Highly active and reusable polymeric catalysts were produced by a self-assembly process of non-cross-linked amphiphilic polymeric ligands with inorganic species. Thus a new insoluble tungsten polymeric catalyst PWAA 1 was prepared from H3PW12O40 and poly[(N-isopropylacrylamide)-co-(acrylamide with ammonium salt)], which was suitable for the oxidation of alcohols, amines, and sulfides in aqueous hydrogen peroxide. A new insoluble palladium polymeric catalyst PdAS 2 was produced by self-organization of (NH4)2PdCl4 and poly[(N-isopropylacrylamide)10-co-diphenylphosphinostyrene], which is an excellent recyclable catalyst for the Suzuki-Miyaura reaction in water, water-organic solvents, and organic solvents. It is commercially available from Tokyo Kasei Kogyo (TCI). An improved insoluble palladium polymeric catalyst PdAS-V 3 was assembled from (NH4)2PdCl4 and poly[(N-isopropylacrylamide)5-co-diphenylphosphinostyrene], providing a reusable system for the Mizorogi-Heck reaction. A solid-phase titanium asymmetric polymeric catalyst TiSS 4 was made from Ti (O-i-Pr)4 and poly(styryl-linked binaphtholate-co-styrene) which promotes an enantioselective carbonyl-ene reaction as a recyclable catalyst.
In this review we report our development and applications of the highly selective cycloaddition reactions of unsaturated hydrocarbons such as conjugated enynes, electron-deficient allenes, and electron-deficient methylenecyclopropanes in the presence of nickel and palladium catalysts. Homocoupling reactions as well as co-cyclization reactions proceed with high atom economy, which is an attractive feature of these reactions. The efficient synthesis of 4-7 membered carbocycles was achieved.
Using a unique character of the chiral palladium complexes 1 and 2, several types of novel catalytic asymmetric reactions have been developed. In contrast to the conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine compounds were activated to form chiral palladium enolates, which underwent the enantioselective Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid activating the electrophiles, formed concomitantly during the formation of the enolates, whereby the C-C bond-forming reaction was promoted. In addition, this palladium enolate chemistry was also applicable to the electrophilic asymmetric fluorination reactions, and thus various carbonyl compounds including β-ketoesters, β-ketophosphonates, and oxindoles were fluorinated in a highly enantioselective manner (up to 98% ee). It is advantageous that these reactions were carried out in environmentally friendly alcoholic solvents such as ethanol, and exclusion of air and moisture is not necessary.
This article reviews the in vitro metabolic and the in vivo pharmacokinetic drug-drug interactions with antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole. In the in vitro interaction studies, the effects of antifungal drugs on specific activities of cytochrome P450s (CYPs), including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, in human liver microsomes are compared to predict the possibility of drug interactions in vivo. Fluconazole, micafungin, and voriconazole have lower inhibitory effects on CYP3A4 activities than itraconazole and miconazole, and IC50 and/or Ki values against CYP2C9 and CYP2C19 activities are the lowest for miconazole, followed by voriconazole and fluconazole. In in vivo pharmacokinetic studies, it is well known that itraconazole is a potent clinically important inhibitor of the clearance of CYP3A4 substrates, and fluconazole and voriconazole are reported to increase the blood or plasma concentrations of not only midazolam and cyclosporine (CYP3A4 substrates) but also of phenytoin (CYP2C9 substrate) and/or omeprazole (CYP2C19/CYP3A4 substrate). On the other hand, no inhibition of CYP activities except for CYP3A4 activity by micafungin is observed in vitro, and the blood concentrations of cyclosporine and tacrolimus are not affected by coadministration of micafungin in vivo, suggesting that micafungin would not cause clinically significant interactions with drugs that are metabolized by CYPs via the inhibition of metabolism. Miconazole is a potent inhibitor of all CYPs investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. Therefore the differential effects of these antifungal drugs on CYP activities must be considered in the choice of antifungal drugs in patients receiving other drugs.
The feasibility of a simple Fourier transform (FT)-Raman spectroscopic method for the quantitative determination of unexpected active drug polymorphs or amorphous in drug products was explored. In this study, calibration samples were prepared by physically mixing drug substances with their polymorphs or amorphous, without using excipients. A partial least-squares (PLS) method was applied to the quantitative analysis of the FT-Raman spectra obtained. As model drug products, compound A drug substances (form α) containing several ratios of polymorph, (form β), were physically mixed with excipients to prepare powder samples corresponding to compound A tablets (30 and 120 mg). The mixture of compound B, form I and amorphous, were also mixed with excipients to mimic powdered compound B tablets (32 mg). Satisfactory relationships between the theoretical contents of polymorph or amorphous and determined contents were obtained; quantitation limits were 5—10%. In the case of powder samples corresponding to compound A tablets (30 mg) and compound B tablets (32 mg), differentiating the FT-Raman spectra prior to PLS analysis was required to improve the precision of the determinations.
A simple and rapid capillary gas chromatographic (CGC) method with flame ionization detection has been newly developed for analysis of the essential oil from Radix Bupleuri. Twenty components were identified with gas chromatography-mass spectrometry. E-2-heptenal, furan, 2-pentyl, and E-2-nonenal were quantified simultaneously using the internal standard method. Decane was used as an internal standard. Separation and quantification were achieved on a DB-5 capillary column (30 m×0.25 mm i. d., 0.25-μm film thickness). The oven temperature was programmed as follows: 60°C to 70°C at 1°C/min rate, 70°C for 10 min, 3°C/min to 120°C, 20°C/min to 250°C, and held at 250°C for 5 min. The oven pressure was programmed as follows: 46.1 kPa for 25 min, 20.0 kPa/min to 77.6 kPa, and then held for 22 min. Split injection was conducted with a split ratio of 10:1; flow-rate, 1.00 ml/min; carrier gas, nitrogen; injector temperature, 280°C; and detector temperature, 280°C. The system proved effective in resolving E-2-heptenal, furan, 2-pentyl, and E-2-nonenal peaks from their interfering components. The method displayed excellent linearity in the range of 26.8—1072 μg/ml (E-2-heptenal), 6.5—1292 μg/ml (furan, 2-pentyl), and 7.8—1564 μg/ml (E-2-nonenal). The average recovery rates of E-2-heptenal, furan, 2-pentyl, and E-2-nonenal were 100.3%, 102.8%, and 97%, respectively. CGC is a quick and accurate method for analysis of the essential oil from Radix Bupleuri.
In recent years, the concept of gender-specific medicine has become generalized in Japan. We need to understand gender differences in the pattern of use prescription drugs for the appropriate use of medications. We therefore investigated gender differences in the use of prescription drugs based on data form nine hospitals in Japan. The data were extracted from their drug ordering systems in the month from March 1 to 31, 2003. We analyzed the data from the viewpoints of sex and age. The frequency of prescriptions for central nervous system drugs and Kampo medicines was higher for women than for men. The same trend was seen for hormones and vitamins. On the other hand, the frequency of prescriptions for cardiovascular drugs for men was higher than that for women. The same trend was found for unclassified metabolic drugs such as arthrifuges. As a result of detailed analysis by age-group, it is suggested that a correlation exists between the age specificity of prescription drugs and gender differences in disease occurrence. This information had not previously been investigated in Japan. Since the results appear useful, we to improve perform more detailed analyses and accumulate evidence to improve drug therapy.
An environmentally benign new synthetic method of zinc(II) complexes without the use of organic solvents and alkali was developed, and several types of zinc(II) complexes in high yields were prepared by mixing solid ligands with solid Zn(OH)2 or ZnO.