Robert E. Johnson

Antiviral activity of some beta-diketones. 2. Aryloxy alkyl diketones. In vitro activity against both RNA and DNA viruses.

The synthesis and in vitro antiviral evaluation of a series of substituted benzyl beta-diketones are described. The introduction of a styryl group onto the phenyl ring enhanced activity against herpesvirus type 2. The 4-methoxystyryl homologue 8 was evaluated extensively in vitro and was found to be effective against both RNA and DNA viruses. Compound 8 was evaluated in the mouse vagina against herpes simplex type 1 and produced a significant increase in survival rate as well as in survival time.

Synthesis of novel tetrahydrobenzazepinones

Abstract The synthesis of novel tetrahydrobenzazepinones 1, 2, and 3 is described, as well as an improved synthesis of 4. The palladium catalyzed arylation approach to 1, 2, and 4 allows facile entry to benzazepinones lacking electron donating substituents on the benzo ring.

On intramolecular dyotropy: structural effects on reaction rates and X-ray crystal structure-molecular mechanics correlations

Abstract Differential kinetic behaviour in thermal dyotropic rearrangement of compounds containing a cyclohexa-1,3-diene ring as 2H donor held proximate to a variously-substituted norbornene element as acceptor is discussed in terms of parameters derived by single crystal X-ray structure analysis and Molecular Mechanics calculations.

On intramolecular dyotropy: structural effects on reaction rates, crystal structure–molecular mechanics correlations and primary deuterium kinetic isotope effects. (Parameters for intramolecular recognition)

Previous attempts to prepare the pentacyclic triene 17 for comparison of the rate of intramolecular dyotropy with the kinetics of similar irreversible rearrangements of norbornene ring-substituted analogues had given only dyotropomer 18 with an estimated minimum ratio K1(17)/K1(5)∼ 2 × 105 at 36 °C. In the following it is shown that the steric proximity, dCH, of transferring H atoms to receptor sp2 carbons in the reaction zone cavity together with M M-calculated π-energy differences between dyotropomers can rationalise the large rate enhancement observed for the triene 17 compared with 5 and its analogues. For a series of compounds modelled on 5, in which dCH variations are quite small, observed differences in dyotropic rate are identified as arising from the interplay of molecular geometry changes and small changes in π-energy at the receptor alkene site occasioned by proximate polar groups, the electronic changes associated with aromatisation of the appended donor-site ring remaining essentially constant across the series. When the electronic energy changes associated with dyotropy for a pair of analogous structures are very closely similar, a rate-spread of ca. 104 can be identified with a change in dCH of 0.1–0.17 A. Similar kinetic effects concomitant on small parallel structural variations, virtually identical in relative-rate terms to those in the triene series, are seen in the irreversible dyotropy of a series of analogous pyrazolines modelled on compound 36 and may be likewise rationalised. Kinetic comparisons for a group of aryl-ring substituted analogues of pyrazoline 36 reveal quite modest substituent effects, consistent with reactant-like transition-states for these quantitative, exothermic rearrangements. Inter-series comparison of alicyclic trienes with pyrazolines indicate that when dCH values are essentially identical in representative examples, a rate-differential of 102–103 between the two series can be identified principally with the differing electronic requirements for triene and (slower) pyrazoline rearrangements. Primary deuterium kinetic isotope effects (K12H/K12D, dln[K12H/K12D]/dt and especially A2H/A2D) reveal strong evidence for non-classical behaviour especially for pyrazoline 38.

The synthesis of 1H-pyrazol-4-ols from 2-(2-alkylidenehydrazino)acetic acids

Abstract A new general method for synthesizing 1H-pyrazol-4-ols by cyclizing2-(2-alkylidenehydrazino) acetic acids with acetic anhydride in pyridine is reported.

Chapter 20. Complement Inhibitors

Publisher Summary It is generally accepted that the treatment of certain diseases may be effected through the control of complement consumption by interrupting the generation of or the action of cellular stimuli attending inflammatory processes. Such stimuli include chemoattractants for polymorphonuclear leukocytes, inducements for noncytotoxic enzyme secretion, histamine releasing agents, and permeability factors. Three fenamic acids, flufenamic, mefanamic, and niflumic, block the classical pathway activity. Flufenamic acid was the most active of this group, showing significant inhibition at 0.05 mM with human complement. Aromatic amino acids represent another class of compounds that alter complement activity at more than a single reaction step. Aromatic amino acids possessing a phenolic hydroxyl group were shown to be especially active in inhibiting the generation of C4 sites (IIc). Certain peptides have been shown to interfere with complement function. Leupeptin (acetyl-leucyl-leucyl–arginal), a protease inhibitor derived from actinomycete fermentation, is an effective complement inhibitor. In vitro inhibition (50%) was effected at 0.5 mM. Polynucleotides, polyanionic substances, acids, phenols, amines, and other groups have also come under the discussion on complement inhibitors. The discussion on inorganics shows that the zinc cation was reported to reversibly inhibit the whole complement activity from 0.025 to 0.50 mM. The utilization of every complement component except C5 and C9 was inhibited (12%-55%) from 0.025-0.50 mM.

Novel dibenzo[d,f][1,3]dioxepines

Abstract Two novel syntheses of dibenzo[d,f][1,3]dioxepines starting with biphenol are described. Treatment of biphenol 11a with 2-chloroacrylonitrile gave a 47% yield of dibenzo[d,f][1,3]dioxepin-6-acetonitrile 4 , and treatment of 11a with two equivalents of diethyl bromomalonate gave a 95% yield of diethyl dibenzo[d,f][1,3]dioxepin-6,6-dicarboxylate 5a .

The unexpected synthesis of 2-thioxo-1-imidazolidinecarboxamides from 2-oxo-1-imidazolidinethiocarbonyl chloride

Abstract The reaction of 2-oxo-1-imidazolidinethiocarbonyl chloride with aromatic amines gives N-aryl-2-thioxo-1-imidazolidinecarboxamides. This finding is consistent with an ethylene isocyanate isothiocyanate intermediate.