Download Pharmaceutical chemistry 1. Naming chemical

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
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5
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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
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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...
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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
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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.”
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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.
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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.
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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
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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
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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
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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
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