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A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

The sign of the 1Lb Cotton effects (CEs) of the benzene chromophore from about 240 to 270 nm in the circular dichroism (CD) of enantiomers of ring-substituted chiral benzylcarbinamines and benzylcarbinamine salts are correlated with their absolute configurations using the benzene sector rule and a consideration of the equilibrium between their two conformers of lowest energy and of oppositely signed rotatory power. These CEs are the result of vibronic borrowing from allowed transitions of the benzene chromophore at shorter wavelength, but an induced rotatory contribution, the sign of which may be predicted using the benzene chirality rule, is small compared to the vibronic contribution and need not be considered when predicting the sign of the 1Lb CEs.

The sign of the 1Lb Cotton effects (CEs) from about 240 to 270 nm in the circular dichroism (CD) of enantiomers of chiral benzylcarbinamines and benzylcarbinols is correlated with their absolute configurations using the benzene sector rule and a consideration of the equilibrium between their two conformers of lowest energy and of oppositely signed rotatory powers. For chiral benzylalkylcarbinamines, carbinamine salts, and carbinols, which show a single sign for their 1Lb CEs, a shift in the conformational equilibrium can explain a sign reversal of the CEs with a change in solvent, (R)-2-amino-1-phenylpropane showing negative 1Lb CEs in methanol but positive ones in cyclohexane. l-Phenylalanine in water shows positive 1Lb CEs, but in methanol it shows both negative and positive CD maxima. In methanol, the two longest wavelength maxima comprise a double CE associated with the band origin absorption maximum at 267 nm, the conformational equilibrium shifted from the positive conformer of l-phenylalanine to it...

Both enantiomers of trans-2,3-dimethyloxirane-d 0 , trans-2,3-dimethyloxirane-2-d 1 , and trans-2,3-dimethyloxirane-2,3-d 2 are synthesized. Vibrational circular dichroism (VCD) sepctra for these compounds are obtained in the 1600-700-cm -1 region. Ab initio theoretical calculations using the localized molecular orbital method (LMO-VCD) and the vibronic coupling theoretical method (VCT) are also obtained for these molecules

Enantioenriched 1-substituted indans were prepared from (R)- 1-indancarboxylic acid and (R)-1-indanylacetic acid as model compounds for the correlation of their absolute configurations with the sign of the 1 L b Cotton effects (CEs) from about 250 to 270 nm in their circular dichroism spectra. The CEs are the result of vibronic and induced contributions to the rotational strength, and their sign is in agreement with that predicted on the basis of the benzene sector and the benzene chirality rules

The positive sign of the 1 L b Cotton effects (CEs) from about 250 to 270 nm in the circular dichroism (CD) spectrum of (R)-mandelic acid and its soduim salt is determined by vibronic borrowing from allowed transitions at shorter wavelength. On ring substitution, transition moments are induced in the benzene ring bonds adjacent to the attachment bond of the chiral group, resulting in enhanced coupling of the 1 L b transition with the chiral group

Variable-temperature proton nuclear magnetic resonance studies have shown that 5-(2-propylidene)-10-(4-methylpiperazino)-5H-dibenzo[a,d] cycloheptene, a 5,11-dicarbo analogue of the atypical neuroleptic agent clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine], exists as thermally stable configurational isomers. The presence of the 2-propylidene group at C-5 on the 5H-dibenzo[a,d]cycloheptene moiety did not interfere greatly, as compared to clozapine, with the in vitro affinity of this 5,11-dicarbo analogue of clozapine for muscarinic and dopamine D-1 and D-2 binding sites in rat brain. Since the presence and position of a chloro substituent on the 5H-dibenzo[b,e][1,4]diazepine moiety have a marked influence on the respective binding affinities of 1,4-diazepines related to clozapine, chloro-substituted 5,11-dicarbo analogues of clozapine were prepared in order to further examine structure-activity relationships. Evaluation of these analogues for binding to muscarinic and dopamine binding sites in comparison with clozapine and other 5H-dibenzo[b,e][1,4]diazepine analogues of clozapine shows that the dopamine D-1 and D-2 receptor affinities of both the 5-(2-propylidene)-5,11-dicarbo analogue and its corresponding distal-chloro derivative, 2-chloro-5-(2-propylidene)-10-(4-methylpiperazino)-5H- dibenzo[a,d]cycloheptene, are retained. Because of the susceptibility to acid-catalyzed hydrolysis of these tertiary enamines, however, these compounds serve only as model compounds for their structure-activity evaluation. Since the proximal nitrogen atom of the piperazine ring is redundant for biological activity, 5-(2-propylidene)-10-(1-methyl-4-pyridyl)-5H-dibenzo[a,d]cycloh eptene and its 2-chloro derivative are excellent candidates for resolution into enantiomers as a means to separate antimuscarinic and antidopaminergic activity, respectively, associated with only a single stereoisomer.