This book thoroughly overviews the role of fluorine in pharmaceutical scienceand development, including the classification of marketed and in-development fluorinated pharmaceuticals. The first part introduces the preparation of fluorinated compounds and their specific properties. The second part deals with fluorinated analogues of natural products, fluorinated amino acids and peptides,and derivatives of sugars. This section also includes a detailed chapter about the conception of enzyme inhibitors. In the final part, the main fluorinatedpharmaceuticals, marketed or in development, are classified according to their therapeutic classes. INDICE: Foreword. 1. General remarks on structural, physical and chemical properties of fluorinated compounds. 1.1 Structural effects. 1.2 Physical properties. 1.2.1 Boiling point. 1.2.2 Surface tension and activity. 1.2.3 Solubility. 1.2.4 Lipophilicity. 1.3 Effects on electronic properties and reactivity.1.3.1 Effects of fluorination on bond energies and reactivity. 1.3.2 Effects of fluorination on the electronic repartition of a molecule. 1.3.3 Acidity, basicity and hydrogen bond. 1.3.4 Steric effects. 1.3.5 Fluorination effects on the stability of reaction intermediates (carbocations, carbanions, radicals). References. 2. Overview on the preparation of fluorinated compounds. 2.1 Preparation of monofluorinated compounds. 2.1.1 Nucleophilic fluorination. 2.1.2 Electrophilic fluorination. 2.1.3 Formation of carbon-carbon bonds starting frommonofluorinated synthons. 2.2 Preparation of difluorinated compounds. 2.2.1 Nucleophilic fluorination. 2.2.2 Electrophilic fluorination. 2.2.3 Starting from di- and trifluoromethylcompounds. 2.3 Preparation of trifluoromethyl compounds. 2.3.1 Fluorination. 2.3.2 Nucleophilic trifluoromethylation. 2.3.3 Electrophilic fluorination. 2.3.4 Radical trifluoromethylation. 2.3.5 Metal-catalysedtrifluoromethylation. 2.3.6 Formation of carbon-carbon bonds from trifluoromethyl compounds. 2.4 Synthesis of perfluoroalkyl compounds. References. 3. Effects of fluorine on biological properties. 3.1 Affinity for the macromolecular target. 3.1.1 Steric effects. 3.1.2 Conformational changes. 3.1.3 Dipolar interactions and electric field. 3.1.4 Hydrogen bond. 3.1.5 pKa of amines. 3.1.6 Fluorous interactions. 3.2 Absorption. 3.2.1 Lipophilicity. 3.2.2 pKa and solubility. 3.3 Metabolism. 3.3.1 Oxidative metabolism. 3.3.2 Hydrolytic metabolism. 3.4 Modification of the chemical reactivity: conception of enzyme inhibitors. 3.4.1 Analogue of substrates as inhibitors.. 3.4.2 Inhibition by stabilisation or destabilisation of intermediates of biological processes. 3.4.3 Irreversible inhibition with based-mechanism inhibitors (suicide-substrates). References. 4. Fluorinated analogues of natural products. 4.1 Fluorinated products in nature. 4.2 Steroids. 4.2.1 Corticosteroids. 4.2.2 Steroids with trifluoromethyl groups in angular position. 4.2.3 Fluorinated analogues of metabolites of vitamin D3. 4.2.4 Other fluorinated steroids. 4.3 Terpenes. 4.3.1 Artemisinin. 4.3.2 Taxol. 4.4 Pigments and vitamins. 4.4.1 Retinoids. 4.4.2 Carotenoids. 4.4.3 Vitamins D. 4.4.4 Vitamins E and K. 4.4.5 Porphyrins. 4.5 Lipids and prostanoids. 4.6 Pheromons and toxins. 4.7 Alkaloids. 4.7.1 Vinca alkaloids. 4.7.2 Cinchona alkaloids. 4.7.3 Camptothecin. 4.7.4 Other alkaloids. 4.8 Macrolides.4.8.1 Epothilone. 4.8.2 Erythromycin. 4.8.3 Amphotericin B. 4.8.4 Avermectin.4.9 Anthracyclines. References. 5. Fluorinated derivatives of ?-amino acids and proteins. 5.1 Fluorinated aliphatic amino acids. 5.1.1 Alanines. 5.1.2 Valines, leucines and isoleucines. 5.1.3 Prolines. 5.2 Aromatic amino acids: phenylalanine, tyrosine, histidine and tryptophane. 5.3 Functional fluorinated amino acids. 5.3.1 Serines and threonines. 5.3.2 Aspartic acids and arginines. 5.3.3 Glutamic acids and glutamines. 5.3.4 Lysine, ornithine, arginine. 5.3.5 Cysteines and methionines. 5.4 ?-Fluoroalkyl amino acids. 5.4.1 Mono- and difluoromethyl amino acids. 5.4.2 ?-Trifluoromethyl amino acids. 5.5 Incorporation offluorinated amino acids in peptide and proteins. 5.5.1 Polypeptides. 5.5.2 Proteins. References. 6. Saccharidic Fluorinated Derivatives. 6.1 Glycosyl fluorides. 6.2 Mono- and difluorinated analogues of sugars. 6.2.1 Fluorinated furanoses and nucleosides. 6.2.2 Fluorinated pyranoses. 6.3 Fluoromethyl derivatives of sugars. 6.3.1 Difluorovinyl compounds. 6.3.2 Difluoromethylene-C-glycosides. 6.3.3 C-Difluoromethyl glycosides. 6.3.4 Trifluoromethylated sugars. 6.4 Perfluoroalkylated sugars. 6.4.1 Preparation of C-perfluoroalkyl sugars. 6.4.2 O- and S-fluoroalkyl glycosides. 6.4.3 Applications of amphiphilic fluoroalkylsugars. References. 7. Inhibition of enzymes by fluorinated compounds. 7.1 Substrate analogues. 7.1.1 Fluorine replaces an hydrogen involved in the catalytic cycle. 7.1.2 Fluorine replaces an hydroxyl. 7.1.3 Fluorinated analogues of substrates in which fluorine is not directly involved in the inhibition. 7.2 Destabilisation of reaction intermediates (or of transition states) of enzymatic processes by fluorinated groups. 7.2.1 Prenyl transfer. 7.2.2 Inhibition of glycosidases and glycosyltransferases. 7.2.3 Inhibition of the UDP-GlcNAC enolpyruvyl transferase (MurZ). 7.2.4 Enol pyruvate shikimate phosphate synthase (EPSPS). 7.3 Inhibitors that are analogues of the transition state: di- and trifluoromethyl ketones. 7.3.1 Serine enzymes. 7.3.2 Inhibition of aspartyl protease. 7.3.3 Inhibition of metalloproteases. 7.3.4 Cysteine protease and thiol enzymes. 7.4 Mechanism-based inhibitors. 7.4.1 inhibition of pyridoxal phosphate enzymes. 7.4.2 Thymidilate synthase. 7.4.3 Inhibition of monoamine oxidases.7.4.4 D-Ala-D-Ala dipeptidase (VanX). 7.4.5 Inhibition of the ribonucleotide diphosphate reductase. 7.4.6 Inhibition of S-adenosylhomocystein hydrolase (SAH hydrolase). 7.4.7 Inhibition of the cytidine-5?-diphosphate-D-glucose 4,6-dehydratase (CDP D-glucose 4,6-dehydratase). 7.4.8 Other irreversible inhibitors. 7.5 Fluorinated inhibitors involving a still unknown mechanism. 7.5.1 Inhibition of the steroid C17(20)lyase. 7.5.2 Phosphatidylinositol phospholipase C (PI-PLC). 7.5.3 Inhibition of the protein of transfer of cholesteryl esters (CEPT). 7.5.4 ?-Fluoropolyamines as inhibitors of the biosynthesis of polyamines.. 7.5.5 Inhibition of the biosynthesis of the cholesterol. References. 8. Fluorinated drugs. 8.1 Antitumoral and antiviral fluorinated drugs . 8.1.1 Fluoronucleosides . 8.1.2 Other antitumor and antiviral drugs . 8.2 Anti-infectious drugs. 8.2.1 Fluorinated antibiotic drugs . 8.2.2 Antifungal drugs. 8.2.3 Fluorinated drugs for parasitic diseases . 8.3 Drugs for CNS disorders. 8.3.1 Neuroleptics. 8.3.2 Drugs for depressive disorders. 8.3.3 Anxyolitics and sedatives. 8.3.4 Other drugs for CNS disorders . 8.4 Drugs of inflammatory and immunitary disorders. 8.4.1 Fluorocorticosteroids . 8.4.2 H1 Antagonist antiallergics.8.4.3 Drugs for asthma and respiratory disorders. 8.4.4 Analgesic and anti-arthritic drugs.. 8.5 Drugs for cardiovascular disorder treatments. 8.5.1 Cholesterol lowering drugs. 8.5.2 Drugs for hypertension treatment. 8.5.3 Drugs for arrhythmias . 8.5.4 Anti-thrombosis and anticoagulant fluorinated agents. 8.6 Drugs for treatments of gastrointestinal disorders. 8.6.1 Prevention and treatment of ulcer. 8.6.2 Antiemetic agents. 8.6.3 Drugs for bowels disorders treatment. 8.7 Drugs for endocrinous and metabolic disorders. 8.7.1 Drugs acting onsteroid hormon receptors. 8.7.2 Drugs for treatment of prostatic benign hypertrophy (BHP). 8.7.3 Drugs for other urologic disorders. 8.7.4 Drugs for calcemia disorders. 8.7.5 Drugs for diabetes treatments. 8.7.6 Drugs for hepatic disorders. 8.8 Miscellaneous. 8.9 Highly fluorinated compounds with clinical uses. 8.9.1 General anaesthetics. 8.9.2 Therapeutical uses of per?uorocarbons. 8.10 Fluorinated functions and motifs in medicinal chemistry. 8.10.1 Fluorinated ethers. 8.10.2 Fluorinated alcohols . 8.10.3 Fluorinated ketones. 8.10.4 Fluoroalkyl groups. Annex: INN and trademark names. References.
- ISBN: 978-0-470-27830-7
- Editorial: John Wiley & Sons
- Encuadernacion: Cartoné
- Páginas: 384
- Fecha Publicación: 30/05/2008
- Nº Volúmenes: 1
- Idioma: Inglés