title: Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines.
abstract: 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-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) 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 beta-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, ED(50) = 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.
authors.affiliation: Rhône-Poulenc S.A., Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesde, B.P. 14, F 94403 Vitry-sur-Seine Cedex, France.
authors.forename: P
authors.initials: P
authors.lastname: Jimonet
authors.forename: F
authors.initials: F
authors.lastname: Audiau
authors.forename: M
authors.initials: M
authors.lastname: Barreau
authors.forename: J C
authors.initials: JC
authors.lastname: Blanchard
authors.forename: A
authors.initials: A
authors.lastname: Boireau
authors.forename: Y
authors.initials: Y
authors.lastname: Bour
authors.forename: M A
authors.initials: MA
authors.lastname: Coléno
authors.forename: A
authors.initials: A
authors.lastname: Doble
authors.forename: G
authors.initials: G
authors.lastname: Doerflinger
authors.forename: C D
authors.initials: CD
authors.lastname: Huu
authors.forename: M H
authors.initials: MH
authors.lastname: Donat
authors.forename: J M
authors.initials: JM
authors.lastname: Duchesne
authors.forename: P
authors.initials: P
authors.lastname: Ganil
authors.forename: C
authors.initials: C
authors.lastname: Guérémy
authors.forename: E
authors.initials: E
authors.lastname: Honor
authors.forename: B
authors.initials: B
authors.lastname: Just
authors.forename: R
authors.initials: R
authors.lastname: Kerphirique
authors.forename: S
authors.initials: S
authors.lastname: Gontier
authors.forename: P
authors.initials: P
authors.lastname: Hubert
authors.forename: P M
authors.initials: PM
authors.lastname: Laduron
authors.forename: J
authors.initials: J
authors.lastname: Le Blevec
authors.forename: M
authors.initials: M
authors.lastname: Meunier
authors.forename: J M
authors.initials: JM
authors.lastname: Miquet
authors.forename: C
authors.initials: C
authors.lastname: Nemecek
authors.forename: S
authors.initials: S
authors.lastname: Mignani
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid; D000860:Hypoxia / Q000401:mortality; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C120789:2-imino-3-(2-methylsulfinylethyl)-6-trifluoromethoxy-2-benzothiazoline; C120790:2-imino-3-(2-methylthioethyl)-6-trifluoromethoxy-2-benzothiazoline; D052160:Benzothiazoles; D018691:Excitatory Amino Acid Antagonists; D007097:Imines; D018696:Neuroprotective Agents; D013454:Sulfoxides; D013844:Thiazoles; D018698:Glutamic Acid; D019782:Riluzole