Synthesis and aromatase inhibition of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones

Abstract

The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.

Highly Selective Preparation of a Chiral Quaternary Allyl Aryl Piperidinedione by Palladium‐Catalyzed Asymmetric Allylation Under Solid–Liquid Phase‐Transfer Catalysis

“…Finally, γ-cyano ester 6 was converted into imide 2 through heating in glacial acetic acid in the presence of a catalytic amount of H 2 SO 4 , [13] and 2 was isolated, after purification, in 86 % yield. Compound 2 was next used in palladium-catalyzed AAA (Scheme 3).…”

“…Compound 2 was next used in palladium-catalyzed AAA (Scheme 3). The results are reported in Table 1 13 C NMR spectroscopy in the presence of Eu(hfc) 3 . Configuration attributed according to the negative sign of rotation measured by polarimetry.…”

“…J. Org yield of 9 % and with 15 % ee (determined by 13 C NMR spectroscopy in the presence of a chiral shift reagent).…”

(4RS)-Methyl 4-cyano-4-cyclohexyl-4-phenylbutanoate

“…For general background to pharmaceutical applications of methyl 4-cyano-4-cyclohexyl-4-phenylbutanoates, see: Hartmann & Batzl (1986), Hartmann et al (1992); Fadel & Garcia-Argote (1996).…”

Transcriptional inhibition of the estrogen response element by antiestrogenic piperidinediones correlates with intercalation into DNA measured by energy calculations

“…Moreover, an increasing number of piperidinediones and closely related compounds (see structures in Fig. 1) were demonstrated to have antineoplastic effects, including analogs that have been used in the treatment of breast cancer [30][31][32]. A10 was shown to fit between base pairs (intercalate) in DNA, along with more active A10 analogs that were designed from our modeling studies [27,28].…”