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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

CH2CH2NH2 Ethylamine

Imidazole

4(5)-(2-aminoethyl) imidazole

(a) NX-tautomer

(a) NT-tautomer Side chain N = NE

Properties and Action of Histamine


+NH3

H 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

histidine NH2 HN N MAO (brain) -B ( DAO (peripheral) ) dehydorgenase ( ) Aldehyde

histidine decarboxylase

Biosynthesis and metabolism of histamine

SAM SAH

histamine N-methyl Ntransferase

NH2 H3C N N HN N

COOH

N-methyl histamine N-
MAO (brain)( -B ) DAO ( (peripheral) ) Aldehyde dehydorgenase

imidazolyl acetic acid ribose phosphate transferase


COOH

COOH H3C N N

HO HO

OH

N-methylimidazolyl N- acetic acid

Imidazolyl acetic acid necleoside

Classification of H1 receptor antagonists


N N

diamines piperazines aminoethers Propylamine Piperdines tricyclics

lipophilic aromatic moiety

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 Ard CHO- replace ArCH2 diamines, then you get aminoethers. Ar N- moiety in ethyl

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 N O N

Cl

Clemastine

Setastine

Propylamines H1 receptor antagonists


When ArCH2(Ard)N- in ethyldiamines is replaced by Ar(Ard)CH- moiety or omitted -O- in aminoether, then propylamine is there.
R' Ar Ar' N R

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 N O . OH OH

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


t-BuOH N CN H2SO4 N O NHBu-t 1) n-BuLi/NaBr, THF 2) Cl Cl N O NHBu-t Cl POCl3

Cl Cl N CN 1) ClMg 2) HCl N N N N O PPA N

Cl

ClCOOC2H5 PPA, P2O5 Cl N O O N COOC2H5 N Zn, TiCl4 N O O Cl

Piperazines H1 Receptor Antagonists


When Ar Ard CHN- replaces ArCH2 Ard 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 N

NH

Cl Cl(CH2)2OCH2CN K2CO3 N

O Cl 1.KOH 2.HCl N 2HCl N O OH

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 HN

2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2yl]-4-piperidinyl]methylamino]-4(1H)-pyrimidinone 21- 14-1H-2-4-4 3H -

Process for Synthesizing Mizolastine


F HN H N O Cl N K2CO3 F HBr N H N
S HN O N HN H N

F O N N F NaH CH 3I

N NaOCH 3

H N O

N N

N N N N

N O

N HN

SAR of Antihistamines
Ar X Ar'
X = O, C, or N N = 2 or 3
N N

R (CH2)n N R'

diamines piperazines aminoethers Propylamine Piperdines tricyclics

lipophilic aromatic moiety