1-Methylpyridinium iodide (1a), derived from pyridine (1a), was stirred in chloroform solution in the presence of sodium hydroxide and triethylbenzylammonium chloride, at room temperature, and a mixture of 1, 1, 3, 3-tetrachloro-1a, 2, 2a, 3a, 4, 4a-hexahydro-2-methyl-4-trichloromethyl-1H, 3H-dicyclopropa [b, e] pyridine (12a) and 1, 1, 4, 4-tetrachloro-1a, 2, 3, 3a, 4a, 4b-hexahydro-3-methyl-2-trichloromethyl-1H, 4H-dicyclopropa [b, d] pyridine (13a) formed. Similarly, corresponding dicyclopropa [b, e] pyridine derivative (12b) and dicyclopropa [b, d] pyridine derivative (13b) were obtained from 1-ethylpyridinium iodide (11b). In order to examine the substitution effect, the quaternary salts (11d-m) derived from 2-, 3-, or 4-methylpyridine, 2, 3-, 2, 4-, 2, 6-, 3, 4-, or 3, 5-dimethylpyridine, and 2, 4, 6-trimethylpyridine were submitted to the same reaction and only one of either dicyclopropa [b, e] pyridine or dicyclopropa [b, d] pyridine derivative was formed according to the position of the methyl group substituted in the pyridine ring.
The influence of ointment composition and storage temperature on the conversion of the prednisolone anhydrous form (A-PD) to its hydrated form (C-PD) in O/W type ointment was studied using an X-ray diffractmeter and a polarizing microscope. When either stearyl alcohol or cetyl alcohol alone was added to the ointment, A-PD was easily converted into C-PD, especially at low storage temperature. On the other hand, when a mixture of alcohols was used in a proper ratio, the conversion of A-PD to C-PD was retarded. Particularly, when stearyl alcohol and cetyl alcohol were mixed in the ratio of approximately 2 : 3, A-PD remained most stable. When O/W type ointment, including A-PD, was stored at high temperature (37°) for a long time and then moved to a low temperature (5°) for storage, it was not easy to convert into C-PD. These results were due to the property of three polymorphisms (α, β, and γ) of long-chain alcohols. The ointment structure containing the α-form was stable enough to stabilize A-PD, while that containing the β- or γ-form was less stable.
The structure-activity relationships of new semisynthetic cephalosporins, 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido) phenylacetamido] cephalosporanic acids (Ia-h) were investigated. Ia-h were found to possess a broad spectrum of antibacterial activity against clinical isolates of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, 7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)-acetamido]-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (Ih) showed the strongest activity. Ia-h were more stable than Cefazolin (CEZ) to cephalosporinases. In acute toxicity, 3-acetoxymethyl-7-[D (-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-cephem-4-carboxylic acid (Ib), 7-[D(-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl) acetamido]-3-[(1, 3, 4-thiadiazol-2-yl) thiomethyl]-3-cephem-4-carboxylic acid (Id) and Ih showed good tolerance upon i.v. administration to mice. Serum protein binding, serum level and urinary excretion of the three compounds varied remarkably among animal species. Regarding the protective effect against experimental infection in mice, Ih was the most effective among the three compounds, and more effective than CEZ against gramnegative bacterial infection.
3, 4-Diaminothiophenes (Xa-b) were synthesized by cleavage of the pyridine ring in to 3-aminothien-4-ylpyridinium iodides (Va-d), which were prepared by the reaction of 1-cyanomethylpyridinium chloride with carbon disulfide and alkylating agents (chloroacetonitrile, ethyl bromoacetate, phenacyl bromide, chloroacetamide) in the presence of alkali, followed by base-catalyzed intramolecular cyclization. The reaction of 3, 4-diaminothiophenes with acetic anhydride, benzoyl chloride, and benzaldehydes gave the corresponding products in good yields.
The fate of 3H-labeled 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (3H-M73101) in rats and the excretion of M73101 from dog kidney were studied. When 3H-M73101 was given orally to rats, it was rapidly absorbed from the gastro-intestinal tract and widely distributed throughout the tissues. Particularly, higher radioactivity was detected in the stomach, kidney and liver. Plasma concentration reached maximum at 1 hr after administration and maintained that level for 3 hr ; thereafter, radioactivity rapidly decreased. The time courses of radioactivity in many tissues were similar to those in plasma. Autoradiographic results were in good accord with those described above. Radioactivity was found also in the inflammed site and carboxymethyl cellulose (CMC) pouch of rats at 1 hr after administration. At 6 hr, radioactivity in the skin and muscle in contact with the CMC pouch was higher than that at normal sites. Excretions into the urine and feces within 24 hr were 68.6% and 18.9% of the dose, respectively. About 10% of the dose was excreted into the bile within 24 hr, in which parent compound and 6 metabolites were detected. When the excreted bile was administered into the duodenum, 23% of the dose was excreted again into the bile. From the result of the experiment using a renal clearance method in dogs, it was found that more than 95% of M73101 was reabsorbed from the renal tubule by passive transport. The relationship between the fate and the pharmacological activity of M73101 is also discussed.
In order to study cis-trans photo-isomerization of phylloquinone (K) and menaquinone-4 (MK-4), a high-performance liquid chromatographic method for the determination of cis-trans isomers was developed. After removal of the surface active agent and photo-decomposition products, cis-trans isomers were separated on a Nucleosil 50 (particle size ; 5 μm) column using di-n-butyl ether-n-hexane (6 : 94) as a mobile phase. The internal standards used were MK-4 for K and K for MK-4. When either cis or trans compound of K and MK-4 were photo-irradiated in benzene, cis⇌trans photo-isomerization was observed and an equilibrium favoring the trans isomers was attained. Trans→cis photo-isomerization of MK-4 was also observed in injection and in infusion solution. Photo-isomerization and photolysis in their solution were inhibited considerably by using a light-intercepting shade.
N-Phthaloyl-D, L-phenylalanine was converted to 2-phthalimido-1-indanone (3). Reduction of 3 with sodiumborohydride gave undesired compounds, 5 and 6. Compound 3 was hydrolyzed to give an aminoketone (4) which was reduced to cis- and trans-amino-indanols (7a and 7b). The reduction condition was examined to obtain cis-isomer (7a). The reductive N-alkylation of 7a with carbonyl compounds by sodium cyanoborohydride gave 2-alkylamino- or aralkylamino-1-indanols (8-12) which were shown to be inactive for antibacterial and β-adrenergic blocking effects. The phthaloylphenylalanyl chloride (2) was treated with aluminum chloride in benzene to give 14, which was reduced to the corresponding alcohol (15).
The constituents of Osmorhiza aristata (THUNB.) MAKINO et YABE (Umbelliferae) were examined. The essential oil obtained by steam distillation was separated by silica gel column and gas liquid chromatography. Benzoic acid, phenylacetic acid, β-phenylpropionic acid, 10 fatty acids, phenol, cresol (o-, p-), guaiacol, chavicol, p-anol, chavibetol, isochavibetol, β-ocimene, p-cymene, γ-terpinene, terpinolene, estragole, anethole, 1-allyl-2, 4-dimethoxybenzene, 2, 4-dimethoxy-1-propenylbenzene, n-hexyl acetate, n-octyl acetate, n-decyl acetate and 5 n-paraffins were detected in the rhizoma. From the leaves, β-farnesene, β-caryopyllene, cis-3-hexen-1-ol, linalool, benzyl alcohol, phenethyl alcohol and the same substances contained in rhizoma were identified. Phytosterol, phytosteryl glucoside and 9 long-chained primary alcohols were also isolated from the rhizoma and leaves.
Salicylic acid (SA) release from the model cream base, density of oily phase, partition coefficient of SA between the oily and water phase (Pd), diffusion coefficient of SA in the oily phase and in the membrane (Fuji film Co. FR-40), and particle size distribution of model cream were measured and the ratio (R-value) between the percent release of SA and the theoretically releasable amount of SA, which can be calculated from the volume and partition coefficients of drug, membrane, and receptor phase were compared with the R-value of emulsion quoted from Ref. 1). The obstruction effect of droplet on drug release was also proved by the decrease in R-value with an increase in the volume fraction (VF) of the oily phase. The obstruction effect in the cream is greater than that in the emulsion. X-value of cream base, which is the special resistance of drug penetration at the droplet surface, was 1380 times greater than the X-value of emulsion. The percent release in the cream was determined by the SA amount in the continuous phase, because the SA in the droplet cannot be released practically.
The synthesis of novel tricyclic β-lactams, 1, 9b-dihydro-2H, 4H-2-oxoazeto [1, 2-c] [1, 3]-benzoxazine-4-carboxylic acid (3), were examined by two approaches involving imineacid chloride cycloaddition reaction as a key step. The cyclization was found to proceed stereoselectively to form 4-(4-chlorophenyl)-1, 9b-dihydro-9b-methylthio-1-phenoxy-2H, 4H-2-oxo-azeto [1, 2-c] [1, 3] benzoxazine (8), cis-1-benzyl-4-(2-benzyloxyphenyl)-3-phenoxy- and cis-1-benzyl-4-(2-benzyloxyphenyl)-2-oxo-3-phthalimidoazetidine (16 and 17).
Cyclization of the diastereoisomeric mixture of 2, 2, 2-trichloro- and p-nitrobenzyl 2-hydroxy-2-[cis-4-(2-hydroxyphenyl)-2-oxo-3-phthalimido-1-azetidinyl] acetates (17 and 18) gave stereoselectively the corresponding 1, 2-benzo-3-oxacephams (20 and 26) together with 21, a stereoisomer of 20. The starting compounds (17 and 18) were prepared via the cycloaddition reaction of N-(2-benzyloxybenzylidene)-2, 4-dimethoxybenzylamine (8) with phthaloylglycyl chloride, followed by oxidative cleavage of 2, 4-dimethoxybenzyl group of the adduct (9). Deprotection of the N-phthaloyl and ester groups of 20 and 26 was also investigated and 1-amino-1, 9b-dihydro-2H, 4H-2-oxoazeto [1, 2-c] [1, 3] benzoxazine-4-carboxylate (22) and 1, 9b-dihydro-2H, 4H-2-oxo-1-phthalimidoazeto [1, 2-c] [1, 3] benzoxazine-4-carboxylic acid (27) were obtained.
Seven kinds of lectins were examined for their effects on platelet aggregation. Three lectins separated from Ulex europeus, Ricinus communis and Glycine max (Soybean) induced the aggregation of human platelets. Furthermore, lectins from Ricinus communis and Glycine max (Soybean) aggregated the platelets from rabbits ; only soybean agglutinin induced the aggregation of platelets from rats. ADP was released in the reaction between soybean agglutinin and human platelets and the addition of D-galactose or N-acetyl-D-galactosamine to this reaction mixture inhibited aggregation.
The distribution, excretion and metabolism of p-phenylenediamine, a constituent of oxidative hair dye, was studied after intraperitoneal administration of p-phenylenediamine-14C (1.5 mg/kg) to male rats. In tissues other than the small and large intestines, the highest concentration of radioactivity was found at 1 hr, followed by a rapid decrease in concentration. Only small amounts of radioactivity were found in the tissues 48 hr after administration. The low levels of radioactivity in tissues, together with the large amounts of radioactivity found in the intestinal tract and in urine, indicated the rapid excretion of administered p-phenylenediamine. Within 24 hr after administration, 69% of the administered radioactivity was excreted in the urine, 29% in the feces, and 26% of the intravenously administered radioactivity was excreted in the bile. Thin-layer chromatography of the urine indicated the presence of several urinary metabolites. The reverse isotope dilution method identified one of the metabolites as N, N'-diacetyl-p-phenylenediamine, which accounted for 30% of the radioactivity in the urine.