The effect of stabilizing enols of carboxamides by several two β-electron-withdrawing substituents was studied with the R 1 R 2 CHCONHPh systems. When R 1 R 2 CH 2 ) Meldrum's acid (MA), the solid-state structure is that of the enol R 1 R 2 CdC(OH)NHPh (7). In CDCl 3 solution the structure is 7, but there may be some exchange on the NMR time scale with a tautomer. B3LYP/6-31G** calculations show a significant preference for the enol R 1 R 2 CdC(OH)NH 2 (12a) (R 1 R 2 C ) MA moiety) and a small preference for (MeO 2 C) 2 CdC(OH)NHPh (11b) over the amide structures. However, solid 11 has the amide structure (MeO 2 C) 2 -CHCONHPh (11a). NMR spectra in CDCl 3 show >90% of 11a, but a minor species, probably 11b, is also present. In DMSO this species is not observed. The analogous dimedone-substituted anilide 10 exists both in the solid state and in solution as an enol of a ring carbonyl. Calculations show that HC(CO 2 Me) 3 has a lower energy than its tautomeric enol. The effects of the push-pull structures of the enols on structural and spectrometric parameters, of the β-substituents, of the planarity of the system, of the acid derivative group (ester or anilide), and of the solvent as enol-stabilizing factors are discussed. Destabilization of the acid form contributes to the increased relative stability of the enols.

A search for the enol structures of several amides YY'CHCONHPh with Y,Y' = electron-withdrawing groups (EWGs) was conducted. When Y = CN, Y' = CO(2)Me the solid structure is that of the enol (8b) MeO(2)CC(CN)=C(OH)NHPh, whereas in solution the NMR spectrum indicate the presence of both the amide MeO(2)CCH(CN)CONHPh (8a) and 8b. When Y = NO(2), Y' = CO(2)Et the main compound in CDCl(3) is the amide, but <10% of enol(s), presumably EtO(2)CC(NO(2))=C(OH)NHPh (9b), are also present. When Y = COEt, Y' = CO(2)Me or Y = COMe, Y' = CO(2)Et (10 and 11) enolization in solution and of 11 also in the solid state occurs at the carbonyl rather than at the ester site. With Y = Y' = CN a rapid exchange between the amide (NC)(2)CHCONHPh (12a) and a tautomer, presumably the enol, take place in several solvents on the NMR time scale. With YY' = barbituric acid moiety the species in DMSO-d(6) is an enol of an amide although which CONH group enolizes is unknown. B3LYP/6-31G calculations showed that the enol (NC)(2)C=C(OH)NH(2) (13b) is more stable by DeltaG of 0.4 kcal/mol than (NC)(2)CHCONH(2) (13a) due to a combination of stabilization of 13b and destabilization of 13a and both are much more stable than the hydroxyimine and ketene imine tautomers. The effect of Y,Y' and the solvent on the relative stabilization of enols of amides is discussed.

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A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted arylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes, were prepared, and their abilities to inhibit high-affinity uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes) were evaluated. First, a systematic screening of a variety of different substituents on the phenyl ring indicated that the substitution pattern plays an important role in the monoamine transporter activity. Most compounds in this series possessed a very low activity at the DA transporter (DAT) but a good to excellent affinity for the 5-HT transporter (SERT). In the case of para-substituted phenyl analogues, the electronic character of the substituent did not affect uptake inhibition as dramatically as observed in some benztropine analogues. Among these compounds, the 4-bromophenyl and 4-isopropylphenyl analogues 8d and 8j exhibited the highest potency at the SERT with a K(i) value of 10 nM. In the 3,4-disubstituted phenyl series, even more potent and highly selective compounds were discovered. Compound 8o has a K(i) value of 2.3 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 2360, and a NET/SERT uptake ratio of 200. Compound 8p exhibited a K(i) value of 1.8 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 1740, and a NET/SERT uptake ratio of 151. These compounds are 3-4-fold more potent than the antidepressant medication fluoxetine, and the selectivities for SERT over DAT and NET are also better than those of fluoxetine. Second, a variety of functional modifications on the ester moiety were investigated. Substitution by other esters or amides as well as alkenes did not increase potency, while most of the acetates or benzoates (16-21, 23, and 24) and the ketone 28 exhibited significantly improved activity. A good hydrogen-bonding ability of the substituent is believed to be required for high activity. The most potent and selective ligand is compound 23, which displayed a K(i) value of 0.06 nM and has essentially no activity at the DAT or NET. The present results have important implications for drug addiction as well as a number of psychiatric diseases.