80012-43-7

Epinastine hydrochloride, an orally active antihistaminic agent, was marketed in Japan for the treatment of bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, and psoriasis vulgaris.Epinastine is one of the most effective peripherally acting histamine H₁-receptor antagonists without sedative effects.In addition, it exhibits potent anti-PAF and anti-LT activity which may also contribute significantly to its antiallergic activity. Chronic epinastine has been reported to effectively inhibit airway hyper-responsiveness in rats. Potent inhibitory effects of epinastine on bronchoconstriction induced by histamine and bradykinin, but not by other chemical mediators, has also been reported. Studies have indicated that there are no significant differences in pharmacological properties among D-, L-, and racemic epinastine.

Boehringer lngelheim (Germany)

Epinastine is antihistamine and mast cell stabilize that is used in eye drops for the treatment of allergic conjunctivitis.

ChEBI: A benzazepine that is 6,11-dihydro-5H-dibenzo[b,e]azepine in which the azepine ring is fused to the e side of 4,5-dihydro-1H-imidazol-2-amine.

Aleslon

Epinastine is a potent, long-acting H1 antihistamine and an inhibitor of the release of histamine and other transmitters from mast cells. It has some affinity for H2 receptors as well. It is used as an eye drop for allergic conjunctivitis. It does not penetrate into the CNS and is classified as a nonsedating antihistamine.

Several patents on the synthesis of epinastin (VIII) have appeared in Europe and Japan. The synthesis described below is taken partly from the US patent and a Japanese patent. All the syntheses utilized 6-aminomethyl-6,11-dihydro-5H-dibenzo[b.e]azepine (80) as the key intermediate which was converted to the final guanidine epinastine by reacting with cyanogen bromide. The solution of 80 in ethanol was treated with a solution of cyanogen bromide in THF at room temperature and stirred overnight. The hydrobromide salt was collected in 79% yield after adding ether to the reaction mixture. The salt was free based with a solution of sodium hydroxide and then treated with an ethereal solution of HCl to obtain the epinastine hydrochloride salt VIII. For the preparation of the key intermediate, chloroimine 78, presumably obtained from ketone 77 via Beckmann rearrangement, was reacted with sodium cyanide in DMSO to give the nitrile 79 in 70% yield. Reduction of the imino nitrile was carried out in THF in the presence of an acid with LAH to give the key intermediate 80 in 67% yield.
An alternate approach to preparation of 80 is shown in Scheme 8 as well. Reaction of the commercially available chloride 81 with phthalimide in the presence of a base gave the phthalimide 82. Reduction of the imine with sodium borohydride gave 83, which was then reacted with hydrazine hydrate to free up the amine in 90% yield. The amine intermediate was isolated as the fumarate salt.

4°C, protect from light, stored under nitrogen