In preclinical studies, it has been established that the 5-HT2C receptor subtype is involved in the regulation of appetite in animals through the use of 5-HT2C receptor agonists, antagonists, and transgenic mouse models. In clinical studies, the nonse ...
In preclinical studies, it has been established that the 5-HT2C receptor subtype is involved in the regulation of appetite in animals through the use of 5-HT2C receptor agonists, antagonists, and transgenic mouse models. In clinical studies, the nonselective 5-HT2C receptor agonist, m-chlorophenylpiperazine (m-CPP, 5) was shown to decrease food intake and body weight of obese subjects. The main side-effects of hallucinogenesis and valvular hypertrophy are caused by the activation of 5-HT2A and 5-HT2B receptor, respectively. Recently, a series of pyrazinoquinoxalinones, exemplified by 7, were reported by Wyeth-Ayerst as potent and selective 5-HT2C agonists in in vitro and in vivo. Compound 7 is structurally similar to the known nonselective 5-HT2C agonist m-CPP (5). However, 7 was reported to exhibit 5-HT2C agonist binding and functional activity as well as in vivo activity tested using a rat feeding model. It was reasoned that converting quinoxalinone portion of 7 to benzoxazinone and maintaining only two basic nitrogen atoms of the piperazine ring of m-CPP (5) might produce new analogues with improved selectivity and oral potency.
General synthetic route was developed for the preparation of 2,3,4,4a-tetrahydropyrazino[2,1-c][1,4]benzoxazin-5-(1H)-ones as outlined in Scheme 1. (o-Nitrophenyl)piperazine derivatives (8-12) were prepared in excellent yields by heating appropriately substituted o-nitrofluorobenzenes with 4-carbobenzyloxy-2-cyanopiperazine and triethylamine in N,N-dimethylforamide. Reduction of the substituted nitrophenyl to the aniline was accomplished in high yield using iron in acetic acid. Diazotization of the aniline compounds (13-17) followed by hydroxylation of the aryldiazonium salts afforded the phenol intermediates that lactonized under acidic conditions to give benzoxazinones directly. Apparently the phenol intermediates underwent intramolecular Pinner cyclization followed by hydrolysis to afford benzoxazinones under the reaction conditions. Incidentally the carbobenzyloxy-protecting group of the piperazine nitrogen was also hydrolyzed under the acidic reaction conditions to yield the desired products (18-22).
All of the synthesized compounds (18-22) were tested for their 5-HT2C agonist and antagonist binding affinities and these results are presented in Table 1. From the binding data available, it can be generalized that all of the compounds tested displayed a higher selectivity for agonist binding over antagonist binding. Substitution at R1 and/or R2 increased agonist affinity (18 vs 19-22). Disubstitution at R1 and R2 has a pronounced effect on binding affinity compared to no substitution or monosubstitution at R1 and R2 (19 vs 18, 20-22). Monosubstitution at R1 (similar to m-CPP) gave a higher binding affinity (19, 21) than monosubstitution at R2 (20, 22). The most active and selective agonist was dichlorosubstitution at R1 and R2 (19). In general, 2,3,4,4a-tetrahydropyrazino[2,1-c][1,4]benzoxazin-5-(1H)-ones exhibited weaker agonist binding affinities compared to 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)-ones.
From this series, compound 19 emerged as a potent, selective 5-HT2C receptor agonist that could be used as an anoretics for the clinical treatment of obesity.