The synthesis of cyclic and acyclic long-chain arylpiperazine derivatives of salicylamide as serotonin receptor ligands

The 1-arylpiperazine series of N-substituted 1,3 -benzoxazine-2,4-diones as well as 0- and N-substituted salicylamides with an n-propyl chain were synthesized in order to explore the effect of cyclic and acyclic salicylamide moieties on their binding affinity for 5-HT1A, 5-HT2A and 5-HT7 receptor sites. Target compounds 1 and 2 were prepared by a two-step procedure, i.e. by alkylation of 1,3-benzoxazine-2,4-dione or salicylamide with 1,3-dibromopropane and next by condensation of 3-bromopropyl intermediates with arylpiperazines; syntheses of 3-bromopropyl intermediates were performed in solvent-free conditions. Compounds 3 were prepared by hydrolysis of 1. In respect of salicylamide moieties, binding affinities for 5-HT1A and 5-HT7 receptors increase according to the rank of derivatives 3 < 1 < 2, for the same arylpiperazines. Regarding 5-HT2A receptors, increased activity of ligands was changed in reverse order to the affinity for 5-HT1A, i.e. 2 < 1 < 3. 5-HT1A and 5-HT7 receptor binding constants were the highest for the 2-methoxyphenyl ligand 2c, while the 3-chlorophenyl ligand 3b was most active for 5-HT2A receptors.