The crystal and molecular structures of ceftizoxime (CZX) and its monohydrochloride monohydrate (CZX-HCl) were elucidated by X-ray structure analysis. The aminothiazolyl-methoxyimino group in the cephem C(7) substituent of both substances is in a quasi coplane, as in other cephalosporins with this C(7) substituent. The orientations of these coplanes to the cephem moiety vary such that the rotation of the cephem C(7) side chain seems not to be rigidly constrained. The exocyclic amido groups in both CZX and CZX-HCl are also planar, with intermolecular hydrogen bonds between the nitrogen and the oxygen atoms of adjacent molecules. The conformations resemble those described for the peptide bond moiety in proteins.

抄録全体を表示

D-Pantolactone crystals showed anomalous thermal behavior, that is, two endothermic peaks (62.0 and 91.6°C) were observed in the differential scanning calorimetry curves. The entropy change of the first transition was calculated as 44.4 JK^-1 mol^-1 and that of the second transition was 9.20 JK^-1 mol^-1. The powder X-ray diffraction patterns of D-pantolactone differed significantly before and after the transition (62.0°C) and only one sharp peak at 2θ=17.4° was observed at 75°C. At 75°C, carbon-13 nuclear magnetic resonance chemical shifts of D-pantolactone were clearly observed by the pulse Fourier-transform technique.It was concluded that D- and L-pantolactone showed a stable plastic crystal phase between 62.0 and 91.6°C, and that DL-pantolactone is in a plastic crystal phase at room temperature.

抄録全体を表示

An X-ray structural analysis of the 1 : 2 complex between copper(II) and pyridoxylidenetryptamine Schiff base has shown that the copper atom is co-ordinated to phenolic oxygen and imino nitrogen atoms of two ligands related by a pseudo twofold symmetry, forming a tetrahedrally distorted square plane. Conformational analysis using the classical empirical potential energy function and CNDO/2 methods provided reasonable conformers accounting for the metabolic pathway of tryptophan→tryptamine→indoleacetoaldehyde.

抄録全体を表示

cis-Dichloroplatinum complexes of nitrogen cyclic compounds and sulfur-containing compounds were synthesized through the reaction of K₂PtCl₄ with the corresponding ligands in water or an interfacial layer between water and an organic solvent. The effect of substituents of pyridine derivatives on the synthesis of the cis-platinum complexes depended greatly on their position. The coordination of 2-substituted pyridines required a long reaction time and the yields were low. That of 3- or 4-substituted pyridines proceeded smoothly in high yields. The complexes coordinating dimethyl- or trimethyl-substituted pyridines were obtained in low yields, but a methyl group at the para position increased the coordination activity of pyridines. The reactivity of other nitrogen cyclic compounds depended greatly on their structures and no clear correlation between structure and reactivity was observed. In some cases, polynuclear or unidentified complexes were formed. Sulfurcontaining compounds reacted smoothly in high yields.Three synthesized cis-dichloroplatinum(II) complexes coordinating di(3-methylpyridine), di(quinoline) and di(isoquinoline) and a polynuclear platinum piperidine complex (Pt₄Cl₅(OH)₃-(C₅H₁₁N)₆·3H₂O) had high antitumor activities against Sarcoma 180 ascites in female ICR/CRJ mice. The required platinum weight of these effective complexes for antitumor activity was in the range of 23-94 mg/kg in mice compared with 5 mg/kg in the case of cis-dichlorodiammineplatinum.

抄録全体を表示

Synthesis of imidazo[4, 5-e][1, 4]diazepines using caffeidine (1) was studied. Caffeidine was condensed with various α, β-unsaturated carboxylic acid derivatives to give N-(α, β-unsaturated acyl)caffeidines (4). Intramolecular Michael addition of 4 having an electron-withdrawing group at the β-position of the α, β-unsaturated acyl group afforded imidazo[4, 5-e][1, 4]diazepines (5, 6). Compounds of the same type (14) were also prepared by treatment of N-(α-halogenoacyl)caffeidines (13) with EtONa in abs. EtOH. On the other hand, heating of 13 in H₂O gave imidazo[4, 5-e][1, 4]oxazepines (15). Compounds 5d, 15b, and 15c showed arterial relaxing activities.

抄録全体を表示

Treatment of 2-methyl-4-phenyl-2, 3-dihydro-1H-pyrazolo[2, 3, 4-de][1, 5]naphthyridine 2-oxide (10a) with acetic anhydride and triethylamine or trifluoroacetic anhydride (TFAA) in the presence of dimethyl acetylenedicarboxylate (DMAD) gave the Polonovski reaction products 11-14 as the major products. The 3, 4-diphenyl derivative 10b, when treated with acetic anhydride and triethylamine either in the presence or the absence of DMAD, gave only the O-acetylhydroxylamine 17, while treatment of the same N-oxide 10b with TFAA in the presence of DMAD at -20°C afforded the expected cycloadduct 22 as the major product.

抄録全体を表示

Reactions of 1, 3-dithianes, 1, 3-dithiolanes, and benzenethioacetals with tris(2, 2'-bipyridyl)-iron(III) perchlorate, Fe(bpy)₃(ClO₄)₃·3H₂O, gave the parent carbonyl compounds in high yields, immediately. These reactions may proceed by one-electron abstraction from the sulfur atom of acetals by the iron(III) complex, and they provide a new convenient and mild dethioacetalization method.

抄録全体を表示

The reaction of 2-chlorocyclohexanone with phenylmagnesium bromide in refluxing tetrahydrofuran unexpectedly afforded the ring-contracted product, cyclopentyl phenyl ketone, as the main product in moderate yield. The reactivities of several cyclic 2-haloketones were examined.

抄録全体を表示

Several new 3-diphenylmethylene-2, 4-dimethylpyrrolidinium derivatives (2-6), structurally related to 3-diphenylmethylene-1, 1-diethyl-2-methylpyrrolidinium bromide (1) (Prifinium Bromide, an antispasmodic agent), were synthesized so as to examine the pharmacological effect of a methyl group at the 4-position of 3-diphenylmethylenepyrrolidinium salts. The stereochemistries of tertiary pyrrolidines (10-20) and quaternary pyrrolidinium salts (2-6) were confirmed on the basis of equilibrium reactions, Grignard reactions, and/or spectroscopic methods. The presence of a methyl group at the 4-position of 3-diphenylmethylenepyrrolidinium salts was found to reduce the anticholinergic activity.

抄録全体を表示

Irradiation of a methanolic solution of 3-methoxycyclohexenone and ethoxyethylene with 254 nm light gave four stereoisomeric head-to-tail [2+2] cycloadducts in the ratios indicated in Fig. 3. The structure and stereochemistry of all the isomers were determined by chemical correlations and spectroscopic means, respectively. The time-course product analysis suggested that, in this reaction, the exo and endo oriented π-complexes are equally formed, and both give the cycloadducts with a slight preference for antara-selectivity. The analogous cycloadduct of 3-aminocyclohexenone to ethoxyethylene decomposed into 2-ethoxycyclooctane-1, 5-dione on silica gel chromatography.

抄録全体を表示

Reaction of 5-chloro (or bromo)-6, 2'-O-cyclouridine (IIa or IIb) with N-bromo(or chloro)-succinimide gave 5-bromo-5-chloro-5, 6-dihydro-6, 2' : 6, 5'-di-O-cyclouridine (VI). A similar reaction of 5-nitro-6, 2'-O-cyclouridine (VII) afforded the 5-chloro(or bromo)-5-nitro analog (VIII or IX). Both VI and VIII were mixtures of two diastereoisomers and each isomeric mixture was separated by preparative high-performance liquid chromatography. The steric configurations and mass spectra of VI, VIII and IX are discussed.

抄録全体を表示

Two C-3/C-3"-biflavanones named sikokianin A and sikokianin B were isolated from Wikstroemia sikokiana FRANCH. et SAV. and their structures were elucidated on the basis of spectral data.

抄録全体を表示

N⁶, N⁶-Dimethyl-8-methylsulfonyladenosine, obtained from N⁶, N⁶-dimethyl-8-methylthioadenosine by highly selective oxidation with KMnO₄, was treated with cyanide ion to give 8-cyano-N⁶, N⁶-dimethyladenosine. The conversion of the cyano group to methyl imidate, methoxycarbonyl, carbamoyl, carbothioamide, and carboxylic acid moieties was achieved. These 8-substituted N⁶, N⁶-dimethyladenosines may possess resonances structures involving positions 6 and 8 in adenosine, as indicated by the spectroscopic data. They showed no antitumor activity.

抄録全体を表示

The cyclic 1-ethoxycarbonylmethyl-2-ethynyl sulfonium salts (15Aa-d, 15Ba-d, and 15Ca-d), prepared from thiolane (12A), thiane (12B), and thiepane (12C), were treated with 1, 5-diazabicyclo[5.4.0]undec-5-ene (DBU) to result in ring expansion, giving thiocins (18Aa-d), thionins (18Ba-d), and thiecins (18Ca-d), respectively, presumably via the allenic intermediates (17) derived from the initially formed sulfonium ylides (16) by [2, 3]-sigmatropic rearrangement. Similarly, the 1- (27a-c) and 3-benzothionins (30a-c) were obtained from 2-ethynylthiochromans (21) and 1-ethynylisothiochromans (22), respectively, via the sulfonium ylides (25, 28) and the allenic compounds (26, 29) successively.

抄録全体を表示

Photolysis of 1-β-D-ribofuranosyl-5-aminoimidazole-4-carboxamide (AICA-riboside) gave 2-amino-N-(β-D-ribofuranosyl)malondiamide, which was cyclized by treatment with ethyl orthoformate to furnish 1-β-D-ribofuranosyl-5-hydroxyimidazole-4-carboxamide (bredinin), a potent immunosuppressive nucleoside antibiotic.

抄録全体を表示

Intramolecular photoaddition reactions of 2-(ω-alkenyl)isoquinolin-1(2H)-ones and 1-(ω-alkenyl)pyridin-2(1H)-ones were examined, and the regioselectivity and dependence of these reactions on the length of methylene chain in the alkenyl group were clarified. By utilizing these reactions, a synthetic route to indolizine and quinolizine derivatives was elaborated. By an extension of this approach to the intermolecular reaction, 6-methoxy-3-methyl-1, 2-dihydrocyclobuta[b]pyridin-4(3H)-one was synthesized from 4, 6-dimethoxy-1-methylpyridin-2(1H)-one.

抄録全体を表示

The photochemical behavior of 3-(3-butenyl)-4(3H)-quinazolinone (2a) and its 2-chloro(2b) and 2-trifluoromethyl derivatives (2c) was examined in methanol at a variety of wavelengths (254, 300, and 350 nm). The intramolecular 2+2 photoadducts (10 and 14) were obtained only when 2c and its higher methylene homologue (13) were irradiated. Though the 2-unsubstituted quinazolone (2a) was photostable, is 2-chloro derivative (2b) afforded the cyclized product (4) via homolytic fission of the C-Cl bond. An enhancement of the photocycloaddition reactivity of the C=N bond in the quinazolone ring by introduction of a trifluoromethyl group was also demonstrated by the formation of the intermolecular adducts from 2-trifluoromethyl-4(3H)-quinazolinone (1c) by irradiation in the presence of olefins. The reactions due to C-N bond fission of the azetidine ring in these adducts are also described. Finally, by utilizing photo-induced C-Cl bond fission as found in 2b, rutecarpine (26) was synthesized by irradiation of 2-chloro-3-[2-(indol-3-yl)ethyl]-4-(3H)-quinazolinone (25).

抄録全体を表示

Thermolysis of the cyclic α-vinyl sulfonium p-toluenesulfonylimides (6a-c), prepared from 2-vinylthiolane (5a), 2-vinylthiane (5b), and 2-vinylthiepane (5c) by treatment with chloramine T, resulted in [2, 3]-sigmatropic rearrangement with ring-expansion to give the 1, 2-thiazocine (7a), 1, 2-thiazonine (7b), and 1, 2-thiazecine derivative (7c), respectively. Similarly, the 1, 2-benzothiazonine (17) and the 3, 4-benzothiazonine (18) were obtained from 2-vinylthiochroman (13) and 1-vinylisothiochroman (14) via the imides (15 and 16), respectively. The stereochemistry of the rearrangement is discussed.

抄録全体を表示

A nonadecanucleotide duplex, dCATCACCATAATGTTCATT·dAATGAACATTATGGTGATG, having a sequence identical to that of phage φ80 O_R2 has been synthesized by the phosphoro-p-anisidate method. 5'-O-Dimethoxytrityl-N-protected deoxynucleotide 3'-(o-chlorophenyl)phosphates and N-protected deoxynucleoside 3'-(o-chlorophenyl)phosphoro-p-anisidates were used to prepare di- and trinucleotide blocks. Oligomers were elongated either in the 5'-direction by dedimethoxytritylation or in the 3'-direction by treatment with isoamyl nitrite, and isolated by chromatography on silica gel or alkylated silica gel. The deblocked nonadecamers were purified by reversed phase and ion-exchange chromatography and the duplex was isolated by gel filtration.

抄録全体を表示

Sixteen new triterpene acids isolated as the methyl esters from the gills of Ganoderma lucidum (Polyporaceae) along with five known triterpenes. The structures of seven new compounds among them, ganoderic acids C2, E, I, and K, compounds B8 and B9 and lucidenic acid F, were elucidated. Detailed analyses of their proton and carbon-13 nuclear magnetic resonance (¹H- and ¹³C-NMR) spectra were also done by application of two-dimensional NMR techniques.

抄録全体を表示

Oxidation of the enamine (6) with dibenzoyl peroxide followed by reduction with NaBH₄ gave the benzoate (8), which was converted to the cis-hydroxyl compound (9), while hydroboration-oxidation of 6 gave the trans-isomer (11). Treatment of a mixture of the enamines (13 and 14) with dibenzoyl peroxide/NaBH₄ gave the benzoates (15 and 16), which were converted to 14α-hydroxy-3-isorauniticine (17) and the acetal (18), respectively. Hydroboration-oxidation of 13 gave 14α-hydroxyrauniticine (2), which was found to be identical with the natural alkaloid whose structure had erroneously been proposed as 14β-hydroxy-3-isorauniticine (4).

抄録全体を表示

Reaction of the corticoids 1-6 with iodotrimethylsilane in MeCN produced the regiospecifically deoxygenated products, 21-hydroxy-20-ketones 7-11, in moderate to high yields. On the other hand, employment of CHCl₃ as a solvent resulted in lower yields of the 21-ketols 7 and 8, accompanied by increased production of the 20-ketones 12 and 13. The 21-ketol 7 was efficiently converted into the 20-ketone 12, while the 17α-hydroxy isomer 14 was recovered unchanged. Rapid and quantitative conversion of the 21-iodo-20-ketone 17 into the 20-ketone 12 by this iodosilane treatment suggests that the conversion of the ketol 7 into the ketone 12 probably occurs via the iodide 17.

抄録全体を表示

From the fronds of Sceptridium ternatum var. ternatum a new bibenzyl derivative, ternatin(I), was isolated besides quercetin 3-O-α-L-rhamnosyl-7-O-β-D-glucoside. The structure of the new compound was established as 2(S)-2-methyl-2-[(Z)-4-hydroxymethyl-3-pentenyl]-6-(2', 3'-dihydroxyphenetyl)chromene(I) by means of spectroscopic methods.

抄録全体を表示

D-(and L-)Aminoglycosidic variants of 4'-O-demethyl-1-epipodophyllotoxin were synthesized by glycosidation of 4'-O-benzyloxycarbonyl- or 4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (8 or 22) with the corresponding aminosugar derivatives. Cyclic acetals of 1-O-(2-amino-2-deoxy- and 3-amino-3-deoxy-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxins (13 and 21) gave a significant survival time increase in mice with leukemia L-1210, and showed superior activity to VP-16-213 (etoposide, 5).

抄録全体を表示

D-(and L-)2, 6-Dideoxy-2-aminoglycosidic variants of 4'-O-demethyl-1-epipodophyllotoxin were synthesized by glycosidation of 4'-O-benzyloxycarbonyl- or 4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (6 or 14) with the corresponding aminosugar derivatives. 1-O-(2-Amino-2-deoxy-4 : 6-O-ethylidene-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (18) reacted with aldehydes in the presence of sodium cyanoborohydride, or reacted with α, β-unsaturated esters, or with α, β-unsaturated nitriles to yield the corresponding N-alkyl analogs. A number of the 4'-O-demethyl-1-epipodopyllotoxin β-D-aminoglycoside derivatives gave significant survival time increases in mice with leukemia L-1210. In particular, 1-O-(2-dimethylamino-2-deoxy-4 : 6-O-ethylidene-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (19) showed superior activity to VP-16-213 (etoposide, 1).

抄録全体を表示

A seires of (R)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acids (8) and (S)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzoxazepine-5-acetic acids (9) having an (S)-1-carboxy-ω-(4-piperidyl)alkyl group on the amino group at the 3-position was prepared as part of a search for long-acting inhibitors of the angiotensin converting enzyme (ACE). The length (n) of the carbon chain in the piperidylalkyl moiety was varied from two six in order to determine the optimal structure. The most prolonged activity in vivo was observed with (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid (8c : CV-5975) on i.v. and p.o. administrations.

抄録全体を表示

New antitumor cyclic hexapeptides RA-IV, RA-III, RA-II and RA-I were isolated as minor constituents of Rubia cordifolia. Their structures were elucidated by means of various instrumental and chemical analyses. From a comparison of the antitumor activities of 7 products derived by oxidizing RA-V with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone and 6 native cyclic hexapeptides isolated from R. cordifolia, it is surmised that the active site in the RA-series is present at the α-side of RA molecules.

抄録全体を表示

Four new guaiane-type sesquiterpene glycosides have been isolated from Youngia denticulata (HOUTT.) KITAM. (Compositae), in addition to two known compounds, picriside C and crepidiaside A. Their structures were elucidated on the basis of spectral data and some chemical transformations.

抄録全体を表示

A fluorometric method for the determination of menadione (K₃) with 3-amino-2(1H)-quinolinethione (AQT) was developed. The method is based on the reaction of K₃ with AQT, followed by extraction of a red fluorescent product (excitation maxima, 533 and 573 nm; emission maximum, 600 nm) with carbon tetrachloride after making the reaction mixture strongly basic. The calibration curve was linear in the range from 0.01 to 1.0 μg/ml of K₃. This method was applicable to the determination and detection of K₃ contaminating phytonadione.

抄録全体を表示

The degradation and kinetics of carumonam (1) in aqueous solution were investigated by highperformance liquid chromatography (HPLC) at 35°C and an ionic strength of 0.5 over the pH range of 0 to 10. All the main degradation products observed by HPLC were isolated and identified. It was concluded that these products were formed by a combination of five reactions, a β-lactam ring-opening reaction, reversible C₃-epimerization, reversible syn-anti isomerization, desulfonation, and a decarbamoylation reaction. The overall rate of degradation was of pseudo-first-order type and was influenced by solvolytic, hydrogen ion, and hydroxide ion catalysis. Simultaneous reversible C₃-epimerization and β-lactam ring-opening reaction, which occur in neutral and alkaline solutions, proved to be catalyzed by hydroxide ion. The pH-rate profile for 1 exhibited a unique W-shape due to syn-anti isomerization in a specific pH region. The maximum stability of 1 was observed in the pH range of 4.9 to 5.8. The theoretical pH-rate profile agreed well with the experimental data, and primary salt effect was also considered theoretically. The activation energies determined at μ=0.5 were 22.3, 15.6 and 17.5 kcal/mol at pH 4.40, 7.01 and 8.88, respectively.

抄録全体を表示

Eleven immobilized-colchicine adsorbents were synthesized from deacetylcolchicine (DAC) and Sepharose with various spacers (R) and their tubulin-adsorbing capacity was investigated. The adsorption capacity of DAC-R-Sepharose for tubulin depended on the hydrophobicity rather than the length of the spacer and was three to five times that of DAC-Sepharose without any spacer.The results of the present studies can be summarized as follows. (1) The adsorbed tubulin showed two binding modes : a reversible binding which is abrogated at weak ionic strength (such as 0.1 M NaCl), and an irreversible binding which is abrogated by denaturants such as 6 M urea and 7 M guanidine-HCl. (2) The adsorbed tubulin was not eluted by colchicine but was eluted as colchicine-binding tubulin by 0.1 M NaCl. (3) Tubulin was adsorbed on hydrophobic ligands such as the phenyl, diphenyl, trimethoxyphenyl or naphthyl group. (4) Tubulin-colchicine complex was adsorbed by immobilized colchicine.It is considered that the immobilized colchicine binds tubulin at a hydrophobic region, not necessarily at a specific colchicine-binding site.

抄録全体を表示

An active peptide which stimulates dentinal fluid transport (DFT) through the dentinal tubules in the molar teeth of rats was isolated by aqueous extraction, isoelectric precipitation, ultrafiltration, gel filtration, cation exchange chromatography, a peptide mapping procedure and gel filtration from rat parotid glands. The minimum effective dose of the purified DFT-stimulating peptide was 1 μg per kg of body weight in the bioassay for DFT-stimulating activity, as indicated by the migration of a fluorescent dye through the dentinal tubules in the molar teeth of rats.The complete amino acid sequence of DFT-stimulating peptide was determined by dansyl-Edman degradation, manual Edman degradation, carboxypeptidase digestion and tryptic peptide analysis. The final sequence was Gl^^1y-Val-Ile-Ala-Trp-Glu-Leu-Gln-His-A^^(10)sn-Glu-Pro-Gly-Arg-Lys-Asp-Ser-Thr-Ala G^^(20)ly. The rat DFT-stimulating peptide thus consisted of a total of 20 amino acid residues and the calculated molecular weight was 2165.

抄録全体を表示

In order to differentiate tryptophan residues in the active site of a major glucoamylase from a Rhizopus sp. (Gluc₁), N-bromosuccinimide (NBS) oxidation of Gluc₁ in the presence of maltitol and tris(hydroxymethyl)aminomethane (Tris) was studied.1. When Gluc₁ was oxidized in the presence of maltitol, the hydrolytic activities of Gluc₁ towards both soluble starch and p-nitrophenyl α-D-glucopyranoside (PNPG) were scarcely protected from NBS oxidation. On the other hand, when Gluc₁ was oxidized in the presence of Tris, the activity towards PNPG increased due to NBS oxidation of about 2 mol of tryptophan residues, whereas the activity towards maltose or soluble starch decreased.2. The fluorescence quenching and the ultraviolet (UV) difference spectrum of Gluc₁ induced by the addition of maltitol decreased with NBS oxidation. The decreases were small in the case of Gluc₁ oxidized in the presence of maltitol, but were large and nearly parallel with the decrease in the activity towards maltose or soluble starch when Gluc₁ was oxidized in the presence of Tris.3. It seems that at least two tryptophan residues exist in the catalytic locus of the enzyme active site, and one of them is related to the binding with a glucose moiety of substrates such as maltose but is scarcely related to the binding with the p-nitrophenyl moiety of PNPG. Another tryptophan residue seemed to be involved mainly in the catalytic action and to contribute little to maltose binding.

抄録全体を表示

The effect of Salviae Miltiorrhizae Radix extract on blood constituents was investigated in rats made uremic by feeding an adenine-containing diet. Administration of Salviae Miltiorrhizae Radix extract for 18 d after feeding of the adenine diet for 6 d led to significant reductions of serum urea nitrogen, creatinine, methylguanidine, and guanidinosuccinic acid and an increase of guanidinoacetic acid, suggesting alleviation of the uremic state. In a group fed the adenine diet for 12 d, followed by the extract, there were significant decreases in urea nitrogen and guanidinosuccinic acid. However, the extract no longer caused any reduction of urea nitrogen, creatinine, methylguanidine, or guanidinosuccinic acid, or an increase of guanidinoacetic acid, when the adenine diet was given for 18 d to cause a more severely uremic state.

抄録全体を表示

Rat intestinal salicylate transport showed concentration dependency, especially up to 22.5 mM in the mucosal medium, in an experiment using in vitro everted rat intestinal sac prepared from jejunum, ileum and colon. Thus, it is suggested that both saturatable and unsaturatable transport processes are involved in the intestinal salicylate transport. However, it was also estimated that intestinal salicylate absorption at high concentration in the clinical therapeutic context occurred predominantly through the unsaturatable (passive) transport process. Only the saturatable transport process seems to be influenced by nonprotein thiol levels in the intestinal tissue; there was a decrease of salicylate transport with decrease of nonprotein thiols. Further, since the saturatable transport process was restored even by the exogenous nonprotein thiols such as cysteamine, a process of nonspecific binding to the mucosal membrane rather than a specific carrier system may be involved in the saturatable transport of salicylate.

抄録全体を表示

A method is described which allows simultaneous vascular and luminal perfusion of the jejunal segment of rat intestine. Perfluorochemical artificial blood (FC-43 Emulsion) was utilized as a vascular perfusion medium. The viability of this preparation can be maintained for 1h as indicated by morphological findings, competitive inhibition between L-phenylalanine and L-methionine, and the transport of L-phenylalanine against a concentration gradient. This preparation was used for investigation of the transport behavior of several amino β-lactam antibiotics.

抄録全体を表示

The mechanism of the inhibitory effect of sodium cholate and its taurine and glycine conjugates on the intestinal absorption of nadolol was investigated in rats. It was found that the uptake of nadolol into the intestinal membrane was inhibited by sodium cholate and its conjugates, but the membrane permeability to nadolol was not affected. The inhibitory effect on nadolol absorption can be interpreted in terms of loss of thermodynamic activity of nadolol due to stable micelle formation, resulting in a decrease of the uptake into the intestinal membrane. Other β-blocking agents also form micellar complexes with sodium cholate, but their micelles are ten times less stable than that of nadolol. It is concluded that the stability of the micellar complex may be an important factor in the inhibition of intestinal absorption of nadolol. The micellar stability seems to be associated with not only the chemical nature of the bile salts but also that of the drug.

抄録全体を表示

Anti-ulcerous and anti-secretory effects of (-)-cis-2, 3-dihydro-3-(4-methylpiperazinylmethyl)-2-phenyl-1, 5-benzothiazepin-4-(5H)-one hydrochloride (BTM-1086), a new peptic-ulcer therapeutic agent, were studied in rats. BTM-1086 effectively prevented the ulceration of pylorus-ligated rats. A remarkable inhibition of gastric secretion was found at a dose of 0.1 mg/kg s.c. within a short period (6 h) after pylorus ligation. In the stomach-perfused rats, BTM-1086 (0.02 to 0.04 mg/kg i.v.) distinctly inhibited the teragastrin- and carbachol-induced gastric acid secretion, but only weakly inhibited the histamine-induced secretion. BTM-1086 also had a depressive effect on the gastric secretion stimulated by such secretagogues as tetragastrin, carbachol and histamine in rats with acute gastric fistulae. BTM-1086 increased the gastric mucosal blood flow in normal and indomethacin-induced ischemic rats. It also increased the gastric mucosal blood flow in water-immersion stress mcie at a dose equivalent to that used to prevent the development of ulcers.These results suggest that the antiulcer effects of BTM-1086 are mainly due to the inhibition of gastric acid secretion and to the increase of gastric mucosal blood flow.

抄録全体を表示

In order to identify the active principles in the 50% MeOH extract of the Chinese crude drug "Chang Zhu" (consisting of Atractylodes lancea rhizome), which has a preventive activity against experimental ulcerations, the effects of the benzene, methanol and aqueous fractions from 50% MeOH extract on gastric secretion in pylorus-ligated rats were investigated.The terpenes, β-eudesmol and hinesol, contained in benzene fraction were found to be highly effective. β-Eudesmol markedly inhibited ulcers in Shay rats, as well as histamine- and aspirin-induced gastric ulcers, and showed anti-secretory activity on gastric acid secretion stimulated by histamine in a perfused rat stomach preparation.The anti-ulcerogenic activity of 50% MeOH extract of Atractylodes lancea rhizome might be mainly attributable to the H₂-antagonistic effect of β-eudesmol.

抄録全体を表示

Cyclic adensine 3', 5'-monophosphate (cAMP) derivatives were tested for inhibitory effect on the development of experimental disseminated intravascular coagulation (DIC). Two compounds, 2-Cl-cAMP and 2-Br-cAMP, which inhibited the platelet aggregation induced by collagen in vitro, had a strong inhibitory effect on the development of experimental DIC in rats in vivo as judged by five diagnostic laboratory tests, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrin and fibrinogen degradation products (FDP), fibrinogen and platelet count. The effect of these derivatives was preventive rather than therapeutic, and the inhibition of rat platelet aggregation by these substances was marked when the stimulator was collagen or thrombin but less strong when it was calcium ionophore A23187 or adenosine 5'-diphosphate (ADP).

抄録全体を表示

Nitrosation products of antipyrine treated with nitrite under the conditions recommended by the WHO were examined. An unknown product was confirmed to be formed besides 4-nitrosoantipyrine (a known nitrosation product), and was isolated and identified as 1-(2-hydroxyimino-3-oxobutyryl)-2-methyl-2-nitroso-1-phenylhydrazine.This new nitrosation product showed mutagenicity to Salmonella typhimurium TA 98 and TA 100 either with or without S9 mix. Model experiments indicated that antipyrine is probably easily nitrosated in the stomach after administration to give these nitrosation products.

抄録全体を表示

The utility of four urethane type N-protecting groups, benzyloxycarbonyl (Z), p-nitro-benzyloxycarbonyl [Z(NO₂)], trichloroethoxycarboyl (Troc) and tert-butoxycarbonyl (Boc) groups, was tested in the ruthenium tetroxide (RuO₄) oxidation of N-protected L-proline esters. Three groups, but not the Z group, which was decomposed by RuO₄, were found to be stable during the oxidation and afforded high yields of the corresponding L-pyroglutamic acid esters. Removal of the protecting groups from the oxidation products was carried out successfully in the usual manner to give N-unsubstituted (NH-type) L-pyroglutamic acid derivatives without racemization. The first transformation of L-proline into L-pyroglutamic acid and its derivatives has been accomplished.

抄録全体を表示

A new and convenient synthesis of optically pure L-γ-carboxyglutamic acid (L-Gla) (1) from L-proline as a chiral source was developed. Protection of N-tert-butyloxycarbonyl (Boc) prolinol (4) with a tert-butyldimethylsilyl group followed by oxidation with ruthenium tetroxide (RuO₄) afforded the corresponding lactam compound (6), which was carboxylated with lithium diisopropylamide and benzyloxycarbonylimidazole to afford the 4-benzyloxycarbonyl lactam derivative (7). Selective removal of the silyl group from 7, followed by oxidation of the resulting alcohol (8) with pyridinium dichromate gave the carboxylic acid, which was converted into the ester derivatives (10b-d). Cleavage of the lactam bond of 10b with excess benzyl alcohol in the presence of triethylamine gave γ, γ, α-tribenzyl N-Boc-L-γ-carboxyglutamate (11). Finally, 11 was hydrogenated over Pd on charcoal and deprotected with trifluoroacetic acid to produce L-γ-carboxyglutamic acid (1).

抄録全体を表示

The methanolic extract of the aril of Myristica fragrans HOUTT. (mace) had anti-plaque action against a cariogenic becterium, Streptococcus mutans. Through fractionation of the extract followed by microbial assay by using the tube dilution technique, dehydrodiisoeugenol (1) and 5'-methoxydehydrodiisoeugenol (2) were identified as the major antibacterial principles. Both compounds completely inhibited the bacterial growth at a concentration of 12.5 μg/ml. During this experiment, threo-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(4-hydroxy-3-methoxyphenyl)propan-1-ol methyl ether (6) and guaiacin (8) were isolated for the first time from mace.

抄録全体を表示

The pharmacokinetics of theophylline in the steady state, following multiple oral dosing of a sustained-release theophylline tablet formulation, were studied in six asthmatic patients. The pharmacokinetic parameters were calculated by utilizing a one-compartment model with zero-order of first-order absorption according to the Davidon-Fletcher-Powell method. The computer-predicted theophylline concentrations based on the zero-order absorption model fitted the observed data points better than those based on the first-order absorption model. The nonlinear least-squares curve based on the first-order absorption model underestimated the maximum observed plasma concentrations of theophylline. Linear relationships were obtained between observed and calculated maximum plasma concentration (C_max) data based on the two absorption models. There was a highly significant relationship between observed and calculated time to C_max data based on the zero-order absorption model. These results show that the drug absorption from the sustained-release theophylline tablet formulation used in this study is best described by an apparent zero-order rather than a first-order absorption model.

抄録全体を表示

The crystal and molecular structures of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl]-propionic acid hydrochloride, which is an anti-ulcer agent, have been determined by X-ray analysis. The crystal belongs to space group P2₁/n, with lattice parameters a=5.3443(2), b=57.616(3), c=5.5881(2)Å, β=90.080(5)°, and Z=4. The structure, in which the aminomethylcyclohexyl moiety and phenylpropionic acid moiety are connected by the planar carbonyl group, takes a rigid bentrod like conformation. In the crystal the molecules are dimerized in a head-to-head fashion with hydrogen bonding between the carboxy groups at one end. Protonated amino groups at the other end of the molecules and the chloride ions gather at y⋍b/4 and (3/4)b.

抄録全体を表示

The reduction of a veriety of functional groups with the new diborane-nickelous chloride system was systematically investigated. This system reduced aromatic nitro compounds to the corresponding primary amines under mild conditions in good yields. However, ketone, aldehyde, carboxylic acid, ester, amide and olefin moieties were unaffected by this system. The nitro group in aromatic nitro compounds bearing a ketone, aldehyde, ester, amide or nitrile functionality was selectively reduced with this system to give the corresponding primary amines in good yields.

抄録全体を表示

New hexahydro-dibenz[d, f]azecines, 11 and 12, were synthesized from the homoerythrinan-enone 3. Their 6-oxo derivatives were shown to exist in two conformations in solution due to the rotational isomerism of the ten-membered lactam group. An example of remarkably large separation of two methylenedioxy protons in the proton nuclear magnetic resonance spectrum due to their non-equivalence is also presented.

抄録全体を表示

Subsequent to our synthesis of human calcitonin gene-related peptide (hCGRP) (J. Chem. Soc., Chem. Commun., 1985, 602), its analog, des-1-Ala-des-α-amino-hCGRP, was synthesized. This peptide, prepared by replacement of the N-terminal Ala-Cys residues with 3-mercaptopropionic acid, followed by air oxidation, was more active than the parent peptide in respect of Ca-lowering and Pi-lowering activities in rat serum.

抄録全体を表示

The presence of vitamin C during the photo-induced rearrangement reaction of spirobenzylisoquinolines in ethanol suppressed the formation of the oxidation product, improving the yield of the berbinium compound, which yields the tetrahydroprotoberberine type compound on reduction with sodium borohydride. Synthesis of two alkaloids, (±)-xylopinine and (±)-tetrahydropalmatine, was accomplished by this method in fair yield.

抄録全体を表示