The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2-[(2-methoxypheoxy)methyl]-3-[2-(acetylthio)acetyl]- 1,3-thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety. Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.

kg-', s.c.) did not antagonize its antitussive effects. 6 Moguisteine had-no antitussive effect after i.c.v. administration (20 ftg), whilst codeine (2-10 yg) and dextromethorphan (2.5-20 gg) were highly effective. 7 Our findings demonstrate that moguisteine is a novel peripherally acting non-narcotic antitussive agent, the mode of action of which remains to be elucidated fully.

Plasma testosterone (T), dihydrotestosterone (DHT), 17 beta-estradiol (E2), 17-hydroxyprogesterone (17-OHP), androstenedione (delta), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), 5-androstene-3 beta-17 beta-diol (A-diol) and cortisol (F) have been measured in a group of normal males and in a group of patients with Klinefelter's syndrome (KS) before and after hCG stimulation. Significantly lower baseline levels of T and DHT and significantly higher baseline levels of E2 were found in patients with KS. No significant differences were found between baseline levels of 17-OHP, delta, DHEA, DHEAS, A-diol, and F. After hCG stimulation between T, DHT, E2 and 17-OHP levels showed a significant increase in the two groups of subjects. The percentage variation of T and DHT, however, was much less important in Klinefeiter patients, while E2 and 17-OHP did not show a significantly different pattern from that of normal controls, hCG administration did not produce any significant variation of delta, DHEA, DHEAS, and F in the two groups of subjects, while A-diol levels increased significantly in normal subjects, but not in Klinefelter patients. Our data may be consistent with the hypothesis that testicular steroidogenesis in Klinefelter patients is impaired below the 21-C-steriod level not only at delta 4 but also at the delta 5 pathway.

This disease was first noted in the area in February 1993 (2), when a soybean (Glycine max (L.) Merr.) disease survey was conducted in several localities of southern Santa Fe province, the core soybean region of Argentina. At that time, its incidence ranged from 5 to 8% in isolated fields. However, in March 1997, stem canker reached a dramatic 70 to 100% incidence, probably helped by the extensive use of susceptible cultivars, favorable climatic conditions, and inoculum availability from no-till fields. Observed symptoms on stems consisted of V-shaped longitudinal lesions at petiole insertion, with reddish brown margins and discolored centers, where the pycnidia of the anamorph Phomopsis phaseoli (Desmaz.) Sacc. meridionalis Morgan-Jones were found. The lesions coalesced and consequently the main stem and branches died. Foliage symptoms started as yellow blotches, later developing into interveinal chlorosis and necrosis. Perithecia of the teleomorph Diaporthe phaseolorum (Cooke & Ellis) Sacc. var. meridionalis F. A. Fernandez (1) were obtained from infected stems in several crop seasons. Once ripe, the ascospores were cultured on potato dextrose agar (PDA) acidified with lactic acid (0.2%), amended with streptomycin (100 mg/liter), and maintained in darkness at 20 to 25°C. Yellowish white colonies were obtained, later becoming tan and developing perithecia. Perithecia had a beak length of 868 ± 183 μm, neck width of 126.2 ± 17 μm, the asci of 36.7 ± 4.7 μm length and bicellular biguttulate ascospores of 10.2 ± 1 μm length and 3 ± 0.13 μm width. All features match the available descriptions of the pathogen (1). Pathogenicity trials were performed on seedlings of resistant and susceptible cultivars up to second trifoliar leaf stage; these cultivars were classified according to inoculations and field behavior. Plants were wounded with a scalpel in the cotyledonary node and inoculated with a 3-mm-diameter PDA mycelial plug, covered with vaseline. Control seedlings were either not wounded or similarly wounded and covered with vaseline but no PDA plugs were applied. Symptom development was observed within 4 days from inoculation in the top leaf, and in 7 days most seedlings of susceptible cultivars were dead. Resistant cultivars survived and showed only reddish discoloration in wounds. The control seedlings were symptomless and the pathogen was not isolated from them. Conversely, inoculated seedlings with visible symptoms consistently yielded D. phaseolorum var. meridionalis from stem sections at different distances from the inoculation point.When cultured on water agar, alpha conidia from pycnidia and ascospores from the perithecia were obtained. References: (1) F. A. Fernandez and R. T. Hanlin. Mycologia 88:425, 1996. (2) R. N. Pioli et al. Comun. Biol. 11:156, 1993.

The objective of this study was to characterize the pathogenicity of several local isolates of Diaporthe phaseolorum (Cooke & Ellis) Sacc. var. meridionalis Fernández and its anamorph, Phomopsis phaseoli (Desmaz.) Sacc. meridionalis Morgan-Jones, the causal agent of southern stem canker of soybean (Glycine max (L.) Merr.), in soybean lines carrying major resistance genes. Soybean plants with typical stem canker symptoms were collected during the 1996 to 1997 and 1997 to 1998 growing seasons in the central and southern areas of Santa Fe Province, Argentina. The pathogen was isolated from the internal tissues of infected stems, cultured on potato glucose agar acidified with 0.2% lactic acid (APGA), amended with streptomycin at 100 mg/liter, and maintained in the dark at 25 ± 1°C. Isolates were characterized based on the morphology of colonies, perithecia, and pycnidia and measurement of asci, bicellular, biguttulate ascospores, and alpha conidia (1). Soybean cultivars used to assay pathogenicity included Tracy M (Rdc1 and Rdc2 genes), Isoline I (Tracy Misoline with only the Rdc1 gene), Isoline II (Tracy M isoline with only the Rdc2 gene), Crockett (Rdc3 gene), Hutchinson (Rdc4 gene), and RA 702 (susceptible cultivar). Hypocotyls of 14-day-old seedlings grown in the greenhouse were inoculated by the toothpick method. Four replicates of nine seedlings each were used. Seedlings punctured with sterile toothpicks served as controls. The experiment was repeated twice with similar results. The D. phaseolorum var. meridionalis isolates assayed and their collection locations were Dpm1 (Malabrigo), Dpm2 (Los Molinos), Dpm3 (San Justo), Dpm5 (Oliveros), Dpm6 (San Jerónimo), and Dpm7 (Clarke). Twenty-eight days after inoculation, stem canker reactions were measured as the percentage of dead plants. The pathogen was reisolated from stems of randomly chosen symptomatic plants on day 14 after inoculation. These plants were included in the calculation of the percentage of dead plants. In control plants, lesions were not detected, and mycelial growth did not occur from stem portions plated on APGA. Tracy M and RA 702 had 0 to 7% dead plants and 70 to 95% dead plants, respectively, with all assayed isolates. Cultivars with single resistance genes reacted differently to various isolates. Isolates Dpm1 and Dpm3 caused little or no stem canker (<10% dead plants) on all cultivars with resistance genes. Isolates Dpm2 and Dpm6 killed 56 and 52%, respectively, of Isoline II (Rdc2 gene) plants. Isolates Dpm2 and Dpm7 killed 25% of cv. Hutchinson (Rdc4 gene) and Isoline I (Rdc1 gene) plants, respectively. Isolate Dpm5 killed <12% of plants with genes Rdc1, Rdc2, or Rdc3. The reaction of isolate Dpm5 with Hutchinson (Rdc4 gene) was not evaluated. The pathogenic diversity of these isolates of D. phaseolorum var. meridionalis may have been induced by the wide diffusion of resistant host cultivars (2). References: (1) F. A. Fernández and R. T. Hanlin. Mycologia 88:425, 1996. (2) A. W. Zhang et al. Phytopathology 88:1306, 1998.