87233-62-3

White or yellowish powder

Antihistaminic, H1-receptor; asthma prophylactic; anti-allergic.

ChEBI: The fumaric acid salt of emedastine containing two molecules of fumaric acid for each molecule of emedastine. A relatively selective histamine H1 antagonist, it is used for allergic rhinitis, urticaria, and pruritic skin disorders, and in eyedrops for the symptomatic relief of allergic conjuntivitis.

Emadine (Alcon).

A poison by ingestion.

Emedastine difumarate, a potent H₁-receptor antagonist, was launched in Japan for the treatment of allergic rhinitis and urticaria. Emedastine exerts its antiallergic effect via inhibition of substance P-induced histamine release. It has been demonstrated both in vitro and in vivo that this effect is mediated by the inhibition of Ca²⁺release from extracellular stores and of Ca²⁺ influx into mast cells. In a clinical trial with bronchial asthma, emedastine improved asthmatic symptoms in 55.3% of patients.

Emedastine is a histamine H₁ receptor antagonist (K_i = 1.3 nM). It is selective for histamine H₁ over H₂ and H₃ receptors (K_is = 49 and 12.43 μM, respectively), as well as α₁-, α₂-, and β₁-adrenergic and dopamine D₁ and D₂ receptors, and the serotonin (5-HT) receptor subtypes 5-HT₁ and 5-HT₂ at 10 μM. Emedastine inhibits histamine-induced phosphoinositide turnover and intracellular calcium mobilization in primary human conjunctival epithelial cells (HCECs; IC₅₀s = 1.6 and 2.9 nM, respectively). It also inhibits histamine-stimulated secretion of IL-6, IL-8, and GM-CSF by primary HCECs (IC₅₀s = 2.23, 3.42, and 1.50 nM, respectively). Ocular application of emedastine prior to histamine challenge inhibits vascular permeability in guinea pigs. Formulations containing emedastine have been used in the treatment of allergic conjunctivitis.

Kanebo (Japan)

Preparation of 2-(4-methyl-1-piperazinyl)benzimidazole. A mixture of 2- chlorobenzimidazole (10.00 g) and N-mehylpiperazine (20.00 g) is stirred at 125°C for 5 hours. A 10% aqueous sodium hydroxide (100 ml) is added to the reaction mixture, and the precipitated crystals are separated by filtration. The filtrate is extracted with chloroform, and the chloroform extract is evaporated to dryness to give the same crystals. The crystals are combined and recrystallized from water-methanol to give 2-(4-methyl-1- piperazinyl)benzimidazole (7.02 g) as colorless needles, m.p. 225°-226°C.
2-(4-Methyl-1-piperazinyl)benzimididazole (5.00 g) prepared as above is dissolved in N,N-dimethylformamide (50 ml) and thereto is added sodium hydride (concentration: 50%) (1.50 g) at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added 2-bromoethyl ethyl ether (4.00 g), and the mixture is stirred at 70°C for 10 hours. To the reaction mixture is added water (150 ml), and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a brown oily substance (5.40 g). The brown oily substance is treated with fumaric acid (3.26 g) in hot ethanol. The crude crystals thus obtained are recrystallized from ethyl acetate-ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole 3/2 fumarate (6.31 g) as colorless plates, melting point 167.5°-168.5°C. Elementary analysis for C22H30N4O7: Calcd. (%): C, 57.13; H, 6.54; N, 12.11; Found (%): C, 57.04; H, 6.44; N, 12.02.
1-[2-(Ethoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole can be prepared using 2-chloro-(1-[2-(ethoxy)ethyl]benzimidazole), (last one can be produced from 2-bromoethyl ethyl ether 2-chlorobenzimidazole) and N-methylpiperazine and fumaric acid there are obtained crude crystals, which are recrystallized from ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-methyl-1- piperazinyl)benzimidazole 3/2 fumarate. This product has the same physical properties as those of the product above described.

Antiallergic, Antihistaminic

[1] N A SHARIF  J M Y  S X Su. Emedastine: a potent, high affinity histamine H1-receptor-selective antagonist for ocular use: receptor binding and second messenger studies.[J]. Journal of ocular pharmacology, 1994, 10 4: 653-664. DOI: 10.1089/jop.1994.10.653
[2] J M YANNI. Preclinical efficacy of emedastine, a potent, selective histamine H1 antagonist for topical ocular use.[J]. Journal of ocular pharmacology, 1994, 10 4: 665-675. DOI: 10.1089/jop.1994.10.665
[3] SHARIF N.A. . Human Conjunctival Epithelial Cells Express Histamine-1 Receptors Coupled to Phosphoinositide Turnover and Intracellular Calcium Mobilization: Role in Ocular Allergic and Inflammatory Diseases[J]. Experimental eye research, 1996, 63 2: Pages 169-178. DOI: 10.1006/exer.1996.0105
[4] L K WEIMER  J M Y  D A Gamache. Histamine-stimulated cytokine secretion from human conjunctival epithelial cells: inhibition by the histamine H1 antagonist emedastine.[J]. International Archives of Allergy and Immunology, 1998, 115 4: 288-293. DOI: 10.1159/000069459