Analgesics - antipyretics
= „weak“ analgesics
= non-opioid analgesics
Most of them also
• non-steroidal anti-inflammatory drugs (NSAIDs)
•antirrheumatics
©Oldřich Farsa 2013
Metabolism of eicosanoids
COOH
C
H2
C
H2
O R1
OR2
O
O
O
P O
O
OH
N
+
CH3
CH3
CH3
OHR2
O
COOHO
O
OOH
COOH
OOH
arachidonic acid
=
PG G2
PG H2
TX A2
trombocytes PG D2 PG E2
PG F2α
all the cells
PG I2 = prostacyklin
endothelium cells LT A4
LT C4
LT D4
LT E4
LT B4
cyclooxygenases (COX1 + COX2) lipoxygenase
phspholipase A2inhibitors of
prostaglandins
sythesis =
= "weak"
analgesics +
+ NSAIDs
glucocorticoids
lipoxygenase inhibitors
arachidonic
acid
tromboxan synthase prostacyklin synthase
isomerases
cyklooxygenases
5-hydroperoxy-6-trans-8,11,14-cis-eikosatetraenoic acid
(5-HPETE)
Effects of prostaglandins
Prostaglandin E, F2α : ache, fewer, inflammation, secretion of HCl↓,
stomach mucosa capillaries dilation, contraction of
uterus, kidneys: excretion of Na+
and H2O ↑
Prostacyclin (prostaglandin I2
): vasodilation, platelets aggregation inhibition
Tromboxan: vasokonstriction, platelets aggregation activation
Leukotriens: allergic reactions (e.g. asthma bronchiale)
Cyclooxygenases (= prostaglandin G/H synthases)
COX1
Constitutive: in all the tissues
Functions:
•protection of stomach mucosa (vasodilation)
•diuresis
•platelets aggregation (TXA)
COX2
Constitutive: kidneys, brain (co-localized with cyclins D1
and E)
Inducible: macrophages, neutrophils, fibroblasts, endothelium cells
Functions:
•vasodilatation (PG I2)
•childbirth (uterus contractions)
•inflammation processes
COX3 ?? (= COX1b; brain ?)
Philipp Needlemann
discoverer of COX
isoenzymes
(1989)
Classification of COX inhibitors
(antipyretics, NSAIDs)
Non-selective (COX1 + COX2)
•Anilides
•Salicylates
•Phenamates
•Aryl- and heteroaryl alkanoic acids
•Aryl- and heteroaryl acetic acids
•Aryl- and heteroaryl propionic acids
•Oxicames
•1,2-Dihydropyrazolidine-3-ones
•2,5-Pyrazolidinediones
Selective (COX1<COX2): nimesulide
Specific (COX2)
•Coxibes
Anilides
NH O NH O
OH
NH O
O
acetanilide paracetamol
(acetaminophen)
4-(acetylamino)phenol
phenacetin
N-(4-ethoxyphenyl)acetamide
N-phenylacetamide
1886: Antifebrin®
para-(acetylamino)phenol
p-(acetylamino)phenol
Paralen®
, Panadol®
….
nephrotoxicity
Dinyl® - analg.
mixture with caffeine,
aminophenazone and
barbiturates
Paracetamol
NH O
OH
• inhibits COX only in CNS (COX3 ?) not in periphery ⇒
•effects: analgesic, antipyretic (not antiinflamatory,
antirheumatic)
Usage in mixtures with
•codeine, caffeine ⇒ effect enhancement (Korylan tbl.®,
Panadol tbl.®, Efferalgan codein tbl. eff.®)
•expectorants (guajfenesin, terpin)
•antitussives (dextromethorphan)
•H1-antihistaminines (pheniramine, chlorphenamine,
dimenhydrinate, promethazin, doxylamin) together with
α-sympatomimetics (phenylefrine, pseudoephedrine)
•spasmolytics (pitophenon)
•myorelaxants (chlorzoxan, carisoprodol)
•NSAID (acetylsalicylic acid, propyphenazon – Valetol®)
Metabolism of paracetamol
O
N
CH3
O
OH
N
CH3
O
OH
N
CH3
O
S
R
N
CH3
O
O
S
O
O
O
O
O
OHOH
OH
OH
O
N
O
CH3
N-acetyl-p-benzoquinoneimine
N-(4-oxocyclohexa-2,5-diene-1-ylidene)acetamide
NAPQI
HEPATOTOXIC
R-SH
(glutahione,
N-acetylcysteine)
conjugationconjugation
4 %
42 % 52 %
2% urine
paracetamol glucuronide paracetamol sulfate
urine
urine
urine
cytochrome
P-450
R-SH = glutathion ⇒
⇒ merkapturic acid
Thiols detoxicating N-acetyl-p-benzoquinoneimine
N
OSH
OH
CH3
O
H
N
O O
N
O
SH
H N
O
OHHH H
OH
N-acetyl-L-cysteine
glutathione
γ − Glu-Cys-Gly
mucolytic
ACC®, Mucobene®
Synthesis of paracetamol
OH
OH
NO2
OH
NO2
OH
NH2
CH3
CH3
O
O
O
OH
NH
CH3
O
OH
NO2
OH
NH
CH3
O
HNO3 Fe, HCl
phenol
2-nitrophenol
4-nitrophenol 4-aminophenol 4-(acetylamino)phenol
Sn
CH3COOH
Morse, Chem. Ber. 11, 232 (1878)
Propacetamol – paracetamol prodrug
• for intravenous application
NH
CH3
O
O
N
+
O
H Cl
NH
CH3
O
O
N
O
NH
CH3
O
O
H
N
O
OH
4-(acetylamino)phenyl-N,N-diethylglycinate hydrochloride
2-[4-(acetylamino)phenoxy]-N,N-diethyl-2-oxoethaneaminium chloride
propacetamol hydrochloride
esterase
+H2O
Pro-Dafalgan®
(UPSA Laboratoires)
Salicylates
O
O
OHOH
OH
OH
OH OHO
OH
CH3
CH3
O
O
O
OHO
O CH3
O
salicin
(2-hydroxymethylphenyl)-β -D-glucopyranoside
1827 Leroux: isolation from willow
hydrolysis
oxidation
salicylic acid
2-hydroxybenzoic acid
1838 Piria: the first synthesis
since 1878 used as antipyretic
and antirheumatic
acetylosalicylic acid
2-acetoxybenzoic acid
1897 Felix Hoffmann - industrial
synthesis
Felix Hoffmann Sir John R. Vane
1899 – Aspirin®
(Bayer)
Effects of acetylosalicylic acid
OHO
O CH3
O
„Wanted“:
•antipyretic
•analgesic
•anti-inflamatory
•antirheumatic
•antithrombotic (↓ platelets aggregation) – Anopyrin®
„Unwanted“:
•ulcerogenic
•Rey syndrom in childern after viral infection
(hepatopathy, encefalopathy) ⇒ contra-indication in
childern
•bleeding (e.g. from nose - ↓ platelets aggregation)
Intoxication = „salicylism“ – infliction of CNS (psychical
malfunctios, buzz in ears, dizzines, deafness),
methabolic acidosis
Mechanis of action of acetylosalicylic acid (ASA)
• irreversible inhibition od cyclooxygenases by acetylation of serine rest
O
NH2
OH
OH O
OCH3
O
O
NH2
O
CH3
O
OH
OOH
COX
+
Ser
COX
+
+
Metabolism of ASA
• proceeds in liver
•all metabolits are excreted
by urine
OHO
O CH3
O
OHO
OH
O
OH
OH
O
OH
O
OH
O OH
O
O
OHOH
OH
OH
O OH
O
O
OH
NH
OH
O
OHO
OH
OH
ASA
salicylic acid.
10 %
+ CH3COOH
O1-salicyoylglucuronic acid
5 %
O1-(2-carboxyphenyl)glucuronic acid
10 %
glucuronation
salicyluric acid
(N-salicyoylglycine)
75 %
conjugation with Gly
gentisic acid
< 1 %
hydroxylation
t1/2= 15 min.
Syntheses of ASA
OHO
OH CH3
Cl
O OHO
O
CH3
O
OHO
OH
OHO
O
CH3
O
CH3
CH3
O
O
O
Gerhardt, Justus Liebigs Ann. Chem. 87, 164 (1853)
Gilm, Justus Liebigs Ann. Chem. 112, 181 (1859)
Kraut, Justus Liebigs Ann. Chem. 150, 10 (1869)
Felix Hoffmann
Other salicylates
O
OH
OH
F
F
O
O
CH3
O
OO
O
CH3
O
O
Al
O
Al
O
Al
O
O
CH3
O
O
O
O
CH3
O
O
O
O
CH3
O
O
2',4'-difluoro-4-hydroxy-1,1'-biphenyl-3-carboxylic acidpentakis(acetylosalicyoyloxy)trialuminium dioxide
aloxiprin diflunisal
Superpyrin®
Unisal®
tbl.
Anthranilic acid derivatives – phenamates
= substitution derivatives of 2-phenylaminobenzoic acid
•derived from salicylates by substitution of hydroxy group with
(phenyl)amino moiety
O OH
N
R
1
R
2
R
3
H
•aromatic amino acids
•substituted on the aniline ring only
•inhibit both COX1 and COX2 (selectivity?; COX3?)
•analgesics, antipyretics, antimigrenics, anti-inflammatory
Phenamates
O OH
N
R
1
R
2
R
3
H
R1
R2
R3
Chemica name INN / preparation
-CH3 -CH3 -H 2-(2,3-dimethylphenylamino)benzoic
acid
mephenamic acid
-Cl -CH3 -Cl 2-(2,6-dichloro-3methylphenylamino)benzoic
acid
meclophenamic acid
-CH3 -Cl -H 2-(3-chloro-2methylphenylamino)benzoic
acid
tolphenamic acid
Migea rapid®
-H -CF3 -H 2-(3-trifluoromethylphenylamino)benzoic
acid
fluphenamic acid
Tolphenamic acid
Synthesis
NH2
CH3
Cl
O O
Br
K
+
O
N O OH
N
CH3
Cl
H
+
1.(CH3COO)2Cu, DMF
2. H+
Kaltenbronn J.S. et al., Arzneim. Forsch 33, 621-627 (1983)
Selectivity against COXs
10
)2(
)1(
50
50
=
COXIC
COXIC
Grossmann C. J. et al., Inflammation Res. 44, 253-257 (1995)
Niflumic acid and its esters
NN
OH
O
F F
F
H
NC
OH
O
F F
F
H
2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid
fluphenamic acid niflumic acid
•isosteric substitution benzene ⇒ pyridine, or –CH= ⇒
-N=
•inhibit both COX1 and COX2
•anti-inflamatory, antirheumatics; usually topically
administered
Niflumic acid and its esters
•esters are prodrugs which can better penetrate through the skin
NN
O
O
F F
F
R
H
H
N O
O
O
R
2-{[(3-trifluormethyl)phenyl]amino}nicotinic acid
niflumic acid
Niflugel®
, Nifluril®
-||- 2-(morpholine-4-yl)ethylester
morniflumate
-||- 1-oxo-2-(3H)-benzofurane-3-ylester
talniflumate
Aryl- and heteroarylalkanoic acids
Structure-activity relationships (SAR)
•the aliphatic part of the molecule is more specific for the effect
than the aromatic one
ARY O
OH
ARY O
OHCH3
ARY OH
O
OH
O
ARY
ARY OH
O
= = > >
ARY = aryl, heteroaryl
Aryl- and heteroarylacetic acids and their functional
derivatives
CH2
O
R
Y
R = aryl or heteroaryl
Y = OH, NHOH, NHR, OCH2COOH, or other
• antirheumatics, anti-inflamatory, analgesics, antipyretics
•inhibition of both COX1 and COX2
•adverse effects (AE) like in salicylates
Aryl- and heteroarylacetic acids and their functional derivatives
(fenacs)
Cl
N
O
O
O
CH3
O
CH3
R
NH
Cl
Cl
O O
R
R = H
[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid
indomethacin
R = H
{2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid
diclofenac
R= OCH2COOH
{2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid
carboxymethylester
aceclofenac
R = OCH2COOH
[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid
caboxymethylester
acemetacin
•used since 1975
Voltaren®
, Veral®
, Myogit®
,
Dicloreum®
•used since 1963
•now mainly topically
Indobene®
cps, Bonidon®
gel,
Elmetacin®
spr
Heteroarylacetic acids and their derivatives
NCH3
O
O
O O
Cl
N
NO
O
NH
N
O
O
CH3 CH3
CH3
proglumetacin
N
S
OH
O
Cl
N
Cl
N
O
OH
[3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-yl]acetic acid
lonazolac
[4-(4-chlorophenyl)-2-phenyl-1,3-thiazole-5-yl]acetic acid
fentiazac
•isosteres
Aryl- a heteroarylacetic acids
Cl
OH
O
O
CH2
N
O CH3
OH
O
CH3
N
CH3
CH3
Cl
O
OH
O
alclofenac tolmetin zomepirac
Aryl- a heteroarylacetic acids
•examples of isosterism of rings and functional groups
Cl
N
O
O
O
OH
F
OH
O
S
O
[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-
1H-indol-3-ylacetic acid
indomethacin
[6-fluoro-3-(4-methanesulfinylbenzylidene)-2-methyl-
3H-indene-1-yl]acetic acid
sulindac
Nitrogeneous functional derivatives of aryl- and heteroarylacetic acids
O
CH3
N
OHO
H
N
N
O
H
N CH3
O
O N
O
CH3
OH
Cl
H
2-(4-butoxyphenyl)-N-hydroxyacetamide
2-(4-butoxyphenyl)acetohydroxamic acid
bufexamac
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]-
N-hydroxyacetamide
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-yl]acetohydroxamic
acid
oxametacin
1,1´-biphenyl-4-yl-N-pyridine-2-yl-acetamide
difenpiramide
Nabumeton
•a prodrug
O
O
O
OHO
4-(6-methoxynaphtalene-2-yl)butan-2-one
liver
metabolism
2-(6-methoxynaphtalene-2-yl)acetic acid
nabumetone
Relifex®
tbl. obd.
(6MNA)
active metabolit
2-aryl- and 2-heteroarylpropionic acids and their
functional derivatives
CH3
C
H
O
R
Y
*
R = aryl or heteroaryl
Y = OH or NHOH
•chiral compounds (S-enantiomer often much more active)
•pain relief, antirheumatics, anti-inflammatory, antipyretics
•inhibition both COX1 and COX2; COX2 a little more
•AE like salicylates but weaker
2-arylpropionic acids
OH
O
O
OH
O
O
O
CH3
OH
H
R = OH
(R,S)-2-(4-isobutylphenyl)propionic
acid
2-(3-benzoylphenyl)propionic
acid
(+)-S-2-(6-methoxynaphtalene-2-yl-propionic
acid
ibuprofen
Brufen®
, Ibalgin®
(S)- form = dexibuprofen
Seractil®
R = NHOH ibuproxam
ketoprofen
Fastum®
Gel,
Kepabene®
tbl
(S)-form =
dexketoprofen
Sympal®
tbl.obd.
naproxen
Naprosyn®
,
Naprobene®
2-aryl- and 2-heteroarylpropionic acids
S
O
O
CH3
OH
O
N
X
CH3
O
OH
CH3
OH
OF
2-(5-benzoylthiophene-2-yl)propionic
acid
X = Cl
2-[4-(4-chlorophenyl)benzoxa
zole-5-yl]-propionic acid
benoxaprofen
X = F
2-[4-(4-fluorophenyl)benzoxa
zole-5-yl]-propionic acid
flunoxaprofen
2-biphenyl-4-yl-2-fluoropropionic
acid
tiaprofenic acid
Surgam®
, Thialgin®
flurbiprofen
Ansaid®
, Flugalin®
1,2-dihydropyrazole-3-on detivatives
N
N CH3
CH3
O
R
4-substituted-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazole-3-ones
1
2
3
4
5
•inhibit both COX1 and COX2
•pain relief, antipyretics
•contemporarirly usually used in mixtures
N
N CH3
CH3
O
R
CH3
N
CH3
CH3
CH
CH3
R = H
R =
R =
1,2-dihydropyrazole-3-on derivatives
phenazone, syn. antipyrine [JAN]
obsolete
aminophenazone, syn. aminopyrine
[JAN]
Dinyl®
(+ phenacetin, caffeine,
butobarbital, allobarbital)
Eunalgit®
inj. (+ allobarbital)
propyphenazone
Valetol®
, Saridon®
(+ paracetamol, caffeine)
Spasmoveralgin neo®
(+ papaverin,
phenobarbital, ephedrin, codein,
methylatropin)
•isosterism ⇓
Aminophenazone cancerogenity
N
N
O
N
N
N
O
N
H
N
N
O
N
N O
NO3
-
methyltransferase
(nitrite reductase
Campylobacter jejuni)
aminophenazone
1,5-dimethyl-4-methylamino-2-phenyl
-1,2-dihydropyrazole-3-one
(desmethylaminophenazone)
1,5-dimethyl-4-methyl(nitroso)amino
-2-phenyl-1,2-dihydropyrazole-3-one
NO2
-, H+
nitrate reductase
CANCEROGENIC
Synthesis of aminophenazone
NH
NH2
O
O
O
NH
N
O N
N
O
N
N
O
NO
N
N
O
NH
H
N
N
O
N
+
"technical pyrazolone"
(CH3)2SO4
phenazone
NO2
-, H+
red.
NaHSO3
HCOH
HCOOH
aminophenazone
Pyrazolidine-3,5-dione derivatives
N
NO
R
2 O
R
1
•anti-inflammatory, pain relief, antipyretics
•inhibit both COX1 and COX2
•reserved for m. Bechterev in some countries (CH ...)
•in CZ only external and veterinary preparations
• AE: GIT intolerance, diarrhoea, ulcer disease exacerbation and bleeding into
GIT, skin rash, CNS disorders, Na+
and water retention, renal malfunctions,
bone marrow disturbances
N
N
O
R
2
O
R
1
Pyrazolidine-3,5-dione derivatives
R1
R2
Chemical name INN /
preparations
C4H9- 4-butyl-1,2-
diphfenylpyrazolidi
ne-3,5-dione
phenylbutazone
Butasan®
a.u.v
C4H9- 4-butyl-1-(4-
hydroxyphenyl)-2-
phenylpyrazolidine
-3,5-dione
oxyphenbutazone
Tanderil®
sup.
reg. in SR
1,2-diphenyl-4-
(4-
oxobutyl)pyrazoli
dine-3,5-dione
kebuzone
Ketazon®
ung
H- C4H9- 4-butyl-1-
phenylpyrazolidi
ne-3,5-dione
mephebutazone
OH
CH3
C
C
H2
C
H2
O
Heterocyclic enols-“keto-enolic acids“
-oxicams
•contain „keto-enolic“ structural fragment
Tautomerism and dissociation of piroxicam
S
N
O O
OH
N
O
H
N S
N
O O
O
N
O
N
H
H
S
N
O O
O
N
OH
N
H
S
N
O O
O
N
O
N
H
-
H
+
+
Oxicams
•acid character
•inhibit both COX1 and COX2 (meloxicam about 3x more COX2)
•effects: anti-inflamatory, pain relief, antipyretic
•using: arthrosis, rheumatoid arthritis ...
Oxicams
S
N
O O
CH3
OH
N
O N
H
S
S
OH
N
O O
R
CH3
N
H
O N
4-hydroxy-2-methyl-N-pyridine-2-yl-2H-
1,2-benzothiazine-3-carboxamide-1,1-dioxide
R = Cl
6-chloro-4-hydroxy-2-methyl-N-pyridine-2-yl-
2H-thieno[2,3-e][1,2]thiazine-3-carboxamide-1,1-dioxide
R = H
4-hydroxy-2-methyl-N-pyridine-2-yl-
2H-thieno[2,3-e][1,2]thiazine-3-carboxamide-1,1-dioxide
piroxicam
Arthremin®
, Feldene®
,
Flamexin®
- complex with
β-cyclodextrine
tenoxicam
lornoxicam
Xefo®
Oxicams
S
N
O O
OH
N
O
S
N
H
S
N
O O
O N
O
O
N
4-hydroxy-2-methyl-N-
(5-methyl-1,3-thiazole-2-yl)-2H-
1,2-benzothiazine-3-carboxamide-1,1-dioxide
5-methyl-3-pyridin-2-yl-2H,5H-
[1,3]oxazino[5,6-c][1,2]benzothiazine-2,4(3H)-dione-
6,6-dioxide
meloxicam
Movalis®
tbl., Metacam®
a.u.v.,
Melokssia®
droxicam
Selective COX2 inhibitors
Nimesulide
O
N
S
N
CH3
O
O
OO
H
N-(2-phenoxy-4-nitrophenyl)methanesulfonamide
4´-nitro-2´-phenoxymethanesulfonanilide
nimesulide
Coxtral®
, Aulin®
, Mesulid®
Nimesulide
•inhibits COX2 4x more than COX1 ⇒ ↓ AE in GIT and
platelets
•antirheumatic, antiarthrotic, pain relief
•AE: hepatotoxicity; icreased in fever ⇒ not suitable as
antipyretic
O
N
S
N
CH3
O
O
OO
H
„Radical analogy“
•substitution benzene ⇒ cyclohexane
O
N
S
N
CH3
O
O
OO
H
O
N
S
N
CH3
O
O
OO
H
N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide
NS-398
nimesulide
Selectivity
COX2:COX1 4 : 1 30 : 1
Young J.M. et. al.,
Inflammation Res. 45, 246-
253 (1996)
Specific COX2 inhibitors
Coxibs
•aromatic sulfonamides or sulfones (exception: lumiracoxib)
•high selectivity to COX2 ⇒ AE to GIT and increased platelets
aggregation eliminated
•usage: rheumatoid arthritis, osteoarthritis, primary dysmenorrhea
•also neurodegen. diseases (Alzheimer) – colocalization of cyclines D1
and E1 with COX2 in CNS neurones
•AE: ↑ risk of sudden cardiovascular incidents (⇐ ↓ production of
prostacycline which inhibits platelets aggregation but does not affect
production of thromboxane which activates platelets aggregation), skin
damage (mainly valdecoxib)
Coxibs
N
N F
F
F
S
NH2
O
O
S
O
O
N
Cl
N
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-
1H-pyrazole-1-yl]benzenesulfonamide
5-chloro-6'-methyl-3-
[4-(methylsulfonyl)phenyl]-2,3'-bipyridine
celecoxib
Celebrex®
Onsenal® – as an orphan drug for
familial adenomatous polyposis (FAP)
only
etoricoxib
Arcoxia®
Selectivity
COX2 : COX1
30 : 1 340 : 1
Coxibs
O
N
S N
O
O
O
H
O
O
S
O
O
N-{[4-(5-methyl-3-phenylisoxazole-4-yl)phenyl]
sulfonyl}propanamide
4-[4-(methylsulfonyl)phenyl]-
3-phenylfuran-2(5H)-one
Selectivity
COX2 : COX1
parecoxib
•alergic skin reactions mainly in
persons hypersensitive to
sulfonamides
Dynastat®
- for postoperative
pain only
rofecoxib
Ceeoxx®
, Vioxx®
withdrawn due to
dangerous cardiovascular
effects
270 : 1
Coxibs
Selectivity
COX2 : COX1
O
N S NH2
O
O
S
O
O
NH2
F
O
N
4-(5-methyl-3-phenylisoxazole-
4-yl)benzenesulfonamide
4-(4-cyclohexyl-2-methyl-1,3-oxazole-5-yl)-
2-fluorobenzenesulfonamide
valdecoxib
Bextra®
withdrawn
tilmacoxib
60 : 1
Coxibs
O
OH
CH3
N
H
F
Cl
O
OH
N
H
Cl
Cl
2-(2-fluoro-6-chlorfenylamino)-5methylphenylacetic
acid
lumiracoxib
Prexige ®
diclophenac
For comparison: