Amino alkyl ether analogues

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Chapter: Medicinal Chemistry : Antihistamines

i. Diphenhydramine (Benadryl, Bendylate) ii. Dimenhydrinate (Dramamine) iii. Bromodiphendhydramine (Ambodryl hydrochloride) iii. Doxylamine (Decapryn Succinate) iv. Carbinoxamine v. Clemastine vi. Diphenylpyraline (Diaben)


SYNTHESIS AND DRUG PROFILE

 

H1-antagonists with classical structure

 

Amino alkyl ether analogues

 

i. Diphenhydramine (Benadryl, Bendylate)


Synthesis


Properties and uses: Diphenhydramine hydrochloride is a white crystalline powder, soluble in water and in alcohol. In addition, to antihistaminic activity, diphenhydramine exhibits antiemetic, antitussive, and sedative properties.

Assay: Dissolve the sample in alcohol and add 0.01 M hydrochloric acid and titrate against 0.1 M sodium hydroxide. Determine end point potentiometrically.

Dose: Usual dose is 25–50 mg for adult taken orally three to four times per day with maximum of 400 mg per day; for skin: used topically 2% of the cream three or four times per day.

Dosage forms: Diphenhydramine oral solution B.P.

 

ii. Dimenhydrinate (Dramamine)


Synthesis


Properties and uses: Dimenhydrinate is a white crystalline powder or colourless crystals, slightly soluble in water and in alcohol. Used as histamine H1-receptor antagonist, antinauseant, in motion sickness, radiation sickness, and also in the case of nausea during pregnancy.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: Usual dose is taken orally as 50 mg thrice/day.

Dosage forms: Dimenhydrinate tablets B.P.

 

iii. Bromodiphendhydramine (Ambodryl hydrochloride)


Synthesis


Properties and uses: It is effective for mild, local allergic reactions, physical allergy, and for minor drug reactions, characterized by pruritis.

Dose: Usual dose is 25 mg three or four times per day.

 

iii. Doxylamine (Decapryn Succinate)


Synthesis


Properties and uses: Doxylamine succinate is a white powder, highly soluble in water and in alcohol. It is a relatively selective histamine H1-receptor antagonist. In vivo studies have shown that concentrations dependent upon the inhibition of histamine stimulated vascular permeability in the conjunctiva following topical ocular administration. It appears to be devoid of effects on adrenergic, dopaminergic, and serotonin receptors. It is used with antitussives and decongestants for the relief of cough and cold.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: Usual dose is 12.5 to 25 mg for adult taken orally four to six times per day.

 

iv. Carbinoxamine


Synthesis


Properties and uses: Carbinoxamine is available as white, crystalline powder with no odour, soluble in water, alcohol, chloroform, or ether. It is a potent antihistaminic and is available as the racemic mixture. It differs structurally from chlorpheniramine only in having an oxygen atom separate from the asymmetric carbon atom in the aminoethyl side chain. The levo isomer of carbinoxamine is more active than dextro isomer (s-configuration) of chlorpheniramine.

 

v. Clemastine


Synthesis


Properties and uses: Clemastine fumarate is a white crystalline powder, very slightly soluble in water, slightly soluble in alcohol and methanol. It has two chiral centres, each of which is (R) absolute configuration. A comparison of the activities of the antipodes indicates that the asymmetric centre close to the side chain of nitrogen is of lesser importance to antihistaminic activity. It is a long-acting ethanolamine antihistamine with sedative and anticholinergic side effects.

Assay: Dissolve the sample in anhydrous acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.

Dosage forms: Clemastine oral solution B.P., Clemastine tablets B.P.

 

vi. Diphenylpyraline (Diaben)


Synthesis


Metabolism: This type of drugs undergoes N-demethylation (formation of corresponding secondary amine) and subsequent deamination (formation of carboxylic acid metabolites) is the major pathway for diphenylpyraline and some of its analogues. Minor metabolites that are conjugates of the ether cleavage products have been found in some animal species.


Properties and uses: Diphenylpyraline hydrochloride is a white powder, soluble in water and ethanol, practically insoluble in ether. It is structurally related to diphenhydramine with the aminoalkyl side chain incorporated in a piperidine ring. It is a potent antihistaminic agent.

Assay: Dissolve the sample in anhydrous acetic acid and add mercury (II) acetate solution and titrate against 0.1 M perchloric acid using oracet blue B solution as indicator.

Dose: Usual dose for adults taken orally is 5 mg two times per day.

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