The treatment of 1, 3-dimethyl-2-(α-benzyloxybenxyl)benzimidazolium iodides 1 with a base gave deoxybenzoins 2 in moderate yields. Sodium hydride (NaH), potassium carbonate (K₂CO₃), and cesium carbonate (Cs₂CO₃) were effective bases in this reaction. Deoxybenzoins 2 were produced through rearrangement of the benzyl group followed by expulsion of the 1, 3-dimethylbenzimidazolium ylide (A). The rearrangement proceeds in a way similar to Witting rearrangement. Deoxybenzoins 2 were also formed in good yields from 1, 3-dimethyl-2-(α-benzyloxybenxyl)-imidazolium iodides 4 upon similar treatment. However, the quaternary salts having a thiazolium moiety 5a and a pyridinium moiety 6a failed to produce deoxybenzoin (2a).

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Singlet oxygen (¹O₂), a highly reactive and toxic intermediate, may play a role in photo-induced aging. We examined singlet oxygen generation from hematoporphyrin (HP) with UV-A, by monitoring the emission at 1268nm corresponding to ¹O₂→³O₂. Singlet oxygen was formed HP-dose-dependently in this system. We then investigated the reaction of singlet oxygen generated by UV-A irradiation with collagen, which is related to skin elasticity and softness. Collagen from skin was rapidly and dose-dependently cross-linked by singlet oxygen. The reaction was inhibited by NaN₃, a selective quencher of singlet oxygen. In contrast, SOD (superoxide dismutase) and mannitol had no effect. These results suggested that cross-linking of collagen was caused by UV-A-generated singlet oxygen, not by any other reactive oxygen species. Compared with another multisubunit protein, alcohol dehydrogenase, collagen was cross-linked much more efficiently. Further, the finding that semicarbazide inhibited cross-linking of collagen showed that cross-links were formed between photooxidized histidyl residues and amino groups. Singlet oxygen generated by UV-A irradiation may contribute to cross-linkin of collagen in the process of skin photoagaing.

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Mesoionic 1, 3-oxazolium-5-olates (munchnones) react fairly rapidly with oxygen to give the autoxidation products when the C-4 substituent is aromatic. The autoxidation occurred in the munchnones generated from N-acyl tetrahydroisoquinoline-1-carboxylic acids or tetrahydro-β-carboline-1-carboxylic acids. The mechanism was elucidated by ¹⁸O labeling experiments and involved a series of well-precedented autoxidative processes including oxygenation, cyclization of the resulting peroxy anion, and oxidative cleavage.

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Refluxing of a mixture of benzaldehyde (1a), 1, 3-dimethylbenzimidazolium iodide (7), p-nitroaniline (9b) as an oxidizing agent, and 1, 8-diazabicyclo[5, 4, 0]-7-undecene (DBU) in MeOH afforded methyl benzoate (2a) in good yield. Other methyl arenecarboxylates 2 were similarly obtained from arenecarbaldehydes 1. We showed that this aroylation proceeds via the 2-aroyl-1, 3-dimethylbenzimidazolium salt (8). The 1, 2, 4-triazolium salt (18) and the naphtho[1, 2-d]imidazolium salt (19) were also effective catalysts for this oxidative aroylation. However, the aroylation did not proceed with the imidazolium salt (20). In the presence of flavins (25a-c), arenecarbaldehydes 1 reacted in MeOH under aerobic conditions catalyzed by the benzimidazolium salt 7 to give the corresponding methyl arenecarboxylates 2. 1-Methyl-3-[3-(10-phenylisoalloxazin-3-yl)propyl]benzimidazolium bromide (27) is an effective complex catalyst for this oxidative aroylation.

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A stereocontrolled synthesis of the (E)-alkene dipeptide isostere of Trp-Val is described. The stereospecific α-alkylation of the δ-amino-γ-mesyloxy-α, β-unsaturated ester via the organocyanocopper-Lewis acid mediated reaction, based on 1, 3-transfer of chirality, was successfully applied for the key step in the synthetic sequence.

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The C1-C15 unit of halichondrin B was synthesized starting from D-glucose via stereoselective construction of the B and A rings, which have 2, 6-trans- and 2, 6-cis-disubstituted tetrahydropyran rings, respectively. With the aid of MM2 calculations kinetically and thermodynamically controlled Michael reactions were successfully applied for the construction of the B and A rings, respectively.

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The quantitative structure-activity relationship (QSAR) of N-(3-amino-6-chloro-5-ethylisopropylaminopyrazine-4-carbonyl)guanidine (EIPA) 1ac and its derivatives as Na/H exchange inhibitors was analyzed using the steric parameters and an indicator variable. The results indicated that bicyclic aroylguanidines might have Na/H exchange inhibitory activity. Therefore, various bicyclic aroylguanidines were synthesized and tested for Na/H exchange inhibitory activity. The QSAR study of the bicylic aroylguanidines showed that hydrophobic bicyclic rings seemed to be preferable for potent activity. The hydrophobicity of the aroyl ring moiety was thought to be paticularly important. Thus, the QSAR of EIPA and its derivatives was re-analyzed using hydrophobicity and steric parameters. The results indicated that high hydrophobicity of the pseudo-ring moiety and a substituent of appropriate length at the position corresponding to the 5-position of the naphthalene ring enhance the activity. As expected from the results, 5-bromo-2-naphthoylguanidine 3b and 5-methoxy-2-naphthoylguanidine 3c exhibited strong activity. These findings will be helpful to design new, potent Na/H exchange inhibitors.

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New 2-(4-(4-azolybutyl)piperazinyl)-, 2-(4-(4-azolybutyl)piperazinylmethyl)-, 2-(4-(4-azolylbutyl)homopiperazinyl)- and 2-(4-(4-azolylbutyl)homopiperazinyl)methylbenzimidazoles were synthesized, characterized and tested for in vitro and in vivo H₁-antihistaminic activity. Structure-activity relationships impleid that the best antihistaminic activity required the simultaneous presence of a homopiperazinylbenzimidazole system (or a methylene linker between the benzimidazole and the piperazine rings) and an unsubstituted pyrazole ring. 1-(2-Ethoxyethyl)-2-{4-[4-(pyrazol-l-yl)butyl]homopiperazin-l-yl}benzimidazole (17), at its dimaleate salt, has been chosen for further development.

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In order to study the potency of the 5-aminopyrimidine skeleton as an aromatase inhibitor, we synthesized various N, N-disubstituted-5-aminopyrimidine derivatives and evaluated their aromatase-inhibitory activity (in vitro) and their inhibitory activity on pregnant mare serum gonadotropin (PMSG)-induced estrogen synthesis (in vivo). Compounds with the fluoro-substituted benzyl group showed potent aromatase inhibition. Among them, 5-[(4-cyanophenyl)(3, 5-difluorobenzyl)amino]pyrimidine (5w, YM553) was a highly potent compound with an IC₅₀ value of 0.038nM for aromatase from human placenta. Its inhibitory effect was approximately four times greater than that of YM511. In addition, YM553 was a weak inhibitor of other enzymes involved in steroid hormone synthesis. These results indicate that YM553, as well as YM511 (a 4-amino-4H-1, 2, 4-triazole derivative), is a promising agent for the treatment of estrogen-dependent diseases.

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The methanolic extract of a food garnish "Tonburi", the fruit of Japanese Kochia scoparia (L.) SCHRAD. (Chenopodiaceae), was found to inhibit the increase in serum glucose in glucose-loaded rats. Through bioassay-guided separation, momordin Ic and its 2'-O-β-D-glucopyranoside were isolated as the active principles from this medicinal foodstuff together with three new saponins named scoparianosides A, B, and C. The structures of scoparianosides A, B, and C were elucidated on the basis of chemical and pysicohemical evidence as 3β, 22α-dihydroxyolean-12-en-28-oic acid (22α-hydroxyoleanolic acid), 3-O-β-D-xylopyranoxyl (1→3)-β-D-glucopyranosiduronic acid, 3β-hydroxyolean-18-en-28-oic acid (morolic acid), 3-O-β-D-xylopyranosy(1→3)-β-D-glucopyranosiduronic acid, and 3β-hydroxyolean-13(8)-en-28-oic acid, 3-O-β-D-xylopyranosyl(1→3)-β-D-glucopyranosiduronic acid.Momordin Ic and its 2'-O-β-D-glucopyranoside, both of which are the principal saponin constituents of this medicinal foodstuff, were found to potently inhibit glucose and ethanol absorption in rats.

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The constituents of the MeOH extract of Salvia miltiorhiza BUNGE, which showed strong aldose reductase (AR) inhibitory activity, were examined, and two new abietane-type diterpenoids, danshenol A (1) and danshenol B (2), were isolated together with six known ones : dihydrotanshinone I (3), cryptotanshinone (4), tanshinone I (5), tanshinone IIA (6), (-)-danshexinkun A (7), and sugiol (8). Among them, 4, 5, and 8 were weak AR inhibitors with IC₅₀ from 4.80 to >10.0μM, while 1, 2, 3, 6, and 7 were strong inhibitors (IC₅₀ from 0.10 to 1.75μM). Danshenol A (1), the strongest inhibitor, had IC₅₀ of 0.10μM which is comparable to that of epalrestat in clinical use.Moreover, from a consideration of IC₅₀ and yield of each compound, it was concluded that tanshinone IIA (6) is the major active constituent of the MeOH extract and danshenol A (1) and (-)-danshexinkun A (7) are the minor ones.

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Several kinds of theophylline granules were prepared in a high speed mixer by varying the kneading time, and their compression processes were analyzed by Heckel and by Cooper and Eaton equations. The compressibility of those granules was also examined comparatively by analyzing the compression energy applied to the powder layer to determine the relation between the compression behavior, compression energy, tablet hardness and internal structure of the tablet.The granules having the largest pore volumes were found to have high tablet hardness and tended to show larger ratios of compression loss energy to compression energy. It was suggested that in the granules having the largest pore volumes, the pores were easily filled by particle movement, rearrangement, plastic deformation and brittle fracture upon compression and the energy applied to the powder layer upon tableting was consumed efficiently.

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The interaction between amiodarone or desethylamiodarone and dimyristoyl phosphatidylcholine bilayers was investigated by two optical techniques, quasi-elastic light scattering (QLS) and Fourier transform infrared spectroscopy (FT-IR). The results show that in th presence of the drugs, the bilayer phase transition point is lowered and at high drug concentration there is an incresase in the vesicle size. The FT-IR results indicate interactions in the hydrocarbon region and also in the carbonyl interface region of the bilayers. There may be an interdigitation of two leaflets of the bilayer. We discussed these results comparatively with those obtained from propranolol whose effect was analogous and previously studied.

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Since a membrane method which emplys a porous glass membrane for preparation of water-in-oil-in-water (w/o/w) emulsion from water-in-oil emulsions has been developed recently, a comparative study was made of properties of w/o/w emulsions prepared by a two-stage stirring method and this membrane mehtod. w/o/w emulsions encapsulating cytarabine, doxorubicin and vancomycin, were prepared by the two techniques using the same formulation. Particles of the w/o/w emulsion prepared by the stirring method were less homogeneous, whereas particle distribution of the emulsion prepared by the membrane method was sharp and close to monodispersion. The mean particle size depended on pore size of the membrane. The membrane method proved the more useful of the two for encapsulation of low molecular weight drugs. Drug release from the emulsion prepared by this means was slower than that from the emulsion prepared by the stirring method. The membrane method was therefore found useful for preparation of a homogeneous w/o/w emulsion, effective encapsulation of small drugs and control of drug release.

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A monofatty acid ester of glucosamine (PGlcN) was synthesized to provide liposomal membranes with a positive charge, and the trapping efficiency of negatively charged substances (superoxide dismutases, SODs) into cationic liposomes containing PGlcN or stearylamine (SA) prepared by various methods was compared to find the most efficient trapping method. We demonstrated that cationic liposomes, which were prepared in a buffer of low ionic strenght containing sorbitol by a simple hydraiton method, could entrap a large amount of negatively charged SODs which retained their activity, as compared with cationic liposomes prepared in a buffer of high ionic strength. We also showed that a reverse-phase evaporation method entrapped a large amount of SODs. However, SODs were inactivated durgin the preparation; therefore, this method was not suitable to entrap the enzyme. Freeze-thaw method induced the formation of cationic liposomes which were smaller than extruded liposomes and could entrap the SODs in a buffer of low ionic strength. Dehydration-rehydration method with a buffer of low ionic strength also entrapped a large amount of SODs, indicating that the integrity of liposomes was lost in the lipid bilayer after freeze-drying and the SODs were entrapped in the reconstruction of liposomes during rehydration. Thses findings showed that the hydration method based on electrostatic attraction with a buffer of low ionic strength was simple and the most effective for entrapping SODs without loss of their activity.

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Controlled-release beads which can release drugs faster in the higher pH regions (pH 5-7.5) than in the acidic region (pH 1-5) were prepared using the newly developed tumbling melt granulation (TMG) method, in which process a powdered meltable material was coated onto the core beads without use of any organic solvent. This function could be obtained by using a mixture of hydrogenated castor oil (HCO) and higher fatty acids as coating materials. Controlled-release beads containing various kinds of drugs were prepared. Use of stearic acid as a fatty acid resulted in excellent coating producibilities when the mixing ratio of stearic acid (X_FA) was less than 30%. The dissolution rates determined in purified water, 1st fluid, and 2nd fluid tended to increase with the increase of X_FA. This tendency was especially remarkable in the 2nd fluid. The effect of the carbon number (12-22) of the fatty acid was then determined. The permeability coefficient, P, calculated from the dissolution rate, decreased with the increase of carbon number. This seemed to be due to the difference of the release rate of fatty acid from the coating layer composed of HCO and fatty acid. Determination of the dependency of P value on the pH of the dissolution medium showed that the P values changed little in the acidic region (pH 1.2 to 5.0), but increased exponentially with an increase of pH over pH 5.5. Logarithm of relative P values (P_pH/P_w : P_w means the P values in purified water) plotted against pH were distributed on the same line irrespective of fatty acid. An empirical equation which predicts the dissolution rates in the enteric medium was proposed using this relationship.

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Colloidal particles, produced upon the dispersion into water of a solid dispersion system composed of (R)-1-[2, 3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), hydroxypropylmethylcellulose 2910 (TC-5E) and polyoxyethylene hydrogenated castor oil 60 (HCO-60) at a weight ratio of 1 : 3.5 : 0.5, were characterized with respect to their physicohemical properties. From the IR absorption spectroscopic analysis, it was found that the colloidal particles, composed of YM022, TC-5E and HCO-60, have a combined weight ratio of 1 : 0.2 : 0.3. Although colloidal particles were prepared form solid dispersion systems with various weright ratios of YM022/TC-5E/HCO-60, they showed a similarity in combined ratio, suggesting the presence of specific interactions among the components. Particle diameter seemed to be affected by the composition of colloidal particles. Smaller particles contained less TC-5E which was related to the large portion of YM022 in colloidal particles. The amount of HCO-60 incorporated into colloidal particles was not affected by the particle diameter and correlated with the amount of YM022 at a fixed ratio (1.0 : 0.3). This suggested that TC-5E might function as a 3-dimensional framework for solid dispersion, while HCO-60 might interact with YM022 resulting in a fixed weight ratio between YM022/HCO-60 in colloidal particles.

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Novel conjugates of mitomycin C(MMC) with 4-[3-benzoyloxy-1, 3, 5(10)-estratrien-17β-yloxycarbonyl]butyric acid (EB-glu) and 4-[3-hydroxy-1, 3, 5(10)-estratrien-17β-yloxycarbonyl]butyric acid (E-glu) at the 1a-N position, abbreviated as EB-glu-MMC and E-Glu-MMC, respectively, were synthesized, and the kinetics on their decomposition and the MMC regeneration in various buffered solutions were investigated. EB-glu was synthesized by the reaction of estradiol benzoate (EB) and glutaric anhydride, and EB-glu-MMC was obtained by the condensation of MMC with EB-glu using N, N'-carbonyldiimidazole. E-glu was obtained by the alkaline hydrolysis of EB-glu, and E-glu-MMC was synthesized by the condensation of MMC with E-glu using N, N'-carbonyldiimidazole. The buffered solutions of pH 4, 6, 7, 7.4, 9 and 11 were used as buffered systems. In the stability study, EB-glu-MMC and E-glu-MMC were dissolved in a mixture of the buffer and propylene glycol (1 : 1, v/v) and incubated at 37°C. E-glu-MMC and EB-glu-MMC were subjected to degradation at pH4, and further, their degradation became faster with the increase of pH at the basic condition. MMC was regenerated more easily with the increase of pH, and its regeneraiton was not detected at pH4. The analysis using the pseudo-first order kinetics elucidated the conversion rates. The direct conversion rate from EB-glu-MMC to MMC was found to be close to the regeneration rate from E-glu-MMC to MMC.

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Hydroxypropyl methylcellulose (HPMC) was selected as a base polymer to develop novel enteric coating agents for acid protection which can dissolve at pH around 4, and was modified with trimellitic acid or maleic acid at various degrees of substitution. These carboxylic acids have higher dissociation constants and higher solubility in water than the carboxylic acids of existing enteric coating polymers. The synthesized polymers were micronized and dispersed in aqueous medium to determine their pK_a values by potentiometric titration. The pH of dissolution and the water vapor permeability of the cast films prepared from organic solutions were also evaluated. Hydroxypropyl methylcellulose trimellitate (HPMCT) showed good acid resistance, and the pH at which it dissolves can be controlled in the range of pH 3.5 to 4.5 by varying the content of trimellityl groups and the methoxyl substitution of the base polymer.

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Skin penetration of methyl, ethyl, propyl and butyl parabens through excised guinea pig dorsal skin was examined, and effects of the penetration enhancers, l-menthol plus ethanol, ethanol itself and N-dodecyl-2-pyrrolidone, were observed. Permeability coefficients of the parabens correlated with n-octanol/water partition coefficients. Addition of 1% l-menthol in 15% ethanol about sixteen times increased the permeability coefficient of methyl paraben, whereas this enhancer decreased that of butyl paraben to about one fifth of the control value. A similar, though weaker, tendency was observed for the effects of 15% ethanol itself. 0.025% suspension of N-dodecyl-2-pyrrolidone increased the permeability coefficient of methyl paraben about seven times, whereas it did not change that of butyl paraben significantly. Therefore, dependency of the permeability coefficients of the parabens on n-octanol/water partition coefficients almost disappeared in the presence of this compound. A spin label study with stratum corneum lipid liposomes revealed that increase of fluidity of the lipid bilayer by these penetration enhancers corresponded with their enhancement effects on skin penetration of methyl paraben. Perturbation of stratum corneum lipid lamella thus seems to be related with their enhancement of the absorption of the hydrophiic paraben.

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Complex formation between deoxycholic acid (DCA) and menadione (MND) by grinding and sealed heating was investigated. The complex between DCA and MND was prepared by coprecipitation and showed a stoichiometry of 2 : 1 (DCA : MND). The IR spectrum of the complex suggested that MND molecules were located in the channel formed by DCA molecules. The 10 min ground mixture of DCA-MND gave the same X-ray diffraction pattern as the DCA-MND coprecipitate. Differential scanning calorimetry (DSC) and IR spectroscopy also demonstrated the identical results between the ground mixture and the complex, confirming the complex formaiton between DCA and MND by grinding. The DSC data suggested that the complex formation was expected during heating process of the DCA-MND physical mixture. The sealed heated samples were prepared and compared with the complex prepared by coprecipitation. After heating in a sealed ampoule at 110°C for 10 min or at 80°C for 24h, samples demonstrated the same X-ray diffraction patterns, DSC curves and IR spectra as the complex. These results indicated that the complex formation took place between DCA and MND by sealed heating as well as by grinding.

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DNA formed an insoluble complex on mixing with chitosan (poly-D-glucosamine) in solution. The DNA content of the complex was about 50% and the DNA remained insoluble in aqueous media of pH 2-7; e.g., on treatment of the DNA-chitosan complex with phosphate-buffered saline at pH 7 and 37°C for 26h, the DNA released into the aqueous phase was less than 0.05%. Obviously, DNA and chitosan formed a tight complex due to ionic interactions. The DNA can be solubilized by treatment with 0.1N NaOH. RNA and other polynucleotides formed similar insoluble complexes with chitosan. The DNA attached to chitosan can be digested with a mixture of DNase I and phosphodiesterase. Cytosine residues in the DNA (denatured DNA) can be deaminated by treatment with sodium bisulfite, forming uracil DNA-chitosan. The uracil DNA-chitosan served as a substrate for uracil DNA glycosylase. Using polynucleotide-chitosan as an adsorbent, the affinities of reagents for polynucleotides can be determiend directly. With this technique it was found that carcinogenic heterocyclic amines have an affinity for RNA as well as DNA. The results with homopolyribonucleotide-chitosans as adsorbents for 4 heterocyclic amines indicated that the binding occurs in a purine nucleotide-specific manner. These results suggest that the polynucleotides in the chitosan complex are accessible to enzymes and reagents.This new derivative may be useful in chemical and biological studies of polynucleotides and substances interacting with polynucleotides.

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The title compound, 1-(isocyanomethyloxy)benzotriazole (6) as a new source of isocyanomethyl synthon, was synthesized in 65% yield by the dehydration of 1-(formamidomethyloxy)benzotriazole with phosphorus oxychloride in the presence of triethylamine. Under basic conditions, the reaction of 6 with aldehydes or acid chlorides gave 5-substituted oxazoles or 5-substituted 4-[(1-benzotriazoly)oxy]oxazoles as new 4-hydroxyoxazole derivatives, respectively. The reactivities of 6 toward aldehydes are as high as those of tosylmethyl isocyanide.

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Fifty-four 1-carbamoyl-5-fluorouracils were synthesized from 5-fluorouracil and isocyanate or amine. Antitumor activity was tested in the L-1210 tumor system, and 11 compounds gave better values of therapeutic ratio than HCFU (1-hyxylcarbamoyl-5-fluorouracil). 1-(4-Methoxycyclohexylcarbamoyl)-5-fluorouracil gave the best result.

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A water-soluble porphyrin having four aminophenyl groups 5, 10, 15, 20-tetrakis(4-aminophenyl)porphine (TAPP) diazotizes with nitrite ion and produces a large spectral change (ε : molar absorptivity, Δε=ε_sample-ε_blank=3.0×10⁵M^-1cm^-1, 434nm). The coexistence of L-ascorbic acid (AsA) strongly interferes with this reaction. Therefore, a highly sensitive spectrophotometric determination of AsA was developed using this effect. For the determination of trace amounts of AsA, the calibration curve was linear in the concentration range of 8.0×10^-8M-5.0×10^-7M (14-88ppb). The detection limit (3σ) was 1.0×10^-8M (1.76ppb), and the relative standard deviation was 1.86% (2.0×10^-7M (35ppb) AsA, 6 determinations). This method is more than 20 times highly-sensitive than the indophenol method as standard spectrophotometry for AsA. This method has been applied to the deternation of AsA in soft drinks and drugs.

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A new triterpenoid called ulmoidol was isolated from the leaves of Eucommia ulmoides OLIV. On the basis of spectroscopic analysis, the structure was elucidated as 11α, 12α-epoxy-2α, 3β-dihydroxy-24-nor-urs-4(23)-en-28, 13β-olide.

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Two new steroid alkaloidal glycosides, named solalyratines A and B, were isolated from Solanum lyratum collected in Formasa and their chemical structures were characterized as the diglycoside and triglycoside of soladulcidine by spectroscopy.

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A new model derived from an excess free energy approach which expresses drug solubility in solvent mixtures showing multiple solubility peaks, the chameleonic effect, with respect to the concentrations of solvents in a mixture is proposed. Accuracy and predictability of the model are compared with those of a previous model which expresses drug solubility based on Hildebrand, acidic and basic solubility parameters. The results indicate that the new model is more accurate than the previous model and average percent mean errors are 5.32 and 13.66, respectively.

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Junipenonoic acid (4), a novel C_{9, 10}-secocadinane sesquiterpene, was isolated from the heartwood of Juniperus formosana HAY. var. concolor HAY. The structure was elucidated on the basis of spectral evidence. The abosolute configuration was proposed as S.

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