Synthesis and Affinities for Dopamine (D2) and 5-Hydroxytryptamine (5-HT2A Receptors of 1-(Benzoylpropyl)-4-(1-oxocycloalkyl-2-ethyl)- piperazines as Cyclic Butyrophenone Derivatives.

In vitro efficacy of new antiprotozoals against Philasterides dicentrarchi (Ciliophora, Scuticociliatida)

“…The drugs tested were 85 newly synthesized compounds and 12 commercial compounds belonging to the following chemical groups: (1) simple piperazines: PI-1, PI-2, PI-3, PI-4, PI-5, PI-6 (synthesized as per Raviña et al 1996), PI-8, PI-9 (Raviña et al 1995), PI-10 (Raviña et al 1999), PI-12 (Estévez et al 1998) and the commercial simple piperazines PCP (piperazine citrate pentahydrate, FLUKA), PDH-1 (piperazine dihydrochloride hydrate, FLUKA), PCA-1 (S-2 piperazine carboxylic acid dihydrochloride, FLUKA), PNP (1-phenylpiperazine, SIGMA), P2C (1-(2-chlorophenyl) piperazine monohydrochloride, SIGMA), P3C (1-(3-chlorophenyl) piperazine hydrochloride, SIGMA), P4C (1-(4-chlorophenyl) piperazine dihydrochloride, SIGMA), PBF (1-(α,α,α-trifluoro-m-tolyl) piperazine, SIGMA), PAC (4'-piperazinoacetophenone, SIGMA), CNP (trans-1-cinnamylpiperazine, SIGMA), norfloxacin (PN in Table 1) and lomefloxacin (PL in Table 1) (SIGMA, ALDRICH). (2) Naphthyridines 2b, 2d, 2e, 2f, 2g, 2i, 2j, 2k, 5o (synthesized as per Quintela et al 2003a).…”

Conformationally Constrained Butyrophenones with Mixed Dopaminergic (D2) and Serotoninergic (5-HT2A, 5-HT2C) Affinities: Synthesis, Pharmacology, 3D-QSAR, and Molecular Modeling of (Aminoalkyl)benzo- and -thienocycloalkanones as Putative Atypical Antipsychotics

“…Target compounds 10, 23, 24, and 29 containing as their NRR fragment either a, b, or f (Chart 3) were eventually prepared by amide-linking the two moieties, protecting non-amide carbonyls as ketals, reducing the amide carbonyl, and deprotection (Schemes 2, 4, and 5). For compound 10e and the previously reported 43 compounds 23e and 24e, the Chart 2 moiety was amidelinked to piperazine-Boc (fragment c), Boc was removed, and the rest of fragment e was added after reduction of the amide carbonyl (Schemes 3 and 4). For compounds 35, the cycloalkanone ring was constructed after the thiophene ring was linked as shown in Schemes 6 and 7 to a Chart 3 amine (a, b, or f for 35a,b,f, respectively; piperazine-Boc for 35e, in which the remainder of fragment e was incorporated after construction of the cycloalkanone ring).…”

“…The piperazine-Boc derivatives 8c, 19c, and 20c were transformed into the desired compounds 10e, 23e, and 24e by removal of Boc with trifluoroacetic acid, reduction of the amide carbonyl, alkylation of the piperazine NH group with 4-chloro-1,1-(ethylenedioxy)-1-(4-fluorophenyl)butane in methyl isobutyl ketone containing catalytic amounts of potassium iodide, 43 and cleavage of the resulting bis(ethylene ketal) (overall yields of 35-40% from 8d, 19d, and 20d). The general synthetic strategy used for the 6-(aminomethyl)thiatetralone derivatives 35 (Schemes 6 and 7) parallels the approach used previously for the benzene series.…”

“…As early as 1970, this latter structure was described as an antipsychotic pharmacophore of similar potency to linear butyrophenones, 39 and a SAR study of ketanserin analogues has suggested that the benzoyl carbonyl (present in both Ia,e) may play a prominent role in anchoring or orienting these compounds at receptor 5-HT 2 . 40 We subsequently extended our SAR study to the 2-(aminoethyl)benzocycloalkanones IIa,d-f, IIIa,d-f, and IVa, [41][42][43] the 5-(aminoethyl)-4,5,6,7-tetrahydroindol-4-ones Vd,f, 44 (butyrophenone homologues of the antipsychotic molindone), the 6-aminomethyl analogues VIa-f, 45,46 and the 2-(aminomethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-ones VIIa,b,f. 47 In all these series, the conformation of the butyl chain is restricted by its partial incorporation in a cycloalkanone ring fused to a benzene ring or a heterocycle (Chart 2).…”

Electron impact mass spectrometry of some neuroleptic amino alkyl thieno[β]cycloalkanones

“…1 Pursuing our research in the area of butyrophenone analogues, we thought it of interest to develop the synthesis of a new series of amino alkyl thieno [b]cycloalkanones in which the benzene ring is replaced by the isosteric thiophene group. 2 Analogously to the derivatives of the benzene series, most of the thiophene containing compounds have shown a remarkable antipsychotic activity, in both in vitro and in vivo assays. 3 Mass spectrometry has already been shown to be a valuable analytical tool for the characterization of butyrophenones 4 and, in the present paper, we report on the mass spectrometric behaviour of a series of these compounds, namely: 1-[(4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)methyl]-4-(2'-pyridyl)piperazine (1) 2-Aminoethyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophenes were prepared via DCC (dicyclohexylcarbodiimide) mediated coupling of the corresponding amines and ketoacids followed by amide reduction, while 3-aminomethyl-4oxo-4,5,6,7-tetrahydrobenzo[b]thiophenes were synthesized by acid mediated ring closure of the corresponding acyclic amine derivatives.…”