Description
Betotastine was introduced in Japan for the treatment of allergic rhinitis. This
structurally-related derivative of chlorpheniramine and ebastine is prepared by
condensation of optically-resolved 4-[1-(4-chlorophenyl)-1-(2-pyridyl)-methoxy]piperidine
with ethyl 4-bromobutyrate followed by ester hydrolysis. Betotastine is the seventh
marketed non-sedating histamine H
1 antagonist. Its very low sedative side effect is due to
very poor penetration in the central nervous system. Besides its potent and long-acting
activity in models of allergic rhinitis, betotastine was also shown to act as a PAF antagonist and inhibit LTD
4 in tracheal smooth muscle and ileum, IL-5 production by human peripheral
blood mononuclear cells as well as eosinophil infiltration in the airway and peripheral
blood. As a consequence, it is currently being developed against other allergic and
respiratory disorders.
Description
Bepotastine is an antagonist of the histamine H
1 receptor that is selective over H
3, α
1-, α
2-, and β-adrenergic, dopamine D
2long, serotonin 5-HT
2, muscarinic acetylcholine, and benzodiazepine receptors. It reduces dye leakage from the nasal passages of rats acutely sensitized to an antigen (ED
50 = 0.03 mg/kg) and inhibits histamine-induced bronchoconstriction in the anesthetized dog (ED
50 = 3.2 μg/kg). Bepotastine prevents conjunctival vascular hyperpermeability in a guinea pig model of conjunctivitis in a dose-dependent manner. Formulations containing bepotastine have been used in the treatment of itching associated with allergic conjunctivitis.
Chemical Properties
Off-White to Light Beige Solid
Uses
Bepotastine is a histamine H1 receptor anatagonist. Bepotastine suppresses some allergic inflammatory processes such as allergic rhinitis, chronic urticaria or pruritus associated with skin conditions
(eczema/dermatitis, prurigo or pruritus cutaneus).
Uses
Bepotastine is a non-sedating, selective antagonist of histamine 1 (H1) receptor with pIC50 of 5.7
Definition
ChEBI: An organosulfonate salt obtained by combining equimolar amounts of bepotastine and benzenesulfonic acid. A topical, selective and non-sedating histamine (H1) receptor antagonist used for treatment of itching associated with allergic co
junctivitis.
Manufacturing Process
Manufacturing process for BEPOTASTINE BESILATE includes these steps as follows: Step A: Synthesis of Methyl 2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8b-tetrahydro-
1H-5-cyclopenta[b]benzofurancarboxylate,Step B: Synthesis of Methyl 3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7-
dioxin o[5,4-a]cyclopenta[b]benzofurancarboxylate,Step C: Synthesis of 3-Methyl-trans-4a-cosoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7-
dioxino[5,4-a]cyclopenta[b]benzofuranylmethanol,Step D: Synthesis of 7-Chloromethyl-3-methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10chexahydrodioxino[5,4-a]cyclopenta[b]benzofuran,Step E: Synthesis of 4-[3-Methyl-trans-4a-cisoid-4a,5a-cis-5a-1,4a,5,5a,10b,10c-hexahydro-7-
dioxino[5,4-a]cyclopenta[b]benzofuranyl]butyric acid, Step F: Synthesis of Methyl 4-[2-endo-hydroxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5- cyclopenta[b]benzofuranyl]butyrate, Step G: Synthesis of Methyl 4-[2-endo-acetoxy-1-exo-hydroxymethyl-3a,8b-cis-2,3,3a,8btetrahydro-1H-5-cyclopenta[b]benzofuranyl]butyrate, Step H: Synthesis of Methyl ester of 11,15-dideoxy-11-acetoxy-16-methyl-15-oxo-18,19-
tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2,Step I: Synthesis of 11-Deoxy-11-acetoxy-16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-mphenylene PGI2.To a solution of 54 mg of methyl ester of 11-deoxy-11-acetoxy-16-methyl-
18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2 in 4.5 ml of
anhydrous methanol was added 0.001 ml of 4.8 N sodium methoxide under
argon, and the reaction mixture was stirred for 1.5 hours at room
temperature.
After addition of acetic acid to the reaction mixture and concentration of the
mixture, the residue was dissolved in 20 ml of ethyl acetate, and the solution
was washed with aqueous saturated solution of sodium hydrogen carbonate,
water and aqueous saturated solution of sodium chloride, dried and
concentrated to afford 55 mg of an oily material.
This oily material was purified by column chromatography using ethyl acetate
and cyclohexane (3:1) as eluent to give 48 mg of the methyl ester of 16-
methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2.
Therapeutic Function
Antiallergic
References
[1] M KATO. Pharmacokinetic and pharmacodynamic evaluation of central effect of the novel antiallergic agent betotastine besilate.[J]. Arzneimittel-Forschung-Drug Research, 1997, 47 10: 1116-1124.
[2] T MURATA. [Effect of betotastine besilate (TAU-284), a novel anti-allergic agent, on experimental allergic rhinitis].[J]. Arerugi = [Allergy], 1997, 46 7: 576-584.
[3] De Souza, F.I., Zumiotti, A.V., and Da Silva, C.F. Neuregulins 1-α and 1-β on the regeneration the peripheral nerves[J]. Acta Ortop Bras.
[4] TETSUO KIDA. Bepotastine besilate, a highly selective histamine H1 receptor antagonist, suppresses vascular hyperpermeability and eosinophil recruitment in in vitro and in vivo experimental allergic conjunctivitis models[J]. Experimental eye research, 2010, 91 1: Pages 85-91. DOI:
10.1016/j.exer.2010.04.006
