This article mostly describes a highly efficient method for asymmetric carbon-carbon bond forming reactions based on the strategy of fixing the conformation of the chiral moiety of the imines, prepared from carbonyl compounds and optically active α-amino acid esters, by chelation of appropriate metals with the imine nitrogen and the ester oxygen suitably situated. Two types of reactions, 1, 4-addition reaction of Grignard reagents or diethyl malonate anion to α, β-unsaturated aldimines and alkylation of metalloenamines, have been explored. The present method has advantages in providing β-substituted aldehydes, α-substituted cyclic ketones, trans- and cis-α, β-disubstituted cycloalkanecarboxaldehydes in quite high enantiomeric purities, allowing easy preparation of imines as well as easy recovery of tert-leucine tert-butyl ester, an excellent chiral reagent, without any loss of optical purity for reuse. Some mechanistic explanations on the stereochemical courses of the reactions are presented. Asymmetric Diels-Alder reactions catalyzed by optically active alkoxyaluminium dichlorides are also described.
A new electrochemical method for the assay of hydrogen peroxide was established by using a peroxidase-adsorbed carbon anode, a silver cathode, and o-dianisidine as substrate of peroxidase. Under the optimum assay conditions, a linear relationship was found between hydrogen peroxide concentration in the range of 5 nM to 1000 nM (10-2000 pmol per reaction bath) and voltage, and the coefficient of variation was below 5 percent. One assay can be completed in 1 min and 10μl of sample is reguired for the procedure. The present method is very rapid and sensitive, and should be useful for the determination of hydrogen peroxide.
Adduct formation with dimethylamine was confirmed in 5 barbiturates including allobarbital, amobarbital, barbital, cyclobarbital, and hexobarbital. The thermal and physico-chemical properties of these adducts were investigated by differential scanning calorimetry, thermogravimetry, infrared spectroscopy, and X-ray powder diffractometry. From the weight decrease in thermogravimetry, the combining ratios of adducts (barbiturates : dimethylamine) were determined to be 1 : 1 for allobarbital and hexobarbital, and 1 : 2 for amobarbital and barbital. As the new absorption band arising from NH2+ stretching vibration appeared in infrared spectra of all adducts except hexobarbital-dimethylamine, it was suggested that the bonding of an ionic nature would participate in the adduct formation of four barbiturates. In addition, the complicated thermal behavior of the adducts was discussed.
The effect of additives such as sodium deoxycholate, sodium lauryl sulfate, disodium ethylenediaminetetraacetate, polyethylene glycol 400, polysorbate 80, on the rectal permeability was compared by measuring the rectal absorption of sulfaguanidine from the perfused solution and the apparent rectal clearance of i.v. injected sulfaguanidine in the rat. The absorption and apparent rectal clearance of sulfaguanidine in the rat rectum were increased by the addition of these additives, except for lower concentration of polyethylene glycol 400. There was a very favorable correlation between the increasing ratio of apparent absorption rate and ratio of apparent rectal clearance of sulfaguanidine. In addition the simultaneous change in permeability in both directions (rectum to blood, blood to rectum) was clarified. The cause was found to be due to a histological change in the tissue of the rectum, and it was also found that these changes were different according to the natures of the additives.
Inclusion complexations of 13 aralkylalcohols with three cyclodextrins (α-, β-, γ-CyDs) in water and in solid state were assessed by the solubility method, spectroscopies (ultraviolet (UV), circular dichroism (CD), infrared (IR), 1H-nuclear magnetic resonance (1H-NMR)), X-ray diffractometry, and thermal analyses (DTA, TG). The volatility of aralkylalcohols was significantly retarded by the formation of solid complexes, where the molar ratios (guest : host) of the complexes were generally found to be 1 : 2 and 1 : 1 for α-CyD and β-CyD systems, respectively. In the presence of CyDs, an increase in inhibitory-zone diameter of aralkylalcohols including 2, 4-dichlorobenzyl alcohol (DCBA) was observed by cup-plate method and no reduction of their antimicrobial activities was also found. The dissolution rate and permeation behavior of DCBA through a cellophane membrane were dependent upon the solubility of solid samples (DCBA alone>β-CyD complex>γ-CyD complex). The apparent release of DCBA from poorly soluble β-CyD complex was significantly improved by the addition of α-CyD into the dissolution medium. These results suggest that CyD complexation is practically useful to improve some pharmaceutical properties of aralkylalcohols without reduction of their antimicrobial activities.
Adduct formation with dimethylamine was confirmed in 5 barbiturates (barbituric acid, mephobarbital, metharbital, phenobarbital, and propallylonal) and phenytoin. The thermal, physico-chemical, and micromeritical properties of these adducts were investigated by differential scanning calorimetry, thermogravimetry, thermomicroscopy, infrared spectroscopy, X-ray powder diffractometry, electron microscopy, and BET gas adsorption analysis. From thermogravimetry, the combining ratios of adducts (barbiturates or phenytoin : dimethylamine) were determined to be 1 : 1 for barbituric acid, mephobarbital, propallylonal, and phenytoin, and 1 : 2 for phenobarbital. As the new absorption band arising from NH2+ stretching vibration appeared in infrared spectra of almost all the adducts, it was strongly suggested that the bonding of an ionic nature would participate in the adduct formation. By desorption of dimethylamine from dimethylamine adducts under reduced pressure with or without heat application, effectively micronized original chemicals were recovered. Their specific surface areas were 2 to 3 times larger in comparison with the corresponding barbiturates recovered via ammonia adducts. The difference in effectiveness in particle size reduction would be attributable to the difference in molecular volume of dimethylamine from ammonia.
Effects of diet intake on the bioavailability of experimental tablets and suspension containing bisbentiamine, a lipophylic thiamine prodrug with pH-dependent solubility, were systematically investigated by measuring urinary thiamine excretion in man. A standard breakfast as well as high carbohydrate, high protein and high fat meals were given at fixed time of 9 : 00 A.M., and the dosing time of bisbentiamine varied in relation to the breakfast time otherwise specified. Approximately in common with the two dosage forms, the extent and the rate of bioavailability decreased significantly on preprandial administration and also tended to decrease in postprandial conditions as compared to that of between meals and fasted conditions. The high protein diet decreased greatly and the high fat meal increased slightly the bioavailability. A decrease in the bioavailability was not always accompanied with the delay in gastric emptying in postprandial conditions estimated by maximum urinary excretion time. Good correlations were found between bioavailability and the gastric acidity determined by concomitant administration of commercial diagnostic agent for gastric secretion. Extreme inter-individual variation was noted in the bioavailability of tablets administered in fasted conditions, though situation was greatly different with formulation of tablets. On the basis of the above findings, possible interaction of pharmaceutical and physiological factors affecting bioavailability of bisbentiamine are discussed.
Furosemide (FR) was administered to normal and acute renal failure rabbits by an intravenous administration on a single dosing (10 mg/kg). A peak on chromatogram proposed as FR-glucuronide (FG) was detected by high performance liquid chromatography with fluorometric detector. Assuming that difference in FR concentration between samples before and after hydrolysis with β-glucuronidase was attributed to FG, the concentrations of FR and FG were determined, separately. The plasma concentrations of FR and FG in acute renal failure rabbit were higher than those in normal rabbit during a 2-h period after administration of FR. Approximately 11% and 20% of total FR dosing were excreted as FG in 24-h urine of normal and acute renal failure rabbits, respectively. A larger biliary excretion of FG in acute renal failure than in normal could be also observed.
The pharmacokinetics of flutoprazepam (FP) and its major metabolite, desalkylflutoprazepam (DFP), was studied in dogs. Two tenth mg/kg flutoprazepam-2-14C were administered intravenously and oraly, and 0.2 mg/kg desalkylflutoprazepam-2-14C were administered intravenously to each of three dogs, respectively. The plasma levels of FP or DFP after bolus intravenous injection declined biexponentially and the hybrid pharmacokinetic parameters were estimated as follows (value for parameter±standard error) : A=111.4±43.4 ng/ml, B=21.9±7.3 ng/ml, α=0.0522±0.255 min-1, β=0.00507±0.00116 min-1 for FP ; A=109.2±44.9 ng/ml, B=121.7±38.5 ng/ml, α=0.0455±0.0374 min-1, β=0.00999±0.00139 min-1 for DFP. The first order absorption with a rate constant of 0.069 min-1 was recognized by an application of the Loo-Riegelman method to FP plasma level vs. time data after oral administration. The time course of plasma levels of the active metabolite, DFP, after oral and intravenous administration of FP exhibited in parallel with those of intact drug in terminal phase. The apparent elimination of DFP in the terminal phase could be regarded as being reflected by that of FP, since the inherent β-value for DFP was larger than that for FP. Therefore, it suggests that an administration of FP may prolong the pharmacological efficacies.
Inclusion complexations of indomethacin (ID) and its related compounds with three cyclodextrins (α-, β-, and γ-CyDs) in aqueous solution were studied by solubility method, spectroscopies ultraviolet (UV), circular dichroism (CD), and 1H-nuclear magnetic resonance (1H-NMR), and kinetic method. A spatial relationship between host and guest molecules as well as hydrophobic nature in guest molecules was clearly reflected in the magnitude of the UV and CD spectral changes and the stability constants of inclusion complexes. The chemical shift measurements in 1H-NMR spectra suggested that the chlorobenzene ring moiety of the ID molecule was predominantly included in the cavity of CyDs and that the γ-CyD cavity might be preferable to include the bulky ID molecule. The hydrolysis rates of ID and its related compounds in alkaline solution were affected by three CyDs, depending upon the cavity size of CyDs. The effective deceleration observed by γ-CyD may be due to the inclusion of active amide moiety of ID molecule.
Effects of total saponin from the roots of Platycodon grandiflorum A.DC. and its prosapogenin methyl esters on rat plasma corticosterone level were examined by competitive protein binding method. Total saponin and prosapogenin methyl esters were administered intraperitoneally to rat acclimatized by handling and the rat was sacrificed 30 min thereafter. Total saponin (1 mg/kg or more) elevated plasma corticosterone to the maximal level (about 40μg/100 ml). Plasma adrenocorticotropin (ACTH) was shown to increase significantly at 5 mg/kg of total saponin. Plasma glucose increased significantly at doses of 5 mg/kg or more of total saponin, but not of 1 mg/kg. 3-O-β-D-Glucopyranosyl- and 3-O-β-laminaribiosyl-platycodigenin methyl esters, and 3-O-β-D-glucopyranosyl-and 3-O-β-laminaribiosyl-polygalacic acid methyl esters increased plasma corticosterone maximally at 2μmol/kg (1.4-1.8 mg/kg) of doses. These results showed that the stimulating action on the pituitary-adrenocortical axis might be due to platycodigenin- or polygalacic acid-containing total saponin preparation of Platycoden grandiflorum A.DC.
To study the influence of renal ligation on the kinetics of biliary excretion, cefazolin (CEZ) was i.v. administered to the renal-ligated rats and the sham-operated rats. Plasma concentration of CEZ was significantly higher in the renal-ligated rats than in the sham-operated rats. T1/2β in rats without renal function increased approximately 8 times that in rats with normal kidney function, while the plasma clearance decreased to a similar extent. In the renal-ligated rats, the amount of CEZ excreted into the 6-h bile was 61% of dose which was about 4.5 times that in the sham-operated rats. The apparent biliary clearance also increased more significantly than that in the sham-operated rats. A significant reduction of plasma protein binding of CEZ by renal ligation in vitro, in spite that no changes of albumin concentration was observed. It is suggested that the increase of apparent biliary clearance observed in the renal-ligated rats may be due to the reduction of protein binding. These observations indicated that complete damage of the excretory function of the kidneys may partially be compensated by biliary excretion.
Determination of oxypertine, (5, 6-dimethoxy-2-methyl-3-[2-(4-phenyl-1-piperazinyl)-ethyl] indole), in the human serum by high performance liquid chromatography (HPLC) was described. The compound in the serum was extracted with ether after the addition of sodium carbonate solution. After evaporation of the solvent, the residue was dissolved in HPLC mobile phase composed of methanol-acetic acid-sodium acetate-water (100 : 0.5 : 0.025 : 0.2). An aliquot of the solution was injected onto a high performance liquid chromatograph equipped with Zorbax SIL stationary phase and ultraviolet (UV) detector at 254 nm. Elution was carried out by the above-mentioned mobile phase, and the peak of oxypertine appeared after all the UV-absorbing components in the serum was eluted. The recovery of oxypertine from the normal pooled-serum by this method was 99.5% (n=5, S.D.=2.95), and the limit of detection was 11 ng per ml of serum.