In order to characterize the state of aggregation, dielectric relaxation due to interfacial polarization of a system of aqueous agarose gel particles dispersed in a squalane medium jellified by hydrophobic colloidal silica (denoted below as G/(S·O) emulsion) was investigated over a frequency range from 10kHz to 3MHz. The value of the parameter α, a measure of the distribution of relaxation frequency determined from complex plane plots, was zero when there was no aggregation. It was positive while aggregation was progressing and fell toward zero as the aggregation approached the steady state during storage. When the dependence of α on the uniformity of particle size was taken into account, the transient characteristics of dielectric relaxation represented by the positive value of α seemed to indicate that the mode of ion diffusion through the interface layer between particles in contact changed depending on the magnitude and particle size variation of particle clusters. Microscopic observation during aggregation supported the hypothesis that positive α appeared during the progressive stage of aggregation as a result of a transient deviation from uniformity of aggregation. The influence of aggregation on other dielectric parameters is also discussed.

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The phase transitions among various phases, i.e. crystalline (k), isotropic liquid (i), cholesteric (c) and smectic (s) phases, of cholesteryl oleate (ChO) were studied by using differential scanning calorimetry (DSC) and polarizing microscopy. We used two commercial samples of ChO and a gift with a known history of synthesis and purification. The transition temperatures, T_tr, and enthalpies, Δ_trH, of these samples were all in good agreement with each other. The DSC thermograms of k/i transition showed the coexistence of two kinds of crystals with a higher melting temperature (k₁) and a lower one (k₂) in k. By analysis of the thermograms, we determined the enthalpic and molar fractions of k₁ in k, f₁ and x₁, respectively, which depend on the method and conditions of crystallization. Three types of crystallizing procedures, i.e. solvent evaporation, cooling of ChO solution in ethanol, acetone or 1-pentanol, and in situ crystallization in the DSC pan, were examined at various temperatures. At higher temperature, a higher value of f₁ or x₁ was obtained. Using the values of T_tr and Δ_trH at various transitions, we could draw the curves of relative chemical potential, μ_rel, of the k₁, k₂, i, c and s phases of ChO vs. temperature, The stability of various ChO phases and the thermodynamic nature of the transition paths are discussed on the basis of the above μ_rel diagram.

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The manner of binding of imipramine (IMIP) and amitriptyline (AM) as well as chlorpromazine (CPZ) to single-or multi-bilayers of egg phosphatidylcholine (PC) was analyzed by carbon-13 (¹³C-) and deuterium nuclear magnetic resonance (²H-NMR) methods. For this purpose, we first tried to assign or re-assign the aromatic ¹³C chemical shifts by the selective proton-decoupling method. We observed that the ¹³C-NMR signals from a specific portion of the aromatic moiety of IMIP and AM are differently broadened as a result of binding to single bilayers of egg PC. In contrast, the signals of all carbons adjacent to protons in the aromatic moiety of CPZ were completely suppressed in the presence of egg PC. The observation of such differential linebroadening for IMIP and AM was interpreted in terms of the presence of anisotropic diffusion at the tricyclic moiety incorporated into the bilayers. However, drugs tightly bound to lipids such as CPZ cannot afford signals showing such differential line-broadening because of the slowed molecular motion in the bilayers. The extent of binding to lipids as viewed from the characteristic change of the ¹³C-NMR signals is in parallel with that determined from binding experiments by centrifugation and equilibrium dialysis. The reason why the ¹³C-NMR signals of IMIP and AM are visible even in the presence of lipid bilayers is considered to be the larger proportion of these drugs involved in fast exchange between lipids and the aqueous phase, on the basis of the observation of a major central peak in the ²H-NMR spectra of [2, 4, 6, 8-²H₄] IMIP in the presence of multibilayers of egg PC. Nevertheless, there appears to be some portion of IMIP which penetrates deeply into the hydrophobic portion of egg PC and has a slow exchange rate compared with the inverse of the quadrupole splitting (16kHz).

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β-Galactosidase obtained from Aspergillus oryzae was found to have strong transglycosylation activity. The glycosylation of water-soluble and insoluble alcohols was successfully performed under mild conditions (pH 5 at 4-37°C) with this enzyme. The enzyme was also applied to the onestep synthesis of several cardiac glycosides that are diffcult to obtain by ordinary chemical methods.

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A series of new thiaprostaglandins, 4-thia-, 5-thia-, 6-thia-and 7-thiaprostaglandin E₁ methyl esters (3b, 4b, 5b, and 6b), was synthesized by a three-component coupling process using a chiral common synthon, (R)-4-tert-butyldimethylsilyloxy-2-cyclopentenone (1). Among these thiaprostaglandins, 7-thiaprostaglandin E₁ methyl ester showed the most potent platelet aggregationinhibiting activity.

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The exclusive ortho acylation reaction of aniline derivatives using boron trichloride made possible the one-step synthesis of 2-acyl-N-monoaminoalkylanilines (1) and the corresponding imines (2) from N-monoaminoalkylanilines, even in the case of compounds with a bulky substituent at the nitrogen atom. Conventional methods only give 1 via elaborate procedures.

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A method for in situ generation of boron trichloride from boron trifluoride etherate and silicon tetrachloride in the presence of triethylamine, traced by boron-11 nuclear magnetic resonance (¹¹B-NMR) spectroscopy, was successfully developed, thus eliminating the need to use expensive boron trichloride for the exclusive ortho substitution reaction of N-monoalkylanilines. The method was readily adaptable to the reaction with N-monoaminoalkylanilines.

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Oxidation of 1-acetylindoles 1 with (hexamethylphosphoramide) oxodiperoxomolybdenum (VI), MoO₅·HMPA, in dry methylene chloride gave 1-acetyl-2-hydroxyindoxyls 4. 2-Phenylindole (8) was similarly treated with MoO₅·HMPA to give a dimeric product 11, while oxidation of 8 with three mol eq of MoO₅·HMPA gave 2-phenylisatogen (12). The oxidation of other indoles, 14, 19, 21, and 22, with MoO₅·HMPA in methylene chloride is also described. A possible mechanism for these oxidations is presented.

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A deoxyribonucleic acid (DNA) duplex with a chain length of 46 which contain binding sites for catabolite gene activator protein and ribonucleic acid (RNA) polymerase was synthesized by the solid-phase phosphotriester method, involving condensation of tetramer or pentamer blocks. Eleven oligonucleotide blocks were used to elongate each chain, beginning from polystyrene-linked N-protected 3'-succinyldeoxynucleoside. The estimated overall yields of upper and lower chains were 18% and 17%, respectively. The products were purified by reversed phase chromatography and characterized by sequence analysis using the Maxam-Gilbert method.

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Synthesis of hexofuranosyluracil cyclonucleosides carbon-bridged between C-6 and C-6'is described. Treatment of 6-cyano-5'-iodo-2', 3'-O-isopropylidene-5'-deoxyuridine with tri-n-butyltin hydride and 2, 2'-azobisisobutyronitrile gave the 6'-imino-6, 6'-cyclo-5', 6'-dideoxyallofuranosyluracil, which was converted to the 6'-oxo derivative. The 6'-oxo function was reduced with sodium borohydride and the 6'-hydroxyl group was eliminated to give the 5', 6'-unsaturated cyclodideoxyallofuranosyluracil, which was hydrogenated to furnish 6, 6'-cyclo-5', 6'-dideoxyallofuranosyluracil, a uridine derivative fixed in the anti form.

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Phenolysis of O-cholesteryl S-alkyl dithiocarbonates gave the corresponding S-alkyl S-cholesteryl dithiocarbonates. The rearrangements obeyed first-order rate laws and the rates were affected by the acidity of the phenols. A plot of the substituent effect of the S-alkyl moiety against the Tafts σ^* values was roughly linear. ortho-Substituted phenols such as 2-chlorophenol or 2, 6-dimethylphenol considerably retarded the rearrangement. The role of phenols and the reaction behavior of O-cholesteryl S-alkyl dithiocarbonates are discussed on the basis of kinetic and molecular orbital calculation data indicating that the rearrangement may proceed by specific solvation of phenols at the thiocarbonyl sulfur atom.

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In the 1, 3-dipolar cycloaddition reaction of pyridine N-oxides with phenyl isocyanates, we have isolated 1, 5-sigmatropy products of the primary cycloadduct and carbamation products of 2-anilinopyridines. In connection with the tautomerism of 2-anilinopyridines, the structure of the carbamation products is discussed in detail based on kinetic, molecular orbital calculation and spectral data. A comparison of the spectral data with those of structurally related compounds indicated that the carbamation dose not occur at the ring nitrogen but at the exocyclic one.

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A new oxygenated dimer of 3-methylindole was isolated from the reaction mixture obtained by oxygenation of 3-methylindole in the presence of a sterically crowded cobalt catalyst, N, N'-(cis-1, 2-cyclohexylene) bis (3-tert-butylsalicylideneaminato) cobalt (II). X-Ray crystal structure determination of its acetylated derivative revealed it to be 6-acetyl-5aβ (H), 11aα (H)-12β-hydroxy-10bβ, 12α-dimethyl-5a, 10b, 11a, 12-tetrahydro-6H-oxazolo [3, 2-a : 4, 5-b'] diindole, with a novel C₆-C₄N-C₃NO-C₄N-C₆ ring system. Two conformers due to restricted rotation of the acetyl group of the acetylated derivative was observed by temperature-dependent ¹H-nuclear magnetic resonance spectroscopy.

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Seven 17-ester and thirty-eight 17, 21-diester compounds (3 and 4) of 11β, 17α, 21-trihydroxy-6α-methyl-1, 4-pregnadiene-3, 20-dione (6α-methylprednisolone, 1) were synthesized and thirty-eight selected compounds were tested for vasoconstrictive activity in humans. Except for 4g₁ and 4g₂, they were more active than the mother compound (1). In particular, the activities of ten compounds (3b-g, 4b_{9, 10}, 4c_{2, 3}, and 4c₆) were equal to or greater than that of 9α-fluoro-11β, 21-dihydroxy-16β-methyl-17α-valeryloxy-1, 4-pregnadiene-3, 20-dione (betamethasone 17-valerate, BV). The activities of 21-methoxyacetate compounds (4b₉, 4c₆ and 4d₅) were potent. The structure-activity relationship is discussed.

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The radical scavenging reactions of a vitamin E model compound, 2, 2, 5, 7, 8-pentamethylchroman-6-ol, with radicals from the Fe (II)-induced decomposition of a linoleic acid hydroperoxide, (9Z, 11E)-13-hydroperoxy-9, 11-octadecadienoic acid, were examined extensively. When Fe (II) was added to a mixture of the vitamin E model compound and the linoleic acid hydroperoxide in methanol, (9E)-trans-12, 13-epoxy-erythro-11-, (9E)-trans-12, 13-epoxy-threo-11-, (9Z)-trans-12, 13-epoxy-erythro-11-and (9Z)-trans-12, 13-epoxy-threo-11-(2, 2, 5, 7, 8-pentamethylchromanoxy)-9-octadecenoic acids, and (9E)-13-hydroxy-12-methoxy-11-(2, 2, 5, 7, 8-pentamethylchromanoxy)-9-, (10E)-13-hydroxy-12-methoxy-9-(2, 2, 5, 7, 8-pentamethylchromanoxy)-10-and (11E)-13-hydroxy-10-methoxy-9-(2, 2, 5, 7, 8-pentamethylchromanoxy)-11-octadecenoic acids were obtained as main products. The hydroxymethoxy acids are presumed to be derived from the epoxy acids. A possible reaction pathway for the formation of the products is discussed.

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Reaction of 1-methyl-5-(methylamino) imidazole-4-carboxamide (6a) with a boiling mixture of ethyl orthoformate and acetic anhydride produced 3, 9-dimethylhypoxanthine (7a) in 60% yield and 1-methyl-5-(N-methylformamido) imidazole-4-carboxamide (5a) in 39% yield. Compound 5a was transformed into 7a by treatment with NaH in 78% yield. Compound 7a was alternatively prepared by cyclocondensation of 6a with diethoxymethane followed by oxidation with I₂. The pyrimidine moiety of 7a has been shown to be reactive : 7a affords the 1, 2-dihydro derivative 9 under reductive conditions and undergoes ring opening to 5a in aqueous NaOH. 3-Ethyl-9-methyl-(7b), 3-benzyl-9-methyl-(7c), 9-ethyl-3-methyl-(7d), and 3, 9-dibenzylhypoxanthine (7e) were also prepared from the corresponding carboxamides 6b-e.

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Five new triterpenes, 24 (R/α)-and 24 (S/β)-dihydrocycloeucalenol, dihydrocyclonervilol, cyclonervilol, and cyclohomonervilol, were isolated along with cycloeucalenol and cyclofuntumienol from the triterpene fraction of Nervilia purpurea by the combination of chromatography on silver nitrate-impregnated silica gel and reversed-phase high-performance liquid chromatography (HPLC). The structures 4a, 5a, 7a, 2a, and 10a are proposed for these compounds, respectively.

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gem-Dimethyl olefins (III) were transformed regiospecifically to the terminal β-methallyl sulfides (IV) bearing the methoxycarbonylmethyl substituent on the sulfur atom via (A) methoxycarbonylmethanesulfenyl chloride addition followed by dehydrochlorination or (B) allylic chlorination with SO₂Cl₂ followed by sulfenylation with methyl thioglycolate. Treatment of the sulfides (IV) with tert-BuOK or NaH in N, N-dimethylformamide or dimethyl sulfoxide at room temperature gave stereoselectively the sulfur-free esters (V) through a novel one-pot desulfurizative [2, 3]-sigmatropic rearrangement. By utilizing this method, biologically and pharmacologically important linear degraded terpenoids, a diol component (1) of the pheromonal secretion of the queen butterfly and several ω-quinoid acids (4, n=1, 2) and (5, n=1, 2), which are metabolites of polyisoprenoidquinones, were synthesized.

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Two isothiocyanates, epipolasin-A 1 and-B 2, and two corresponding thiourea derivatives, epipolasinthiourea-A 14 and-B 15, were isolated from the marine sponge E. kushimotoensis. Their structures were elucidated on the basis of chemical and spectral evidence. The thioureas 14 and 15 showed cell growth inhibition activity.

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The first total synthesis of the Alangium alkaloid alangimarckine (8) has been accomplished in the form of a racemic modification by means of an initial coupling of the (±)-tricyclic amino acid 6 with tryptamine and succeeding steps proceeding through the intermediates (±)-7, (±)-10, and (±)-9. The 1'-epimers (±)-12 and (±)-11 were also produced in this reaction sequence. A parallel sequence of conversions starting with the (-)-tricyclic amino acid 6 yielded the chiral molecule (-)-8 via the intermediates (+)-7, (+)-10, and (+)-9, together with the 1'-epimer (-)-11 via (-)-12. The identity of the synthetic (-)-8 with natural alangimarckine unequivocally established the structure and absolute configuration of this alkaoid. The assignments of the configuration at C-1'of 8, 9, 11, and 12 were based on five criteria, namely, the ratio of products from the NaBH₄ reduction of (±)-10, thin-layer chromatographic mobility, and proton and carbon-13 nuclear magnetic resonance and circular dichroism spectroscopic features.

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When a mold, Gloeosporium olivarum, was fermented with (±)-2-alkyl-2-aryloxyacetic acids (1-8), an enantioselective microbial reduction as well as microbial resolution took place, giving rise to (S)-2-alkyl-2-aryloxyethanols (1a-8a) and (R)-2-alkyl-2-aryloxyacetic acids (1b-8b). The configurations of the chiral 2-alkyl-2-aryloxyethanols and 2-alkyl-2-aryloxyacetic acids were consistent with those of the corresponding products formed by Glomerella cingulata, with the sole exception of 8b. The (R)-(+)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) esters of the (S)-2-alkyl-2-aryloxyethanols showed larger lanthanide-induced shifts for the methoxy groups (1a, 4a-8a) or an aromatic proton (2a) in the nuclear magnetic resonance (NMR) spectra than the esters of the corresponding (R)-2-alkyl-2-aryloxyethanols. This result can be applied generally for the determination of the absolute configuration of 2-alkyl-2-aryloxyethanols.

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(±)-β-Acorenol (2) was synthesized by the metal-ammonia reduction of (1R^*, 3aR^*, 5aR^*, 9aR^*)-2, 3, 3a, 4-tetrahydro-1, 4, 4, 7-tetramethyl-1H, 5aH-cyclopenta [c] benzofuran (11a), which was prepared from the spirodienone 9a or 10a by reaction with methyllithium and subsequent Lewis acid treatment.

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Three new compounds named hyperenone-B, mysorenone-B, and mysorenone-C were isolated from Hypericum mysorense HEYNE, collected in Sri Lanka, and their structures were determined. In addition, hyperenone-A and -B, novel γ-pyrone derivatives, were synthesized.

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Dipolar cycloaddition of an intermediary N-trimethylsilyltrimethylsilylmethyliminium salt formed from N-(benzylidene) trimethylsilylmethylamine by the catalytical action of trimethylsilyl triflate to conjugated alkene or alkyne gave N-unsubstituted pyrrolidines. The stereochemistry of all the products was determined.

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Rifamycin S (1) was allowed to react with Na₂SO₃ under mild alkaline conditions to afford sodium rifamycin SV-3-sulfonate (3). Oxidation of 3 with MnO₂ gave sodium rifamycin S-3-sulfonate (4a). The reaction of 4a with aromatic amines and aliphatic secondary amines led to 3-aminorifamycin derivatives 5a-g. A novel cleavage reaction of the ansa-ring occurred to give compounds 7a-g, when 4a was allowed to react with aliphatic primary amines having at least one hydrogen atom at the α-position.

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In order to establish a new process for large-scale production of highly purified secretin, a synthesis based on a new strategy was investigated. A maximal protection method applying the HF deprotecting procedure in the final stage was employed. Six small protected fragments (2-6, 7-10, 11-13, 14-17, 18-22, 23-27) were each prepared by stepwise chain elongation. Thereafter, three protected fragments (1-10, 11-17, 18-27) were synthesized from them, and assembled to prepare the protected secretin. The optical purity of the product after each fragment condensation was checked by high performance liquid chromatography. Completely protected secretin having a high degree of chemical and optical homogeneity was obtained.

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Highly active synthetic secretin was obtained after deprotection of completely protected secretin with hidrogen fluoride/anisole followed by a simple two-step purification, involving ion-exchange chromatography and preparative reverse-phase high performance liquid chromatography (HPLC). The homogeneity of synthetic secretin was assessed by thin layer chromatography, HPLC, disc electrophoresis and other physicochemical methods. The synthetic secretin was found on HPLC to contain none of the diastereoisomers which might be produced during fragment condensation. Its biological activity was 5750 c.u./mg in stimulating exocrine pancreatic juice in the anesthetized rat, and this is the highest value among those of various natural and synthetic secretins (4000 clinical unit/mg). Secretin was found to be unexpectedly stable throughout the purification procedures. Our synthetic method is suitable for the large-scale production of secretin for clinical use.

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Natural porcine secretin was purified by high performance liquid chromatography (HPLC) in order to compare it with synthetic secretin. As a starting material we used partially purified secretin obtained by extraction from porcine duodenum followed by purification by ion-exchange chromatography and gel filtration. Preparative HPLC was performed on a reverse-phase column with a volatile eluent. The biological activity of the purified secretin was 5450 c.u./mg in the anesthetized rat, which is higher than those of other natural secretins reported so far (4000 c.u./mg), and was reasonably close to that of our synthetic secretin (5750 c.u./mg). The natural and synthetic secretins were compared by several physicochemical methods.

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(3S)-2-[N-Substituted N-(2-carboxyethyl) carbamoyl]-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid derivaties (8a-d and 12a-t) and their monoester compounds (13a-k) were synthesized by condensation of (3S)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylates (6a, b), 3-aminopropionates (5a, b or 10a-m) and phosgene, followed by deprotection of ester groups. Their in vitro angiotensin converting enzyme (ACE) inhibitory activities and antihypertensive effects were evaluated, and the structure-activity relationship is discussed. Some of the N-ethylcarbamoyl analogs (12h, 12j, 12k, 12l and 12o), which had hydrophobic substituents (C₈H₁₇-C₁₂H₂₅, CH₂CH₂Ph) at the α-position to the carboxyl group in the side chain, showed potent in vitro ACE inhibitory activities with IC₅₀ values of 4.0-8.8×10^-9M. The monoesters 13e, 13h, and 13i reduced the systolic blood pressure by more than 30 mmHg in spontaneously hypertensive rats (SHR) at an oral dose of 50mg/kg.

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A novel sesquiterpene peroxide, hanalpinol (1a), has been isolated from the rhizomes of Alpinia japonica. Oxidation of 1a with pyridinium chlorochromate gave a crystalline, α, β-unsaturated ketone (2), whose structure was established by means of X-ray analysis. The IR spectrum of 1a revealed the presence of intramolecular hydrogen bonding, and acid treatment of 1a resulted in the formation of furopelargone B (4), which was present naturally in the same plant. This conversion reaction suggests that 4 is biosynthesized from 1a or its analog. Furopelargone A (3) was also isolated.

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The effects of oral administration of the extracts from the leaves of several Artemisia species, and of chlorogenic acid, which is one of their components, and also of caffeic acid (which can be produced by partial hydrolysis of caffeoylquinic acids, which are the main polyphenolic components in these species) on lipid metabolic injury produced in rats by feeding peroxidized oil were investigated. The acetone-water extracts of the leaves of Artemisia princeps, A. montana and A. capillaris reduced the elevation of lipid peroxide concentration in the serum in peroxidized oil-fed rats, and the above extracts reduced the levels of liver triglyceride. The extracts of A. montana and A. capillaris inhibited the elevation of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase. Caffeic acid and chlorogenic acid also inhibited the elevation of serum triglyceride, lipid peroxides, total cholesterol, glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, as well as liver lipid peroxide.

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Alkaline degradation of sodium sulbactam in methanol and in an aqueous solution has been investigated. The degradation in alkaline methanol produced methyl 5-carboxy-6-methyl-6-sulfino-4-aza-2-heptenoate (II) which showed an ultraviolet (UV) absorption maximum at 279 nm. The UV absorption almost disappeared when the solution was acidified with methanolic HCl solution, and reappeared on subsequent realkalization, suggesting interconversion between II and its protonated form. The degradation in aqueous alkaline solutions yielded 5-carboxy-6-methyl-6-sulfino-4-aza-2-heptenoic acid (IV), which showed λ_max at 267 nm. IV was further degraded to 2-amino-3-methyl-3-sulfinobutanoic acid and formylacetic acid. The UV absorption of II and IV almost disappeared in aqueous acidic conditions, and reappeared on subsequent realkalization. These changes could be due to the hydrolysis of enamines II and IV to yield methyl formylacetate and formylacetic acid, respectively, in acidic conditions, and to the generation of the corresponding enolate ions on realkalization.

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Each extract of liver, kidney, heart, lung, small intestine and brain of rat was applied to a diethylaminoethyl (DEAE)-cellulose column (10 mM Tris-HCl, pH 8.0), and glutathione S-transferase (GST) activity in the DEAE-cellulose-unbound and -bound fractions was assayed by using 1-chloro-2, 4-dinitrobenzene (CDNB) as a substrate. The ratio of the bound to unbound GST activity differed considerably from tissue to tissue. In lung, kidney, liver and small intestine, the DEAE-cellulose-unbound fraction contained more GST activity than the DEAE-cellulose-bound fraction, but the opposite was the case in heart and brain. We examined GSTs in the DEAE-cellulose-bound fraction of rat liver in detail. Most GSTs in this fraction had YbYb subunits, and in addition, this fraction contained GSTs having YbYn subunits or YaYa subunits. The antiserum was raised against GST having YbYb subunits (peak II). The double immunodiffusion studies showed that the DEAE-cellulose-bound fraction of each tissue contained GST (s) antigenically similar to peak II. This was confirmed by the result that each GST activity was inhibited by anti-peak II serum on immunotitration.

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A low molecular weight melanoprotein from Ommastrephes bartrami LESUEL (Fr. SM II) has been reported to have a gastric secretion inhibitory activity in rats. The effect of Fr. SM II on the gastric mucosal defensive capability was studied in this investigation. It was demonstrated that Fr. SM II : i) counteracted ulceration induced by phenylbutazone and aspirin; ii) increased the contents of gastric glycoproteins in the ulcerated stomach; iii) lowered the activities of glycoprotein-degrading enzymes; and iv) increased the ³⁵SO^2-₄ uptake into the gastric mucosa in intact rats concomitantly with an increase of glycoprotein content. It is suggested that the anti-ulcerogenic activity of Fr. SM II is based on its glycoprotein-increasing activity in the gastric mucosa.

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A low molecular weight melanoprotein from Ommastrephes bartrami LESUEL (Fr. SM II) has been reported to counteract the ulcer-inducing activities of phenylbutazone and aspirin. Glycoproteins extracted from the stomach were fractionated on a Sepharose 6B column and three peaks were obtained (peaks I, II and III). The amount of peak I was decreased following the onset of ulceration caused by phenylbutazone and aspirin, and was increased by a concomitant administration of Fr. SM II. The amount of lipid peroxide was found to reflect the degree of ulceration. The effect of peak I on lipid peroxidation was studied by incubating peak I with hepatic microsomes, arachidonic acid and gastric mucosa homogenate in vitro. The formation of lipid peroxide was inhibited by the addition of peak I. It was also demonstrated that peak I has a lysosomal membrane-stabilizing activity. These results suggest that Fr. SM II manifests its anti-ulcerogenic activity by increasing peak I.

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The kinetics of the degradation of cinnarizine in aqueous solution at various pH values and four different temperatures were investigated. The degradation of cinnarizine was observed as a pseudo first-order reaction. By determining the degradation rate of cinnarizine at various pH values, it was found that the degradation rate of cinnarizine increased with decreasing pH within the range from pH 3.0 to 1.0. The rate remained unchanged at below pH 1.2, and cinnarizine was stable at above pH 3.0. The pseudo first-order rate constants in aqueous solution (pH 1.20) at 60, 70, 80 and 90°C were 1.85×10^-5, 1.05×10^-4, 4.07×10^-4 and 1.94×10^-3 min^-1, respectively. The activation energy of degradation in aqueous solution (pH 1.20) was calculated to be 36.8 kcal/mol from an Arrhenius plot.

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The kinetics of the isothermal transition of tolbutamide polymorphic forms (form B at 65, 70, 75 and 80°C), as well as mefenamic acid (form I at 142.5, 145, 147.5 and 150°C) were investigated by means of differential scanning calorimetry. Kinetic analysis according to the method of Hancock and Sharp indicated that the transition of form B to form A of tolbutamide proceeds by the mechanism of three-dimensional diffusion (Jander equation). The activation energy for this transition calculated from the slope of the Arrhenius plots was 37.3 kcal/mol. On the other hand, the transition of form I to form II of mefenamic acid appeared to follow the zero-order mechanism (Polany-Winger equation). The activation energy for this transition was calculated to be 86.4 kcal/mol.

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The degradation kinetics of cinnarizine in aqueous solution containing β-cyclodextrin at pH 1.20 and four different temperatures were investigated. The degradation of cinnarizine was found to be a pseudo first-order reaction. The pseudo first-order rate constant with β-cyclodextrin decreased with increase in the concentration of β-cyclodextrin at pH 1.20. From Arrhenius plots, the values of activation energy of the degradation in aqueous solution at pH 1.20 containing 3.26×10^-3 and 15.32×10^-3 M β-cyclodextrin were calculated to be 37.0 kcal/mol and 40.1 kcal/mol, respectively.

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The adsorptive power of commercial activated charcoal preparations was compared in powdered form for adsorbates of medical interest ranging in molecular weight from about 100 to 800. For some adsorbates, the adsorptive powers of the charcoals investigated varied up to threefold. Some activated charcoals showed distinct size-selectivity for adsorbates : the charcoals which favor adsorption of smaller molecules showed less adsorptive power for larger molecules and vice versa. Two types of adsorbates for evaluation of the adsorptive power of medicinal charcoal are proposed.

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The effects of the crystallinity of hydrocortisone acetate and betamethasone dipropionate on their percutaneous absorption were examined. The potency of vasoconstriction of the amorphous corticosteroid was higher than that of the crystalline form and lower than that of the dissolved form. The amorphous state of hydrocortisone acetate in white petrolatum ointment was stabilized by coprecipitation of the drug with polyvinylpyrrolidone. The chemical activity was correlated with the biological activity.

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A kinetic study on the degradations of cefaclor and cefatrizine was carried out at 35°C as a function of pH and initial drug concentration by the use of high-performance liquid chromatography. At constant pH and temperature, the degradation followed pseudo-first-order kinetics at the initial concentration of 5 mM. The shape of the rate-constant-pH profile of cefaclor resembled those for cefatrizine and other aminocephalosporins. At neutral pH, cefaclor was degraded via intramolecular nucleophilic attack of the α-amino group on the β-lactam moiety. The intramolecular reaction rate was very similar to that in the cases of cefatrizine and cephaloglycine, but was ten times faster than those for cefadroxil, cephalexin, and cephradine under the same conditions. Accelerated degradations of the highly reactive aminocephalosporins, cefaclor and cefatrizine, were observed at higher drug concentrations than 10 mM. By simultaneously assaying the disappearances of the α-amino group and the antibiotic itself, it has been confirmed that both antibiotics undergo self-aminolysis in solution through a nucleophilic attack of the free side-chain amino group in one molecule upon the β-lactam bond of a second molecule, forming a dimer. Since the degradation rates of cefaclor and cefatrizine were found to be larger than those of other amino-β-lactam antibiotics, the second-order degradation rate process should be considered in the analysis of their in situ intestinal absorption rates at high concentrations. The above kinetic data were applied to the intestinal absorption of both antibiotics in rats. The disappearance rate of the antibiotics from the intestinal perfusate was successfully interpreted in terms of a combination of Michaelis-Menten absorption, first-order absorption, first-order degradation and second-order dimerization.

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A prolonged release tablet of aspirin was prepared by compressing aspirin agglomerated by massing with an acetic acid solution of chitosan. The parameters controlling the drug release rate were the chitosan content in the tablet, the physical state of chitosan used for granulation i.e. liquid solution or gel, and the pH of the dissolution test solution. When the chitosan solution was used for agglomeration, the drug release rate of the resultant tablet was faster than when the gel was used. The drug release became more prolonged with increasing chitosan content in the tablet or with decreasing pH of the dissolution test solution. The drug release kinetics of the tablet after a short swelling period were represented by equation 10 in the text, which was derived by assuming that the tablet dimensions decreased isotropically during the dissolution. It was found that the decomposition rate of aspirin in the tablet stored at 37°C and at R.H. 75.1% was determined by the amount of water adsorbed by the chitosan in the tablet, leading to zero order kinetics with respect to the aspirin.

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A novel method of estimating Hansch's hydrophobic constant (log P) by making use of the solvent-accessible surface area (S_A) with correction for the hydrophilic effect of any polar moiety (S_H) is proposed. The correlation coefficient (r) between observed and estimated values of log P was 0.995 with 138 miscellaneous compounds. The method can reproduce the differences of log P among geometrical isomers. Such differences are not calculable by using other available methods. An application of S_A and S_H to the regression analysis of water-solubility data of 156 different organic liquids gave r=0.981. The proposed method may offer new insight into the physicochemical nature of hydrophobic phenomena.

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The oxidative demethylation of 4, 7-dimethoxyindoles to the corresponding 4, 7-dihydroindole-4, 7-diones with ceric ammonium nitrate is described.

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Reactions of 2-methyl-3-nitrochromone (1) with guanidine, acetamidine and benzamidine readily gave the corresponding 2-substituted-6-(2-hydroxyphenyl)-4-methyl-5-nitropyrimidine (3a-c) in good yields, and these were converted to 6-(2-methoxyphenyl) pyrimidines (4a-c) by treatment with methyl iodide and to 5-aminopyrimidines (5a-c) by catalytic hydrogenation. 3-Amino-2-methylchromone (2) reacted with guanidine, but not amidines, to give 2, 5-diamino-6-(2-hydroxyphenyl)-4-methylpyrimidine (5a). 3-Acetamido-2-methylchromone (6) was converted more readily than 2 into pyrimidine derivatives (7a, c) by the reactions with guanidine and benzamidine, respectively.

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Methylation of rifamycin S (1) with MeI in CH₃CN or dimethylformamide (DMF) in the presence of Ag₂O afforded 8-O-methyl-N-methylrifamycin S (3). Demethylation of 3 with MgI₂·ether, followed by treatment with L-ascorbic acid and MnO₂, led to N-methylrifamycin S (4). Rifamycin S imino methylethers 5 and 6 gave the corresponding oxazolorifamycin derivatives 7 and 8 on reduction with L-ascorbic acid.

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Amino acid derivatives containing a sulfonamide bond were synthesized and their biological activities were examined. Some sulfonyllysine derivatives exhibited fibrinolytic activity. N⁴-Lysylsulfanilamide was also prepared and treated with trypsin. The results suggest that a drug acylated with an amino acid might have improved solubility in water and might act as a kind of prodrug.

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FUT-175 (nafamstat mesilate) is a novel synthetic protease-inhibiting agent which has potent, reversible and selective inhibitory activity against trypsin-like serine proteases. A determination method for FUT-175 in biological materials, particularly in blood, was established based on the potent trypsin-inhibitory activity of this drug. The procedure consists of two steps : treatment of blood specimens with formic acid-containing ethanol for deproteinization and extraction of FUT-175 with minimal hydrolysis, and a clean-up with n-pentane for removal of remaining blood constituents such as phospholipids, fats and any fluorescent materials. This method shows good reproducibility and sensitivity ; the detection limit was as low as 1 ng of FUT-175/ml blood.

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The muskrat (Suncus murinus) may be useful as a new experimental animal. In order to evaluate some biochemical characteristics of this animal, urinary excretion of homovanillic acid, vanillylmandelic acid and 5-hydroxyindole-3-acetic acid in the muskrat was determined by high-performance liquid chromatography (HPLC) with electrochemical detection. These acid metabolites of catecholamines and serotonin were not detectable or barely detectable (vanillylmandelic acid) in the urine of the muskrat in comparison with human, dog, rat or mouse. The secretion and/or metabolism of these neurotransmitter amines in the muskrat seem to be considerably different from those in other mammals.

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Permeability characteristics in rat jejunal, rectal and nasal absorption of antipyrine (AP) are discussed in terms of water influx and sieving coefficients. The sieving coefficient in nasal absorption was less than half of those in jejunal and rectal absorptions, which were not significantly different from each other. Apparent water influx in the jejunum was twice that in the rectum, and that in the nose was approximately three times larger than that in the jejunum. The pore size of the water channels in each site was calculated from the sieving coefficient and molecular radius of AP by using the modified Levitt equation. It was concluded that : (1) the nasal membrane is composed of smaller-sized pores but is richer in water channel distribution than the jejunal membrane ; (2) the rectal membrane has similar-sized pores to the jejunal membrane but the water channel distribution is poorer.

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