A-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. 

An interesting example of a restructured ring system was designed by Meyer et al. for the design of 5-methoxy-hexahydro-l//-benz[f]isoindole as a surrogate of the very frequently used ort/to-methoxy-A-arylpiperazine. It led... 

A vast array of structurally unrelated compounds interacts with a I-adrenoreceptor subtypes, which makes it inherently difficult to determine the structural requirements leading to receptor subtypes selectivity (Ruffolo et al., 1995 Leonard et al., 1996 Kenny et al., 1997). The majority of a,-adrenoreceptor antagonists displays a competitive mechanism of action and belongs to a variety of different structural classes such as yohimbanes, ergot alkaloids, quinazolines, A-arylpiperazines, imidazolines, phenylalkylamines, benzodioxanes, indoles, 1,4-dihydro-pyridines, hetero-fused 3-benzazepines, dibenzoquino-lizines. 

Fig. 14.27 Hexahydroisoindole as a surrogate of the very frequently used orthomethoxy-A/-arylpiperazine.

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. 

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]. 

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],... 

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. 

Williams and coworkers used a [G4]-PAMAM dendrimer as a scavenger in the reactions of an arylpiperazine with slight excesses of three different electrophiles (an isocyanate, a sulfonyl chloride, and a benzyl halide) [62]. After TLC had indicated that all amine substrate had reacted the dendritic scavenger was added. Solvent removal, adding of chloroform, and filtration of the unsoluble dendrimer afforded the products in high yields (87-99%) and purities (>95%, HPLC). 

Fig. 12.5 Dopamine D2 agonists having a distinct N-arylpiperazine privileged motif and structurally different peripheral fragments.

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