The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

(3R, 5R) Clavulanate-9-aldehyde 1 has been detected in Streptomyces clavuligerus and an NADPH dependent dehydrogenase capable of reducing 1 to clavulanic acid 2 has been isolated from this organism.

SB-202742 [1], an anacardic acid derivative possessing beta-lactamase inhibitory activity, has been isolated from a hexane extract of the plant, Spondias mombin. Its isolation, structure determination, and biological activity are reported herein.

Labelling experiments are described that identify three new compounds, N2-(2-carboxyethyl)arginine, 5-guanidino-(2-oxoazetidin-1-yl)pentanoic acid, and 3-hydroxy-5-guanidino-2-(2-oxoazetidin-1-yl)pentanoic acid as biosynthetic precursors of proclavaminic acid and hence clavulanic acid in Streptomyces clavuligerus TCC 27064 and a new amidino hydrolase, which hydrolyses 3-hydroxy-5-guanidino-2-(2-oxoazetidin-1-yl)pentanoic acid to proclavaminic acid has been characterised.

Two novel arginine derivatives, N2-(2-carboxyethyl)arginine and N2-(2-carboxyethyl)-3-hydroxyarginine, are produced by a mutant of Streptomyces clavuligerus dclH 65, which is blocked in clavulanic acid biosynthesis, and the structures of the compounds indicate that they may be involved in clavulanic acid biosynthesis.

(9S)-9-N-Methylerythromycylamine A (6) and (9S)-9-N,N-dimethylerythromycylamine A (7) have been synthesised and their solution conformations compared with that of (9S)-erythromycylamine A (5) using H-1 and C-13 NMR spectroscopy. Compound 6 reacts with a number of aliphatic aldehydes to give 9,11 -cyclic products which are shown to be diastereoisomeric about the bridging carbon atom C-23. Compounds with the same configuration at C-23 show close similarities in their H-1 and C-13 NMR spectra. In some cases, configurational interconversion at C-23 occurred by the well known 'ring-chain' tautomerism of tetrahydro-1,3-oxazines. The tetrahydro-1,3-oxazine rings of compounds with a (23R) configuration adopt a chair-like conformation while those compounds with a (23S) configuration prefer a twist-boat-like conformation. From NMR spectroscopic studies the solution conformations of the macrocyclic lactones of these compounds is best described as a fast equilibrium between C-3 to C-5 'folded out' and C-3 to C-5 'folded-in' types. Epimerisation at C-23 causes profound changes in the position of this equilibrium:compounds with the (23S) stereochemistry preferentially populate 'folded-out' conformations modelled on the crystal structure of erythromycin A hydroiodide dihydrate, while those possessing the (23R) configuration preferentially populate 'folded-in' conformational types similar to the crystal structure of (9S),(22R)-9,11-N, O-(2-methoxyethoxyethylidine) erythromycylamine A (10).An example of each diastereoisomer at C-23 was chosen for X-ray diffraction studies. The crystal structures of (9S,23S)-9-N-methyl-9,11-N,O-(2-hydroxyethylidene) erythromycylamine A (25) and (9S,23R)-9-N-methyl-9,11-N,O-(3-ethoxypropylidene)erythromycylamine A (28) are thus reported and confirm the structural and conformational conclusions determined by NMR spectroscopy.

(2S)-(E)-9-Deoxo-9-methoxyiminoerythromycin A 9 has been prepared and characterised by NMR spectroscopy, including NOE experiments. In solution, 9 appears to adopt only the C-3 to C-5 ‘folded out’ conformation. This is in contrast to (E)-9-deoxo-9-methoxyiminoerythromycin A 8, itself, which exists in solution as a mixture of ‘folded out’(major) and ‘folded in’(minor) conformations in fast exchange. Epimerisation experiments suggest that, for the derivatives studied here, he 2-epi(2S) configuration is thermodynamically less stable than the natural (2R) configurations. The relative stabilities of the various configurations and conformations suggested by these experiments are supported by molecular mechanics calculations.

High-field nuclear magnetic resonance spectroscopy, mass spectrometry, infrared spectroscopy, and ultraviolet spectroscopy were used to determine the structures of two novel degradation productions of the penicillins sodium nafcillin (1) and sodium oxacillin (2). The degradation products of compounds (1) and (2) were found to possess the novel thietan-2-one structures (3)and (4), respectively. The structure of compound (4) was confirmed by chemical synthesis via two independent routes. The structure of compound (3) was confirmed by single-crystal X-ray crystallography.

AbstractThietanone (IIa) (space group P212121 with Z=4) is isolated from a 20% aqueous solution of sodium nafcillin (Ia) kept at room temp. for 14 days.

AbstractThe aqueous degradation of penicillin derivatives such as (I) at 1 < pH < 11 and the anhydrous degradation of simpler penicillins such as (VIa) and (VIb) is examined.

ChemInformVolume 21, Issue 52 Natural Products ChemInform Abstract: Olivanic Acid Analogues. Part 7. Lead Tetraacetate Oxidation of 3-Alkylthio-7-oxo-1-azabicyclo(3.2.0)heptane-2-carboxylates. J. H. BATESON, J. H. BATESON SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this authorS. C. M. FELL, S. C. M. FELL SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this authorR. SOUTHGATE, R. SOUTHGATE SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this authorJ. W. TYLER, J. W. TYLER SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this author J. H. BATESON, J. H. BATESON SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this authorS. C. M. FELL, S. C. M. FELL SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this authorR. SOUTHGATE, R. SOUTHGATE SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this authorJ. W. TYLER, J. W. TYLER SmithKline Beecham Pharm., Res. Div., Betchworth, Surrey RH3 7AJ, UKSearch for more papers by this author First published: December 25, 1990 https://doi.org/10.1002/chin.199052343Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume21, Issue52December 25, 1990 RelatedInformation

1H and 13C NMR chemical shift data and 3J(H,H) values can be used to predict the conformational blend of new members of a series of erythromycin A derivatives in CDCI3 solution.

Since drugs in clinical use are mostly synthetic or natural products, NMR spectroscopy has been mainly used for the elucidation and confirmation of structures. For the last decade, NMR methods have been introduced to quantitative analysis in order to determine the impurity profile of a drug, to characterise the composition of drug products, and to investigate metabolites of drugs in body fluids. For pharmaceutical technologists, solid state measurements can provide information about polymorphism of drug powders, conformation of drugs in tablets etc. Micro-imaging can be used to study the dissolution of tablets, and whole-body imaging is a powerful tool in clinical diagnostics. Taken together, this review covers applications of NMR spectroscopy in drug analysis, in particular, methods of international pharmacopoeiae, pharmaceutics and pharmacokinetics. The authors have repeated many of the methods described in their own laboratories.

AbstractThe title compound (I) is synthesized from erythromycin A (e.A) in 4 steps and has space group P212121 with Z=4.