Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines.
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.
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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.
Audiau
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Barreau
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Blanchard
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JC
Boireau
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Bour
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Coléno
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MA
Doble
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A
Doerflinger
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Huu
C D
CD
Donat
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Duchesne
J M
JM
Ganil
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Guérémy
C
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Honor
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E
Just
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B
Kerphirique
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R
Gontier
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Hubert
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Laduron
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Le Blevec
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Meunier
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Miquet
J M
JM
Nemecek
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Mignani
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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
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