5-aryl-imidazo[2,1-c][1,4]benzodiazepine derivatives as tricyclic constrained analogues of diazepam and Ro5-4864. Synthesis and binding properties at peripheral and central benzodiazepine receptors.
Four series of 5-aryl-imidazo[2,-c][1,4]benzodiazepine derivatives 1a-f, 2a-f, 3a-f, and 4a-f were synthesized and tested for their affinity at both the peripheral and central benzodiazepine receptors. Among the four series, only N-10 and C-11 sites were changed, mainly [N(CH3)-CO], [N=CH], [NH-CO], [NH-CH2], and in each series the halogen site was varied at the positions C-7, C-2', and C-4'. In particular, 10-methyl-benzodiazepinones 1a and 1b were designed as tricyclic constrained analogues of diazepam and Ro5-4864. All the tested compounds did not show significant binding activity at central benzodiazepine receptors, but relatively good PBzR binding affinities were found for 10-methyl-benzodiazepinone 1c and benzodiazepines 2b, c. Benzodiazepinones 3a-f were prepared by cyclization with 1,1'-carbonyldiimidazole of the corresponding 2-(aryl-imidazol-1-yl-methyl)-arylamines, obtained from the suitable (2-amino-aryl)-aryl-methanols with 1,1'-carbonyldiimidazole in different conditions. N-Alkylation of 3a-f to 1a-f was achieved using dimethylformamide-dimethylacetal. Reduction of 3a-f to 4a-f was accomplished with lithium aluminum hydride or borane and oxidation of 4a-f to 2a-f was performed with manganese (IV) oxide.
Rizzetto
E
E
Dipartimento di Scienze Farmaceutiche, Trieste, Italy. erizzetto@units.it
Castellano
S
S
Florio
C
C
Vadori
M
M
Stefancich
G
G
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D001570:Benzodiazepinones / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D002490:Central Nervous System / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007546:Isoquinolines / Q000493:pharmacokinetics; D017933:Peripheral Nervous System / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*
D001570:Benzodiazepinones; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D007546:Isoquinolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C028513:4'-chlorodiazepam; D003975:Diazepam; C037850:PK 11195