Triprolidine

Absorption

Rapidly absorbed in the intestinal tract.

Toxicity

Symptoms of overdose include drowsiness, weakness, inco-ordination, difficulty with micturition, respiratory depression, hypotension, agitation, irritability, convulsions, hypertension, palpitation and tachycardia.

Originator

Actidil,Burroughs-Wellcome,US,1958

The Uses of Triprolidine

Antihistaminic.

Indications

For the symptomatic relief of seasonal or perennial allergic rhinitis or nonallergic rhinitis; allergic conjunctivitis; and mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Also used in combination with other agents for the symptomatic relief of symptoms associated with the common cold.

Background

First generation histamine H1 antagonist used in allergic rhinitis; asthma; and urticaria. It is a component of cough and cold medicines. It may cause drowsiness.

Definition

ChEBI: An N-alkylpyrrolidine that is acrivastine in which the pyridine ring is lacking the propenoic acid substituent. It is a sedating antihistamine that is used (generally as the monohydrochloride monohydrate) for the relief of the symptoms o uticaria, rhinitis, and various pruritic skin disorders.

Manufacturing Process

4-Methylacetophenone is first reacted with paraformaldehyde and then with pyrrolidine to give p-methyl-ω-pyrralidinopropiophenone. Atomized lithium (26 g, 3.75 mols) and sodium-dried ether (200 cc) are placed in a 3-liter, 3-necked flask fitted with a Herschberg stirrer, thermometer pocket and a water condenser closed by a calcium chloride tube. A slow stream of dry nitrogen is blown through the flask, which is cooled to - 10°C and n-butyl chloride (138 g, 156 cc, 1.5 mols) is run in with rapid stirring; the mixture is stirred for a further 30 minutes, and then cooled to - 60°C
2-Bromopyridine (193 g, 1.22 mols) is then added dropwise over 20 minutes, the temperature of the reaction mixture being maintained at -50°C. The mixture is stirred for 10 minutes at -50°C and p-methyl-ω- pyrrolidinopropiophenone (112.5 g, 0.5 mol) in dry benzene is then added dropwise over ca 30 minutes, at a temperature of -50°C. The mixture is stirred for a further 2 hours, the temperature being allowed to rise to -30°C but no higher.
The mixture is poured onto excess ice, acidified with concentrated hydrochloric acid, the ether layer separated and extracted with water (1 x 200 cc). The combined aqueous extracts are washed with ether (1 x 200 cc) basified with 0.880 ammonia and extracted with chloroform (3 x 350 cc); the extract is washed with water (2 x 100 cc), dried over sodium sulfate, evaporated, and the residue extracted with boiling light petroleum (BP 60° to 80°C; 10 volumes), filtered hot and evaporated to dryness. The residue is recrystallized from alcohol to give a cream solid (119 g, 80%), MP 117° to 118°C. Recrystallization gives 1-(4-methylphenyl)-1-(2-pyridyl)-3- pyrrolidonopropan-1-ol, MP 119° to 120°C.
1-(4-Methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol (10.0 g) is heated in a steam bath for 30 minutes with 85% aqueous sulfuric acid (30 cc). The solution is then poured onto crushed ice, excess of ammonia solution added and the liberated oil extracted with light petroleum (BP 60° to 80°C). The extract is dried over anhydrous sodium sulfate and the solvent evaporated to leave an amber syrup (8.8 g) consisting of the cis and trans isomers of 1-(4- methylphenyl)-1-(2-pyridyl)-3-pyrrolidinoprop-1-ene as described in US Patent 2,712,023. The isomers may be separated by base exchange chromatography. The 4-methyl-ω-pyrrolidinopropiophenone required as the starting product for the preparation of the carbinol is prepared by the Mannich reaction (Blicke, Organic Reactions, 1942, vol 1, p 303; Adamson & Billinghurst, Journal of the Chemical Society, 1950,1039) from 4-methylacetophenone and pyrrolidine. The hydrochloride has a MP of 170°C with decomposition.

brand name

Actidil (GlaxoSmithKline); Myidyl (USl).

Therapeutic Function

Antihistaminic

Pharmacokinetics

In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Triprolidine, is a histamine H1 antagonist that competes with histamine for the normal H1-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. Triprolidine has anticholinergic and sedative effects.

Metabolism

Not Available