The anti-tack action of polyvinylpyrrolidone (PVP) on hydroxypropylmethylcellulose (HPMC) solution was elucidated using a probe test method. The influence of PVP of varying molecular weights at various PVP concentrations and solution temperatures on the tackiness of HPMC solution was studied. The viscosity, surface tension, cloud point and solution spectroscopy of HPMC solutions and glass transition temperature of HPMC films, with and without PVP, were investigated. The tackiness of HPMC solutions in response to the addition of PVP, at different concentrations of HPMC and using HPMC with varying contents of hydroxypropyl/methoxyl substitution, was also evaluated. PVP is a commonly used binder and adhesive. However, it reduced the tack of the HPMC solution when used at low concentrations, without affecting the state of hydration of HPMC. Lower molecular weight PVP was more effective as an anti-tack agent owing to suitable hydrodynamic size to intersperse among the HPMC chains. The degree of reduction in tack values was more pronounced for HPMC that showed a greater extent of interaction between polymer chains such as when high concentration of HPMC or low solution temperature was employed. This indicated that the tack reduction property of PVP relied on its ability to interact with the HPMC chains. The profile of reduction in tack values was affected by the contents of HPMC substitution and was a result of net reduction in the extent of hydrogen bonding between HPMC chains. It was significantly correlated to the changes of viscosity and surface tension of the HPMC solutions but not to the glass transition temperatures of the polymers prepared as solid films. The results suggested that the anti-tack action of PVP was attributed to its ability to interact with HPMC chains in the aqueous medium and consequently to reduce the extent of HPMC–HPMC bonding.

抄録全体を表示

A stable derivative of kojic acid, 5-[(3-aminopropyl)phosphinooxy]-2-(hydroxymethyl)-4H-pyran-4-one (Kojyl-APPA), was synthesized in good yield. The effects of Kojyl-APPA on tyrosinase activity and melanin synthesis were investigated. Kojyl-APPA showed tyrosinase inhibition effect (30%) in situ, but not in vitro. Kojyl-APPA inhibited tyrosinase activity significantly at 24 h after treatment in normal human melanocytes. It means that Kojyl-APPA is not a direct inhibitor of tyrosinase itself, but it is converted to a potential inhibitor kojic acid enzymatically in cells. In addition, Kojyl-APPA decreased melanin content to 75% of control in melanoma cells and decreased neomelanin synthesis to 43% of control in normal human melanocytes. Its permeation through skin increased by about 8 times as compared with kojic acid.

抄録全体を表示

A series of diarylamide urea derivatives were synthesized and evaluated for their inhibitory activities against human coronary artery smooth muscle cells (SMCs) and human coronary artery endothelial cells (ECs). Compound 2h was much superior to Tranilast, in terms of both the potency of its inhibitory activity toward the proliferation of SMCs and the cell selectivity.

抄録全体を表示

A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H₁ receptors in contrast with its complete blockade of peripheral H₁ receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.

抄録全体を表示

Three new pentacyclic triterpenoids, camaryolic acid (1), methylcamaralate (2) and camangeloyl acid (3) and six known compounds β-sitosterol 3-O-β-D-glucopyranoside (4), octadecanoic acid (5), docosanoic acid (6), palmitic acid (7), camaric acid (8) and lantanolic acid (9) were isolated from the aerial parts of Lantana camara. Structures of the new compounds were elucidated by spectroscopic and chemical methods.

抄録全体を表示

We previously reported that (Z)-2-{4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino}-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA^y. This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-γ. We expanded on the structure–activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-{4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino}-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARγ. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARγ, were tested using KKA^y mice. Among these compounds, (E)-4-{4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino}-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.

抄録全体を表示

From the water-soluble portion of the methanol extract of the fresh rhizome of Atractylodes japonica, five new sesquiterpenoid glycosides, including a compound having a secoguaiane skeleton, and a new aromatic compound glycoside were isolated together with ten known compounds. Their structures were clarified by spectral investigation.

抄録全体を表示

¹H-NMR spectrometry was applied to the quantitative analysis of the bilobalide, ginkgolides A, B, and C in Ginkgo biloba leaves and six kinds of commercial Ginkgo products without any chromatographic purification. The experiment was performed by the analysis of each singlet H-12, which were well separated in the range of δ 6.0—7.0 in the ¹H-NMR spectrum. However, the H-12 protons of bilobalide and ginkgolides may have overlapped with H-6 or H-8 protons of the Ginkgo flavonoids. Therefore, the optimum ¹H-NMR solvent for the analysis of the compound was selected through the evaluation of solvent effects on the resolution of these signals from the compounds. Acetone-d₆–benzene-d₆ (50 : 50) was found to be the best one among the solvents evaluated. The quantity of the compounds was calculated by the relative ratio of the intensity of each compound to the known amount of internal standard (25 μg/ml), phloroglucinol. This method allows rapid and simple quantitation of underivatized bilobalide and ginkgolides in 5 min without any pre-purification steps.

抄録全体を表示

In the present study, a series of 2-substituted-pyridines were synthesized and characterized by IR, ¹H-NMR and Elemental Analysis. The compounds were assayed against seizures induced by maximal electro shock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The decrease in the elevated motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) was studied at the dose level of 25 and 50 mg/kg, antihistaminic and cardiac activity were also studied. All the compounds exhibited significant anticonvulsant activity. Compounds 2-(2-hydroxy-3-piperazinopropylamino)-6-aminopyridine, 2-[2-hydroxy-3-(1-imidazolyl)propylamino]-6-aminopyridine, 2-[2-(1-imidazolyl)ethylamino]-6-methylpyridine and 2-[2-(methylamino)ethylamino]-6-methylpyridine were most active of the series against MES-induced seizures. Compounds 2-[2-(phenylamino)ethylamino]-6-aminopyridine, 2-[2-[bis(2-hydroxyethyl)amino]ethylamino]-6-aminopyridine, 2-[2-(diethylamino)ethylamino]-6-methylpyridine and 2-[2-hydroxy-3-(1-imidazolyl)propylamino]-6-methylpyridine exhibited significant decrease in the elevated motor activity at the dose of 50 mg/kg. Remarkable sympathetic blocking activity was observed with 2-(2-hydroxy-3-piperazinopropylamino)-6-aminopyridine, 2-(2-hydroxy-3-morpholinopropylamino)-6-methylpyridine and 2-(2-hydroxy-3-piperazinopropylamino)-6-methylpyridine only. Compounds 2-[2-(diethylamino)ethylamino]-6-aminopyridine, 2-[2-[bis(2-hydroxyethyl)amino]ethylamino]-6-aminopyridine, and 2-[2-(diethylamino)ethylamino]-6-methylpyridine exhibited significant blocking of histamine induced contraction on guinea pig ileum.

抄録全体を表示

Poorly water-soluble drugs N-5159, griseofulvin (GFV), glibenclamide (GBM) and nifedipine (NFP) were ground in a dry process with polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS). Different crystallinity behavior of each drug during grinding was shown in the ternary Drug/PVP/SDS system. However, when each ternary Drug/PVP/SDS ground mixture was added to distilled water, crystalline nanoparticles which were 200 nm or less in size were formed and had excellent stability. Zeta potential measurement suggested that the nanoparticles had a structure where SDS was adsorbed onto the particles that were formed by the adsorption of PVP on the surface of drug crystals. Stable existence of crystalline nanoparticles was attributable to the inhibition of aggregation caused by the adsorption of PVP and SDS on the surface of drug crystals. Furthermore, the electrostatic repulsion due to the negative charge of SDS on a shell of nanoparticles could be assumed to contribute to the stable dispersion.

抄録全体を表示

We previously reported the chemical synthesis of a series of novel monoacylated vitamin C derivatives, 6-O-acyl-2-O-α-D-glucopyranosyl-L-ascorbic acids (6-Acyl-AA-2G) possessing a straight-acyl chain of varying length from C₄ to C₁₈, as effective skin antioxidants. In this paper, we describe branched type of 6-Acyl-AA-2G derivatives (6-bAcyl-AA-2G) synthesized by use of a 2-branched-chain fatty acid anhydride as an acyl donor. The stability of 6-bAcyl-AA-2G in neutral solution was much higher than that of 6-Acyl-AA-2G, while they were susceptible to enzymatic hydrolysis for exerting vitamin C effect. These branched derivatives as well as 6-Acyl-AA-2G increased the radical scavenging activity against 1, 1-diphenyl-2-picrylhydrazyl and the lipophilicity in octanol/water-partitioning systems with increasing length of their acyl group. In addition, the 6-bAcyl-AA-2G derivative with an acyl chain of C₁₂, 6-bDode-AA-2G had the excellent solubility to various solvents, suggesting easy handling in cosmetic use. These characteristics of 6-bAcyl-AA-2G may be available for skin care application as an effective antioxidant.

抄録全体を表示

Dithioacetal monoxides were synthesized from aldehydes and cyclohexanone, and reaction of the dithioacetal monoxides with Grignard reagents was investigated. The dithioacetal monoxide synthesized from alkylaldehyde and 4-chlorobenzenethiol reacted with i-PrMgCl to afford the desired α-thiomagnesium in high yield. The generated α-thiomagnesium was found to be stable at room temperature and to be useful in organic synthesis. In contrast to this, the dithioacetal monoxides derived from benzaldehyde and cyclohexanone did not give satisfactory results.

抄録全体を表示

Four new chalcone derivatives (1, 4, 7, 10) were isolated from the stem bark of Millettia leucantha KURZ (Leguminosae) along with two known ones (2, 6) and five known flavones (3, 5, 8, 9, 11). Structure elucidation and unambiguous assignment of the isolates were achieved with the aid of 1D and 2D NMR extensive studies. Correlation of 10 to 4 was successfully done by reduction with Et₃SiH/CF₃CO₂H. Moderate cytotoxic activity was observed in chalcones (1, 10), whereas dihydrochalcones (4, 6) showed moderate anti-Herpes Simplex Virus (HSV) activity. Interestingly, flavone 8 showed significant anti-inflammatory effects inhibiting both cyclooxygenase (COX)-1 and -2.

抄録全体を表示

Two new flavonoids, 5, 7, 2′, 5′-tetramethoxyflavanone (1) and 5-hydroxy-7, 2′-dimethoxyflavone (2), together with two known flavones, skullcapflavone I (3) and echioidin (4) were isolated from the whole plant of Andrographis rothii. The structures of the new compounds were established by extensive one- and two-dimensional (1D- and 2D-) NMR spectral studies.

抄録全体を表示

A new coumestan, tephcalostan (1) has been isolated from the whole plant of Tephrosia calophylla BEDD. together with two known flavonoids, 7-O-methylglabranin (2) and kaempferol 3-O-β-D-glucopyranoside (3). The structure of tephcalostan was elucidated as 5′-(R)-8, 9-methylenedioxy-5′-isopropenyl-4′, 5′-dihydrofurano[2′, 3′:2, 3]coumestan by extensive one-and two-dimensional (1D- and 2D-)-NMR techniques including ¹H–¹H correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC) and nuclear Overhauser enhancement spectroscopy (NOESY) experiments.

抄録全体を表示

A new ent-clerodane diterpene, named bacchariol (1) was isolated from the aerial parts of Baccharis gaudichaudiana DC. (Compositae), together with known ent-clerodane diterpenes (2, 3), eight known flavonoids (4—11) and 3, 5-dicaffeoylquinic acid (12). Their structures were determined by spectroscopic analyses. Flavonoids (7, 8, 11) and 12 showed moderate scavenging activities toward 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals.

抄録全体を表示

A new triterpene glucosyl ester, rubusside A, has been isolated from the fruit of the blackberry (Rubus allegheniensis PORT.) along with a known triterpene glucosyl ester, niga-ichigoside F1. The chemical structure of rubusside A was determined on the basis of spectroscopic data as well as chemical evidence.

抄録全体を表示

Metabolism of 7-O-methylnaringenin (sakuranetin) by Cunninghamella elegans NRRL 1392 yielded naringenin and naringenin-4′-sulfate. C. elegans also converted 5, 3′, 4′-trihydroxy-7-methoxyflavanone into eriodictyol-4′-sulfate. Furthermore, incubation of 5, 4′-dihydroxy-7, 3′-dimethoxyflavanone with the same fungus gave homoeriodictyol (5, 7, 4′-trihydroxy-3′-methoxyflavanone) and homoeriodicytol-7-sulfate. The structures of the new metabolites were established by spectral analysis including 2D-NMR, HR-ESI-FT-MS beside hydrolysis by acid.

抄録全体を表示

A new cassane diterpene was isolated from Amazonian crude drug, “Acapu, ” the wood of Vouacapoua americana, together with two known cassane furanoditerpenes, (+)-vouacapenic acid and (+)-methyl vouacapenate. The structure was characterized as cassa-13(14), 15-dien-19-oic acid on the basis of spectroscopic evidence.

抄録全体を表示

The Stille coupling reaction of the stannylindole 13 with the 5-iodoimidazole derivative 14 (or 27) in the presence of PdCl₂(PPh₃)₂ gave the corresponding indole-imidazole coupling product 15 (or 28), thereby affording a synthetic approach to 10-methylgranulatimide (7), 15-methylgranulatimide (11), and 10, 15-dimethylgranulatimide (12), as well as 10-methylisogranulatimide B (5).

抄録全体を表示

Three new saponins, designated as bacopasides III, IV and V have been isolated from Bacopa monniera WETTST. and their structures have been elucidated as 3-O-α-L-arabinofuranosyl (1→2)-β-D-glucopyranosyl jujubogenin (1), 3-O-β-D-glucopyranosyl (1→3)-α-L-arabinopyranosyl jujubogenin (2) and 3-O-β-D-glucopyranosyl (1→3)-α-L-arabinopyranosyl pseudojujubogenin (3) mainly on the basis of two dimensional (2D) NMR and other spectral analyses.

抄録全体を表示

Calcium-induced alginate gel beads (Alg-Ca) containing various polysaccharides, including an alginate hydrolysate, were prepared and the drug release profiles were investigated. Hydrocortisone (HC) was gradually released from Alg-Ca into the mimic gastric fluid, while in intestinal fluid, it was quickly released with the dissolution of Alg-Ca. However, with Alg-Ca containing 5% chitin (CT), dissolution of Alg-Ca was not observed, and release of HC showed apparent zero-order kinetics. Furthermore, addition of the alginate hydrolysate altered the HC-release profile for Alg-Ca.

抄録全体を表示

Chiral bis(α, α-diphenyl-2-pyrrolidinemethanol) carbonate (DPP₂·H₂CO₃) is a useful asymmetric auxiliary for the asymmetric borane reduction of prochiral ketones. Chiral DPP₂·H₂CO₃ is recoverable from the reaction and directly reusable for the reaction. The intermediate of KUR-1246, which we are developing as a new uterine relaxant, was synthesized using the methodology.

抄録全体を表示

The enantioselective hydrolysis of the amino acid esters, p-nitrophenyl-N-dodecanoyl-D(L)-phenylalaninates (C₁₂-D(L)-Phe-PNP) catalyzed by active tripeptide, N-(benzyloxycarbonyl)-L-phenylalanyl-L-histidyl-L-leucine (Z-PheHisLeu) in the presence of coaggregates (hybrid membranes) composed of native phospholipid, L-α-dimyristoylphosphatidylcholine (DMPC) and nonionic surfactant, polyoxyethylene (8) lauryl ether (C₁₂(EO)₈) was easily controlled by regulating the reaction temperature and changing the composition of coaggregates. Furthermore, excellent correlations were observed between the enantioselectivity in the hydrolysis of C₁₂-D(L)-Phe-PNP catalyzed by Z-PheHisLeu in the presence of coaggregates and physical properties of hybrid membranes. It is assumed that catalytic activities of tripeptide catalyst in hybrid membranes should be regulated by changing the microenvironments of reaction fields.

抄録全体を表示

The crystal structure of inclusion complex between ursodeoxycholic acid (UDCA), and phenanthrene has been determined. UDCA molecules formed hydrogen bond network to provide the channel structure along b axis, and phenanthrene molecules were accommodated in the cavity with a stoichiometry of 1 : 1 molar ratio. The channel structure observed in the UDCA-phenanthrene complex was significantly different from that of inclusion complex previously reported for deoxycholic acid (DCA) and cholic acid (CA). Because of the mesh-like hydrogen bond network, channel framework of UDCA could have less flexibility than that of DCA and CA. The difference of molecular state of phenanthrene was clearly observed in solid-state fluorescence measurement.

抄録全体を表示

A novel bis(L-carnitinato)Zn(II) complex, Zn(car)₂Cl₂, was prepared, and its insulinomimetic and antidiabetic activities were examined. The complex showed a tendency to lower the high blood glucose levels of KK-A^y mice with type 2 diabetes mellitus when given by oral administration at a dose of 20 mg Zn/kg body weight for 16 d. In addition, the complex improved glucose tolerance ability when examined by the oral glucose tolerance test (1 g glucose/kg body weight).

抄録全体を表示

Three monoterpenoid gluco-indole alkaloids, 3β-isodihydrocadambine, cadambine, and 3α-dihydrocadambine, were isolated from Nauclea cadamba ROXB. growing in Thailand. The stereochemistry at C19 in 3β-isodihydrocadambine was elucidated to be R by spectroscopic analysis. Treatment of 3α-dihydrocadambine with β-glucosidase in aqueous ammonium acetate solution gave an indolopyridine alkaloid, 16-carbomethoxynaufoline, and an unusually rearranged compound.

抄録全体を表示

A major novel steroidal alkaloid glycoside, possessing cytotoxic activity has been isolated from the fruits of Lycopersicon esculentum.

抄録全体を表示