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A nitrite-catalyzed ring contraction reaction of substituted tetrahydrofurans by oxidation of bromide under aerobic conditions as a dehydrogenative dual functionalization was developed to provide 2-acyltetrahydrofurans in good yields. On the other hand, the oxidation reaction of 1-substituted isochromans occurred via the bromohydroxylation to give 1-(dibromoalkyl)-1-hydroxyisochromans in high yields.

A 1,3-iodo-amination with iodine reagent that involved the Csp2-Csp3 dual functionalization of 2-methyl indoles was developed to provide 2-aminomethyl-3-iodo-indole derivatives. The iodo-amination proceeded via a 1,4-transfer of an imide group through the formation of an indolyl(phenyl)iodonium imide using PhI(OAc)2, followed by an iodination using DIH or a double iodination of indole using excess DIH.

A 1,3-iodo-amination with iodine reagent that involved the Csp2-Csp3 dual functionalization of 2-methyl indoles was developed to provide 2-aminomethyl-3-iodo-indole derivatives. The iodo-amination proceeded via a 1,4-transfer of an imide group through the formation of an indolyl(phenyl)iodonium imide using PhI(OAc)2, followed by an iodination using DIH or a double iodination of indole using excess DIH.

Catalytic dehydrogenative dual functionalization (DDF) of ethers via oxidation, dealkylation, and α-bromination by the aerobic oxidation of bromide was developed to obtain the corresponding α-bromo ketones in high yields. In particular, the reaction of substituted tetrahydrofurans as cyclic ethers provided 3,3-dibromo tetrahydrofuran-2-ols in high yields selectively through the double α-bromination.

The metabolism of emedastine difumarate(KG-2413) after oral administration in human was studied. In human urine, 5-hydroxy-and 6-hydroxyemedastine and their conjugated metabolites were found as major metabolites and emedastine corresponding to 3.6% of dose was also excreted. Moreover 5-hydroxy and 6-hydroxy-5'-oxoemedastine, and emedastine N-oxide were found as minor metabolites. The sum of urinary excretion ratio of emedastine and its metabolites was about 44% for 24h after dosing. Taking urinary excretion ratio and plasma concentration of emedastine into consideration, the extent of bioavailability of emedastine difumarate in human might be similar to that in guinea pigs. However, the metabolic pattern in human was similar to that in rats, in which 5-hydroxy and 6-hydroxyemedastine were urinary major metabolites and emedastine N-oxide was minor metabolites.

Human, guinea pig and rat sera or plasma protein binding of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1, 4-diazepin-1-yl)benzimidazole difumarate (KG-2413) were investigated by equilibrium dialysis. There were pronounced interspecies differences in binding affinity and binding capacity which were the highest in guinea pig and human species, respectively. In humans, the binding index (n1P1/Kd1) of isolated alpha 1-acid glycoprotein (alpha 1-AG) was seven times higher than that of isolated albumin, and the dissociation constant for human serum at the high affinity binding site was comparable to that for alpha 1-AG. These facts suggested that the free base of KG-2413 was mainly bound to alpha 1-AG in human serum. The contribution of albumin to the binding of KG-2413 in guinea pig and rat plasma may be relatively small. The interspecies differences in KG-2413 binding observed in this study may be due to species differences in the binding affinity and/or capacity of alpha 1-AG.

A new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H- benzimidazole difumarate (KG-2413), was orally administered to guinea pigs at a dose of 2 mg/kg. The drug levels in the plasma measured by the radioreceptor assay (RRA) method were significantly higher by 7% than those by the gas chromatographic (GC) method which was selective for the intact drug. Among the metabolites of KG-2413, 1-(2-ethoxyethyl)-2-(hexahydro-1H-1,4-diazepin-1-yl)- 1H-benzimidazole (desmethyl metabolite) and 1-(2-ethoxyethyl)-5-hydroxy-2-(hexahydro-4-methyl-1H-1,4-diazepin- 1-yl)-1H- benzimidazole (5-hydroxy metabolite) had relatively high cross-reactivities of 29% and 21%, respectively, on the RRA method. However, the 5-hydroxy metabolite was not extracted with benzene under strongly basic conditions on the extraction procedure carried out prior to the receptor assay. Therefore, it was suggested that the desmethyl metabolite might affect the RRA method. In order to determine the amount of the desmethyl metabolite in the plasma, a high-performance liquid chromatographic method was established to determine the dansyl derivative of the desmethyl metabolite. By using this method, it was found that the desmethyl metabolite corresponding to 21-32% of the intact drug was present in the plasma after oral administration of KG-2413 at a dose of 2 mg/kg. Taking account of the cross-reactivity (29%) and extraction ratio (83%) of the desmethyl metabolite, this active metabolite affects the RRA method to give 5.1-7.7% overestimation of the intact drug concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

A gas chromatographic method for the quantitative determination of the new antiallergic agent, 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413), in plasma has been developed. This method, which was based on solvent extraction and flexible fusedsilica capillary gas chromatography with a nitrogen-sensitive detector and a moving needle solvent cut sample injector, is simple, sensitive and selective.The detection limit was about 1 ng (as free base)/ml and the calibration curve was linear over the range of 2 to 100 ng/ml. Moreover, the intra- and inter-assay coefficients of variation for the determination of KB-2413 were 3.1-4.0% and 1.5-6.7%, respectively. This assay was applied to the determination of the plasma concentration of KB-2413 base after oral administration to dogs.

Interspecies differences in the pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimid azole difumarate (KG-2413) after intravenous administration were investigated in rats, guinea pigs and dogs. The disappearance of unchanged KG-2413 base was described by biexponential curves in all three animal species. The areas under the plasma concentration-time curves (AUC) in rats, guinea pigs and dogs were 218, 421 and 369 ng.h/ml, respectively, at a dose of 2 mg/kg. The volume of distribution in rats was comparable to that in dogs, and was about three times greater than that in guinea pigs. This might be due to the difference in the unbound fractions of KG-2413 base in plasma (fu), that is, the values of fu in rats, dogs and guinea pigs were 0.607, 0.603 and 0.189, respectively. The first-order elimination rate constant from the central compartment (kcl) in dogs were smaller than those in rats and guinea pigs. Total body clearances (CLtot) of KG-2413 base in rats and guinea pigs were comparable to the hepatic blood flow rate (Q) of each animal. Assuming that KG-2413 base is only eliminated in the liver, relatively rapid metabolism of KG-2413 base occurred in the liver of rats and guinea pigs. In dogs, extrahepatic elimination was suggested because the value of CLtot seemed to be greater than that of Q.

The metabolism of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413), was studied in rats and guinea pigs after oral administration of the 14C labelled compound.KG-2413 and its metabolites in the urine, bile, plasma and liver of rats were quantified. The major metabolites of KG-2413 in rats were 5-hydroxylated compound (M 5 b), 6-hydroxylated compound (M 5 a) and their conjugated metabolites. Tracer concentration of the unchanged drug was found, so it was assumed that KG-2413 was rapidly metabolized in rats.The urinary metabolites in guinea pigs were also quantified. The major metabolite was N-oxide compound (M9), and M 5 a and M 5 b were present mostly as conjugated metabolites, but the amounts of them were about one sixth of M9. The urinary excretion of the unchanged drug in guinea pigs was higher than that in rats.There were remarkable interspecies differences in the urinary excretion of the metabolites after oral administration of KG-2413.

Absorption, metabolism and excretion of an antiallergic agent, 1-(2-ethoxyethyl)2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413), were investigated in dogs.The plasma levels of radioactivity reached the maximum at 1 h after oral administration of 14C labelled KG-2413 at a dose of 2 mg/kg, and then declined in three-exponential manner. After intravenous administration of 2 mg/kg, the plasma levels of radioactivity temporarily rose at the initial stage of dosing, and then delined in three-exponential manner. No difference was observed between half-life times of radioactivity following administration by both routes.The area under the plasma concentration-time curve of radioactivity and the radioactivity excreted into the urine after oral administration were close to those after intravenous dosing.The plasma levels of unchanged KG-2413 accounted for only about 1 % of total plasma radioactivity even at the initial stage of oral dosing. About 25 % of total plasma radioactivity was related to the N-oxide compound (M 9) over 6 h after dosing.In the both dosing routes, the radioactivity was mainly excreted into urine, and the cumulative urinary and fecal radioactivity accounted for 97 % of administered dose within 96 h.After oral administration, the major urinary metabolites of KG-2413 found in dogs were M 9 and the 6-hydroxylated compound (M 5 a), while M 5 a and the 5-hydroxylated compound (M 5 b) in rats and M 9 in guinea pigs. A remarkable interspecies differences in the metabolism of KG-2413 were observed.

The selective and sensitive method for the determination of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-1H-b enzimidazole difumarate (emedastine difumarate, KG-2413), in the human plasma has been developed. Emedastine was determined by the receptor assay after the separation from its metabolites by the use of high-performance liquid chromatography (HPLC). This combined method (HPLC-radioreceptor assay (RRA) method) allowed us the quantification only of 0.3 ng/ml of emedastine in the human plasma. The intra-assay coefficients of variation for the determination were below 12%. Furthermore, the total pharmacologically active metabolites, including unchanged emedastine, was determined by the extraction of the unconjugated metabolites in the human plasma with chloroform followed by the receptor assay (RRA method). The human plasma concentrations measured by the HPLC-RRA method were in good agreement with those by the RRA method. These results suggested that in human pharmacological activities occurred by unchanged emedastine itself.

The urinary and biliary metabolites of a new antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepine-1-yl)-1H-b enzimidazole difumarate (KG-2413) in rats were identified by using a 14C-labelled drug and instrumental analyses, e.g., high performance liquid chromatography, gas chromatography (GC), 1H nuclear magnetic resonance, mass spectrometry (MS) and GC/MS. A slight amount of KG-2413 free base was detected only in the unconjugated fraction of urine. The main pathways of biotransformation of KG-2413 in rats were: (a) aromatic hydroxylation in the benzimidazole ring, (b) N-oxidation and N-demethylation in the 1,4-diazepine ring, (c) alpha-carbon oxidation (lactam formation) in the 1,4-diazepine ring (d) O-deethylation in the N-ethoxyethyl side chain. Regioselectivity was observed for aromatic hydroxylation, as only two of the four possible monohydroxylated metabolites could be detected. Furthermore, N-oxidation and lactam formation reactions were found to be regiospecific, that is, the former took place only at the position of 4-N atom and the latter at 5-C atom, respectively.

A radioreceptor assay (RRA) for the quantitative determination of a new antiallergic agent, 1- (2-ethoxyethyl) -2- (4-methyl-1-homopiperazinyl) benzimidazole difumarate (KB-2413), has been developed. This RRA method, based upon competitive binding of [3H] mepyramine and KB-2413 to histamine H1 receptors in guinea pig cerebellum, allows the simple, sensitive and reproducible determination of KB-2413 in plasma. The determination limit was 0.1 ng (as free base) /ml and the standard curve was linear over the range of 0.1 to 5.0 ng/ml. The intra-and inter-assay coefficients of variation for the determination of KB-2413 were 5.2-11.1 % and 3.4-5.6%, respectively. The active metabolites, 1- (2-ethoxyethyl) -2- (1-homopiperazinyl) benzimidazole and 1- (2-ethoxyethyl) -5-hydroxy-2- (4-methyl-1-homopiperazinyl) benzimidazole, cross-reacted to the extents of 28.6 and 21.1 %, respectively. However, plasma levels obtained by the RRA method and the gas chromatographic method for the intact drug were well correlated in guinea pigs after oral administration of KB-2413.

A simple, rapid and sensitive reversed-phase high performance liquid chromatographic (HPLC) method for the quantitative determination of ferulic acid in plasma was developed. Ferulic acid in plasma was extracted with ethyl ether, separated on a reversed-phase C18 column with a mixture of acetonitrile and 0.1м acetic acid (1 : 3, v/v) as a mobile phase, and quantitated by ultraviolet (UV) absorbance measurement at 313nm. 3, 4-Dimethoxycinnamic acid was used as an internal standard. The detection limit (signal-to-noise ratio=3) and the mean recovery from plasma were 1 ng (as amount injected) and 99.5±3.3%, respectively. The plasma levels of ferulic acid following oral administration of γ-oryzanol were determined by the present method and the mass fragmentographic (MF) method. A close correlation between the results of HPLC and those of MF was observed (γ=0.988). The present HPLC method was found to be applicable to the determination of ferulic acid in plasma in place of the MF method.

The pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413) after oral administration were studied in rats, guinea pigs and dogs. Maximum plasma level (Cmax) appeared at 23, 32 and 51 min after dosing in rats, guinea pigs and dogs, respectively. Plasma half-lives of the terminal phase were comparable to those after intravenous administration in each animal species. Pronounced interspecies differences were observed in the Cmax/dose and area under the plasma concentration-time curve (AUC)/dose, namely, these values were high in guinea pigs and low in rats and dogs. The extents of bioavailability were 0.036 in rats (20 mg/kg), 0.50 in guinea pigs (2 mg/kg) and 0.052 in dogs (2 mg/kg). These variations in the pharmacokinetic parameters in the animals were assumed to be mostly due to the species difference in the hepatic intrinsic clearance.