ChemInform Abstract: Synthesis, Reactions, and Preliminary Evaluations of Enaminone Esters.

Department of Medicinal Chemistry, College of Pharmacy and Pharmacal Sciences, Howard University, Washington, DC 20059.
Journal of Pharmaceutical Sciences (Impact Factor: 2.59). 05/2010; 83(1):79-84. DOI: 10.1002/jps.2600830119
Source: PubMed


The objective of this work was to design enaminone esters that would possess potential medicinal properties. The reaction between beta-hydroxyketo esters and primary or secondary amines yielded secondary or tertiary enaminone esters, respectively. The UV spectra of the enaminone esters were determined in acidic, alkaline, and neutral media; the spectra have a hypsochromic shift in acidic media in comparison with neutral media. The enaminone esters provided nucleophilic and electrophilic sites for a variety of reactions. Thus, the enaminone esters were converted into enaminone amides and O-alkylation products exclusively. Although the enaminone esters were generally resistant to reduction by metal hydrides, one unhindered enaminone ester was reduced to an alcohol with sodium borohydride. Another enaminone ester reacted with guanidine to give the corresponding quinazolinone. Due to the variety of nucleophilic and electrophilic sites in the enaminone system, enaminone esters possess a great potential as reaction intermediates and medicinal compounds. Preliminary evaluations of the enaminone esters revealed a histaminergic effect, uterine relaxant properties, and anticonvulsant activity.

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    ABSTRACT: 1H nuclear magnetic resonance (NMR) spectra of enaminones were determined and compared to the anticonvulsant activity of the compounds. Although the precise employment of the NMR data to predict anticonvulsant activity of the enaminones could not be established, general inferences were made. The NMR data confirmed that the enaminones existed predominantly in the amino tautomer, and no evidence was found for the imino tautomer. The ketamine form of the enaminones was supported by the observed spin-spin splittings of the NH with the alpha-protons on certain enaminones. The NH of secondary enaminones was very important in conferring anticonvulsant activity to the enaminones. The peak for the NH proton which could be seen between delta (ppm) 4.50 and 9.70 was present in all of the active enaminones. The tertiary enaminones, which were devoid of the NH proton, were uniformly inactive. It appeared that a combination of steric and electronic effects, lipophilicity, and hydrogen bonding were necessary for the anticonvulsant activity of the enaminones. The cyclic enaminones existed in the trans-S-trans fixed conformation, and the NMR data supported our hypothesis that enantioselectivity is retained in synthesizing enaminones from cyclic, diasteriomeric 1,3-diketones. In addition, the AB system and many unique features were observed in some enaminones. The para, meta, and ortho substituted patterns were observed for monosubstituted phenyl protons, and the NMR patterns for di- and trisubstituted phenyl groups were elucidated.
    No preview · Article · Aug 1994 · Journal of Pharmaceutical Sciences
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    ABSTRACT: The crystal structures of three anticonvulsant enaminones: methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-3-cyclohexen-1-carboxylate (1), methyl 4-[(p–ethylphenyl)amino]-6-methyl-2-oxo-3-cyclohexen-1-carboxylate (2), and methyl 4-[(4′-chloro-2′-pyridinyl)amino]-6-methyl-2-oxo-3-cyclohexen-1-carboxylate (3) have been determined. The cyclohexene rings adopt sofa conformations, with the methyl substituent at the out-of-plane carbon atom in equatorial position. The dihedral angle between the mean planes of cyclohexene and aromatic ring is significantly smaller for pyridinyl derivative as compared with phenyl ones; for the former an intramolecular C–H⋯N(pyridinyl) hydrogen bond closes nearly planar six-membered ring. For all compounds, the intermolecular N–H⋯OC hydrogen bonds form infinite chains of molecules. Both the graph-set notation and resonance-assisted hydrogen bond approach have been used for description of hydrogen bond networks. For 1 and 2, there is a significant disorder of the carbomethoxy groups, caused by a rotation of 180° around the C–C(OOC) single bond.
    Preview · Article · Jul 2000 · Journal of Molecular Structure
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    ABSTRACT: A simple high performance liquid chromatography (HPLC) method has been developed for the stability study of an anticonvulsant enaminone (E139). Using a Chiral HSA column and a mobile phase of n-octanoic acid (5 mM) and isopropyl alcohol and disodium hydrogen phosphate solution 1:9 v/v at a flow rate of 1 mL/min., the chromatograms exhibited well resolved peaks at retention times of < 5 min. for the predominant diastereoisomer.The stability study for E139 was carried out in acid, alkaline, neutral solution, and in a phosphate buffer solution of physiological pH. The results confirmed that the hydrolysis of E139 was fastest in acid medium, indicating that protonation of the enaminone system enhanced hydrolysis at a degradation rate constant (Kdeg) of 0.044 min. and a degradation half-life (t½) of 15.75 min. at room temperature (25°C). Deprotonation of E139 in alkaline solution also resulted in hydrolysis, but at a slower rate (Kdegof 0.017 min.) and longer degradation half-life (t½: 40.76 min.) at 25°C. The enaminone E139 was very stable in the buffer solution of physiological pH (Kdeg of 0.001 hr, and t½ of 24 days at 25°C).Analysis of the acid hydrolysis of E139 by liquid chromatography – mass spectrometry (LC-MS) revealed that the decarboxylated product of E139 was formed. This study offers a great potential for the application of HPLC and LC-MS methods in the bioassay of enaminone compounds.
    No preview · Article · Jan 2001 · Journal of Liquid Chromatography & Related Technologies
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