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Basic Esters and Amides of α-Substituted Diphenylacetic Acids

Journal of the American Chemical Society (Impact Factor: 11.44). 04/2002; 72(7). DOI: 10.1021/ja01163a057
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    ABSTRACT: A principal component analysis is applied to -monosubstituted ethyl acetates (YCH2CO2Et), where the observed chemical shifts for the -carbon atom, the carbonyl carbon, and the -hydrogen atoms are correlated with theoretically derived molecular properties, i.e. the partial charges on the same atoms and the electronegativity and hardness. The effects on 1H and 13C NMR chemical shifts of 12 -substituents: F, Cl, Br, I, OMe, OEt, SMe, SEt, NMe2, NEt2, Me, and Et were investigated. A strong grouping of the same heteroatom substituents is observed, showing the chemical shift dependence on the type of substituent. Halogenated compounds represent a heterogeneous group, where the large effect of the fluorine substituent is similar to that of the oxygen derivatives (OMe and OEt). Theoretical calculations show that fluorine and oxygen derivatives exhibit similar energy curves with respect to the YCCO dihedral angle and the same conformational equilibrium between cis and trans rotamers. Sulfur, neutral substituents and halogen derivatives (Cl, Br and I) give an equilibrium between cis and gauche rotamers, with a predominance of the gauche conformers. The rotational equilibrium in solution was confirmed by 1H chemical shift calculations utilizing the CHARGE 7H program. The calculated -hydrogen atom chemical shifts are in very good agreement with the measured values. Copyright © 2002 John Wiley & Sons, Ltd.
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    ABSTRACT: A series of "binary prodrugs" called carbaphens,(1) carbamylated derivatives on one or both of the aromatic rings of the muscarinic receptor antagonist aprophen [(N,N-diethylamino)ethyl 2,2-diphenylpropionate], were synthesized to develop binary prophylactic agents against organophosphorus intoxication. As a group, the carbaphens retained the muscarinic receptor antagonist properties of aprophen but also preferentially inhibited butyrylcholinesterase (BChE) in contrast to acetylcholinesterase (AChE). Therefore, a new series of compounds named pyridophens were designed and synthesized to achieve binary prodrugs to preferentially inhibit AChE over BChE, while still retaining the muscarinic receptor antagonism of aprophen. The pyridophens consist of the basic pyridostigmine skeleton combined with the 2,2-diphenylpropionate portion of aprophen by replacement of the diethylamino group. Three compounds, 9 (a tertiary pyridine), 10 (a quaternary pyridine), and 12 (a tertiary tetrahydropyridine), were found to be effective inhibitors of both BChE and AChE. However, 10, N-methyl-3-[[(dimethylamino)carbonyl]oxy]-2-(2'2'-diphenylpropionoxy-methyl)pyridinium iodide, inhibited AChE selectively over BChE, with a bimolecular rate constant similar to pyridostigmine. In contrast to their potent cholinesterase inhibitory activity, all of the pyridophen analogues were less potent antagonists of the muscarinic receptor than aprophen.
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