.2 Losartan (
19
) and clopidogrel (
21
) as bioprecursors of carboxylic acid derivatives.
Figure 1.4 Baclofen (
23
) and its bioisosteres phaclofen (
24
) and saclofen (
25
) [26].
Figure 1.5 Heterocyclic bioisosteres of carboxylic acid derivatives.
Figure 1.6 Four active ingredients, which rely on an amide function linking important parts of the molecule.
Chapter 2: Carboxylic Ester Containing Norepinephrine–Dopamine Reuptake Inhibitors (NDRIs)
Figure 2.1 Structures of norepinephrine (
1
) and dopamine (
2
).
Figure 2.2 Structures of racemic-methylphenidate ((±)-
threo
-
3
, Ritalin®) and its (+)-
threo
-enantiomer dexmethylphenidate ((+)-
threo
-
3
, Focalin®) and (±)-ethylphenidate ((±)-
4
).
Figure 2.3 Structures of the
threo
and
erythro
isomers found in Centedrin™ (
3
).
Scheme 2.1 Initial route toward methylphenidate (
3
).
Scheme 2.2 Modified route toward methylphenidate analogs.
Scheme 2.3 Stereoselective route to (±)-
threo
-3
.
Scheme 2.4 Stereoselective routes to (+)-
threo
-3
utilizing a chiral auxiliary.
Scheme 2.5 Stereoselective routes to (+)-
threo
-3
utilizing a chiral ligand.
Scheme 2.6 Epimerization to provide (+)-
threo
-3
.
Figure 2.4 Schematic diagram of a synapse.
Figure 2.5 Summary of SAR exploration around the methylphenidate scaffold.
Figure 2.6 SAR exploration around the methylphenidate scaffold.
Chapter 3: Analgesic and Anesthetic Amides
Figure 3.1 Representative anilides lidocaine (
7
) and acetaminophen (
8
).
Scheme 3.1 Discovery of fentanyl (
1
) via sequential modifications of meperidine (
9
).
Figure 3.2 Selected representatives of the “-caine” family of local anesthetics.
Scheme 3.2 Chemical structures of acetanilide (
14
) and phenacetin (
15
) and the pathways involved in the metabolic production of acetaminophen (
8
).
Scheme 3.3 General approaches toward the synthesis of fentanyl (
1
).
Scheme 3.4 Modified pathways toward 4,4-disubstituted fentanyl analogs.
Scheme 3.5 Ugi synthesis of carfentanil (
2
).
Scheme 3.6 General process for the synthesis of lidocaine (
7
).
Scheme 3.7 Short synthesis of acetaminophen (
8
).
Scheme 3.8 Summary of selected SAR results derived various modifications of fentanyl (
1
). Potency ratios with respect to ED
50
in rat tail withdrawal reflex.
Scheme 3.9 Effects of selected modifications in the “-caine” family.
Chapter 4: Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPARα Activators)
Figure 4.1 Chemical structures of fibric acid (
1
), clofibrate (
2
), clofibric acid (
2a
), and the currently commercially available fibrates and fibrate derivates (
3–8
).
Scheme 4.1 Synthesis of clofibrate (
2
) employing a Bargellini reaction.
Scheme 4.2 Synthesis of ciprofibrate (
4
).
Scheme 4.3 Synthesis of clinofibrate (
7
).
Scheme 4.4 Synthesis of gemfibrozil (
6
).
Scheme 4.5 Synthesis of bezafibrate (
3
).
Scheme 4.6 Synthesis of fenofibric acid (
5a
) and fenofibrate (
5
).
Scheme 4.7 Synthesis of etofibrate (
8
), ronifibrate (
9
), and binifibrate (
10
).
Figure 4.2 Overall structure of the PPARα LBD bound with AZ242/tesaglitazar (shown as sticks). Key agonism-related hydrogen-bonding residue (Tyr464) highlighted.
Figure 4.3 General structure of PPARα activators as exemplified by fenofibric acid (
5a
).
Chapter 5: Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events
Figure 5.1 Development pathway of antiplatelet thienopyridines leading to the discovery of prasugrel (
4
).
Figure 5.2 Structures of newer antiplatelet agents acting as irreversible (
5c
) and reversible (
6
) antagonists of the P2Y
12
receptor.
Scheme 5.1 The Daiichi Sankyo synthesis pathway of prasugrel (
4
).
Scheme 5.2 Synthesis pathway for prasugrel (
4
) proposed by Kikuo
et al.
[11].
Scheme 5.3 High-yield synthetic pathway to prasugrel (
4
) [13].
Figure 5.3 Activation and metabolic pathway of clopidogrel (
3
); CYPs: cytochromes P450.
Figure 5.4 Activation and metabolic pathways of prasugrel (
4
) [1, 2, 16–20]. CYPs: cytochromes P450; PON-1: paraoxonase-1; and GSH: glutathione.
Figure 5.5 Stereoisomers of the prasugrel active metabolites
30
.
Chapter 6: Carboxylic Acids and Lactones as HMG-CoA Reductase Inhibitors
Scheme 6.1 General structure of statins and the interconversion of acid
3
and lactone
4
. L is a hydrophobic group.
Figure 6.1 Marketed statins [10].
Scheme 6.2 Production of simvastatin (
2
) from lovastatin (
7
).
Scheme 6.3 Production of pravastatin (
10
).
Scheme 6.4 Convergent synthesis of some Type II statins.
Scheme 6.5 Industrial production of fluvastatin (
8
).
Scheme 6.6 Industrial production of rosuvastatin (
11
).
Scheme 6.7 Industrial production of atorvastatin (
9
).
Scheme 6.8 Biocatalysis approaches for the synthesis of the chiral side chain
24.
Figure 6.2 Biosynthesis of cholesterol (
1
).
Figure 6.3 Structural features of potent statins.
Figure 6.4 (a) X-ray cocrystal structure of rosuvastatin (
11
) with human HMG-CoA reductase. (b) The key interactions of rosuvastatin (
11
) with enzyme residues [31].
Chapter 7: Angiotensin II Receptor Antagonists with Carboxylic Functionalities in Cardiovascular Disease
Figure 7.1 Basic structure and numbering of 2-(1-benzyl-1
H
-imidazol-5-yl)acetic acid (
1
).
Figure 7.2 Structure of compounds CV-2198 (
2
) and CV-2973 (
3
).
Figure 7.3 Structures of angiotensin II receptor blockers marketed in the United States: losartan (
4
), valsartan (
5
), irebesartan (
6
), candesartan cilexetil (
7
), olmesartan Medoxomil (
8
), eprosartan (
9
), telmisartan (
10
), and azilsartan medoxomil (
11
).
Scheme 7.1 Evolution of original 2-(1-benzyl-1
H
-imidazol-5-yl)acetic acid scaffold into losartan (
4
).
Scheme 7.2 Synthesis of losartan (
4
) from key intermediate
17
.
Scheme 7.3 Synthesis of valsartan (
5
).
Scheme 7.4 Modified synthesis of valsartan (
5
) using a Suzuki coupling reaction between the intermediate
26
and the trityl-protected tetrazole-boronic acid ester
27
.
Scheme 7.5 Synthesis of irbesartan (
6
).
Scheme 7.6 Synthesis of candesartan cilexetil (
7
).
Scheme 7.7 Synthesis of olmesartan medoxomil (
8
).
Scheme 7.8 Synthesis of eprosartan (
9
).
Scheme 7.9 Synthesis of telmisartan (
10
).
Scheme 7.10 Synthesis of azilsartan medoxomil (
11
).
Figure 7.4 The renin–angiotensin system (RAS) pathway.
Figure 7.5 The interaction of angiotensin II with the AT
1
receptor.
Chapter 8: Carboxylic Acid Containing Direct Thrombin Inhibitors for the Treatment of Thromboembolic Diseases
Figure 8.1 Carboxylic-acid-containing direct thrombin inhibitors dabigatran (
1
) dabigatran etexilate (
Pro-1
), argatroban (
2
), melagatran (
3
), and ximelagatran (
Pro-3
).
Figure 8.2 Hirudin analog bivalirudin (
4
).
Scheme 8.1 Synthesis of argatroban (
2
) from
N
-nitro-Boc-
l
-arginine.
Scheme 8.2 Synthesis of melagatran (
3
).
Scheme 8.3 Discovery synthesis of ximelagatran (
Pro-3
).
Scheme 8.4 Synthesis of dabigatran (
1
) and dabigatran etexilate (
Pro-1
).
Figure 8.3 Coagulation cascade pathway.
Scheme 8.5
N
-α-Tosyl-
l
-arginine methyl ester (TAME) (
25
) as a starting point for argatroban (
2
).
Scheme 8.6 Historic path to melagatran (
3
).
Scheme 8.7 Historic path to dabigatran (
1
).
Figure 8.4 Conversion of ximelagatran (
Pro-3
) into melagatran (
3
).
Figure 8.5 Conversion of dabigatran etexilate (
Pro-1
) into dabigatran (
1
).
Chapter 9: Tetracycline Amide Antibiotics
Figure 9.1 The naphthacene ring system (
1a
) and the basic structure and numbering conventions for tetracyclines (
1b
).
Figure 9.2 Examples of tetracycline natural products.
Figure 9.3 Examples of semisynthetic tetracyclines.
Figure 9.4 Structure of tigecycline (
10
), an example of a fully synthetic tetracycline.
Scheme 9.1 Historic development of tetracycline antibiotics at Pfizer.
Scheme 9.2 Historic development of tetracycline antibiotics at Lederle.
Scheme 9.3 Chemical sensitivity of 6-methyl-6-hydroxy tetracyclines toward acids and bases.
Scheme 9.4 Woodward's total synthesis of (±)-6-demethyl-6-deoxytetracycline (
22
).
Scheme 9.5 Key step in Muxfeldt's synthesis of (±)-oxytetracycline (Terramycin (
3
)).
Scheme 9.6 Key steps in Stork's total synthesis of (±)-12a-deoxytetracycline (
29
).
Scheme 9.7 First asymmetric total synthesis of natural (−)-tetracycline (
4
) by Tatsua.
Figure 9.5 Structural requirements for biological activity of tetracyclines.
Figure 9.6 Stereochemical and substitution requirements for optimal antibacterial activity.
Chapter 10: Carboxylic-Acid-Based Neuraminidase Inhibitors
Figure 10.1 Neuraminidase inhibitors: zanamivir (
1
), oseltamivir (
2
), laninamivir (
3
), and peramivir (
4
).
Figure 10.2 Natural substrate sialic acid (
5
) and first neuraminidase inhibitor 2-deoxy-2,3-dehydro-
N
-acetylneruaminic acid (DANA,
6
).
Scheme 10.1 First synthesis of zanamivir (
1
) from sialic acid (
5
).
Scheme 10.2 Optimized scalable synthesis of zanamivir (
1
).
Scheme 10.3 Initial synthetic route toward oseltamivir carboxylate
26
by Gilead Sciences.
Scheme 10.4 Hoffmann-La Roche improved process route to oseltamivir (
2
) phosphate.
Scheme 10.5 Asymmetric Diels–Alder reactions toward the core of oseltamivir (
2
).
Scheme 10.6 Hayashi's one pot synthesis of oseltamivir (
2
).
Scheme 10.7 Facile synthesis of peramivir (
4
).
Figure 10.3 Mechanism of action of neuraminidase inhibitors against influenza virus replication. Hemagglutinin (HA), Neuraminidase (NA), Neuraminidase inhibitor (NAI).
Chapter 11: Oxazolidinone Amide Antibiotics
Figure 11.1 General structure of oxazolidinone-based antibacterial agents.
Figure 11.2 Structures of representative oxazolidinone-based drugs.
Figure 11.3 Structures of the first oxazolidinone antibiotics.
Figure 11.4 Representative oxazolidinone analogs from Upjohn.
Scheme 11.1 DuPont synthesis of oxazolidinones via chiral resolution.
Scheme 11.2 Synthesis of DuP 721 (
13
).
Scheme 11.3 The Upjohn synthesis pathway of linezolid (
1
).
Scheme 11.4 Alternative enantioselective synthesis of linezolid (
1
).
Schemes 11.5 Synthesis of eperezolid (
19
).
Figure 11.6 Synthesis of sutezolid (
2
).
Scheme 11.7 Synthesis of radezolid (
3
).
Figure 11.5 Schematic representation of the mode of action of oxazolidinones, which bind to the peptidyl transferase center (PTC) of the 50S ribosomal subunit, preventing the formation of the 70S initiation complex and blocking the protein synthesis. IFs: initiation factors; EFs: elongation factors; and fMet-tRNA: formylmethionyl-tRNA.
Figure 11.6 Scheme of the main metabolic pathways of linezolid (
1
).
Figure 11.7 The reversible inhibitors of MAO-A (RIMAs) befloxatone (
51
) and cimoxatone (
52
).
Figure 11.8 Structure–activity relationships of 2-oxazolidinone-based antimicrobials around the structure of linezolid (
1
).
Chapter 12: Sovaldi, an NS5B RNA Polymerase-Inhibiting Carboxylic Acid Ester Used for the Treatment of Hepatitis C Infection
Figure 12.1 Sovaldi (
1
) and other ProTide-based antiviral agents.
Figure 12.2 Invention pathway of Sovaldi (
1
).
Scheme 12.1 Discovery-stage synthetic route to Sovaldi (
1
) and analogs.
Scheme 12.2 Large-scale synthesis of uridine nucleoside building block (
11
).
Scheme 12.3 Stereoselective preparation of
1
via phosphoramidate ester building block
15
.
Scheme 12.4
In vivo
activation of Sovaldi (
1
) to the uridine triphosphate PSI-7409 (
18
) [9].
Figure 12.3 Geminal dimethyl substituted (
19
) and cyclopropyl congener (
20
) of Sovaldi (
1
).
Chapter 13: Dipeptidyl Peptidase-4 (DPP-4)-Inhibiting Amides for the Treatment of Diabetes
Figure 13.1 The nine approved DPP-4 inhibitors with the year of first approval.
Figure 13.2 DPP-4 substrate specificity and the design of early inhibitors.
Scheme 13.1 Reversible imidate formation of nitrile-containing inhibitors with Ser630.
Figure 13.3 Early inhibitors used to probe the role of DPP-4 in glucose regulation.
Scheme 13.2 The development of sitagliptin (
5
) from the HTS hits
21
and
22
.
Scheme 13.3 Synthesis of vildagliptin (
1
).
Scheme 13.4 Synthesis of saxagliptin (
2
).
Scheme 13.5 Synthesis of sitagliptin (
5
).
Scheme 13.6 The roles of GLP-1 and DPP-4 in blood glucose regulation.
Figure 13.4 General structural features of glycine-based DPP-4 inhibitors.
Figure 13.5 Steric restrictions at the P2 site of glycine-based inhibitors.
Scheme 13.7 NVP-DPP728 (
20
) and issues of solution stability.
Figure 13.6 SAR development leading to vildagliptin (
1
).
Figure 13.7 SAR development leading to saxagliptin (
2
).
a
Data obtained using porcine DPP-4.
b
Data obtained using human DPP-4.
Figure 13.8 SAR development leading to sitagliptin (
5
).
Figure 13.9 Key interactions of sitagliptin (
5
) with the DPP-4 active site.
Chapter 14: Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton's Tyrosine Kinase
Figure 14.1 The chemical structure of ibrutinib (
1
) and optimization starting point PCI-29732 (
2
).
Scheme 14.1 Original synthesis of the carboxylic acid acrylamide ibrutinib (
1
).
Scheme 14.2 Alternate synthesis of ibrutinib (
1
) and related analogs.
Figure 14.2 Btk potency of inhibitors incorporating different electrophiles.
Figure 14.3 Irreversible fluorescence probe PCI-33380 (
17
) used in Btk occupancy studies.
Figure 14.4 ABPP probes developed to study the selectivity profile of irreversible Btk inhibitors.
Figure 14.5 Irreversible Btk inhibitors incorporating carboxamide moiety.
Figure 14.6 The cyanoacrylamide-based covalent reversible Btk inhibitor
23.
Chapter 15: Fumaric Acid Esters
Figure 15.1 Basic structure of fumaric acid esters (
1
).
Figure 15.2 Simplified diagram of the Keap1 Nrf2 pathway.
Figure 15.3 Combined immunomodulatory, anti-inflammatory effects attributed to DMF directly or by way of interaction with Nrf2.
Figure 15.4 Reaction between DMF (
1a
) and glutathione in which the initial rate of reaction is pH-dependent.
Figure 15.5 Reaction between MMF (
1b
) and deprotonated glutathione provides equimolar amounts of
6
and
7
via path a or b. Glutathione reacting with neither protonated MMF (
1b
) does not occur nor does deprotoned glutathione react upon deprotonated MMF (
1b
).
Chapter 16: Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Figure 16.1 Selected examples of NSAIDs.
Scheme 16.1 Synthesis of aspirin (
1
).
Scheme 16.2 Boots synthesis of ibuprofen (
2
).
Scheme 16.3 Hoechst synthesis of ibuprofen (
2
).
Scheme 16.4 First commercial synthetic route for naproxen (
3
).
Scheme 16.5 Zambon process for asymmetric synthesis of naproxen (
3
).
Scheme 16.6 Catalytic asymmetric hydrogenation synthesis of naproxen (
3
).
Scheme 16.7 Merck's Fischer Indole synthesis-based route to indomethacin (
4
).
Scheme 16.8 Synthesis of diclofenac (
5
).
Scheme 16.9 Catalytic reaction of AA to PGs.
Figure 16.2 (a) Arachidonic acid (AA,
39
) bound to COX1 (pdb code: 1DIY). (b) Ibuprofen (
2
) bound to COX1 (pdb code: 1EQG).
Figure 16.3 COX2 Ser530 modified as bromoacetate by bromoaspirin (pdb code: 1PTH).
Scheme 16.10 Reaction mechanism of aspirin (
1
) acetylating Ser530 of COX.
Figure 16.4 Adapted molecular interaction map of AA (
39
) with COX1 generated by MOE (pdb code: 1DIY).
Figure 16.5 Comparison of COX1 ((a), pdb code: 1DIY) and COX2 ((b), pdb code: 1CX2), active site binding pockets, gray shapes, generated with ICM PocketFinder.
Figure 16.6 (a) Diclofenac (
5
) bound to COX2 (left, pdb code: 1PXX). (b) Lumiracoxib (
8
) bound to COX2 (right, pdb code: 4OTY).
Chapter 17: Carboxylic-Acid-Containing Antihistamines*
Figure 17.1 Second-generation carboxylic-acid-containing antihistaminic drugs that are metabolites or derivatives of first-generation antihistaminic drugs.
Figure 17.2 Antihistaminic drugs designed to contain a carboxylic acid moiety.
Scheme 17.1 Synthesis of cetirizine (
2
).
Scheme 17.2 Synthesis of bilastine (
9
).
Scheme 17.3 Synthesis of fexofenadine (
5
).
Scheme 17.4 Synthesis of acrivastine (
7
).
Chapter 18: Corticosteroid Carboxylic Acid Esters
Figure 18.1 Hydrocortisone monoesters (
2a
,
2b
) and diester (
2c
).
Figure 18.2 Glucocorticoids with more elaborate
d
rings or with extended C
21
-ester chains.
Scheme 18.1 First synthesis of a 16β-methyl corticosteroid (
32
).
Scheme 18.2 The sulfoxide–sulfenate rearrangement to introduce a 17α,21-dihydroxy acetone side chain.
Scheme 18.3 Synthetic approach to halopredone acetate.
Scheme 18.4 Optimized access to 17α-acyloxy-21-chloro corticosteroids.
Scheme 18.5 Expedient synthesis of cortexolone acetate (
51
).
Scheme 18.6 β-Cyanohydrins as precursors to 17-dihydroxyacetone-corticosteroids.
Scheme 18.7 Discovery of fluticasone propionate (
18p
).
Scheme 18.8 A new synthetic approach to triamcinolone acetate (TCA,
26
).
Scheme 18.9 An improved synthetic approach to the
DX
-type scaffold from commodity raw material.
Scheme 18.10 Synthesis of
72
from fluocinonide (
16
).
Figure 18.3 The general structure of GCEs with essential functionalities for activity highlighted.
Chapter 19: Prostaglandins with Carboxylic Functionalities for the Treatment of Glaucoma
Figure 19.1 Structure of PGF
2α
(
1
).
Figure 19.2 Marketed prostaglandins for the treatment of glaucoma.
Figure 19.3 Structures and numbering of prostanoic acid (
7
) and PGF
2α
(
1
).
Scheme 19.1 Synthesis of intermediate
10a/b
using the gold-catalyzed Meyer–Schuster (M–S) rearrangement [10].
Scheme 19.2 Synthesis of latanoprost (Xalatan®,
2
) [14].
Scheme 19.3 Synthesis of bimatoprost (Lumigan®,
3
) [15].
Scheme 19.4 Synthesis of travoprost (Travatan Z®,
4
) [15].
Schemes 19.5 Synthesis of tafluprost (
5
) [16, 17].
Figure 19.6 Synthesis of unoprostone isopropyl ester (
6
) [18].
Chapter 20: Herbicidal Carboxylic Acids as Synthetic Auxins
Figure 20.1 The phenoxy-carboxylic acid auxin herbicides 2,4-D (
1
), MCPA (
2
), dichlorprop (
3
), mecoprop (
4
), 2,4-DB (
5
), and MCPB (
6
).
Figure 20.2 The benzoic acid auxin herbicide dicamba (
7
).
Figure 20.3 The pyridinecarboxylic acid auxin herbicides picloram (
8
), clopyralid (
9
), and aminopyralid (
10
).
Figure 20.4 The pyridyloxy-carboxylic acid auxin herbicides triclopyr (
11
) and fluroxypyr (
12
).
Figure 20.5 The quinolinecarboxylic acid auxin herbicide quinclorac (
13
).
Figure 20.6 The pyrimidinecarboxylic acid auxin herbicide aminocyclopyrachlor (
14
).
Figure 20.7 The aryl pyridinecarboxylic acid auxin herbicides Arylex™ active (
15
) and Rinskor™ active (
16
).
Scheme 20.1 Synthesis of phenoxy-carboxylic acid auxin herbicide 2,4-D (
1
) [22].
Scheme 20.2 Synthesis of benzoic acid auxin herbicide dicamba (
7
) [4].
Scheme 20.3 Synthesis of pyridyloxy-carboxylic acid auxin herbicide fluroxypyr (
12
) [23–25].
Scheme 20.4 Synthesis of pyridinecarboxylic acid auxin herbicides picloram (
8
), clopyralid (
9
), and aminopyralid (
10
) and the aryl pyridinecarboxylic acid auxin herbicides Arylex™ active (
15
) and Rinskor™ active (
16
) [18, 20, 21, 26–29].
Chapter 21: Chloroacetamide Herbicides
Figure 21.1 The 14 commercialized chloroacetamide herbicides.
Scheme 21.1 Invention pathway of alachlor (
2
), the first 2,6-dialkylated chloroacetanilide [12].
Scheme 21.2 Synthesis of acetochlor (
1
).
Scheme 21.3 Synthesis of metolachlor (
8
) and enantioselective synthesis of (
S
)-metolachlor (
25
).
Scheme 21.4 Synthesis of pethoxamid (
9
).
Scheme 21.5 Four-step reaction sequence for the elongation of fatty acids to very long-chain fatty acids [26, 27].
Figure 21.2 The general structure of chloroacetamide herbicides I and their acetamide analogs II [12].
Figure 21.3 The four different stereosiomers of metolachlor (
8
).
Figure 21.4 Some herbicidally active chloroacetamide analogs.
Chapter 22: Carboxylic-Acid-Containing Sulfonylurea Herbicides
Figure 22.1 General structure of sulfonylurea herbicides.
Figure 22.2 The sulfonylurea herbicides nicosulfuron (
1
) and mesosulfuron-methyl (
2
).
Figure 22.3 Commercial sulfonylureas containing an
ortho
-carboxylate derivative.
Scheme 22.1 Methods for the synthesis of sulfonylureas.
Scheme 22.2 AHAS or ALS biochemical pathway [16, 17].
Figure 22.4 The three regions of sulfonylurea herbicides.
Figure 22.5 Linkers to the
ortho
-ester
s.
Figure 22.6 “Tied-up” phenylacetic esters.
Figure 22.7 “Tied-up” cinnamate esters.
Figure 22.8 “Tied-back” esters.
Chapter 23: Amino Acids as Nonselective Herbicides
Figure 23.1 Examples of amino acid herbicides.
Scheme 23.1 Synthesis of glyphosate (
1
) involving dimethyl phosphite (
6
) and glycine (
8
).
Scheme 23.2 Synthesis of glyphosate (
1
) involving phosphorous acid (
10
) and
N
-benzyl glycine (
11
).
Scheme 23.3 Synthesis of glufosinate (
4
) involving a Strecker reaction.
Scheme 23.4 Synthesis of glufosinate (
4
) involving a Schiff base.
Scheme 23.5 Enantioselective synthesis of
l
-phosphinothricin (
5
).
Figure 23.2 Some structure–activity relationships of glyphosate (
1
).
Figure 23.3 Some structure–activity relationships of glufosinate (
4
).
Chapter 24: Herbicidal Aryloxyphenoxypropionate Inhibitors of Acetyl-CoA Carboxylase
Figure 24.1 Structures of some commercial aryloxyphenoxypropionate herbicides.
Figure 24.2 The first fop herbicide, diclofop-methyl (
4
), and the synthetic auxin mecoprop (
5
).
Scheme 24.1 Typical routes for the synthesis of fluazifop-butyl (
6
).
Scheme 24.2 Alternative route for the synthesis of diclofop-methyl (
4
).
Scheme 24.3 Biocatalytic resolution of fluazifop.
Scheme 24.4 Late-stage modifications of substitution.
Figure 24.3 Structures of pinoxaden (
7
) and sethoxydim (
8
), a typical dim herbicide.
Figure 24.4 Structures of some ester variations.
Figure 24.5 Compounds with ester replacements that show herbicidal activity.
Figure 24.6 Cyclic analogs of haloxyfop.
Scheme 24.5 Extended analogs of fluazifop and possible routes for their metabolism.
Figure 24.7 Further analogs that show herbicidal activity.
Chapter 25: Pyridines Substituted by an Imidazolinone and a Carboxylic Acid as Acetohydroxyacid-Synthase-Inhibiting Herbicides
Figure 25.1 The imidazolinone herbicides imazamethabenz methyl (
1
), imazapyr (
2
), imazapic (
3
), imazethapyr (
4
), imazamox (
5
), and imazaquin (
6
).
Scheme 25.1 Invention pathway of the herbicidal imidazolinones.
Scheme 25.2 Synthesis of imazethapyr (
4
).
Scheme 25.3 General route of metabolism of imidazolinone herbicides in plants, with example of imazamox (
5
) and imazaquin (
6
).
Figure 25.2 General structure of the imidazolinone herbicides.
Figure 25.3 Carboxylic acid mimics of imidazolinone herbicides.
Chapter 26: Carboxylic-Acid-Containing Protoporphyrinogen-IX-Oxidase-Inhibiting Herbicides
Figure 26.1 Examples of Protox herbicides containing the carboxylic acid functional group.
Figure 26.2 Chemical structures of two early examples of Protox inhibitors.
Figure 26.3 Diphenyl ether Protox herbicides with a carboxylic acid group directly attached to the aromatic ring.
Figure 26.4 The Protox herbicide butafenacil (
15
) [27].
Figure 26.5 Protox herbicides with ester functional groups not directly attached to the aromatic ring.
Scheme 26.1 Synthesis of saflufenacil (
1
) [1, 2].
Scheme 26.2 Synthesis of carfentrazone-ethyl (
5
) [6, 7].
Figure 26.6 Structure–activity relationships of the 2,4,5-trisubstitutedphenyl heterocycles.
Figure 26.7 Structure–activity of 3-(benzoheterocyclic)-1-methyl-6-trifluoromethyluracil Protox-inhibiting herbicides.
Figure 26.8 Protox inhibitor
23
used in protoporphyrinogen IX oxidase-binding studies.
Chapter 27: Phenylamide Fungicides
Figure 27.1 Commercial phenylamides fungicides [2, 3].
Scheme 27.1 Invention pathway of metalaxyl (
1
) and metalaxyl-M (
R
)-(
1
) [8].
Scheme 27.2 Chiral pool synthesis of metalaxyl-M (
R
)-(
1
) [11].
Scheme 27.3 Enantioselective hydrogenation routes to metalaxyl-M (
R
)-(
1
) [17].
Scheme 27.4 Enantioselective imine hydrogenation routes to metalaxyl-M (
R
)-(
1
) [20].
Figure 27.2 SAR of phenylamide fungicides [5b, 9c].
Figure 27.3 Alkylthio analog of metalaxyl [28].
Chapter 28: Complex III Inhibiting Strobilurin Esters, Amides, and Carbamates as Broad-Spectrum Fungicides
Figure 28.1 The methoxyacrylate strobilurin fungicides azoxystrobin (
1
), enoxastrobin (
2
), picoxystrobin (
3
), coumoxystrobin (
4
), flufenoxystrobin (
5
), and pyraoxystrobin (
6
).
Figure 28.2 The methoxyiminoacetate strobilurin fungicides kresoxim-methyl (
7
) and trifloxystrobin (
8
), the methoxyiminoacetamide strobilurin fungicides orysastrobin (
9
), metominostrobin (
10
), dimoxystrobin (
11
), and fenaminostrobin (
12
) as well as the methoxyacetamide strobilurin mandestrobin (
13
).
Figure 28.3 The methoxycarbamate strobilurin fungicides pyraclostrobin (
14
), triclopyricarb (
15
), and pyrametostrobin (
16
) as well as the benzylcarbamate strobilurin pyribencarb (
17
).
Scheme 28.1 Invention pathway from the natural product strobilurin A (
18
) to azoxystrobin (
1
) and to kresoxim-methyl (
7
) [6, 7, 10].
Scheme 28.2 Synthesis of the methoxyacrylate strobilurin azoxystrobin (
1
) [2, 7, 8].
Scheme 28.3 Synthesis of methoxyiminoacetate strobilurin fungicide kresoxim-methyl (
7
) [2].
Scheme 28.4 Synthesis of the methoxycarbamate strobilurin fungicide pyraclostrobin (
14
) [2].
Figure 28.4 Model of the strobilurin target binding via hydrogen bridge between Glu272 and the pharmacophore carbonyl group [2].
Figure 28.5 The general structural requirements of strobilurin fungicides.
Figure 28.6 Strobilurins with the side chain in the
meta
-position of the pharmacophore.
Figure 28.7 Fluoxastrobin (
41
) and DPX KZ165 (
42
), two strobilurins with a cyclic pharmacophore.
Figure 28.8 The strobilurin acaricide fluacrypyrim (
43
).
Chapter 29: Scytalone-Dehydratase-Inhibiting Carboxamides for the Control of Rice Blast
Figure 29.1 The commercial scytalone dehydratase inhibitors (MBI-D).
Figure 29.2 An amino-quinazoline melanin biosynthesis inhibitor from Sankyo.
Scheme 29.1 The discovery of carpropamid (
1
).
Scheme 29.2 The discovery of diclocymet (
2
) from the herbicide bromobutide (
8
).
Scheme 29.3 Scytalone mimics from DuPont.
Scheme 29.4 Reoptimized MBI-Ds from DuPont.
Scheme 29.5 The synthesis of carpropamid (
1
).
Scheme 29.6 The synthesis of diclocymet (
2
).
Scheme 29.7 The synthesis of fenoxanil (
3
).
Scheme 29.8 The melanin biosynthetic pathway with the steps inhibited by the three classes of MBIs noted.
Figure 29.3 Tolprocarb (
40
) and its structural similarity to both MBI-D and CAA chemistry.
Chapter 30: Carboxylic Acid Amide Fungicides for the Control of Downy Mildew Diseases
Figure 30.1 The seven commercialized carboxylic acid amide fungicides [1].
Scheme 30.1 Invention pathway of mandipropamid (
7
) [8].
Scheme 30.2 Synthesis of the cinnamic acid amide dimethomorph (
1
) [1].
Scheme 30.3 Synthesis of the valinamide iprovalicarb (
4
) [1].
Scheme 30.4 Synthesis of the mandelamide mandipropamid (
7
) [1, 8, 12].
Figure 30.2 The general structural requirements of carboxylic acid amide fungicides.
Figure 30.3 The
N
-sulfonylated amino acid amide fungicides
9
and
10
[10].
Figure 30.4 Compounds
24
and
25
, two highly active analogs of mandipropamid [8, 15].
Figure 30.5 The mandipropamid analogs
26–29
[1, 8, 16, 18].
Figure 30.6 The valinamide
30
, a crossover compound with structural features of dimethomorph (
1
) and iprovalicarb (
4
), and the aminosulfone XR-539 (
31
) [19, 20].
Chapter 31: Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides
Figure 31.1 The FRAC listed SDHI carboxamides not belonging to the pyrazole-4-carboxamide group (chemical groups
A–D
and
F–G
).
Figure 31.2 The complete list of the pyrazole-4-carboxamides, the most important SDHI carboxamide group (chemical group
E
).
Figure 31.3 General structures of the biphenyl-type and phenylcycloalkyl-type amides.
Scheme 31.1 Evolution of boscalid, bixafen, and isopyrazam structures.
Scheme 31.2 Retrosynthetic analysis of the pyrazole carboxylic acid
20
.
Scheme 31.3 First Syngenta synthesis of the CF
2
H group containing mixture of β-ketoesters
24a,b
[5].
Scheme 31.4 Completion of the β-ketoester route [4, 6].
Scheme 31.5 Bayer CS/BASF/Central Glass approach to the pyrazole acid
20
using the 3-(dialkylamino)acrylate route.
Scheme 31.6 BASFs protecting group approach for the regioselective synthesis of the pyrazole acid
20
[21].
Scheme 31.7 Synthesis of bixafen (
16
) using the Goossen approach for the synthesis of the aniline part [24, 25].
Scheme 31.8 Synthesis of isopyrazam (
14
) (aniline part only) – first optimized synthesis [28–31].
Scheme 31.9 Synthesis of sedaxane (
15
) (example: trans/cis ratio about 2 : 1) [32–36].
Scheme 31.10 Synthesis of benzovindiflupyr (
18
) using a new cycloaddition approach [37, 38].
Figure 31.4 Schematic representation of the respiration chain (containing complexes I–IV).
Figure 31.5 Simplified SAR picture for the pyrazole-4-carboxamide class covering brown rust and
Zymoseptoria
leaf blotch on wheat, gray mold on grapes, and early blight on tomato (related to glasshouse data).
Figure 31.6 Structures of the phenylbenzamides
3–5
, the pyridine-3-carboxamide boscalid (
8
) and pyraziflumid (
52
).
Figure 31.7 Examples of other five-membered ring containing SDHI fungicides.
Figure 31.8 Structures of SDHI carboxamides not derived from aromatic amines.
Chapter 32: Esters and Carbamates as Insecticidal Juvenile Hormone Mimics
Figure 32.1 Four commercialized ester- or carbamate-bearing juvenile hormone mimics.
Figure 32.2 Naturally occurring juvenile hormones.
Figure 32.3 Juvenile hormone mimics with ester or carbamate replacements: diofenolan and pyriproxyfen.
Scheme 32.1 Key steps in research route to hydroprene (
1
).
Scheme 32.2 Key steps in a second-generation approach to methoprene (
3
).
Scheme 32.3 Importance of chirality of juvenile hormone mimics.
Scheme 32.4 Synthesis of fenoxycarb.
Figure 32.4 SAR of juvenile hormone analogs (a-d).
Figure 32.5 From juvenile hormone esters to aryl ethers: discovery of fenoxycarb.
Chapter 33: N-Benzoyl-N′-Phenyl Ureas as Insecticides, Acaricides, and Termiticides
Figure 33.1 The 11 commercialized BPUs mainly used as (a) insecticides/acaricides, (b) insecticides, and (c) insecticides/termiticides.
Figure 33.2 Identification of the insecticidal active
N
-(2,6-dichlorobenzoyl)-
N
′-(3,4-dichlorophyl)-urea (
14
, DU1911) by combination of the herbicide structures dichlobenil (
12
) and diuron (
13)
.
Scheme 33.1 Synthesis of key the intermediates benzoyl isocyanates
15
and substituted arylamines
23
and
26
. (a) Synthesis of benzoyl isocyanates. (b) Synthesis of halogen-substituted amino- or nitrophenols. (c) Synthesis of pyridine-2-yl-substituted aminophenols.
Scheme 33.2 Preparation of the
O
-[(4-aminophenyl) methyl]oxime key intermediate
31
for the synthesis of flucycloxuron (
2
).
Scheme 33.3 Methods I and II for syntheses of
N
-benzoyl-
N
′-phenyl ureas (
1
)–(
11
).
Figure 33.3 The general structures of BPU insecticides, acaricides, and termiticides.
Figure 33.4 Structures of novel BPU insecticides
32–34
.
Figure 33.5 Structures of the BPU insecticides NK-17 (
35
) and
36
.
Chapter 34: Pyrethroid Esters for the Control of Insect Pests
Figure 34.1 Selected commercialized pyrethroids.
Figure 34.2 The classification of pyrethrins in two classes.
Figure 34.3 The journey to the discovery of pyrethroids.
Figure 34.4 The nomenclature convention for the stereochemistry of pyrethroids.
Scheme 34.1 The synthesis of lambda cyhalothrin (
1
).
Scheme 34.2 The synthesis of deltamethrin (
2
).
Scheme 34.3 The synthesis of esfenvalerate (
5
).
Figure 34.5 Proposed mode of binding of fenvalerate to housefly voltage-gated Na channel.
Chapter 35: Ecdysone Receptor Agonistic Dibenzoyl Hydrazine Insecticides
Figure 35.1 The insecticides methoxyfenozide (
1
), tebufenozide (
2
), halofenozide (
3
), chromafenozide (
4
), and fufenozide (
5
).
Figure 35.2 The lead compound RH-5849 (
6
) and the insect-molting hormone 20-hydroxyecdysone (
7
).
Scheme 35.1 Synthesis of methoxyfenozide (
1
) [7, 10, 11].
Scheme 35.2 Synthesis of tebufenozide (
2
) [7, 12].
Scheme 35.3 Synthesis of halofenozide (
3
) [7, 12].
Scheme 35.4 Synthesis of chromafenozide (
4
) [7, 13].
Scheme 35.5 Synthesis of fufenozide (
5
) [14, 15].
Figure 35.3 Ponasterone A (
37
) and dibenzoyl hydrazine BY106830 (
38
).
Figure 35.4 Pharmacophore model based on commercial dibenzoyl hydrazine insecticides.
Figure 35.5 Effect of the replacement of the
N-tert
-butyl dicarbonyl hydrazine backbone on the biological activity against
Spodoptera eridania.
Figure 35.7 Influence of the substituents on the A-ring or B-ring of dibenzoyl hydrazine insecticides on the biological activity against
Spodoptera eridania.
Figure 35.6 Effect of replacements of the A-ring or B-ring on the biological activity against
Spodoptera eridania.
Figure 35.8 Effect of different bicyclic systems on the biological activity against
Spodoptera litura
(F.).
Figure 35.9 New structural types related to the dibenzoyl hydrazine insecticides.
Chapter 36: Diamide Insecticides as Ryanodine Receptor Activators
Figure 36.1 The first three diamides from Nihon Nohyaku and DuPont.
Figure 36.2 Diamides from ISK and Bayer.
Figure 36.3 Diamide structures from Sumitomo, Syngenta, Bayer, SRICI/Sinochem, Jiangsu, and BASF.
Figure 36.4 Phthaldiamide structures from Bayer and ZRICI/Sinochem.
Scheme 36.1 Early-stage synthesis of flubendiamide.
Scheme 36.2 Late-stage introduction of the iodine atom via C–H activation.
Scheme 36.3 Synthesis of chlorantraniliprole (
2
) and cyantraniliprole (
3
).
Scheme 36.4 Synthesis of tetraniliprole (
5
).
Figure 36.5 SAR of the phthalamides.
Figure 36.6 SAR of the anthranilamides (
1
).
Figure 36.9 Analogy in the SAR of the phthalamides and the anthranilamides.
Figure 36.7 SAR of the anthranilamides (
2
): aliphatic amide variations.
Figure 36.8 SAR of sulfoximine derivatives (binding assay [6], IC
50
, n.d.: not determined).
List of Tables
Chapter 3: Analgesic and Anesthetic Amides
Table 3.1 Fentanyl (
1
) and important drug analogs.
Table 3.2 Potency comparisons for various fentanyl derivatives in rat tail withdrawal reflex [2, 3]
Chapter 4: Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPARα Activators)
Table 4.1 Currently available fibrate-derived hypolipidemics
Table 4.2
In vitro
PPAR agonist potency data, human plasma half-life, and doses of selected fibrates
Table 4.3 SAR for pirinixic acid derivatives: EC
50
values and relative activation compared to a positive control (pioglitazone for PPARγ and GW7647 for PPARα) from GAL4 reporter gene assays [60]
Table 4.4 SAR and PPAR selectivity profiles for ureidofibrates and ureido-thioisobutyric acids
Chapter 5: Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events
Table 5.1 Effects of antiplatelet thienopyridines on platelet aggregation parameters in Phase-I studies.
a
Table 5.2 Pharmacological properties in humans of clopidogrel (
3
) and prasugrel (
4
)
Table 5.3 Inhibition of ADP-induced platelet aggregation in rats
a
and structure–activity relationships of 2-hydroxytetrahydropyridine ester derivatives
Chapter 7: Angiotensin II Receptor Antagonists with Carboxylic Functionalities in Cardiovascular Disease
Table 7.1 SAR for 2- and 4-disubstituted imidazole analogs of compound
14
Table 7.2 SAR for bioisosteric replacements of the carboxylate on the biphenyl imidazole core
Chapter 10: Carboxylic-Acid-Based Neuraminidase Inhibitors
Table 10.1 Influenza neuraminidase inhibition by oseltamivir carboxylate analogs
Table 10.2 Inhibitory activities against wild-type and mutant influenza neuraminidases
Table 10.3 IC
50
values (nM) of influenza neuraminidase inhibition for phosphonic acid bioisosteres
Table 10.4 SAR of N-substituted oseltamivir (
2
) derivatives as potent and selective inhibitors of H5N1 NA
Chapter 15: Fumaric Acid Esters
Table 15.1 Approved drugs that contain dimethyl fumarate (
1a
)
Chapter 16: Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Table 16.1 HWB activity of NSAIDs for COX1/2.
Chapter 17: Carboxylic-Acid-Containing Antihistamines*
Table 17.1 Alkylamines
Table 17.2 Piperazines
Table 17.3 Piperidines
Chapter 18: Corticosteroid Carboxylic Acid Esters
Table 18.1 Currently approved or marketed glucocorticoids carboxylic acid esters
Chapter 20: Herbicidal Carboxylic Acids as Synthetic Auxins
Table 20.1 Herbicides, weed control spectrum, and major uses for each auxin family [2]
Chapter 33: N-Benzoyl-N′-Phenyl Ureas as Insecticides, Acaricides, and Termiticides
Table 33.1 Biological profiles of commercialized
N
-benzoyl-
N
′-phenyl urea insecticides (
1–11
)
Chapter 34: Pyrethroid Esters for the Control of Insect Pests
Table 34.1 The relation between stereochemistry and insecticidal activity exemplified with cyhalothrin (
20
) diastereoisomers
Table 34.2 The impact of benzyl ester substituents and halogen substituents on insecticidal activity
Table 34.3 The impact of the alkenyl substituents and of the stereochemistry on the α position on insecticidal activity
Table 34.4 Selected physicochemical properties of some pyrethroids
Edited by Clemens Lamberth and Jürgen Dinges
Bioactive Carboxylic Compound Classes
Pharmaceuticals and Agrochemicals
The Editors
Dr. Clemens Lamberth
Syngenta Crop Protection AG
Chemical Research
Schaffhauserstr. 101
4332 Stein
Switzerland
Dr. Jürgen Dinges
Abbvie Inc.
Global Pharmaceutical R&D
1 N. Waukegan Road
North Chicago, IL
United States
Cover
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List of Contributors
Irini Akritopoulou-Zanze
Abbvie Strategic Portfolio Management
Dept. R4SP, Bldg. AP10
1 N Waukegan Road
North Chicago
IL 60064
USA
Cosimo D. Altomare
University of Bari “Aldo Moro”
Department of Pharmacy – Drug Sciences
via E. Orabona 4
I-70125 Bari
Italy
Fides Benfatti
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Simone Bigi
Takeda California, Inc.
Medicinal Chemistry Department
10410 Science Center Drive
San Diego
CA 92121
USA
Modesto de Candia
University of Bari “Aldo Moro”
Department of Pharmacy – Drug Sciences
via E. Orabona 4
I-70125 Bari
Italy
Fabrizio Carta
University of Florence
Laboratorio di Chimica Bioinorganica
Dipartimento di Chimica “U.Schiff”
Via della Lastruccia 3
Polo Scientifico
50019 Sesto Fiorentino
Italy
Saverio Cellamare
University of Bari Aldo Moro
Department of Pharmacy-Drug Sciences
Via E. Orabona 4
70125 Bari
Italy
Harry R. Chobanian
Department of Medicinal Chemistry
Merck and Co.
2015 Galloping Hill Road
Kenilworth
NJ 07033
USA
Nunzio Denora
University of Bari “Aldo Moro”
Department of Pharmacy – Drug Sciences
via E. Orabona 4
I-70125 Bari
Italy
Pratik Devasthale
Bristol-Myers Squibb
Discovery Chemistry Research and Development
350 Carter Road
Princeton
NJ 08540
USA
Jürgen Dinges
AbbVie, Global Pharmaceutical Research and Development
1 North Waukegan Road
North Chicago
IL 60064
USA
Alastair Donald
Rheinische Strasse 15
42279 Wuppertal
Germany
Jeffrey Epp
Dow AgroSciences
Research Department
9330 Zionsville Road
Indianapolis
IN 46268
USA
Thomas Erhard
AbbVie Deutschland
GmbH & Co. KG
Neuroscience Discovery
Medicinal Chemistry Department
Knollstrasse
67061 Ludwigshafen
Germany
Maurizio Franzini
Gilead Sciences
Chemicals and Biologics Operations
333 Lakeside Dr
Foster City
CA 94404
USA
Roger Gast
Dow AgroSciences
Research Department
9330 Zionsville Road
Indianapolis
IN 46268
USA
Tony S. Gibson
Takeda Pharmaceuticals
Medicinal Chemistry Department
10410 Science Center Dr.
San Diego
CA 92121
USA
Ottmar F. Hüter
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Ingo Janser
Eastern Michigan University
Department of Chemistry
541 Science Complex
Ypsilanti
MI 48197
USA
André Jeanguenat
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Stephane Jeanmart
Syngenta Crop Protection Muenchwilen AG
Chemical Research
Schaffhauserstrasse 101,
4332 Stein
Switzerland
Peter Jeschke
Bayer Crop Science Division
Small Molecules Research, Pest Control Chemistry
Alfred-Nobel-Strasse 50
D-40789 Monheim am Rhein
Germany
Clemens Lamberth
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Paul H. Liang
DuPont Crop Protection
Science and Technology
Stine-Haskell Research Center
1090 Elkton Road
Newark
DE 19711
USA
Xiaodong Lin
Novartis Institutes for BioMedical Research
Global Discovery Chemistry
5300 Chiron Way
Emeryville
CA 94608
USA
William Lo
Dow AgroSciences
Research Department
9330 Zionsville Road
Indianapolis
IN 46268
USA
Yan Lou
Principia Biopharma
400 East Jamie Court
Suite 302
South San Francisco
CA 94080
USA
Régis Mondière
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Jeff Nelson
Dow AgroSciences
Research Department
9330 Zionsville Road
Indianapolis
IN 46268
USA
Gavin O'Mahony
Cardiovascular and Metabolic Diseases
Innovative Medicines and Early Development Biotech Unit
AstraZeneca
Pepparedsleden 1
43183 Mölndal
Sweden
David J. O'Neill
Navitor Pharmaceuticals
Department of Medicinal Chemistry
1030 Massachussetts Ave.
Cambridge
MA 02138
USA
Timothy D. Owens
Principia Biopharma
Research Department
400 East Jamie Court
Suite 302
South San Francisco
CA 94080
USA
Atul Puri
DuPont Crop Protection
Science and Technology
Stine-Haskell Research Center
1090 Elkton Road
Newark
DE 19711
USA
Laura Quaranta
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Naomi S. Rajapaksa
Novartis Institutes for BioMedical Research
Global Discovery Chemistry
5300 Chiron Way
Emeryville
CA 94608
USA
Sebastian Rendler
Syngenta Crop Protection
Chemical Research
Schaffhauserstrasse 101
4332 Stein
Switzerland
Paul Schmitzer
Dow AgroSciences
Research Department
9330 Zionsville Road
Indianapolis
IN 46268
USA
Dale Shaner
USDA-ARS (retired)
2508 Centre Ave
Fort Collins CO 80526
2815 Stonehaven Drive
Fort Collins
CO 80525
USA
Claudiu T. Supuran
University of Florence
Neurofarba Department
Sezione di Farmaceutica e Nutraceutica
Via Ugo Schiff 6
Polo Scientifico
50019 Sesto Fiorentino
Italy
Steve Swann
Takeda California, Inc.
Medicinal Chemistry Department
10410 Science Center Drive
San Diego
CA 92121
USA
Andrew E. Taggi
Discovery Chemistry, DuPont Crop Protection
Stine-Haskell Research Center
1090 Elkton Road
Newark
DE 19711
USA
George Theodoridis
The College of New Jersey
Department of Chemistry
2000 Pennington Road
Ewing
NJ 08628
USA
Stacy Van Epps
AbbVie Bioresearch Center
Global Pharmaceutical Research and Development
381 Plantation Street
Worcester
MA 01605
USA
Harald Walter
Syngenta Crop Protection AG
CP R&D Projects and Portfolio
Schwarzwaldallee 215
CH-4058 Basel
Switzerland
William G. Whittingham
Syngenta Ltd
Chemical Research
Jealott's Hill International Research Centre
Bracknell
Berkshire RG42 6EY
United Kingdom
Mathew M. Yanik
Intercept Pharmaceuticals
4671 Torrey Circle F104
San Diego
CA 92130
USA
Xiang-Yang Ye
Bristol-Myers Squibb
Discovery Chemistry Research and Development
350 Carter Road
Princeton
NJ 08540
USA
Cristiana A. Zaharia
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City
CA 94404
USA
Jiang Zhu
Principia Biopharma
400 East Jamie Court
Suite 302
South San Francisco
CA 94080
USA
Preface
Three years ago, shortly after the publication of our first book “Bioactive Heterocyclic Compound Classes,” we had been contacted by several readers, but also contributors, who praised the concept of combining all important heterocyclic active ingredient classes with short, educational, similarly structured chapters within one book. This positive feedback encouraged us to apply the same concept also to the second major group of functional groups, which play an important role in pharmaceuticals and agrochemicals. These are, besides the already covered heterocycles, the derivatives of carboxylic acids, which means not only the acids themselves but also their esters, amides, ureas, carbamates, hydrazides, thioesters, and so on.
According to our definition, such a carboxylic compound class is made up of three or more commercialized active ingredients that (i) bear the same carboxyl functionality, means acyclic C=O functions except aldehydes and ketones; (ii) possess the same or at least a similar scaffold and a similar substitution pattern; and (iii) have the same mode of action. To be able to cover the most important carboxylic active ingredient families in medicine and crop protection within one book, we had to focus. Therefore, we declared the following functional groups or compound classes to be “out of scope”: (i) all functional groups based on a C=S motif; (ii) cyclic carboxylic compounds with a C=O group (lactones, lactams, diketopiperazines), as they have been covered already in “Bioactive Heterocyclic Compound Classes”; (iii) sulfonic acid derivatives with a SO2 function; and (iv) peptides and macrocycles.
As it was already the case for “Bioactive Heterocyclic Compound Classes,” also the chapters of this book are divided into the same five sections: (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” to describe the target spectrum of the active ingredients.
We are very grateful to the authors of the 36 chapters of this book, all of them expert in their field and several of them already contributing to “Bioactive Heterocyclic Compound Classes,” for spending their scarce time summarizing the historical background, typical chemical syntheses, biochemical modes of action, biological activities, and structure–activity relationships of their area of interest.
It was again Anne Brennführer of Wiley-VCH to whom we are thankful for her help in starting also this book, from a first discussion at the Wiley booth during the German Chemical Society conference “Wissenschaftsforum Chemie 2013” in Darmstadt, our alma mater, through different phases such as creating the concept, finding the authors, and writing the chapters.
Finally, one more big thank you to our wives Annette and Petra, who again accepted that science sometimes took over too much of our spare time, you are the greatest!
Stein and North Chicago, March 2016
Clemens Lamberth
Jürgen Dinges
Chapter 1Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals
Clemens Lamberth and Jürgen Dinges
