Cryoscopy and nuclear magnetic resonance (NMR) spectroscopy showed that the species formed from β-nitrostyrenes in trifluoromethanesulfonic acid (TFSA) are O, O-diprotonated dications (N, N-dihydroxyiminium benzyl dications). Further studies demonstrated that nitroethylene in TFSA yielded the N, N-dihydroxyiminium methylium dication, which is stabilized probably by Y-delocalization, consisting of six delocalized electrons (two π-electrons of the olefinic bond and four electrons of lone pairs of two hydroxy groups) in the whole system. From an alternative point of view, these dipositive systems can be regarded as substituted ethylene dications. The intervention of related substituted ethylene dications is proposed in the reaction of diphenylmethyl cations bearing a ketone or an ester group which gives the fluorenes and phenylphenanthrol in TFSA. Direct observations of 1, 1-diaryl-2-hydroxy-2-methoxyethylene dications and 1, 1, 2-triaryl-2-hydroxyethylene dications by means of NMR spectroscopy supported the postulation.

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The affinities of bovine serum albumin (BSA) with six kinds of steroidhormones (α-estradiol, ethynylestradiol, progesterone, androsterone, dehydroisoandrosterone and testosterone) were studied, and BSA was employed as a carrier to transport these hormones through the liquid membrane system, which consists of a hexane sauce phase (I), a BSA solution phase (1/15 phosphate buffer) and a hexane receiving phase (II). These steroid-hormones dissolved in hexane were extensively transferred into a water phase containing BSA compared to the case of control (without added BSA). This suggests that these hormones are bound to BSA in a water phase. The ratio of hormone, BSA-binding form/free-form, is in the following order : ethynylestradiol>androsterone>testosterone>progesterone>dehydroisoandrosterone>α-estradiol in the water phase at the equilibrium conditions. The initial rate of hormone transfer from the hexane phase (I) to the water phase is followed by the first-order kinetics, and BSA induces an increase in the transfer rate except for the case of α-estradiol and ethynylestradiol. On the other hand, as for the increase rate of hormone concentration in the hexane phase (II), BSA makes the rate of transfer of progesterone faster than that of control, but it makes the rate of transfer of dehydroisoandrosterone more slowly. The results show the transport behaviors of steroidhormones across a water membrane are governed primarily by the partition coefficient between water and hexane phase and the addition of BSA accelerates the transport of hormones in the case of lower partition coefficients.

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2-Nitroquinoxaline (II) was synthesized and the chemical properties were investigated. The reaction of 2-iodoquinoxaline (III) with silver nitrite in the presence of tetrabutylammonium fluoride gave II in 44% yields. II is quite reactive toward various nucleophiles and the ipso-substitution reaction of II with O-nucleophiles (OH^-, CH₃O^-, C₂H₃O^-, C₆H₅O^-), S-nucleophiles (CH₃S^-, C₆H₅S^-, p-CH₃C₆H₅SO₂^-), N-nucleophiles (hexylamine, cyclohexylamine, piperidine, morpholine, aniline), C-nucleophiles (CN^-, diethyl malonate, malonodinitrile, benzyl cyanide, ethyl cyanoacetate, nitroethane, acetophenone) readily afforded the corresponding 2-substituted quinoxalines (IV, X-XXI, XXIV-XXVIII, XXXI, XXXIII).

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The optical resolution of racemic 4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3, 5-dimethylbenzoic acid (dl-I), a new potent and long lasting thromboxane synthetase inhibitor, was investigated. (S)-3-(3, 5-Dinitrobenzoylthio)-2-methylpropionyl group was introduced to α-hydroxy moiety of methyl ester of dl-I by three steps of reaction to give the corresponding ester compound (VIa). Then, two diastereomers of VIa, α-VIa and β-VIa, were separated by column chromatography using on silica gel. Alkaline hydrolysis of α-VIa and β-VIa, followed by reactions with sodium ethylate gave optically pure sodium salts of (-)-I and (+)-I, respectively. The separative determination methods for the diastereomers of VIa, and for the enantiomers of the sodium salts of dl-I by high performance liquid chromatography were also established.

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Several imidazolylpyridinemethanols and imidazolylbenzenemethanols were prepared and evaluated for an inhibitory activity against arachidonic acid-induced platelet aggregation. The result shows that the arylmethanol moiety is essential for the activity and may correspond to the 15-OH group of prostagrandin H₂ (PGH₂). Among the compounds tested, 4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3, 5-dimethylbenzoic acid (XV) was found to have a potent inhibitory activity and a long duration of action. Structureactivity relationships are also discussed briefly.

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After intravenous administration of liposomes containing a novel glycolipid, trehalose 2, 3, 6'-trimycolate, isolated from Rhodococcus aurantiacus, the granuloma formation was observed distinctively in the lungs, spleen and liver of ICR mice. The concentration of the glycolipid in liposomes influenced profoundly on the inducibility for granulomas and the liposomes containing 10 mol% of trehalose 2, 3, 6'-trimycolate showed the highest activity for the granuloma formation in mice without a significant loss of body weight of mice with a less toxicity. EggPC liposomes are of more highly inducible for the granuloma formation in mice than eggPC : PS (7 : 3, mol ratio) liposomes or eggPC : Chol (9 : 1, mol ratio) liposomes, suggesting that cholesterol in liposomes was not necessarily essential for inducing granulomas in mice. Among the various PC liposomes, synthetic dimyristoylphosphatidylcholine (DMPC) or dipalmitoylphosphatidylcholine (DPPC) liposomes were of highly inducible, although a high responsiveness was also observed with natural lecithines such as egg or soy PC. However, distearoylphosphatidylcholine (DSPC) liposomes did not show any activity for the granuloma formation in any organs of mice. Organ responsiveness differed significantly in the micelle forms injected. Glycolipid entrapped with eggPC-Chol liposomes showed a lower lung index below 1.0, in contrast to w/o/w micelles containing Freunds'incomplete adjuvant, which showed a higher granuloma formation in the lungs. It was also noted that the toxicity of glycolipid containing liposomes was comparatively lower than the toxicity of glycolipid containing w/o/w micelles, indicating that the liposomes appeared to be more suitable for the induction of the immunomodifying activities of mycolic acid-containing glycolipids than w/o/w micelles.

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Polyamine concentrations, ornithine decarboxylase (ODC) activity and S-adenosyl-L-methionine decarboxylase activity in the spleen of ICR mice after s.c. inoculation of 2×10⁶ Sarcoma-180 ascites tumor cells were studied. ODC activity and putrescine concentration in spleen were markedly elevated at 1 and 5 d after inoculation of tumor cells, and spleen weight increased from 3 to 7 d after the inoculation. The elevations at 5 d after inoculation corresponded to the enlargement of spleen. By s.c. inoculation of 2×10⁶ METH-A ascites tumor cells into BALB/c mice, ODC activity and putrescine concentration in the spleen were also elevated at about 1 d after inoculation. On the other hand, when normal cells (spleen cells) were inoculated into ICR mice, those variations were not observed. From these facts, it was thought that elevations of ODC activity and putrescine concentration in the spleen at 1 d after inoculation of tumor cells were related to the immune response. Further, those were elevated according to the number of inoculated cells, and when cell membranes of 2×10⁶ Sarcoma-180 ascites tumor cells were inoculated, those were also elevated at about 1 d after the inoculation. From the above facts, it was proved that elevations of ODC activity and putrescine concentration in the spleen at 1 d after the inoculation of tumor cells were due to antigenicity of tumor cell membranes and those were dependent on the number of inoculated tumor cells.

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A high perfomance liquid chromatographic (HPLC) method was developed for the determination of chlorpheniramine (I) in the plasma. By this method, 1 ng of I could be measured. Plasma levels of I were determined by the HPLC method after oral administration of d-chlorpheniramine maleate (II) or l-chlorpheniramine maleate (III) to healthy subjects and dogs. Plasma levels of I brought about by oral administration of II were evidently higher than those by III both in humans and dogs. On the other hand, there was no difference in plasma levels of I when II or III was injected intravenously into dogs. Therefore, it was considered that the discrepancy in plasma levels of I after oral administration of II and III to dogs was neither due to a difference in elimination rate nor a distribution volume but rather in first-pass effect in absorption process. The result observed in the human study could be also explained in the same way as that in dogs.

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The displacing effect of serum protein binding on the intestinal absorption of sulfadimethoxine (SDM) in rabbits was examined by using N⁴-acetylsulfadimethoxine (N⁴-AcSDM), a major metabolite of SDM, as a displacing drug. N⁴-AcSDM markedly decreased the in vitro serum protein binding of SDM, while many drugs including phenylbutazone and salicylic acid did not display such a marked decreasing-effect. The intravenous administration of N⁴-AcSDM clearly decreased the in situ intestinal absorption of SDM. As expected, the intravenously administered N⁴-AcSDM enhanced the serum concentration of unbound SDM in the common jejunal vein. However, the intravenously administered N⁴-AcSDM caused no change in the transfer of SDM across the intestinal membrane. These results indicate that the displacement of serum protein binding can become one of factors decreasing the intestinal absorption of SDM.

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