- Synthesis and quantitative structure-activity relationships of anticonvulsant 2,3,6-triaminopyridines
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The synthesis of 2,3,6-triaminopyridine derivatives, representing a unique chemical structure for anticonvulsants, is described. The synthetic program was performed (a) to identify more potent analogs, (b) to determine structural properties controlling potency as well as neurotoxicity, and (c) to reduce the requirements for animal testing. As a result, besides other structural properties, the overall molecular lipophilicity (log k', octanol- coated column) explained changes in anticonvulsant potency and neurotoxicity. Mimicking the interaction of the amphiphilic triaminopyridines with biological membranes, NMR experiments in the presence of lecithin vesicles were conducted in order to measure the phospholipid-binding parameter log Δ(1/T2). Replacement of log k' with log Δ(1/T2) in the correlation analysis afforded a more significant equation describing the anticonvulsant activity of 21 derivatives.
- Seydel,Schaper,Coats,Cordes
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p. 3016 - 3022
(2007/10/02)
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- 2,3-Dihydrospiro[1H-4- and 5-azabenzimidazole-2,1'-cyclohexane] (= spiro[cyclohexane-1,2'(3'H)-1'H-imidazo[4,5-b]pyridine] and spiro[cyclohexane-1,2'(3'H)-1'H-imidazo[4,5-c]pyridine]): Reactions with nucleophiles
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The readily available title compounds 4a and 24 react with N-, O-, S-, and C-nucleophiles in presence of MnO2 to give the corresponding mono- or disubstituted 2H-azabenzimidazoles (= azaisobenzimidazoles), e.g., 11-18 and 26a-h, respectively, or 2,3-dihydro-1H-azabenzimidazoles (= dihydro-azabenzimidazoles) such as 9 and 10 and 27 and 28, respectively, by a 1,4- or 1,6-Michael addition (Schemes 2 and 4). The bromo-dihydro-1H-azabenzimidazole 4b lost the Br-atom when treated with piperidine or morpholine yielding the corresponding disubstituted 2H-azabenzimidazole 21 (Scheme 3). Reductive ring opening of the substituted spiro compounds leads to mono- and disubstituted diaminopyridines which are intermediates for fused pyridine ring systems with substituents often not available by conventional routes and of potential pharmaceutical interest (see 32-37). E.g., starting from 4a, a three-step synthesis of the analgesic flupirtine maleate (= ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate maleate = Katadolon; 39) and of its non-fluorinated derivative D-7195 is described. Its analogue 40 was similarly made from the spiro compound 24.
- Schwoch,Kramer,Neidlein,Suschitzky
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p. 2175 - 2190
(2007/10/02)
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