4- Arylpiperazines

Although A-aUcyl- and A-arylpiperazines abound in the pyrazine literature, ° the corresponding reduced quinoxalines are rarely encountered. However, reductive alkylation of quinoxaline gave products such as l,4-diethyl-l,2,3,4-tetrahydroqui-noxaline (see Section 2.1.3), and several other typical preparative routes are illustrated in the following examples. 

N-Arylpiperazin-2-ones, N-arylpiperazin-2,5-diones and N-aryl-3,4-dihydro-quinolin-2(lff)-ones have been synthesized via a microwave-enhanced Goldberg reaction [105]. N-arylation reactions with 4-benzylpiperazin-2-one and 4-benzylpiperazin-2,5-dione performed in the microwave (reflux conditions) were tremendously accelerated in comparison with the same transformations performed under classical heating at reflux (Schemes 103 and 104). The phenylation of 3,4-dihydroquinolin-2(lH)-one under microwave irradiation was also faster but less pronounced. 

HYBOT Hydrogen Bond Thermodynamics LCAP Long-chain arylpiperazine... 

Arylpiperazines have immensely important effects on various and diverse biological targets, in particular on CNS receptors. In the case of serotonin (5-HT) receptors, compounds containing this arylpiperazine moiety represent the largest systematically studied class of 5-HTia receptor ligands [63]. Structural alterations within long-chain arylpiperazines (LCAPs) occur mainly at the two opposite ends of a molecule and have been described by many authors [64-71]. 

Paluchowska et al. (2002) reported the synthesis, pharmacological studies, and conformational analysis utilizing classical molecular modeling approaches of some arylpiperazine or 1,2,3,4-tetrahydroisoquinoline derivatives of the known and flexible 5-HT ia receptor ligands with different intrinsic activities at nanomolar levels [63]. The SAR is shown in Table 4. The synthetic steps involved for some of the compounds mentioned in Table 4 are shown in Scheme 2 [63]. 

Paluchowska MH et al. (2002) Active conformation of some arylpiperazine postsynap-tic 5-HT(lA) receptor antagonists. Eur J Med Chem 37(4) 273-283... 

Glennon RA et al. (1988) Arylpiperazine derivatives as high-affinity 5-HTlA serotonin ligands. J Med Chem 31(10) 1968-1971... 

Mokrosz JL et al. (1995) Structure-activity relationship studies of CNS agents, XIX Quantitative analysis of the alkyl chain effects on the 5-HTlA and 5-HT2 receptor affinities of 4-alkyl-1-arylpiperazines and their analogs. Arch Pharm (Weinheim) 328(2) 143-148... 

Lopez-Rodriguez ML et al. (1996) Synthesis and structure-activity relationships of a new model of arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-l-yl]methyl]-1, 3-dioxoperhydroimidazo[l,5-alpha]pyridine a selective 5-HTlA receptor agonist. J Med Chem 39(22) 4439-4450... 

Compared to other classes of vanilloid antagonists, the 4-hetero-arylpiperazine-1-carboxamides are characterized by the presence of a mildly basic nitrogenous polar head. Based on the published studies [79, 82], the structure-activity relationships of this class of vanilloid antagonists can be summarized as follows ... 

The glass plate was exposed to microwave irradiation, eluted, and viewed by standard TLC visualization procedures to assess the results of the reaction. In this particular example, the synthesis of an arylpiperazine library (Scheme 4.25) was described, but the simplicity and general utility of the approach for the rapid screening of solvent-free microwave reactions may make this a powerful screening and reaction optimization tool. The synthesized compounds were later screened for their antimicrobial activity without their removal from the TLC plate utilizing bioautogra-phical methods [84],... 

Cocchi, M., Fanelli, F., Menziani, M.C. and De Benedetti, P.G. (1997) Conformational analysis and theoretical quantitative size and shape-affinity relationships of N4-protonated Nl-arylpiperazine 5-HT1A seroto-ninergic ligands. Journal of Molecular Structure (Theochem), 397, 129-145. 

Kuipers, W., van Wijngaarden, I., Kruse, C.G., ter Horst-van Amstel M., Tulp, M. T. and IJzerman, AP. (1995) N4-Unsubstituted Nl-arylpiperazines as high-affinity 5-HT1A receptor ligands. Journal of Medicinal Chemistry, 38,1942-1954. 

Menziani, M.C., De Benedetti, P.G. and Karelson, M. (1998) Theoretical descriptors in quantitative structure-affinity and selectivity relationship study of potent N4-substituted arylpiperazine... 

F. (2006) A genetic-function-approximation-based QSAR model for the affinity of arylpiperazines toward alphal adrenoceptors. Journal of Chemical Information and Modeling, 46, 1466-1478. 

Lopez-Rodrigues, M.L., Ayala, D., Benhamu, B., Morcillo, M.J. and Viso, A. (2002) Arylpiperazine derivatives acting at 5-HTia receptors. Current Medicinal Chemistry, 9, 441-469. 

Lopez-Rodriguez, M.L., Morcillo, M.J., Fernandez, E., Porras, E., Murcia, M., Sanz, A.M. and Orensanz, L. (1997) Synthesis and structure-activity relationships of a new model of arylpiperazines. 3.2-[o-(4-Arylpiperazin-l-yl)alkyl]perhydropyrrolo-[l,2-c] imidazoles and -perhydroimidazo[l,5-a] pyridines study of the influence of the terminal amide fragment on 5-HTiA affinity/selectivity. Journal of Medicinal Chemistry, 40, 2653—2656. 

Illescas BM, Martinez-Alvarez R, Femandez-Gadea J, Martin N (2003) Synthesis of water soluble fulleropyrrolidines bearing biologically active arylpiperazines. Tetrahedron 59 6569-6577. 

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