Benzodiazepine receptor ligands. Synthesis and pharmacological evaluation of 3-, 7- and 8-substituted [5,1-c][1,2,4]benzotriazines and 5-oxide derivatives. Part I

Synthesis and Pharmacological Evaluation of Novel GABAA Subtype Receptor Ligands with Potential Anxiolytic‐like and Anti‐hyperalgesic Effect

“…All compounds described here are listed in Table . A first attempt to obtain the 3‐iodo‐7‐arylalkylaminopyrazolo[5,1‐c][1,2,4]benzotriazine derivatives was made starting from compound 1 , the 7‐aminopyrazolo[5,1‐c][1,2,4]benzotriazine that was undergone to reductive N‐alkylation by using the suitable aromatic aldehyde and sodium cianoborohydride in the presence of Lewis acid as ZnCl 2 . The first term of this series, the 7‐benzylamino derivative 3 , was easily obtained through the intermediate Schiff base ( 2 ) that was isolated and reduced.…”

“…Thus, because the final iodination represented the critical step to obtain the desired compounds, we followed a different synthetic strategy using the 3‐iodio‐7‐aminopyrazolo[5,1‐c][1,2,4]pyrazolobenzotriazine, 6a , as key intermediates (Scheme ). This compound was indifferently obtained either by acid hydrolysis of 5 or by reduction with SnCl 2 of 8 synthesized from the corresponding 3‐unsubstituted compounds 4 and 7 , respectively , by treatment with iodine monochloride. Instead, to obtain the 3‐methyl‐7‐aminopyrazolo[5,1‐c][1,2,4] pyrazolobenzotriazine, 6b , the reduction of 9 (3‐carboxylic derivative) with borane dimethyl sulfide complex (Me 2 SBH 3 ) was performed (Scheme ).…”

“…Reagents and conditions: (i) ICl/CH 2 Cl 2 ; (ii) HCl, NaOH; (iii) SnCl 2 /EtOH; (iv) THF/(CH 3 ) 2 SBH 3 . a See . b See .…”

“…A solution of 7‐aminopyrazolo[5,1‐c][1,2,4]benzotriazine ( 1 ) (0.25 mmol) in methanol (10 mL) and five drops of acetic acid was maintained under anhydrous N 2 for 1 h. Benzaldehyde (1:1, 0.026 mL) was added, and the reaction was maintained under reflux until the starting material disappeared (TLC). The solvent was evaporated to dryness, and the formation of the intermediate Base of Schiff 2 was evaluated by 1 H‐NMR on raw material.…”

“…From 4 ; yellow crystals; yield 70% from ethanol; TLC eluent: toluene/ethyl acetate/methanol 8:2:1 v /v/v; IR ν cm −1 3214, 1680; 1 H‐NMR (DMSO‐d 6 ) δ 10.56 (s, 1H, NH exch. ); 9.01 (d, 1H, H‐6); 8.52 (s, 1H, H‐2); 8.42 (d, 1H, H‐9); 8.15 (dd, 1H, H‐8); 2.12 (s, 3H, CH 3 ).…”