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Pharmaceutical chemistry 1. Naming chemical substances Popular names vs chemical names Common names and systematic names Popular name „Please pass the α-D-glucopyranosyl-(1,2)- β-Dfructofuranoside!” „Please pass sucrose!” 1 Names... Formula sodium tetraborate decahydrate Na2 B4O7·10 H2O calomel mercury(I) chloride Hg2Cl2 milk of magnesia magnesium hydroxide Mg(OH)2 muriatic acid hydrochloric acid HCl (aq) oil of vitriol, battery acid sulfuric acid H2SO4 green vitriol iron(II)sulfate FeSO4 saltpeter sodium nitrate NaNO3 slaked lime calcium hydroxide Ca(OH)2 2 Nonproprietary names ¾ Chemical name - unambiguous description of the chemical structure: 2-hydroxybenzoic acid ¾ Trivial name, nonsystematic name - a common or popular name for a substance, does not describe its exact chemical composition: salicylic acid ¾ Proprietary name, trade name, brand name - individual names used by manufacturers: Dr. Scholl's Corn Removers, Keragit, Saligel... ¾ Nonproprietary name - common, established name of a drug irrespective of its manufacturer. Choosen by official agencies Chemical name borax 3 Names ¾ U.S. Adopted Names (USAN), British Approved Name (BAN) ¾ Worldwide scale: WHO selects, approves and disseminates the generic names of drugs. INN: Paracetamol British Approved Name (BAN): Paracetamol United States Adopted Name (USAN): Acetaminophen Other generic names: N-acetyl-p-aminophenol, APAP, pAcetamidophenol, Acetamol, ... Proprietary names: Tylenol, Panadol, Panamax, Perdolan, Calpol, Doliprane, Tachipirina, Ben-u-ron, Atasol, Rubophen, ... ¾ International Nonproprietary Names (INN) IUPAC name: N-(4-hydroxyphenyl)-acetamide 4 5 6 1 Names used in Pharmacopoeias Traditional Latin nomenclature, genitive case Traditional Latin nomenclature ¾ -ide → -atum Potassium hydroxide – Kalium hydroxydatum Sodium bromide – Natrium bromatum Hydrogen chloride – Acidum chloratum Ethyl chloride – Aethylium chloratum ¾ -ate → -icum Sodium nitrate – Natrium nitricum Methyl benzoate – Methylium benzoicum ¾ -ite → -osum Sodium nitrite – Natrium nitrosum ¾ British Pharmacopoeia, United States Pharmacopoeia, Indian Pharmacopoeia, Hungarian Pharmacopoeia, European Pharmacopoeia, etc: – national names – INN names – Latin names 7 8 Nonproprietary names guiding principles Names ¾ One-word names are preferred; ¾ Salts should be named without modifying the acid name (oxacillin sodium, ibufenac sodium, etc.) ¾ ”ph” → ”f”, ”th” → ”t”, ”ae”, ”oe” → ”e”, ”y” → ”i”, etc. ¾ Use of common stems: ¾ Inhouse code names of manufacturers – used in scientific literature for drugs in experimental phase: SKF12345 ¾ Shorthand code names – unofficial abbreviated names used in scientific publications mainly: CEX – cefalexin, 5FU – 5-fluorouracil etc. – – – – – – – – -apine: psychoactive tricyclic compounds; -azepam: substances of the diazepam group; -cillin: antibiotics of the penicillin group; -conazole: antifungals of the azole group; -mab: drugs based on monoclonal antibodies; -trexate: folic acid antagonists; sulfa- : sulfonamides; etc... etc... 10 ¾ -id → -um Sodium iodide → Natrii iodidum Ethyl chloride → Aethylii chloridum Doxorubicin hydrochloride → Doxorubicini hydrochloridum ¾ -ate → -as Calcium carbonate → Calcii carbonas Methyl benzoate → Methylii benzoas Testosteron propionate → Testosteroni propionas ¾ -it → -is Sodium nitrite → Natrii nitris ¾ Lower valence form: → os Iron(II)gluconate → Ferrosi gluconas Iron(III)chloride hexahydrate → Ferri chloridum hexahydricum 9 What is a drug? 11 ¾ WHO definiton: „Any substance used in pharmaceutical product that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient.” ¾ Pharmaceutical product: „a dosage form containing on or more drugs along with other substances included during the manufacturing process.” 12 2 Distribution of drugs regarding their sources (WHO 1995) Central nervous system depressants Very volatile and flammable liquid. Obsolate, not used today. General anaesthetics Preparation: Inhalation general anaesthetics Vaccines 4% Microbial 6% Sera 2% Animal 9% Ether Diethyl ether Aether ad narcosim Aether anaestheticus Mineral 9% C2H5OSO2OH + H2O Partial synthesis 10% 13 CH3CH2 CH3CH2 Introduced into surgery: William Morton, 1846 Chloroform C2H5 O C2H5 + H2SO4 Decomposition via peroxyd formation: (Stabilized with hydroquinone) C2H5–O–C2H5 Synthesis: Valerius Cordus, 1543 Chloroform Chloroformium Trichloromethane H2SO4 C2H5OSO2OH + C2H5OH Synthesis 49% Plant 11% o 130-140 C C2H5OH + O hν O2 CH3CH O OH - H2O O - H2O2 CH3COOC2H5 CH3CH2 O - C2H5OH 49 * H C O O CH3 n * 50 Chloroform Cyclopropane, ethylene – explosive gases, not used. Preparation: CH3CH2–OH CHCl3 Cl2 2 CCl3–CHO Preparation: Liebig, Souberian and Guthrie, 1831 Introduced as anaesthetic: J. Y. Simpson, 1847 CH3CHO - 2 HCl Ca(OH)2 3 Cl2 - 3 HCl H 2C CCl3–CHO CH2 Chloral CHCl3 1/2 O2 hydrolysis HCl + O hν Cl O 51 Cl Cl H2O + 2 C2H5OH Preparation: 2 HCl + CO2 Cl O NH4NO3 o 190 C N2O + 2 H2O ammonium nitrate OC2H5 OC2H5 CH2 Nitrous oxide Dinitrogen oxide Dinitrogenium oxydatum Dinitrogenii oxydum 2 CHCl3 + (HCOO)2Ca Decomposition to phosgene and HCl, stabilization with ethanol: Obsolate, not used, toxic (liver) H2 C H 2C 52 53 3 Nitrous oxide Halogenated compounds ¾ „Laughing gas” (pleasant and erotic hallucinations in the initial phase) ¾ Preparation: Priestley, 1776 ¾ Applied in dentistry: Horace Wells, 1844 ¾ Colorless and tasteless gas. Weak anesthetic, but good analgesic. ¾ Used as 75% N2O + 25% O2 in small surgical operations. Nearly ideal drug, but not potent enough (hypoxia). Usually used in combination with another more potent drug. ¾ Very rapid elimination, practically no toxic effects. 54 Methoxyflurane Methoxyfluranum Penthrane® Halothane Halothanum 2-Bromo-2-chloro1,1,1-trifluoroethane Enflurane Enfluranum Enthrane® ¾ Used since 1952 ¾ Highly volatile heavy liquid. ¾ About 80% eliminates in unchaged form, the rest is metabolised metabolism F2CH–O–CF2–CHFCl 2-Chloro-1,1,2-trifluoroethyldifluoromethyl ether Isoflurane Isofluranum Forane® CF3COOH F3C–CHBrCl CF3CONHCH2CH2OH Cl2CH–CF2–OCH3 2,2-Dichloro-1,1-difluoroethylmethyl-ether F3C–CHBrCl 55 1-Chloro-2,2,2-trifluoroethyldifluormethyl ether F2CH–O–CHCl–CF3 56 Mode of action Desflurane Desfluranum 1,2,2,2-Tetrafluoroethyldifluoromethyl ether F2CH–O–CHF–CF3 Sevoflurane Sevofluranum Fluoromethyl-1,1,1,3,3,3hexafluoro-2-propyl ether FCH2–O–CH(CF3)2 57 ¾ Difficult to explain with one theory. ¾ Structurally very diverse and highly lipophilic compounds. ¾ Lipid theory: adsorption into the hydrophilic region the phospholid bilayer → the membrane expands by fluidizing → disordering → prevention of the ionic conductance (Overton-Meyer, ~1900, Mullins, 1954.) 58 Modell of posphatidyl choline bilayer 59 4 Action potential Surface anesthesia Ethyl chloride Aethylium chloratum Aethylii chloridum Inhalation general anaesthetics (narcotics) ¾ Rapid loss of consciousness ¾ Rapid elimination → Insufficient anaesthesia and muscular relaxation ¾ Used in brief minor surgical procedures or in combination CH3–CH2–Cl Barbital type anaesthetics (narcotics) Boiling point: 12 °C → chilling effect when sprayed on skin. 60 61 CH3 Barbiturates ¾ Ultrashort acting barbiturates, thiobarbiturates ¾ High logP, rapid crossing of BBB and rapid redistribution into tissues. ¾ Unconsciousness within seconds, lasts ~ 30 mins. Thiopental sodium Thiopentalum natricum Pentothal Trapanal® N * O Non-barbital type intravenous narcotics O * H3C H3C N H SNa Ketamine hydrochloride Ketamini hydrochloridum Ketalar® Thiamylal sodium Surital sodium® and enantiomer ¾ Human and veterinary medicine developed by ParkeDavis (Pfizer) in 1962. Hexobarbital Hexobarbitalum Novopan® 63 62 64 65 5 Ketamine Ketamine NMDA receptor Synthesis: ¾ I.v. or i.m., useful for anaesthesia, sedating uncontrollable patients, minor surgical procedures ¾ Dissociative properties at higher dose → hallucinations (abuse!) ¾ Complex action: NMDA receptor antagonist, at higher concentration binds to the opioid receptor as well. 66 Etomidate, Propofol Etomidate Etomidatum (R)-ethyl 1-(1phenylethyl)-1Himidazole-5-carboxylate Propofol Propofolum Diprivan® 2,6-Diisopropylphenol Etomidate, Propofol N (R) N CH3 H3C OH CH3 68 Sedative and hypnotic drugs ¾ Etomidate Rapid, short acting intravenous anaesthetic agent used for the induction of general anaesthesia and for sedation for short procedures. Side effects: imidazole ring suppression of steroid synthesis (?) ¾ Propofol Water-immiscible oil, applied as 1% aq. emulsion. Rapid and safe agents for induction and maintenance of anaesthesia. H3C C2H5OOC 67 ¾ Nonselective, general depressants of CNS to reduce restlessness and emotional tension. ¾ No sharp distinction of the two groups. ¾ Sedation in: emotional strain, chronic tension, potrentiation of analgetics, control of convulsions; Hypnotics: sleep disorders, insomnia. ¾ Very wide group in chemical structure. CH3 ¾ Both compounds are positive allosteric modulators of the GABA-A receptor, possibly by slowing the channel closing time. 69 70 soporific = sleep inducing agent 71 6 Stages of sleep Ethanol Ethanolum Ethylalcohol Alcohol ¾ Ideal natural sleeping cycle (~90-120 mins) – NREM phase (~75%) Metabolism in the liver (~6.5 g/hour): CH3–CH2–OH CH3–CH2–OH • Drowsy sleep, N1 ⇓ Preparation: • Profound sleep, N4 alcoholdehydrogenase CH3–CHO aldehydedehydrogenase CH3COOH acetaldehyde o H2C CH2 + H2O 1) Hydration: – REM phase (~25%) Ethylene ¾ Disturbances: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, etc. ¾ Ideal sedative-hypnotic drug → natural sleep. ¾ Adverse reactions: drowsiness, letargy, hangover etc. ¾ Prolonged use → tolerance, physical dependance 300 C pressure, H3PO4 HS–CoA CH3–CH2–OH 2) Reppe-synthesis: HC CH + H2O Hg 2+ H2 / Ni CH3CHO H2C CH–OH 100-130 oC citrate cycle CH3–CH2–OH O CH3–C–S–CoA 3) Classical fermentation: 72 Disulfiram Disulfiramum Antabus, Antaethyl® N,N,N’,N’-Tetraethylthiuramdisulfide C6H12O6 Saccharomyces cerevisiae 2 C2H5OH + 2 CO2 73 74 Chloral hydrate Chloralhydratum Hemorid® Synthesis: CH3 HN + CS2 S H3C KOH N H3C CH3 SK I2 oxydation ¾ Used to support the treatment of chronic alcoholism. ¾ Inhibits acetaldehyde dehydrogenase enzym → 5-10 x concentration of acetaldehyde in blood → severe hangover. ¾ Can be used only under controll. H3C ¾ Used since 1869. Strong and rapid hypnotic ¾ Probably only a prodrug, metabolised quickly to trichloroethanol. ¾ Weak local anaesthetic (ointments against hemorrhoid). ¾ Today obsolete. S N H3C CH3 S S N S CH3 Disulfiram 75 76 77 7 Carbamates Paraldehyde Paraldehydum Chlorobutanol Chlorobutanolum 1,1-Dimethyl-2,2,2trichloroethanolhemihydrate O Ethyl carbamate Urethanum H5C2 O NH2 ¾ ¾ ¾ ¾ ¾ Slight sedato-hypnotic and antiemetic. ¾ Often component of tablets against travel illness. Known since 1883 Strong characteristic odour, unpleasant taste Institutional treating of delirium tremens Today obsolate 78 Sedatohypnotic acylureas ¾ Carbamoylation of alcohols usually increases depressant activity. Seldom used. 79 80 Sedato-hypnotic acylureas Synthesis: R N H Carbromal Carbromalum Urea O O 2-bromo-N-carbamoyl2-ethylbutanamide NH2 O O 2 C2H5Br H3C OC2H5 OC2H5 NaOC2H5 H3C OC2H5 H2C O Bromisoval Bromisovalum NaOH H3C OH H3C OH O O Diethyl malonate 2-bromo-N-carbamoyl3-methylbutanamide + H O H3C Br H3C Sedatives with medium potency. Often used as components 81 O OC2H5 82 O O N H – CO2 NH2 H2N NH2 – HBr H3C Br H3C O Br Br2 / P H3C O H3C OH 83 8 Structure-activity relationships Barbiturates 5 3 1 Barbituric acid Adolf von Bayer, 1863 First derivative used as drug: veronal, 1903 Emil Fischer (diethyl barb. acid) Once a very popular family of sedatives and hypnotics, not very much used today, replaced by benzodiazepines. Still used in tranquillizer and analgesic combinations. Barbiturates have narrow therapeutic range. Classification: long duration of action (6 hours or more) intermediate duration (3-6 hours) short and ultrashort duration ¾ Both C-5 hydrogens must be replaced ¾ Duration of action depends mainly on the C-5 substituents → the more lipophilic the more hypnotic; ¾ Replacement of N-1 or N-3 H with alkyl groups: quicker onset and shorter duration of action; ¾ Replacement of O by S on C-2 increases lipid solubility and onset of action → very fast uptake into CNS. ¾ Optical activity has no influence on the pharmacokinetical properties. Both enantiomers bind to the receptor, R : S = 1 : 1.7-3.5 84 Synthesis: Phenobarbital Phenobarbitalum Sevenal® 5-Ethyl-5-phenylbarbituric acid O 3NH 5 O 1 N H O Barbituric acid ¾ Long acting sedative and hypnotics ¾ Nowadays used mainly as antiepileptics 85 86 Metabolism Barbital Barbitalum 5,5-Diethylbarbituric acid - oxidation of the sidechain at C-5 - removal of the N-substituent (if any) - >C=S → >C=O - increasing logP increases rate of metabolism (c.f. rapid, ultrashort action narcotics) Amobarbital Amobarbitalum 5-Ethyl-5-(3-methylbutyl)-barbituric acid Allobarbital Allobarbitalum 5,5-Diallylbarbituric acid 87 88 89 9 Use of barbiturates Mode of action ¾ GABA receptor agonist or mimetic, enhances the inhibitory effect of neurotransmission. ¾ Frequent target for sedative drugs benzodiazepine tranquilizers, sedatives, anesthetics ¾ Increased Cl- influx → hyperpolarization, inhibiting the firing of new action potentials. Cl- Gluthetimide ¾ Extended use may lead to tolerance (10x dose) and dependence; ¾ Narrow therapeutic range; ¾ Once very popular every-day hypnotics – nowadays their use is very limited, have been replaced by benzodiazepines; ¾ Still used as – rapid action narcotics; – components in analgetics; – treatment of epilepsy, anticonvulsant Glutethimide Glutethimidum 2-Ethyl-2phenylglutarimide H3C O N H O ¾ In action and toxicity similar to barbiturates Cl90 Thalidomide (Contergan) 91 92 Structural relationships Miscellaneous sedative-hypnotics O Zopiclone Zopiclonum Imovane® , Lunesta® 4-Methyl-1-piperazincarboxylic acid-6-(5-chloro-2-pyridinyl)6,7-dihydro-7-oxo-5Hpyrrolo[3,4b]pyrazin-5-yl ester ¾ Potent teratogen in primates and humans, sever malfunctions, birth defects: abnormally short limbs. ¾ Today: allowed to use against multiple myeloma and in leprosy N Cl N N N O O N N CH3 93 94 ¾ ¾ ¾ ¾ ¾ In use since 1985 Short-acting hypnotic agent Similar to benzodiazepines Dependence and withdrawal problems. Has high affinity for the GABAA receptor 95 10 1,4-Benzodiazepines Benzodiazepines Zolpidem tartarate Zolpidemi tartaras Ambien ®, Stilnox® electron withdrawing group is essential Nitrazepam Nitrazepamum Eunoctin®, Hypnotex®, etc Rapidly acting (within 15 minutes) hypnotic with short half-life (2–3 hours). O CH3 H3C N Zaleplon Sonata® N N CN N Ultra short acting sedative hypnotic drug for the treatment of insomnia characterised by difficulty in falling asleep. Might cause anterograde amnesia. 96 Benzodiazepines N 97 98 1,4-Benzodiazepines Chlordiazepoxide Chlordiazepoxidum Librium®, Elenium® ¾ Drugs that help to reduce the symptoms of anxiety, psychic tension. H3C O2N O ¾ Treating of short term insomnia (difficulty falling asleep, frequent awakenings, early awakening) ¾ Prolonged action (~10 h), can impair driving skills. Anxiolytics (minor tranquillants, ataractics) Temazepam Temazepamum Signopam® Midazolam Midazolamum Dormicum® ¾ Synthetized by L. H. Sternbach (1956, Hoffmann-La Roche) serendipitously. ¾ One of the most important class of psychoactive drugs with varying hypnotic, sedative, anxiolytic, antidepressive, anticonvulsant, muscle relaxant and amnesic properties. ¾ Two main groups: hypnotic and anxiolytic benzodiazepines. ¾ Tolerance, dependance, abuse problems 7-nitro-5-phenyl-1,3-dihydro2H-1,4-benzodiazepin-2-one H N 7-Chloro-2-methylamino-5phenyl-3H[1,4]benzodiazepine-4-oxide N N-oxide N Cl N Benzodiazepines F ¾ The first anxiolytic (1960) – „This drug restores the patient’s mental equilibrium” ¾ Prepared accidentaly by L. H. Sternbach Non-benzodiazepines ¾ Rapid onset, short elimination half-life. Useful in the case of anxieties. 99 100 101 11 First synthesis Biochemical transformation Diazepam Diazepamum Valium®, Seduxen® Synthesis: 102 103 Medazepam, Clobazam 1,3,4-triazol ring Alprazolam Midazolam Triazolam Medazepam Medazepamum Lerisum®, Rudotel®, etc. H3C Clobazam Clobazamum Frisium® Both have anticonvulsant activity as well N R=H R=F R = Cl O CH3 CH3 N Tofisopam Tofisopamum Grandaxin® O 105 * H3CO N N 1,2-diazepin H3CO OCH3 106 104 Flumazenil Flumazenil Flumazenilum Anexate®, Romazicon® H3CO Cl Widely used for anxiety states, premedication in anesthesiology etc. imidazole ¾ Antagonizes the actions of benzodiazepines on the central nervous system,competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. ¾ Antagonizes overdose, reversal of sedative effects ¾ Extreme rapid distribution, short half-life, used as injection. 107 12 Synthesis Carbamates Mode of action ¾ GABA receptor agonist or mimetic, enhances the inhibitory effect of neurotransmission. ¾ Frequent target for sedative drugs benzodiazepine tranquilizers, sedatives, anesthetics ¾ Increased Cl- influx → hyperpolarization, inhibiting the firing of new action potentials. Cl- NH2 O Meprobamate Meprobamatum Equanil®, Andaxin® 2-Methyl-2-propyl-1,3propanediol-dicarbamate O CH3 H3C O NH2 O ¾ Mild sedative-hypnotic and antianxiety agent with some skeletal muscle relaxation action. Useful before surgical procedures. ¾ Does not act through the GABAergic system. Cl108 Metabolism HOOC O HO 109 Other anxiolytics, tranquillizers OH (OR) OH OH ß-D-glucuronic acid 110 Trimetozine Trimethozinum Trioxazin® 4-(3,4,5-Trimethoxybenzoyl)-morpholine Other anxiolytics, tranquillizers Buspirone hydrochloride Buspironi hydrochloridum Anxiron®, Spitomin® ¾ Mild anxiolytic against stage fright, overexcitement, etc. 8-(4-(4-(Pyrimidin-2-yl)piperazin-1-yl)butyl)8-azaspiro[4.5]decane-7,9-dione * HCl Synthesis: 111 Originally developed as antipsychotic agent. Possesses anxiolytic and antidepressant activities Partially 5HT (serotonin) receptor agonist. Tolerance and addiction have not been noticed (contr. to benzodiazepines). ¾ 1 to 3 weeks elapse before the anxiolytic activity 113 becomes evident. ¾ ¾ ¾ ¾ morpholine 112 13