mc 13 anti histamines

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Chapter 3.4

Antihistamines



Histamine H1 Antagonists

The term antihistamine historically refersto drugs that antagonize the actions of

histamine at H1

receptors.

Histamine is an important chemicalmediator of hypersensitivity



4 (5-)-(2-aminoethyl)imidazole

NNCH2CH2NH2

H

ImidazoleEthylamine



4(5)-(2-aminoethyl) imidazole

(a) NX-tautomer (a) NT-tautomer

Side chain N = NE



NNH

NH3+

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)

Properties and Action of Histamine



Biosynthesis

andmetabolism

of histamine

×é°·

HN N

NH2

N N

NH2

H3C

N N

COOH

H3C

HN N

COOH

O

OHHO

HON N

COOH

N-¼×»ù×é°·

N-¼×»ùßäßòÒÒËá

ßäßòÒÒËá

ßäßòÒÒËáºËÜÕ

N-

SAM

SAH

-B (´óÄÔ)¶þ°· Ñõ»¯Ã¸ (ÍâÖÜ)

È©ÍÑÇâ Ã¸

×é°±Ëá

×é°±ËáÍÑôÈ Ã¸

HN N

NH2

COOH

-B (´ó ÄÔ)¶þ°· Ñõ»¯Ã¸ (ÍâÖÜ)È©ÍÑÇâ Ã¸

histidine

histidinedecarboxylase

histamine

N-methyltransferase

MAO (brain)

DAO (peripheral)

Aldehyde dehydorgenase

N-methyl histamine imidazolyl acetic acid

MAO (brain)DAO (peripheral)

Aldehyde dehydorgenase

ribose phosphatetransferase

N-methylimidazolylacetic acid

Imidazolyl acetic acidnecleoside



Classification of H1 receptorantagonists

NN

ON

CN

lipophilic

aromatic moiety

diamines

piperazines

aminoethers

Propylamine

Piperdines

tricyclics



Histamine

H1Receptor Antagonists

± ethyl diamines

± aminoethers

± propylamineschlorphenamine maleate

± tricyclicsloratadine

± piperazinescetirizine hydrochloride ± piperidinesmizolastine

± others



Ethyl diamines H1 receptor

antagonists

Ar = Ph p-subPh or thtiophenylAr¶= Ph or 2-

pyridinylR and R¶ = Me or heterocyclyl

Weaker action to H1 receptormoderate central

analgesic effectcausing disorder of gastrointestine

local external use may cause skin hypersensity.

NN

Ar

Ar'



Aminoethers H1 receptor

antagonists If Ar Ar dCHO- replace Ar CH2Ar¶ N- moiety in ethyl

diamines, then you get aminoethers.

The f irst gener ation of H1 receptor antagonist display a pparent

analgesic and anticholiner gic eff ectsusually with side reaction like somnolence, dizzy, or al dryness. But incidence r ate of

gastrointestine reaction is low. Some of dr ugs could be a pplied in the treatment of insomnia.

For those aminoether with two aromatic grou pthe activity of S -isomer is usually higher than that of R-isomer.

ON

R

R'

Ar

Ar'



NO

Cl

Antihistamine drugs without analgesic effect belonged

to aminoether typethey have higher selectivity to

peripheral H1 receptor, belong to second generation

antihistamine drug.

Clemastine

O

Cl

N

Setastine

Aminoethers H1 receptor

antagonists



Propylamines H1 receptor

antagonists When ArCH2(Ard)N- in ethyldiamines is replaced by

Ar(Ard)CH- moietyor omitted -O- in aminoether,then propylamine is there.

Compared to traditional antihistamines likeethyldiamines, aminoethers, tricyclicspropylamineshave stronger antihistamine action but weaker centralanalgesic, and less tendency of inducing somnolence.

NR

R'

Ar

Ar'



Chlorphenamine is an first-generation antihistamines

Chlorphenamine Maleate



Action of Chlorphenamine Maleate

Stronger antihistamine actionless dosageless sideeffectsuitable for children. Mainly use forhypersensitive nasitis, skin mucosa hypersensitivity,urticaria, angiectatic nasitis, hay fevercontactdermatitis and hypersensitivity caused by food anddrugs. Side effect: somnolence, thirsty, diuresis.

.N

Cl

N

O

O

OH

OH



Points Need Your Concerns

One chiral center in Chlorphenaminethere is a pairof optical isomer. The activity of S -isomer is twicestronger than that of racemateacute toxicity is alsoless. The activity of R-isomer is only 1/90 than that of racemateIn clinic, racemate chlorphenamine

maleate is used

N

N

H

Cl

S(+) -Chlorphenamine



Chemical Synthesis



Propylamines H1 receptor

antagonists

Allyl acid make the compound more hydrophilic andit is more difficult for it to enter into central nervesystem.Therefore, acrivastine displays no analgesiceffect.

The activity of E-isomer is great higher than that of

Z-isomer.

N

N COOH

H

Acrivastine



Tricyclics H1 receptor antagonists

If fused together the adjacent position of two aromatic ring,tricyclics H1 receptor antagonist is there.

If X = NY = Sthen phenothiazine

If X= C ( sp2)Y is replaced with bioisostere, -CH=CH-thencyproheptadine

Further modification of cyproheptadine produce loratadine

Y

X

N R

R'



Lor atadine

Strong selective H1 receptor antagonist, but no

anticholiner gic activity and centr al nerve system inhi bition, belong to second gener ation non-sedative antihistamines.

The main diff erence compared to other tricyclics antihistamines, is the replacement of neutr al aminof ormate f or

basic tertiary amine. It is believed this is the reason of its decrease of centr al analgesic .

N

N

OO

Cl



Chemical Synthesis of Loratadine

N CN

t -BuOH

H2SO4 N

NHBu-t

O

1) n-BuLi/NaBr, THF

2)Cl

Cl

N

N

OO

Cl

N

Cl

O

NHBu-t

POCl3

N

Cl

CN

NClMg1)

2) HCl

N

Cl

O

N

PP A N

N

Cl

ClCOOC2H5

PP A, P2O5

NO

Cl NO COOC2H5

Zn, TiCl4



Piperazines H1 Receptor

Antagonists

When ArArdCHN- replaces ArCH2ArdN- moietyin ethyldiamine, and make two nitrogen atom in piperazinering, then the piperazines antihistamines are constructed

Other than stronger H1 receptor antagonism effecttheydisplay other characteristiclike relieving asthma effect, anti-kinetia action, and blocking action of Ca2+ ion channel .

Ar N

Ar'

NR



Cetirizine Hydrochloride

Because of the easy ionization of Cetirizine, the drug isnot easy to permeate blood brain barrier (BBB) , littleamount of the drug is able to arrive central nervesystem, it belongs to non-sedative antihistamine, it isone of the representative drug of second generationantihistamines.

.2HCl

O

O

OHCl

N

N



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

1.KOH2.HCl

Cl(CH2)2OCH2CN

K2CO3

ClN

NH OCl

N

NN

OOH

Cl

N

N

O

2HCl



Piperidines H1 Receptor

Antagonists

Limitation of the entrance to central and increase theselectivity to H1 receptor, is the guiding ideology for designand searchin new antihistamine drugs. This resulted in the

development of non-sedative H1 receptor antagonists.

ClemastineaminoethersAcrivastinepropylaminesLoratadinetricyclics, and Cetirizinepiperazinesallbelong to non-sedative H1-receptor antihistamines. Via theintroduction of hydrophilic group, the drug is difficult to enter

central nerve system because of BBB, therefore the sedativeeffect is overcome (weakened). Whilst Clemastine andLoratadine have higher selectivity to peripheral H1 receptor,therefore avoid side effect to Centrum. Other non-sedativeantihistamine drugs belong to piperidines selective peripheralH1-receptor antagonists.



Mizolastine

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

2-1-1-4--1 H--2--4--43 H -

N N

HN

N

O

N

N

F



Process for Synthesizing

Mizolastine

NN

HN

N

O

N

N

F

N

N

F

Cl

HN HN

O

O

NaOCH3 N HN

NN

F

O

OHN H

NK2CO3

N HN

N

N

F

N N

N

N

F

O

O

NaH CH3I

HBr

S

HN

N

O



SAR of Antihistamines

Ar X

Ar'

(CH2)n NR

R'

X = O, C, or N

N = 2 or 3

NN

ON

CN

lipophilic

aromatic moiety

diamines

piperazines

aminoethers

Propylamine

Piperdines

tricyclics

mc 13 anti histamines

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