Preparation and analgesic activity of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines.

Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good levels of agonist antinociceptive activity. Masking of the 8-oxygen function, as in 6 and 8, dramatically reduced mouse hot-plate activity, as did its loss (9).

Analgesic actions of 3-substituted 6-tert-butyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines.

The synthesis of four 3-substituted 6-tert-butyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines is described. Derivatives with N-Me or N-phenethyl substituents do not differ significantly in their antinociceptive properties from compounds bearing 6-H or 6-Me; however, they are less active than 6-Ph analogues.

Synthesis, stereochemistry, and analgesic activity of 4-mono- and 4,4-disubstituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines.

The synthesis of 4-alkyl-, 4-aralkyl-, and 4-alkenyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines is described together with some 4,4-disubstituted and 8-hydroxy derivatives. Evidence of the stereochemistry of the 4-substituent was from 1H and 13C NMR. In the 4-methyl series the equatorial epimer 1b has a higher analgesic (hot-plate) potency than 1a, and 10a, 10c, and 10f are also good agonists. 5a afforded analgesic properties without an antagonist component. Surprisingly 10d, bearing an 8-OH function, was without analgesic activity, contrasting with the significant hot-plate activity exhibited by 1,2,3,4,5,6-hexahydro-3,5,6-trimethyl-2,6-methano-3-benzazocine. If the assumption is made that the more active enantiomorph in members of this series is configurationally related to (-)-morphine, then it may be that the enantiotopic edge in hexahydro-2,6-methano-3-benzazocines has a narrow steric requirement for analgesic responses.

Studies of carbon-13 n.m.r. spectroscopy in pharmaceutical analysis: the composition of commercial samples of gentamicin sulphate.

Two procedures for applying 13C n.m.r. spectroscopy to the quantitative analysis of the C1, C1a, and C2 components of gentamicin sulphate samples are described. One is based on the use of calibration plots of peak height ratios of analyte to standard (dioxan) resonance intensities recorded under conditions of full relaxation, the other upon a steady-state experiment and the use of weighting factors. Spectrometer operating conditions are discussed, and the need for measurement of longitudinal relaxation time (T1) data described. Results for seven commercial samples are given and comparisons made between the two n.m.r. methods and an h.p.l.c. procedure in terms of accuracy, specificity and convenience.

Optical purity determination by NMR: use of chiral lanthanide shift reagents and a base line technique.

A method for optical purity determination of a range of chiral drug molecules by NMR spectroscopy is reported. This technique involves the use of optically active lanthanide shift reagents and a newly developed base line analysis. Its applicability was demonstrated for a variety of drugs including nonsteroidal antiinflammatory agents and some adrenergic agents. It is established that successful application of the method depends on a constant shift reagent to sample molar ratio, constant instrumental conditions for all solutions, and the use of a calibration curve derived from solutions containing the same total concentration of the two enantiomers. For the examples cited, the correlation coefficient is not less than 0.97, and a mathematical treatment is included which supports the basis of the method.

Chemical ionization and field desorption mass spectrometry of the gentamicins.

Gentamicin sulphate employed in therapeutics consists of a mixture of three major aminoglycoside components, the gentamicins C1, C1a and C2. In the electron impact mass spectra of these components weak parent ions may be observed but they are of no diagnostic value in the commercial mixture. Chemical ionization and field desorption spectra of individual gentamicin components and commercial mixtures are reported and discussed. Isobutane chemical ionization spectra exhibit some fragmentation, but under optimum field desorption conditions little glycosidic cleavage is observed and [M + H]+ ions dominate the spectra.