Riluzole Series. Synthesis and in Vivo “Antiglutamate” Activity of 6-Substituted-2-benzothiazolamines and 3-Substituted-2-imino-benzothiazolines

• Published in: Journal of medicinal chemistry Vol. 42; no. 15; pp. 2828 - 2843
• Main Authors: Jimonet, Patrick, Audiau, François, Barreau, Michel, Blanchard, Jean-Charles, Boireau, Alain, Bour, Yvette, Coléno, Marie-Annick, Doble, Adam, Doerflinger, Gilles, Do Huu, Claudine, Donat, Marie-Hélène, Duchesne, Jean Marie, Ganil, Pierre, Guérémy, Claude, Honoré, Eliane, Just, Bernard, Kerphirique, Roselyne, Gontier, Sylvie, Hubert, Philippe, Laduron, Pierre M, Le Blevec, Joseph, Meunier, Mireille, Miquet, Jean-Marie, Nemecek, Conception, Pasquet, Martine, Piot, Odile, Pratt, Jeremy, Rataud, Jean, Reibaud, Michel, Stutzmann, Jean-Marie, Mignani, Serge
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29.07.1999
• Subjects: Animals; Benzothiazoles; Biological and medical sciences; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Glutamic Acid; Hypoxia - mortality; Imines - chemical synthesis; Imines - chemistry; Imines - pharmacology; Injections, Intraventricular; Male; Medical sciences; Mice; Neuropharmacology; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Riluzole - analogs & derivatives; Riluzole - chemical synthesis; Riluzole - chemistry; Riluzole - pharmacology; Seizures - chemically induced; Seizures - prevention & control; Structure-Activity Relationship; Sulfoxides - chemical synthesis; Sulfoxides - chemistry; Sulfoxides - pharmacology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Sulfur nitrogen heterocycle; Rodentia; Anticonvulsant; Neuroprotective agent; Glutamate receptor; Haloether; Benzothiazole derivatives; Riluzole; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Structure activity relation; Mouse; Animal; Intracerebral administration; Tertiary amine; Bicyclic compound; Aromatic compound; Antagonist; Fluorine Organic compounds; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980202u

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo “antiglutamate” activity were the 6-OCF3 (riluzole), 6-OCF2CF3, 6-CF3, and 6-CF2CF3 substituted derivatives with ED50 values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a β-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED50 = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.