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FCHG361 Organiese Medisinale Chemie

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FCHG361 Organiese Medisinale Chemie

    ORGANIC MEDICINAL CHEMISTRY

    FCHG361 Pharmaceutical Chemistry JC Breytenbach

    TG Dekker

    G Terre’Blanche

Copyright ? 2005

    North-West University, Potchefstroom

    Copyright reserved. No part of this book may be reproduced in any way without the prior written permission of the authors.

    1. TABLE OF CONTENTS

    1. General anaesthetics ........................................................................................................... 1 1.1 The hydrocarbons ....................................................................................................... 2 1.2 Halogenated hydrocarbon compounds ........................................................................ 2 1.3 Ethers ......................................................................................................................... 3 1.4 Alcohols ...................................................................................................................... 3 1.5 Aldehydes and ketones ............................................................................................... 4

    1.5.1 Chloral hydrate .............................................................................................. 4

    1.5.2 Paraldehyde .................................................................................................. 4 1.6 Bibliography ................................................................................................................ 4

    2. The barbiturates ................................................................................................................... 5 2.1 Introduction ................................................................................................................. 5 2.2 Structure ..................................................................................................................... 5 2.3 Chirality and stereochemistry ...................................................................................... 6 2.4 Synthesis .................................................................................................................... 7 2.5 Stability ....................................................................................................................... 8 2.6 Acidic character, solubility and excretion ..................................................................... 8 2.7 Mechanism of action ................................................................................................. 11 2.8 Metabolism ............................................................................................................... 12 2.9 Structure-activity relationships .................................................................................. 13

    2.9.1 Active barbiturates ....................................................................................... 13

    2.9.2 Inactive barbiturates .................................................................................... 13 2.10 Analysis .................................................................................................................... 14

    2.10.1 Identification reactions (qualitative analysis) ................................................ 14

    2.10.2 Quantitative analysis ................................................................................... 15 2.11 Bibliography .............................................................................................................. 16

    3. The benzodiazepines ......................................................................................................... 17 3.1 Introduction ............................................................................................................... 17 3.2 Structure ................................................................................................................... 19 3.3 Synthesis .................................................................................................................. 20 3.4 Stability ..................................................................................................................... 21

    3.4.1 Hydrolysis.................................................................................................... 21

    3.4.2 Isomerisation ............................................................................................... 21

    3.4.3 Dehydration ................................................................................................. 22

    3.4.4 Chlordiazepoxide......................................................................................... 23 3.5 Mechanism of action ................................................................................................. 24 3.6 Structure-activity relationships .................................................................................. 24 3.7 Bibliography .............................................................................................................. 25

    4. The phenothiazines ........................................................................................................... 26 4.1 Introduction ............................................................................................................... 26 4.2 Structure ................................................................................................................... 26 4.3 Synthesis .................................................................................................................. 27 4.4 Stability ..................................................................................................................... 28

    4.4.1 Oxidation of the phenothiazine nucleus ....................................................... 28

    4.4.2 Oxidation of the side chain .......................................................................... 30

    4.4.3 Polymerisation ............................................................................................. 30 4.5 Structure-activity relationships .................................................................................. 30

    4.5.1 Substitution on the phenothiazine nucleus................................................... 30

    4.5.2 Variation of the side chain (on N-10) ........................................................... 30 4.6 Analysis .................................................................................................................... 31 4.7 Bibliography .............................................................................................................. 31

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    5. The salicylic acid derivatives ............................................................................................ 32 5.1 Introduction ............................................................................................................... 32 5.2 Synthesis of derivatives of salicylic acid .................................................................... 33 5.3 Stability ..................................................................................................................... 35

    5.3.1 Hydrolysis.................................................................................................... 35

    5.3.2 Oxidation ..................................................................................................... 35 5.4 The acidity of the hydroxybenzoic acids .................................................................... 36 5.5 Analysis .................................................................................................................... 38

    5.5.1 Qualitative analysis (identification) .............................................................. 38

    5.5.2 Quantitative analysis ................................................................................... 38 5.6 Bibliography .............................................................................................................. 40

    6. The aniline derivatives ...................................................................................................... 41 6.1 Introduction ............................................................................................................... 41 6.2 Synthesis .................................................................................................................. 42

    6.2.1 Paracetamol ................................................................................................ 42 6.3 Analysis .................................................................................................................... 43

    6.3.1 Qualitative analysis (identification) .............................................................. 43

    6.3.2 Quantitative analysis ................................................................................... 44 6.4 Bibliography .............................................................................................................. 44

    7. The pyrazolone derivatives ............................................................................................... 45 7.1 Introduction ............................................................................................................... 45 7.2 Synthesis .................................................................................................................. 46

    7.2.1 Phenazone .................................................................................................. 46

    7.2.2 Phenylbutazone .......................................................................................... 46 7.4 Stability ..................................................................................................................... 47 7.5 Analysis .................................................................................................................... 49

    7.5.1 Qualitative analysis (identification) .............................................................. 49

    7.5.2 Quantitative analysis (determination)........................................................... 50 7.6 Bibliography .................................................................................................................. 51

    8. Narcotic analgesics ........................................................................................................... 52 8.1 The opium alkaloids (opiates) ................................................................................... 52

    8.1.1 Phenanthrene derivatives ............................................................................ 52

    8.1.2 Benzylisoquinoline derivatives ..................................................................... 58 8.2 Opioids ..................................................................................................................... 60

    8.2.1 The 4-phenylpiperidines .............................................................................. 60

     8.2.2 The phenylpropylamines.............................................................................. 61

    8.2.3 The benzomorphane derivatives ................................................................. 63 8.3 Analysis of opioids .................................................................................................... 63 8.4 Bibliography .............................................................................................................. 63

    9 The oxicams ....................................................................................................................... 64 9.1 Introduction ............................................................................................................... 64 9.2 Structure ................................................................................................................... 64 9.3 Chirality and stereochemistry .................................................................................... 65 9.4 Synthesis .................................................................................................................. 65

    9.4.1 Piroxicam .................................................................................................... 65

    9.4.2 Tenoxicam................................................................................................... 66 9.5 Acidic character and solubility ................................................................................... 66 9.6 Mechanism of action ................................................................................................. 67 9.7 Metabolism ............................................................................................................... 68 9.8 Structure-Activity Relationships ................................................................................. 69 9.9 Analysis .................................................................................................................... 69 9.10 Bibliography .............................................................................................................. 70

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    10. The profens ........................................................................................................................ 71 10.1 Introduction ............................................................................................................... 71 10.2 Structure ................................................................................................................... 71 10.3 Chirality and stereochemistry .................................................................................... 72 10.4 Synthesis .................................................................................................................. 72 10.5 Stability ..................................................................................................................... 73 10.6 Acidic character and solubility ................................................................................... 74 10.7 Mechanism of action ................................................................................................. 74 10.8 Metabolism ............................................................................................................... 74 10.9 Structure-activity relationships .................................................................................. 76 10.10 Analysis .................................................................................................................... 77

    10.10.1 Identification ................................................................................................ 77

    10.10.2 Quantitative analysis ................................................................................... 77 10.11 Bibliography .............................................................................................................. 77

    11. The ace inhibitors .............................................................................................................. 78 11.1 Introduction ............................................................................................................... 78 11.2 Structure ................................................................................................................... 78 11.3 Chirality and stereochemistry .................................................................................... 80 11.4 Synthesis .................................................................................................................. 80

    11.4.1 Captopril ...................................................................................................... 80

    11.4.2 Enalapril ...................................................................................................... 81 11.5 Stability ..................................................................................................................... 81 11.6 Mechanism of action ................................................................................................. 82 11.7 Metabolism ............................................................................................................... 83 11.8 Structure-activity relationships .................................................................................. 83 11.9 Analysis .................................................................................................................... 84

    11.9.1 Identification reactions ................................................................................. 84

    11.9.2 Quantitative analysis ................................................................................... 84 11.10 Bibliography .............................................................................................................. 85

    12. The dihydropyridines ........................................................................................................ 86 12.1 Introduction ............................................................................................................... 86 12.2 Structure ................................................................................................................... 86 12.3 Chirality and stereochemistry .................................................................................... 87 12.4 Synthesis .................................................................................................................. 87 12.5 Stability ..................................................................................................................... 89 12.6 Mechanism of action ................................................................................................. 89 12.7 Metabolism ............................................................................................................... 90 12.8 Structure-activity relationships .................................................................................. 91 12.9 Analysis .................................................................................................................... 91

    12.9.1 Identification ................................................................................................ 91

    12.9.2 Quantitative analysis ................................................................................... 91 12.10 Bibliography .............................................................................................................. 92

    13. The statins .......................................................................................................................... 93 13.1 Introduction ............................................................................................................... 93 13.2 Structure ................................................................................................................... 95 13.3 Chirality and stereochemistry .................................................................................... 97 13.4 Synthesis .................................................................................................................. 97

    13.4.1 Lovastatin .................................................................................................... 97

    13.4.2 Synthesis of simvastatin .............................................................................. 98 13.5 Stability ................................................................................................................... 100 13.6 Acidic character, solubility and excretion ................................................................. 100 13.7 Mechanism of action ............................................................................................... 100 13.8 Metabolism ............................................................................................................. 101

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    13.9 Structure-activity relationships ................................................................................ 102 13.10 Analysis .................................................................................................................. 102

    13.10.1 Qualitative analysis ................................................................................... 102

    13.10.2 Quantitative analysis ................................................................................. 102 13.11 Bibliography ............................................................................................................ 103

    14. Penicillins and cephalosporins (-lactam antibiotics) ................................................. 107 14.1 Structure and stereochemistry ................................................................................ 107

    14.1.1 Stereochemistry ........................................................................................ 107 14.2 The penicillins ......................................................................................................... 109

    14.2.1 Introduction .............................................................................................. 109

    14.2.2 Solubility .................................................................................................... 111

    14.2.3 Stability ..................................................................................................... 112

    14.2.4 Chemical incompatibility ............................................................................ 119

    14.2.5 Structure-activity relationships .................................................................. 122

    14.2.6 Manufacturing .......................................................................................... 124

    14.2.7 Methods of analysis ................................................................................... 127 14.3 The cephalosporins ................................................................................................. 129

    14.3.1 Stability ..................................................................................................... 130

    15. The tetracyclines.............................................................................................................. 132 15.1 Introduction ............................................................................................................. 132 15.2 Structure and stereochemistry ................................................................................ 132 15.3 Acid-base character and solubility ........................................................................... 133 15.4 Chelation ................................................................................................................ 134 15.5 Stability ................................................................................................................... 135

    15.5.1 Decomposition in acid medium .................................................................. 135

    15.5.2 Epimerisation (on C-4) (in dilute acid medium) .......................................... 136

    15.5.3 Dehydration (in concentrated acid) ............................................................ 137

    15.5.4 Decomposition in alkaline medium ............................................................ 138

    15.5.5 Photochemical decomposition ................................................................... 138 15.6 Mechanism of action ............................................................................................... 139 15.7 Bibliography ............................................................................................................ 139

    16 Chloramphenicol.............................................................................................................. 140 16.1 Introduction ............................................................................................................. 140 16.2 Structure and stereochemistry ................................................................................ 140 16.3 Synthesis ................................................................................................................ 140

    16.3.1 Chloramphenicol ....................................................................................... 140

    16.3.2 Derivatives ................................................................................................ 141 16.4 Stability ................................................................................................................... 142 16.5 Solubility ................................................................................................................. 142 16.6 Mechanism of action ............................................................................................... 143 16.7 Structure-activity relationships ................................................................................ 143 16.8 Analysis .................................................................................................................. 143

    16.8.1 Treatment with alkali ................................................................................. 143

    16.8.2 Reduction with zinc (identification and determination) ............................... 145 16.9 Bibliography ............................................................................................................ 145

    17 The sulphonamides ......................................................................................................... 146 17.1 Introduction ............................................................................................................. 146 17.2 Structure ................................................................................................................. 147 17.3 Synthesis ................................................................................................................ 148 17.4 Stability ................................................................................................................... 149 17.5 Acid-base character ................................................................................................ 149

    17.5.1 Acidic character ......................................................................................... 149

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    17.5.2 Basic character ......................................................................................... 151 17.6 Solubility ................................................................................................................. 151

    17.6.1 Organic solvents........................................................................................ 151

    17.6.2 Water-solubility .......................................................................................... 152

    17.6.3 Solubility and excretion (crystaluria) .......................................................... 152 17.7 Mechanism of action ............................................................................................... 154 17.8 Structure-activity relationships ............................................................................... 154 17.9 Analysis .................................................................................................................. 155

    17.9.1 Identification .............................................................................................. 155

    17.9.2 Determination ............................................................................................ 155 17.10 Bibliography ............................................................................................................ 155

    18. The quinolone antibiotics ................................................................................................ 156 18.1 Introduction ............................................................................................................. 156 18.2 Structure ................................................................................................................. 156 18.3 Chirality and stereochemistry .................................................................................. 158 18.4 Synthesis ................................................................................................................ 158 18.5 Stability ................................................................................................................... 159 18.6 Acid-base character and water-solubility ................................................................. 160 18.7 Mechanism of action ............................................................................................... 161 18.8 Metabolism ............................................................................................................. 162 18.9 Structure-activity relationships ................................................................................ 163 18.10 Analysis .................................................................................................................. 164

    18.10.1 Identification .............................................................................................. 164

    18.10.2 Quantitative analysis ................................................................................. 164 18.11 Bibliography ............................................................................................................ 164

    19. The steroids ..................................................................................................................... 165 19.1 Introduction ............................................................................................................. 165 19.2 Structure, stereochemistry and nomenclature ......................................................... 167 19.3 Synthesis ................................................................................................................ 172

    19.3.1 Biosynthesis .............................................................................................. 172

    19.3.2 Production and synthesis .......................................................................... 175 19.4 Stability ................................................................................................................... 184

    19.4.1 Oxidation ................................................................................................... 184

    19.4.2 Photochemical composition ....................................................................... 188 19.5 Solibility .................................................................................................................. 189 19.6 Physiological action and structure ........................................................................... 190

    19.6.1 Hormones of the adrenal cortex (adrenocorticoids) ................................... 190

    19.6.2 The androgens (male sex hormones) ........................................................ 195

    19.6.3 The oestrogens and progestines (female sex hormones) .......................... 199 19.7 Analysis .................................................................................................................. 202 19.8 Bibliography ............................................................................................................ 202

    20. The vitamins ..................................................................................................................... 203 20.1 Introduction ............................................................................................................. 203 20.2 The Lipid-Soluble vitamins ...................................................................................... 203

    20.2.1 Vitamin A ................................................................................................... 203

    20.2.2 Vitamin D .................................................................................................. 208

    20.2.3 Vitamin E (tocopheroles) (antisterility vitamin) ........................................... 209

    20.2.4 Vitamin K (anti-blood clotting vitamin) and anticoagulants ......................... 212 20.3 Water-soluble vitamins ............................................................................................ 216

    20.3.1 Vitamin C (L-ascorbic acid) ....................................................................... 216

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Annexure 1: Functional groups ............................................................................................ 219

    Annexure 2: Cyclic and heterocyclic com pounds .............................................................. 221

    Annexure 3: English Afrikaans glossary ........................................................................... 224

INDEX

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    A. CENTRAL NERVOUS SYSTEM SUPPRESSANTS

Introduction

    Central nervous system suppressants are drugs whose primary pharmacological action is suppression of the central nervous system. Amongst these are drugs such as general anaesthetics, sedatives, calmatives, hypnotics, narcotics and anticonvulsants. Most of these classes overlap with regard to their pharmacological activity and their action often is dependent on the dose of route of administration, eg a sedative may cause anaesthesia if administered intravenously or in a large enough dose.

    Chemically these drugs represent an equally diverse group of compounds, ranging from alkanes, alkenes, alkynes, alcohols, amines and amides to aromatic and heterocyclic compounds as well as their halogenated derivatives.

1. GENERAL ANAESTHETICS

Introduction

    General anaesthesia is the controlled, reversible suppression of the functional activity of the central nervous system, causing a loss of sensation and consciousness. These effects were first applied in surgery in 1841 by Crawford W Long (1815-1878) (Georgia, USA) when he used ether for removing a cyst. However, it was the use of nitrogen monoxide (NO, laughing gas) by Horace 2

    Wells (Connecticut, 1844) when extracting a tooth, that made his assistant, William TG Morton (1819-1868), a medical student, aware of the possibility of using anaesthesia during surgery. Morton learnt form his professor in chemistry, Charles Jackson, of the anaesthetic properties of diethyl ether, and he convinced his professor in surgery, JC Warren, to use it during surgery. During the first demonstration of this technique in 1846 in the theatre of the Massachusetts General Hospital, the gallery was packed by a sceptic audience who had heard that a second year medical student has developed a method for an operation without pain. Everyone, including the strong men who had to pin down the patient, was ready, but there was no sign of Morton. After 15 minutes Prof Warren took the scalpel and just when he had announced that he would perform the operation in the conventional manner, Morton showed up with the excuse that he had problems with the device for administering the ether. Morton prepared the device and within minutes the patient was anaesthetised. Warren performed the surgery and the patient indeed felt no pain and was alive and well. The success of this event has lead to the general use of ether and the advancement of surgery. In 1847 the Scottish obstetrician, James Simpson, in Edinburgh introduced chloroform as anaesthetising agent. These two compounds in the course of time were replaced by more effective and safer compounds and are no longer in use (Beattie, 2001; Jacoby & Nieforth, 1995, Saied, 2004).

    General anaesthesia proceeds through various stages, depending on the degree of suppression of the central nervous system:

    Stage I (analgesia): the patient feels no pain but is fully conscious.

    Stage II (delirium): loss of consciousness, but depression of the motor centres of the brain stem and cerebellum causes delirium.

    Stage III (surgical anaesthesia): this stage is divided into four levels, depending on the depth of anaesthesia. Amongst others, complete skeletal muscle relaxation is obtained. Stage IV (medullary paralysis): paralysis of the medulla oblongata causes respiratory and cardiac arrest and consequently death (Jacoby & Nieforth, 1995).

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