Patent Evaluation: CNS Azole-Alkyl-Piperidine Analogues of the Azapirones

Summary

Novelty: 1,4-Disubstituted piperazines are claimed as novel treatments for anxiety, depression, and similar CNS disorders, as well as hypertension.

Biology: In vivo anxiolytic activity was tested using a conditioned avoidance response paradigm. The preferred compounds, 1 and 2, have oral ED₅₀'s of 6.1 and 6.3 mg/kg, respectively, compared to 17.2 and 26.1 for buspirone and ipsapirone, respectively. The preferred compound 3, unlike buspirone and ipsapirone, demonstrated anxiolytic activity in an addiction (to diazepam, alcohol, cocaine and nicotine) withdrawal paradigm (Costall et al. J. Pharm. Pharmacol. (1988) 40:494-500). The method of Janssen et al. (Arzheim. Forsch. (1963) 13:205) was used to test the ability of these compounds to antagonize the hypertensive effects of noradrenaline. The preferred compound 4, at dose of 0.18 mg/kg ip, protected 50% of the rats from death by hypertensive crisis induced by the iv injection of noradrenaline.

Chemistry: Examples of nine standard syntheses of the compounds are given. Forty-five compounds are specifically claimed and characterized by mp, IR and NMR. The specified compound is 1-[4-[4[(2-pyrimidinyl)-1-piperazinyl]butyl]-1 H-benzimidazole (1).

Structure: