Abstract:Aus den Cyclo‐5‐diazouridin (I) erhält man bei der Hydrolyse unter Ringkontraktion das Triazol‐carbonamid (II), wobei der Reaktionsablauf aufgrund der Umsetzung mit der entsprechenden lgO‐markierten Verbindung sichergestellt werden kann.
“…ACEA-1021, 26 L-687,414, 40 methyl 1,2,3-triazole-4-carboxylate, 20 and 2-amino-5,6-dihydro-4H-1,3-thiazine 25 were prepared by methods in the literature.…”
Section: Methodsmentioning
confidence: 99%
“…Two 1,2,3-triazole derivatives ( 26 and 27 ) bearing amine-containing side chains were prepared. Thus, reaction of 35 with methyl 1,2,3-triazole-4-carboxylate (Scheme ) followed by reduction of 41 to the aldehyde 42 and reductive amination with diethylamine or N -methylpiperazine gave 26 and 27 , respectively. 3 …”
Section: Chemistrymentioning
confidence: 99%
“…Finally, bromination with N-bromosuccinimide afforded 35.Two 1,2,3-triazole derivatives (26 and 27) bearing amine-containing side chains were prepared. Thus, reaction of 35 with methyl 1,2,3-triazole-4-carboxylate20…”
A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor was measured using the specific radioligand [3H]-L-689,560, and functional antagonism was demonstrated by inhibition of NMDA-induced depolarizations of rat cortical wedges. The ability to prevent NMDA-induced hyperlocomotion in mice in vivo was measured for selected compounds. Binding affinity increased significantly if the heterocyclic group, e.g. 1,2,3-triazol-1-yl could participate in accepting a hydrogen bond from the receptor. It was difficult to obtain compounds with adequate aqueous solubility and strategies to improve it were investigated. The most potent compound in this series, 6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-dione (17) (binding IC50 = 2.6 nM; cortical wedge EC50 = 90 nM), inhibited NMDA-induced hyperlocomotion in mice (6/9 protected at 20 mg/kg iv). Pharmacokinetic parameters, including extent of brain penetration, for 11 and 17 are reported.
“…ACEA-1021, 26 L-687,414, 40 methyl 1,2,3-triazole-4-carboxylate, 20 and 2-amino-5,6-dihydro-4H-1,3-thiazine 25 were prepared by methods in the literature.…”
Section: Methodsmentioning
confidence: 99%
“…Two 1,2,3-triazole derivatives ( 26 and 27 ) bearing amine-containing side chains were prepared. Thus, reaction of 35 with methyl 1,2,3-triazole-4-carboxylate (Scheme ) followed by reduction of 41 to the aldehyde 42 and reductive amination with diethylamine or N -methylpiperazine gave 26 and 27 , respectively. 3 …”
Section: Chemistrymentioning
confidence: 99%
“…Finally, bromination with N-bromosuccinimide afforded 35.Two 1,2,3-triazole derivatives (26 and 27) bearing amine-containing side chains were prepared. Thus, reaction of 35 with methyl 1,2,3-triazole-4-carboxylate20…”
A series of 6,7-dichloro-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-diones (1-17) were prepared in which the 5-position substituent was a heterocyclylmethyl or 1-(heterocyclyl)-1-propyl group. Structure-activity relationships were evaluated where binding affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor was measured using the specific radioligand [3H]-L-689,560, and functional antagonism was demonstrated by inhibition of NMDA-induced depolarizations of rat cortical wedges. The ability to prevent NMDA-induced hyperlocomotion in mice in vivo was measured for selected compounds. Binding affinity increased significantly if the heterocyclic group, e.g. 1,2,3-triazol-1-yl could participate in accepting a hydrogen bond from the receptor. It was difficult to obtain compounds with adequate aqueous solubility and strategies to improve it were investigated. The most potent compound in this series, 6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H, 4H)-quinoxaline-2,3-dione (17) (binding IC50 = 2.6 nM; cortical wedge EC50 = 90 nM), inhibited NMDA-induced hyperlocomotion in mice (6/9 protected at 20 mg/kg iv). Pharmacokinetic parameters, including extent of brain penetration, for 11 and 17 are reported.
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