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Reaction of dimethyl acylphosphonates (1) with thiosemicarbazide afforded the corresponding dimethyl acylphosphonate thiosemicarbazones (4). Lithium methyl acylphosphonate thiosemicarbazones (5) could be prepared either by monodealkylating compounds 4 by lithium bromide or by reacting lithium methyl acylphosphonates with thiosemicarbazide. Dihydrogen acylphosphonate thiosemicarbazones (6) could be obtained by reacting acylphosphonic acids (3) with thiosemicarbazide. The alternative approach to 6 by di-dealkylating compounds 4 using bromotrimethylsilane was limited by the solubility properties of esters 4. Compounds of types 5 and 6 did not show antiviral activity against herpes simplex type 1 and 2, or toward vaccinia virus.

Some geminal bisphosphonates are used clinically for a number of important bone- and/or calcium-related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bishydroxyiminophosphonates (e.g., adipoyl- and suberoylbisphosphonate dioximes). These compounds significantly inhibited hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. The compounds reported in this paper are less active than the structurally related bisacylphosphonates. The results of this work indicate that the introduction of oxime groups adjacent to the phosphonic function in long-chain bisphosphonates confers calcium interaction capabilities and that complete ionizability of a bisphosphonate may enhance its biological activity.

Some geminal bisphosphonates are used clinically for a number of important bone/calcium related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bisacylphosphonates (e.g., adipoyl- and suberoylbisphosphonate). These compounds were found to inhibit significantly hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. These are the first instances of nongeminal bisphosphonates [P-(C)n-P, n greater than or equal to 2] that have been reported to be active in calcium-related disorders. The reported bisacylphosphonates possess apparent lower toxicity, and their calcium complexes/salts have improved solubility properties. Therefore, they are of potential importance for clinical applications.

The aim of this study was to examine the reliability of histometric and immunocytochemical methods in the diagnosis of stress-induced myopathies in pigs. A total of 33 German Landrace and Mangalitza pigs ranging in age from 4 weeks to 1.5 years were used for the determination of creatine kinase (CK) activity in blood serum and the histological, histometrical and immunocytochemical examination of 10 different skeletal muscles. The results show that a computer-aided histometric analysis of skeletal muscle fibers with special regard to their coefficient of variation and the interquartile range is not valuable for the diagnosis of myopathy in pigs. This contradicts the results reported in other species, where the grade of myopathy was found to correlate positively with the coefficient of variation. Using an antibody against fetal skeletomuscular myosin in immunocytochemistry, an age-dependently varying mixture of small myofibers of a physiological tapered and a pathological regenerating type was observed in porcine muscles, resulting in a relatively constant coefficient of variation of between 30-40% in skeletal muscles over the entire age range examined. In healthy porcine skeletal muscles, fetal myosin is only expressed prenatally. Thereafter, it is reexpressed only from the age of 16 weeks on and exclusively in cases of stress-induced myopathy. Therefore, the still controversial existence of a postnatal hyperplasia of skeletal muscle fibers in pigs must be rejected. The immunocytochemical detection of fetal myosin in skeletal muscles of adult pigs is the first reliable and sensitive method for diagnosis of stress-induced myopathy in pigs including latent forms of the disease.

Quantitative structure-activity relationships between pharmacological activities and physical properties of a series of 2,2-diphenylpropionate compounds were used to define the topography of the antagonist binding site of muscarinic receptors. XICAMM, a computer molecular modeling program, was used to calculate geometrical and topological values of the compounds. The compounds were tested for their antimuscarinic activities by: (a) inhibition of [N-methyl-3H]scopolamine binding to the muscarinic receptors of N4TG1 neuroblastoma cells, (b) inhibition of carbachol-induced alpha-amylase release from rat pancreas acini, and (c) blocking of acetylcholine-induced contraction of guinea pig ileum. To evaluate as clearly as possible only the effect of the bond distance on the potency of the synthesized antimuscarinics, the compounds contained as many constant features as possible. Neither the hydrophobic nor the ester moieties of the compounds were changed, and the rings containing the protonated nitrogen were saturated and restricted. The antimuscarinic activities obtained from the three assays were significantly correlated with each other, with the exception of two compounds, 9 and 13. The latter two compounds demonstrated specificity for the m3 muscarinic receptor subtype expressed in the pancreas. Furthermore, it was demonstrated that the antimuscarinic activities were significantly related to the bond distances between the carbonyl oxygen (constant electronegative locus) and the protonated nitrogen (center of cationic charge) of the 2,2-diphenylpropionate compounds. Parabolic relationships between the pharmacological activities and bond distances were empirically established. The shortest calculated bond distance of these compounds was approximately 4.4 A, whereas the longest was about 5.9 A. The maximum antimuscarinic potency was observed with a calculated bond distance of about 5.2 A in all three assays.

A series of aldehydo sugars was subjected to condensation reactions with active methylene compounds. Acetylacetone was condensed with 2,4-O-benzylidene-3,5-O-dibenzoyl-D-ribose (1), 2,4:3,5-O-dibenzylidene-D-ribose (6), 2,3,4,5-tetraacetyl-D-ribose (7), and 2,3,4,5,6-pentaacetyl-D-glucose (9) to yield 3-ylidene-2,4-pentanedione derivatives 2, 11, 12, and 13, respectively. Sugar derivatives 1 and 6 were also condensed with benzoylacetone to give 14 and 18, with acetoacetanilide to give 16 and 19, with malononitrile to give 17 and 20, and with alpha-(gamma-butyrolactonylidene)triphenylphosphorane to give 21 and 22, respectively. Condensation of 1 with dibenzoylmethane gave 15. The double bond in compounds 2 and 11 was saturated by hydrogenation to give 23 and 24. All alpha, beta-unsaturated carbonyl compounds obtained exhibited antiviral activity and cytotoxicity. Compound 11 was found to have the most significant and selective antiviral activity against herpes simplex virus.

The metabolic fate of aprophen hydrochloride (2-diethylaminoethyl 2,2-diphenylpropionate) was studied in rats after intravenous administration. Both 14C-labeled and unlabeled aprophen were used in these studies. Blood samples were collected and analyzed to determine the identities of the metabolites formed. Utilizing high-performance liquid chromatography, desethylaprophen was identified as a major metabolite in ether-extracted samples from rats, and could be detected in blood samples 1 min after intravenous administration. It was most likely formed by N-de-ethylation of aprophen by a cytochrome P-450-dependent monooxygenase. Synthetic desethylaprophen was found to possess cholinolytic activity (i.e., it functioned as a muscarinic antagonist by blocking the contraction of acetylcholine-stimulated guinea pig ileum, the release of alpha-amylase from pancreatic acinar cells stimulated by carbachol, and also by inhibiting the binding of [3H]N-methyl scopolamine to the muscarinic receptors of guinea pig ileum). It was interesting that although the biological effects of desethylaprophen were 100-fold lower than those of aprophen, it was equally able to compete for the binding sites of muscarinic receptors of the guinea pig ileum.