It has been suggested that ramatroban, by modulatingDP2 receptor, can reverse viremia-associated proinflammatory and prothrombotic processes which are similar to those induced bySARS-Cov-2.[citation needed] Hence, ramatroban, that has been used for the treatment of allergic rhinitis in Japan for the past two decades with a well established safety profile, merits investigation as a novel immunotherapy for the treatment ofCOVID-19 disease, although no clinical trial has yet been conducted.[6]
Ramatroban was developed by the German pharmaceutical companyBayer AG and is co-marketed inJapan by Bayer Yakuhin then marketed by Kyorin Pharmaceutical and Nippon Shinyaku Co., Ltd. under the trade nameBaynas.
The starting material is called1,4-cyclohexanedione monoethylene glycol ketal aka 1,4-Dioxaspiro[4.5]decan-8-one [4746-97-8]. TheBorsche–Drechsel cyclization between (1) andPhenylhydrazine gives 5-Oxo-tetrahydrocarbazole ethylene ketal [54621-12-4] (2). Hydrolysis of the ketal protecting group gives 1,2,4,9-tetrahydrocarbazol-3-one [51145-61-0] (3). Reduction of the ketone with sodium borohydride gives 2,3,4,9-tetrahydro-1H-carbazol-3-ol [14384-34-0] (4). Acetylation by treatment with vinyl acetate [108-05-4] gives (3R)-3beta-Acetoxy-1,2,3,4-tetrahydro-9H-carbazole, PC59051734 (5a) & (3S)-1,2,3,4-Tetrahydro-9H-carbazole-3-ol, PC8142712 (5b). These can be separated at this stage into pure (S) for the next step. AMitsunobu reaction in the presence ofDPPA leads to an Azide with pureWalden inversion kinetics w/o racemization. TheStaudinger reduction of the azide in situ gives (R)-3-Amino-1,2,3,4-tetrahydrocarbazole [874-937-6] [116650-33-0] (6).
^"Ramatroban (compound)".PubChem. National Center for Biotechnology Information. Retrieved22 June 2019.
^Sugimoto H, Shichijo M, Iino T, Manabe Y, Watanabe A, Shimazaki M, et al. (April 2003). "An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro".The Journal of Pharmacology and Experimental Therapeutics.305 (1):347–352.doi:10.1124/jpet.102.046748.PMID12649388.S2CID10016709.
^Endo S, Akiyama K (November 1996). "[Thromboxane A2 receptor antagonist in asthma therapy]".Nihon Rinsho. Japanese Journal of Clinical Medicine (in Japanese).54 (11):3045–3048.PMID8950952.
^Busto E, Gotor-Fernández V, Gotor V (May 2012). "Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases".The Journal of Organic Chemistry.77 (10):4842–8.doi:10.1021/jo300552v.hdl:10651/7247.PMID22515546.
^Rosentreter U, Böshagen H, Seuter F, Perzborn E, Fiedler VB (December 1989). "Synthesis and absolute configuration of the new thromboxane antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropan oic acid and comparison with its enantiomer".Arzneimittel-Forschung.39 (12):1519–21.PMID2624597.
