The metabolic conjugation of morphine, codeine and nalorphine, and the pharmacological activity of their conjugates were studied. A major metabolite in man and animals and one of the minor metabolites of morphine were identified to be morphine-3-glucuronide and 6-glucuronide, respectively. Codeine was transformed mainly to codeine glucuronide and morphine-3-glucuronide, and nalorphine was also conjugated predominantly to 3- glucuronide. No effect was observed with morphine-3-glucuronide and 3-sulfate, but 6-conjugates, glucuronide and sulfate showed more potent analgesic activity than morphine. This finding is very surprising because, in general, conjugation has been believed to be the true detoxication. Other evidence supported the view that this modification at the 6-position raises the affinity of morphine to the receptor.
The biological fate of phenylisopropyl-p-phenylenediamine (PIPD) in the rabbit was examined by GLC and GC-MS methods. It was found that a major metabolite of this compound in the urine was PIPD N-glucuronide, and that the amount of this glucuronide excreted in the urine within 24 hours was 4 times higher than that of the unchanged form. Both PIPD and PIPD N-glucuronide were excreted in the bile more rapidly than in the urine. PIPD was rapidly eliminated from the plasma following intravenous administration, and 25% of the dose accumulated in the liver within 5 hours, of which nearly 70% was PIPD N-glucuronide. In contrast, it was found that the plasma level of PIPD was extremely low following intraduodenal administration, and that 22% of the dose accumulated in the liver within 2 hours. It was suggested that PIPD accumulated rapidly and in large amounts in the liver and was excreted slowly in the urine and in the bile.
6-[D (-)-α-(Acylamino)-4-hydroxyphenylacetamido] penicillanic acids (1-12) were prepared by reacting amoxicillin with the active esters of nitrogen-containing heterocyclic compounds (11). These penicillins were tested for in vitro activities against S. aureus, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. Structure-activity relationships were discussed. The 4-hydroxyquinoline derivative (5) and the 4-hydroxy-1, 5-naphthyridine derivatives (8-11) were found to have potent antibacterial activity against E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. Among the penicillins tested, sodium 6-[D (-)-α-(4-hydroxy-1, 5-naphthyridine-3-carboxamido)-4-hydroxyphenylacetamido] penicillanate (8) exhibited the highest activity against P. aeruginosa, its MIC being 1.56μg/ml.
Catalysts consisting of three different metaloxides were effective in activating the direct amination reaction of pyridine by ammonia in the heterogeneous vapor-phase. The cobalt oxide catalyst supported by silica magnesia exhibited the greatest activity for amination. 2-Aminopyridine and hydrogen were formed as the main products of the desired reaction. On the other hand, pyridine-N-oxide, water, and carbon dioxide, which were obtained simultaneously, were found to be the by-products. From a catalyst containing 10 wt% of cobalt, and supported by 80 wt% silica gel-containing silica magnesia, 2-aminopyridine was obtained initially at a yield of ∼11% at 450°, and formed at a yield of 5.5% at 50 hours after the beginning of the reaction. However, the yield of 2-aminopyridine decreased if the reaction temperature rose above 500° due to the decomposition of 2-aminopyridine. Finally, the direct catalytic amination reaction of α-picoline, β-picoline, and γ-picoline by ammonia confirmed the formation of the respective aminopicolines.
A number of partially saturated 2-naphthalene- and 2-naphthylidene-acetic acid derivatives were prepared by the Wittig reaction of the corresponding tetralones. The former was converted to the latter by treatment with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone. Their antiinflammatory activity was examined by the inhibition of carrageenin foot edema.
Solid complex of theophyline and trimethylenediamine was examined by X-ray diffraction, differential thermobalance, and infrared spectrophotometry, and it was found that theophylline and trimethylenediamine formed a solid complex in 2 : 1 molar ratio in absolute ethanol. This complex contains 1 mol of crystal water. The binding of theophyline and ethylenediamine was considered to be the same as in the case of aminophylline. Differential thermoanalysis of the solid complex in air with thermobalance, at the rate of 2.5°/min temperature rise, showed that weight loss begins at around 80°, accompanied with endothermic peaks, with appearance of a small endothermic peak at around 102°, large endothermic peak at around 122°, and an endothermic peak shoulder at around 128°, resulting in the completion of thermal change and weight loss at around 136°. These phenomena may be explained by two routes of thermal decomposition ; one of simultaneous liberation of the crystal water and trimethylenediamine to form anhydrous theophylline, and the other of formation of an anhydrous solid complex by the release of crystal water, followed by liberation of trimethylenediamine to form anhydrous theophylline, and the observed endothermic peaks were the overlap of these thermal reactions.
3-Cyano-1, 1-dibromo-2-methoxy-1a, 2, 3, 7b-tetrahydro-1H-cyclopropa [c] quinoline derivatives (I) are obtained in a high yield/by the application of dibromocarbene to the pseudo-base, 1-cyano-2-methoxy-1, 2-dihydroquinoline derivatives, obtained from quinoline derivatives, in the presence of triethylbenzylammonium chloride as a phasetransfer catalyst. Heating of I under a reduced pressure converts them easily to 4-bromo-1-cyano-1H-benz [b] azepine derivatives.
Ouinaldine was dissolved in chloroform not containing any ethanol, 50% sodium hydroxide was added, and was stirred at room temperature in the presence of triethylbenzoylammonium chloride as a phase-transfer catalyst, by which 3'-formyl-1, 1, 1', 1'-tetrachloro-1a', 2', 3', 7b'-tetrahydrospiro (cyclopropane-2, 2'-1H-cyclopropa [c] quinoline) (1a) was formed in a high yield. Treatment of 1a with lithium aluminum chloride in tetrahydrofuran gave a 3'-methyl compound (2a). Formation of 1a passes through the intermediate formation of 1, 1-dichloro-1'-formyl-1', 2'-dihydrospiro [cyclopropane-2, 2-quinoline] (3a). Presence of a small amount of polar solvent in the reaction mixture during formation of 1a results in the formation of 2-(2-chlorovinyl)-1, 1-dichloro-1a, 7b-dihydro-1H-cyclopropa [c] quinoline (6a) as the major product. Reaction for the formation of compounds possessing a spiro ring, like 1a was found to be specific for quinoline derivatives having an active methylene in the 2-position and to have a fair general character. Spiro-ring compound was not formed from 1-methylisoquinoline.
The relationship between the strength of compressed powder compacts and compaction pressure was investigated in several kinds of powders. Boring hardness measurements were carried out on the compacts prepared by static compression. The reciprocal of boring speed 1/v and the constant k in eq. (1) were used as measures of compact strength. Crushing strength for tablets made by a rotary tablet machine was also measured. The strength of each compact reached a limited value under high compaction pressure, which was considered to be the characteristic value for each powder. Compact strength decreased with the addition of a lubricant. Because the additivity of tablet strength could be observed, tablet strength in binary powder systems could be estimated from the strength of each component and from the mixing ratio.
When Dowex 1×2 (OH- form) was suspended in an aqueous solution, glucose epimerized to fructose and mannose, and degraded to arabinose. The conditions of this reaction were investigated and it was found, first, that strongly basic anion-exchange resins universally reacted while weakly basic ones did not, second, that the reaction produced a better result at 30° than at 50°, and, third, that a sugar concentration of 100μg/ml was the most desirable for both epimerization and degradation. Comparison of effects of resin forms (OH-, Cl-, BO-2, H2PO-4, and SO2-4) of Dowex 1×2 on yields of arabinose and fructose from glucose showed that glucose epimerized and degraded only in the case (OH- form or BO-2 form) where glucose combined with the resin. The fact that the yield of arabinose from fructose with Dowex 1×2 (OH- form and BO-2 form) was much lower than those from glucose and mannose suggested that a structure having a carbonyl group at C-1 was necessary for degradation to arabinose. Autoradiography and radio-gas chromatography of reaction products from 14C-glucoses with Dowex 1×2 (OH- form) proved that the C-1 carbon of glucose split off as formic acid. A hypothetical degradation reaction-mechanism was postulated.
3, 7-Dimethyl-1-(5-oxohexyl) xanthine (pentoxifylline) (I) was synthesized by the following alternate methods : (1) oxidation reaction by PdCl2-O2-H2O of 1-(5-hexenyl)-3, 7-dimethylxanthine (IV), (2) alkylation-cleavage reaction of 1-(3-halogenopropyl)-3, 7-dimethylxanthine (IIa-c) with 2, 4-pentanedione in the presence of a base, and (3) ring closure reaction of caffeidine (IX) with N, N'-di-(5-oxohexyl) urea (X). In addition, several 1-substituted 3, 7-dimethylxanthine (XI-XVI) were synthesized and examined for their c-AMP phosphodiesterase inhibitory activity.
Hydrocortisone (HS), prednisolone (PS), and cortisone (CS) were fluorometrically determined by conversion to 21-aldehyde with cupric acetate and by subsequent reaction with pyrrole. Hydrocortisone acetate (HSA), prednisolone acetate (PSA), and cortisone acetate (CSA) were successfully determined by alkaline hydrolysis prior to fluorescence development. The relationship between fluorescence intensity and the concentrations of HS, PS, CS, HSA, PSA, and CSA, showed linearity in the range of 1.25-12.5 ng/ml for HS, PS, and CS, and 2.5-30 ng/ml for HSA, PSA, and CSA. This method was applied to commercial ointments and eye ointments, and the analytical data were compared with those by BT and INAH methods. The values were almost identical to those by BT and INAH methods.
Apalcillin sodium was hydrolyzed to (3S, 5R, 6R)-[(R)-α-(4-hydroxy-1, 5-naphthyridine-3-carboxamido) benzyl] penicilloic acid (A1) in aqueous sodium hydroxide solution. The optimal reaction was achieved by adding two equivalent amounts of sodium hydroxide to apalcillin sodium in water. The sodium salt of A1 was converted to the (3S, 5S, 6R)-isomer (A2) by heating in aqueous solution, and A1 was degraded to (3S)-[(R)-α-(4-hydroxy-1, 5-naphthyridine-3-carboxamido) benzyl] penilloic acid (B) in acidic aqueous solution at 60°.
A rapid method for determining paeonol in Moutan Cortex ("Mudanpi"-root bark of Paeonia moutan) was established by high-speed liquid chromatography. Paeonol was separated in a 25 cm column of Zorbax CN, using a Shimadzu-Du Pont Model LC-2 liquid chromatograph, with 50% acetonitrile as the desorption solution. Separation was completed within 7 min. Paeonol in Moutan Cortex was extracted with methanol and the extract was injected directly into the column. Paeonol content was estimated from previously prepared calibration curves based on standard paeonol. At 275 nm, the precision of the determination was about ±1% and the detection limit was about 2 ng (S/N ratio, 3). It was concluded that this method is useful for the evaluation of Moutan Cortex.
Two isomers, (5) and (6), 1-phenyl-1, 2, 3, 4-tetraline-1, 4-dicarboxylic acid discopine ester, were isolated from the leaves of Duboisia leichhardtii F. MUELL (Solanaceae), and their structures and stereochemistry were studied on the basis of spectral data and synthesis. Also, four known alkaloids, isobutyroyl tropine (1), norhyoscyamine (2), aposcopolamine (3), and apoatropine (4), were identified. 13C-nuclear magnetic resonance spectral data regarding these alkaloids and corresponding compounds were discussed.
Nine kinds of fatty acids, fifteen hydrocarbons, three sterols, and six amino acids were detected by gas chromatography-mass spectrometry and amino acid analysis, from the dried fruits of Capsicum annuum L. var. fasciculatum IRISH. The distribution of N-(13-methyltetradecyl) acetoamide isolated from Capsicum annuum L., and named Capsi-amide, was investigated in four varieties of Capsicum annuum L., i.e. C. annuum L. var. fasciculatum IRISH, var. grossum SENDT., var. longum SENDT., and var. minimum ROXB. Capsi-amide was detected in all four varieties.
A method for the rapid determination of paeoniflorin in Moutan Cortex was established by high-speed liquid chromatography. Paeoniflorin was separated in a 25 cm column of Zorbax CN, using a Shimadzu-Du Pont Model LC-2 liquid chromatograph, with 0.1 M HClO4 (pH 3.5)-CH3CN (9 : 1, v/v) as the desorption solution. Paeoniflorin in Moutan Cortex was extracted with water and the aqueous extract was injected directly into the column. Paeoniflorin content was calculated from previously prepared calibration curves based on standard paeoniflorin. In this method, crude paeoniflorin can be determined exactly by separating it from other components.