Download (2-aminoethyl) imidazole

Chapter 3.4
Antihistamines
Histamine H1 Antagonists
The term antihistamine historically refers
to drugs that antagonize the actions of
histamine at H1 receptors.
Histamine is an important chemical
mediator of hypersensitivity
4 (5-)-(2-aminoethyl)imidazole
H N
N
CH 2CH 2NH2
Ethylamine
Imidazole
4(5)-(2-aminoethyl) imidazole
(a) N-tautomer
(a) N-tautomer
Side chain N = N
Properties and Action of Histamine
+NH3
H N
N
At pH 7.4, histamine exists almost exclusively (96.6%) in
a monocationic form
Most histamine is synthesized and stored in mast cells
and basophilic granulocytes
Histamine is mediated by specific cell surface receptors
(H1, H2, and H3)
NH2
HN
N
COOH
×é°±Ëá
histidine
histidine
decarboxylase
×é°±ËáÍÑôÈø
NH2
HN
Biosynthesis
and
metabolism
of histamine
SAM
SAH
N
×é°·
histamine
N-methyl
N-甲基转移酶
transferase
MAO (brain)
单胺氧化酶-B
(´ó ÄÔ)
DAO (peripheral)
¶þ°·
Ñõ»¯Ã¸dehydorgenase
(Íâ ÖÜ)
Aldehyde
È©ÍÑÇâø
NH2
H3C
N
COOH
N
HN
N
imidazolyl
acetic
ßäßòÒÒ
Ëá acid
N-¼×»ù×é°·
N-methyl
histamine
ribose phosphate
磷酸核糖转移酶
MAO (brain)(´ó ÄÔ)
单胺氧化酶-B
DAO
(peripheral)
¶þ°·
Ñõ»¯Ã¸
(Íâ ÖÜ)
Aldehyde
È©
ÍÑÇâø dehydorgenase
transferase
COOH
COOH
H3C
N
O
HO
N
N
N
N-methylimidazolyl
N-¼×»ùßäßòÒÒ
Ëá
acetic acid
HO
OH
Imidazolyl
acetic
acid
ßäßòÒÒ
ËáºËÜÕ
necleoside
Classification of H1 receptor
antagonists
N
lipophilic
亲脂性芳环部分
aromatic moiety
O
C
N
N
N
diamines
乙二胺类，哌嗪类
piperazines
氨基醚类
aminoethers
Propylamine
丙胺类、哌啶类、三环类
Piperdines
tricyclics
Histamine H1 Receptor Antagonists
–
–
–
–
–
–
–
ethyl diamines
aminoethers
propylamines：chlorphenamine maleate
tricyclics：loratadine
piperazines：cetirizine hydrochloride
piperidines：mizolastine
others
Ethyl diamines H1 receptor
antagonists
• Ar = Ph、p-subPh or thtiophenyl；Ar’= Ph or 2pyridinyl，R and R’ = Me or heterocyclyl。
Ar
Ar'
N
N
• Weaker action to H1 receptor，moderate central
analgesic effect，causing disorder of gastrointestine，
local external use may cause skin hypersensity.
Aminoethers H1 receptor
antagonists
• If Ar（Ar）CHO- replace ArCH2（Ar’）N- moiety in ethyl
diamines, then you get aminoethers.
Ar'
Ar
O
R'
N
R
• The first generation of H1 receptor antagonist display apparent
analgesic and anticholinergic effects，usually with side reaction
like somnolence, dizzy, oral dryness. But incidence rate of
gastrointestine reaction is low. Some of drugs could be applied in
the treatment of insomnia.
• For those aminoether with two aromatic group，the activity of Sisomer is usually higher than that of R-isomer.
Aminoethers H1 receptor
antagonists
Antihistamine drugs without analgesic effect belonged
to aminoether type，they have higher selectivity to
peripheral H1 receptor, belong to second generation
antihistamine drug.
Cl
O
O
N
Cl
Clemastine
Setastine
N
Propylamines H1 receptor
antagonists
• When ArCH2(Ar)N- in ethyldiamines is replaced by
Ar(Ar)CH- moiety，or omitted -O- in aminoether,
then propylamine is there.
R'
Ar
N
R
Ar'
• Compared to traditional antihistamines like
ethyldiamines, aminoethers, tricyclics，propylamines
have stronger antihistamine action but weaker central
analgesic, and less tendency of inducing somnolence.
Chlorphenamine Maleate
Chlorphenamine is an first-generation antihistamines
Action of Chlorphenamine Maleate
Cl
O
N
.
OH
OH
N
O
• Stronger antihistamine action，less dosage，less side
effect，suitable for children. Mainly use for
hypersensitive nasitis, skin mucosa hypersensitivity,
urticaria, angiectatic nasitis, hay fever，contact
dermatitis and hypersensitivity caused by food and
drugs. Side effect: somnolence, thirsty, diuresis.
Points Need Your Concerns
Cl
N
H
N
S(+) -Chlorphenamine
• One chiral center in Chlorphenamine，there is a pair
of optical isomer. The activity of S-isomer is twice
stronger than that of racemate，acute toxicity is also
less. The activity of R-isomer is only 1/90 than that of
racemate。In clinic, racemate chlorphenamine
maleate is used。
Chemical Synthesis
Propylamines H1 receptor
antagonists
N
H
N
COOH
Acrivastine
• Allyl acid make the compound more hydrophilic and
it is more difficult for it to enter into central nerve
system.Therefore, acrivastine displays no analgesic
effect.
• The activity of E-isomer is great higher than that of
Z-isomer.
Tricyclics H1 receptor antagonists
• If fused together the adjacent position of two aromatic ring,
tricyclics H1 receptor antagonist is there.
Y
X
N R
R'
• If X = N，Y = S，then phenothiazine
• If X= C (sp2)，Y is replaced with bioisostere, -CH=CH-，then
cyproheptadine
• Further modification of cyproheptadine produce loratadine
Loratadine
Cl
N
N
O
O
• Strong selective H1 receptor antagonist, but no
anticholinergic activity and central nerve system inhibition,
belong to second generation non-sedative antihistamines.
• The main difference compared to other tricyclics
antihistamines, is the replacement of neutral aminoformate for
basic tertiary amine. It is believed this is the reason of its
decrease of central analgesic .
Chemical Synthesis of Loratadine
N
CN
H2SO4
Cl
1) n-BuLi/NaBr, THF
t-BuOH
O
N
Cl
2) Cl
POCl3
O
N
NHBu-t
NHBu-t
Cl
Cl
N
1) ClMg
N
Cl
O
N
PPA
N
2) HCl
CN
N
N
ClCOOC2H5
PPA, P2O5
Cl
O
Cl
N COOC2H5
N
N
O
Zn, TiCl4
N
O
O
Piperazines H1 Receptor
Antagonists
• When Ar（Ar）CHN- replaces ArCH2（Ar）N- moiety in
ethyldiamine, and make two nitrogen atom in piperazine ring,
then the piperazines antihistamines are constructed
Ar'
Ar
N
N
R
• Other than stronger H1 receptor antagonism effect，they
display other characteristic，like relieving asthma effect, antikinetia action, and blocking action of Ca2+ ion channel .
Cetirizine Hydrochloride
O
Cl
N
N
O
OH
.2HCl
• Because of the easy ionization of Cetirizine, the drug is
not easy to permeate blood brain barrier (BBB) , little
amount of the drug is able to arrive central nerve
system, it belongs to non-sedative antihistamine, it is
one of the representative drug of second generation
antihistamines.
The advantages of Zyrtec is that
1. Once-daily dosing
2. Rapid onset of activity (20-60 min)
3. Minimal CNS effects
Process for Synthesizing Cetirizine
Hydrochloride
Cl
Cl
NH
Cl(CH2)2OCH2CN
K2CO3
N
N
O
Cl
1.KOH
2.HCl
N
O
N
OH
N
2HCl
O
N
Piperidines H1 Receptor
Antagonists
• Limitation of the entrance to central and increase the
selectivity to H1 receptor, is the guiding ideology for design and
searchin new antihistamine drugs. This resulted in the
development of non-sedative H1 receptor antagonists.
• Clemastine（aminoethers）、Acrivastine（propylamines）、
Loratadine（tricyclics）, and Cetirizine（piperazines）all
belong to non-sedative H1-receptor antihistamines. Via the
introduction of hydrophilic group, the drug is difficult to enter
central nerve system because of BBB, therefore the sedative
effect is overcome (weakened). Whilst Clemastine and
Loratadine have higher selectivity to peripheral H1 receptor,
therefore avoid side effect to Centrum. Other non-sedative
antihistamine drugs belong to piperidines selective peripheral
H1-receptor antagonists.
Mizolastine
F
N
N
N
N
N
HN
O
• 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2yl]-4-piperidinyl]methylamino]-4(1H)-pyrimidinone
• 2-〔〔1-〔1-〔（4-氟苯基）甲基〕-1H-苯并咪唑-2基〕哌啶基-4-基〕甲基氨基〕嘧啶-4（3H）-酮
Process for Synthesizing
Mizolastine
F
HN
N
Cl
H
N
N
NaH
F
HBr
N
H
N
N
O
O
H
N
F
N
N
NaOCH3
N
HN
O
O
N
K2CO3
F
H
N
S
N
F
CH3I
N
O
N
N
O
N
N
HN
O
N
N
N
N
HN
O
SAR of Antihistamines
Ar
R
X
(CH2)n
N
Ar'
R'
X = O, C, or N
N = 2 or 3
N
lipophilic
亲脂性芳环部分
aromatic moiety
O
C
N
N
N
diamines
乙二胺类，哌嗪类
piperazines
氨基醚类
aminoethers
Propylamine
丙胺类、哌啶类、三环类
Piperdines
tricyclics