1-Cyano-2-methoxy (or ethoxy)-1, 2-dihydroquinoline (4a, b) was obtained in a high yield by the reaction of quinoline (1) with cyanogen bromide in methanol (or ethanol) or by the reaction of 1-cyano-2-hydroxy-1, 2-dihydroquinoline (2) in methanol (or ethanol). 3-Bromo-1-cyano-2, 4-dimethoxy (or diethoxy)-1, 2, 3, 4-tetrahydroquinoline (5a, b), obtained in a high yield by the application of bromine to 4a, b in methanol (or ethanol), followed by reaction with sodium carbonate, was reacted with conc. hydrochloric acid in methanol, and 3-bromoquinoline (7) was obtained quantitatively. 7 was also obtained by the application of sodium borohydride to 5a in ethanol. Reaction mechanism for these reactions was considered from some byproducts obtained at the same time. This reaction condition was applied to 2-, 4-, 6-, 7-, and 8-methylquinolines, and 3-bromomethylquinolines (16, 23-25), which were difficult to synthesize, were obtained in a high yield from 4-, 6-, 7-, and 8-methylquinolines (14, 17-19), via 3-bromo-1-cyano-2, 4-dimethoxymethyl-1, 2, 3, 4-tetrahydroquinolines (15, 20-22). 2-Methylquinoline (quinaldine) (26) formed ω-dibromoquinaldine (27) by reaction with cyanogen bromide in methanol and could not be derived to 3-bromoquinoline (28).
Phenobarbital was pulverized by recrystallization from glycols and their derivatives, and correlation of difference in the degree of pulverization with the solvent was studied. The crystalline form of the pulverized phenobarbital were also examined. The degree of pulverization of phenobarbital by recrystallization from glycols and their derivatives decreased with increase in the carbon atoms in the hydrophobic chain of these solvents. Two different solid phases (hydrate and form II) of pulverized phenobarbital were examined, and the hydrate (with 1 mol H2O) was transformed into form II (anhydrate) on being kept in a desiccator under a reduced pressure at room temperature.
All the biological activities of nitrofuran derivatives, including antibacterial action, mutagenicity, and carcinogenicity, are considered to be initiated by the enzymic reduction of their nitro groups. Enzymic reduction of 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2) was compared with those of p-nitrobenzoate and New Coccine by using a bacterial enzyme, rat liver microsomes, and cytosol. The nitroreductions of AF-2 and p-nitrobenzoate by bacterial enzyme depended on NADPH and NADH to the same extent, but only the NADPH-dependent nitroreduction of p-nitrobenzoate was stimulated by flavin mononucleotide (FMN). On the other hand, the reduction of New Coccine depended more on NADH than NADPH and stimulation by FMN was also found in the NADPH-dependent reduction. In both microsomal and bacterial enzymes, the nitroreduction of AF-2 was hardly inhibited by quinacrine, SKF 525A, CO, and air, while that of p-nitrobenzoate was strongly inhibited by them. In cytosol, the nitroreduction of AF-2 and p-nitrobenzoate was clearly inhibited by these compounds, the inhibitory effect of which was to the same extent in both substrates. These results suggest that the mechanism of nitroreduction of AF-2 in liver microsomal and bacterial enzymes is somewhat different from that of p-nitrobenzoate, while in liver cytosol, the nitro groups of AF-2 and p-nitrobenzoate are mainly reduced by xanthine oxidase through the same mechanism.
An X-ray diffraction method was developed for evaluating the preferred orientation of crystalline particles within a tablet. The selected faces of a tablet, the upper surface and faces cut parallel, oblique, and normal to the upper surface, were presented to the X-ray beam, and X-ray diffraction patterns for these faces were measured. From the difference in X-ray diffraction patterns for these faces of aspirin, phenacetin, ascorbic acid, DL-methionine, and talc tablets, the preferred orientation of crystals within a tablet was found to be induced during compression, and this result was also confirmed by the scanning electron microscopic observation. For example, in the case of an aspirin tablet, X-ray diffraction peak of (100) was observed for the upper surface and parallel face, while this peak was observed only a little for the normal face. This result showed that (100) faces of aspirin crystals aligned themselves parallel to the upper flat punch face during compression.
The metabolic fate of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9), a newly developed anti-inflammatory drug, was examined in rats after intravenous administration of 14C-DKA-9. It was found that DKA-9 was metabolised mainly through two major pathways, glucuronide formation and demethylation followed by sulfate formation. The matabolites in urine and bile were fractionated by the combination of solvent extraction and preparative thin-layer chromatography. Five metabolites were detected and the structure of these metabolites was investigated from spectral and elemental analysis data. The major metabolites were identified as potassium 4'-chloro-5-hydroxy-3-biphenylylacetic acid O-sulfate (72.4% of the dose in 24 hr) in urine, 1-(4'-chloro-5-methoxy-3-biphenylylacetoxy) glucuronic acid (28.0% of the dose in 6 hr) in bile, and DKA-9 (5.2% of the dose in 48 hr) in feces, and the minor metabolites were also identified as 4'-chloro-5-hydroxy-3-biphenylylacetic acid, 2-(4'-chloro-5-methoxy-3-biphenylyl)-2-hydroxyacetic acid and (4'-chloro-5-methoxy-3-biphenylylacetyl) glycine. The anti-inflammatory action of DKA-9 and its metabolites were also investigated by the inhibition of carrageenin-induced edema. There was no active metabolite and, therefore, the anti-inflammatory effect of DKA-9 in the rat seemed to be due to the action of DKA-9 itself.
Chemical constituents of the leaves and stem bark of Acer nikoense MAXIM. (Aceraceae) were examined. β-Amyrin, β-sitosterol contaminated with campesterol and stigmasterol, and β-sitosterol glucoside were obtained from both parts of the plant. β-Amyrin acetate, quercetin, quercitrin, and ellagic acid were isolated from the leaves, and scopoletin, (+)-rhododendrol (VIII), (+)-catechin, and two new glycosides named aceroside I (XI), C25H32O8, mp 170-171° (from acetone), [α] D-7.7°, and epi-rhododendrin (XII), C16H24O7, mp 81-84°, [α] D -15.5°, from the stem bark. The absolute configuration of VIII was proposed to be S from empirical rule on optical rotation-chirality relationship. Hydrolysis of aceroside I (XI) afforded acerogenin A (XIII) as its aglycone, whose structure has already been reported. The structure of epi-rhododendrin (XII) was elucidated to be (S)-4-(p-hydroxyphenyl) butan-2-ol 2-β-D-glucopyranoside from chemical and spectral evidences.
Piperazine and pyrazine derivatives were obtained by the dehydration of diamine and glycol on the alumina-packed bed reactor. After examination of various catalysts, alumina catalyst was found to be more active than the silica-alumina or zeolite catalyst. Addition of a promoter (K2O) increased the yield of piperazine by suppressing the decomposition of glycol. K2O decreased the catalyst acidity, which was measured by the butylamine absorption method. More than 7% K2O addition decreased the yield of piperazine and changed the pore size distribution. Namely, the excessive alkali breaks micropores of the catalyst. This catalyst (alumina+K2O) was found to be applicable for preparation of triethylenediamine and 2-methylhomopiperazine.
A method was developed for the simultaneous determination of 10 phenolic acids, including homovanillic acid, vanilmandelic acid, and 5-hydroxyindole-3-acetic acid, in urine by gas chromatography with hydrogen flame ionization detection. It consists of extraction of the free acids in urine into ether followed by isobutyloxycarbonylation of the phenolic hydroxyl groups with isobutyl chloroformate in aqueous alkaline medium and methylation of carboxylic acid groups with diazomethane. The derivatives thus obtained have good chromatographic properties and are stable under normal laboratory conditions. The calibration graphs of each phenolic acid for quantitation were constructed with the use of trans-m-cinnamic acid as an internal standard. Separation of the derivatives of phenolic acids from other urinary constituents was achieved by using two columns of 1.5% OV-17 and 0.65% Poly-A-101A. The peaks of phenolic acid derivatives derived from urine were identified by means of gas chromatography-mass spectrometry. The results of recovery experiments with urine samples fortified with a known amount of each phenolic acid were satisfactory, the average recovery ranging from 89.5 to 105.0%.
The dissolution rate of sulfisoxazole was markedly increased in sulfisoxazole-polyvinylpyrrolidone (PVP) coprecipitate. The X-ray diffraction revealed that sulfisoxazole in the coprecipitate did not have its crystal structure. When the ratio of PVP to sulfisoxazole was 1 : 10, the coprecipitation did not take place. The dissolution rate of sulfisoxazole in the coprecipitate was greater when the ratio of PVP to the drug was higher. The concentration of sulfisoxazole released from the coprecipitate into water reached supersaturation within a few minutes, then passed the peak, and decreased gradually indicating recrystallization. The solution remained supersaturated for a long period. The dissolution rate of sulfisoxazole was greater when PVP of smaller molecular weight was used for the preparation of the coprecipitate. After oral dose of these test preparations to human subjects, excretion rate and cumulative amount of total sulfisoxazole from the coprecipitate were greater than those of other test preparations, indicating that sulfisoxazole was absorbed faster after administration of the coprecipitate.
When a reaction is carried out with pyridine 1-oxide and platinized palladium-carbon catalyst, the 4-position of pyrimidine and 2-position of pyrazine and quinoxaline are highly reactive, and products thereby obtained are 4, 4'-tripyrimidine, 2, 2'-dipyrazine, tripyrazine, and 2, 2'-diquinoxaline. The 2-position of pyridazine and pyrimidine, and quinazoline are entirely unreactive, while phthalazine gives a small amount of phthalonitrile. Among reactive compounds, pyrimidine and quinoxaline undergo reaction with pyrimidine, formed by deoxygenation of the N→O group, and form 4-(2'-pyridyl) pyrimidine and 2-(2'-pyridyl) quinoxaline, respectively, but a corresponding compound is not formed from pyrazine. When a hydroxyl group is introduced into the position adjacent to the ring nitrogen, 3 (2H)-pyridazinone thus formed shows reactivity and forms 6-(2'-pyridyl)-3 (2H)-pyridazinone, while 2 (1H)-pyrazinone gives a minute amount of 3-(2'-pyridyl)-2 (1H)-pyrazinone. Neither forms a dimer. 4 (3H)-Pyrimidinone and 4 (3H)-quinazolinone both form pyridine derivatives at their 2-position and corresponding dimers.
4-(2-Methoxycarbonylanilino)-2-chloro-5-nitropyrimidine derivatives (IIIa-c) were prepared from methyl anthranilate derivatives (1a-c) and 2, 4-dichloro-5-nitropyrimidine. Aminopyrimidines (IVa-c) were prepared by the reduction of nitropyrimidines (IIIa-c) with stannous chloride in acetic acid. 2-Chloro-11H-pyrimido [4, 5-b] [1, 4] benzodiazepin-6 (5H)-one derivatives (Va-c) were synthesized by the intramolecular ring closure of aminopyrimidine derivatives. 2-Chloro-11-methylpyrimido [4, 5-b] [1, 4] benzodiazepin-6 (5H)-one (Vd) was obtained by the reductive cyclization of 4-(2-methoxycarbonyl-N-methylanilino)-2-chloro-5-nitropyrimidine (IIId) with stannous chloride in acetic acid.
A new and simple gas chromatographic method for the analysis of aldoses was devised. This method involves the reaction of aldoses with 2-aminoethanethiol in pyridine followed by trimethylsilylation and injection into a gas chromatograph. The peak of aldoses showed fairly good separation from the corresponding alditols. Therefore, this method was applied to the determination of the degree of polymerization of oligosaccharides, which produce alditol and aldose after reduction and hydrolysis. Since a sulfur atom is introduced into the reaction product, aldoses can be analysed by the flame photometric detector with high sensitivity, suggesting the possibility of selective analysis of aldoses in complex biological materials.
The activities of chlorpromazine ion (aCPZ. H+) and chloride ion (aCl-) were directly obtained by the EMF measurement of a concentration cell separated with cation-exchange membrane and of another concentration cell, which uses Ag-AgCl electrode reversible to Cl- ion, respectively, for aqueous solutions of chlorpromazine hydrochloride (CPZ·HCl). Transport number of CPZ·H+ ion in cation-exchange membrane was not assumed. to be a unity, but found to be t+=0.82, which was estimated by concentration dependence of EMF of the concentration cell. Ionic activity, activity coefficient, and also their mean ionic quantities were calculated. Below the critical micelle concentration (cmc) both the cationic and anionic activities increased with concentration, followed by the theoretical line expected from the Debye-Huckel theory. Above the cmc, the activity aCPZ.H+ gradually decreased, while aCl- showed an abrupt increase just above the cmc, and then, gradually increased with the concentration. Mean activity was not constant, but slightly increased with the concentration above the cmc. The observed decrease in the surface tension of aqueous CPZ·HCl solutions above the cmc was explained by gradual increase in a±. The mass action law was suggested to be the probable explanation for the aggregation mechanism.
4-(p-Tolylsulfonyl)-1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine (I) is hydrolyzed by dil. hydrochloric acid into 1, 5-dihydro-1-phenyl-4H-pyrazolo [3, 4-d] pyrimidin-4-one (III), and the p-tolylsulfonyl group undergoes nucleophilic substitution with hydroxide, methoxide, hydrazine, butylamine, aniline, and cyanide. Application of active methylene compound, nitrile, or ketone in the presence of sodium amide results in substitution with a carbanion. When ketone is used as the carbanion source, reaction product differs with reaction conditions. For example, the use of acetone results in the formation of 1-(P-4-yl)-2-propanone (X7) or 1, 1-bis (P-4-yl)-2-pronone (X7), where P-4-yl denotes 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidin-4-yl group. When 2-butanone (X8) is used, the product is either 3-(P-4-yl)-2-butanone (X8-2) or 1, 1-bis (P-4-yl)-2-butanone (X8'-1). In these cases, III is formed at the same time and its process of formation was discussed. In some cases, 5-(P-4-yl)-1, 5-dihydro-1-phenyl-4H-pyrazolo [3, 4-d] pyrimidin-4-one (XI) is formed as a by-product.
Reaction of pyridine 1-oxide (I) with sulfonic acid chloride (RSO2Cl) and potassium cyanide was carried out. Application of methanesulfonyl chloride or ethanesulfonyl chloride afforded 2-methyl- or 2-ethyl-sulfonylpyridine (IIm or IIe) and 4-methyl- or 4-ethyl-sulfonylpyridine (IVm or IVe). Application of benzenesulfonyl chloride or p-toluenesulfonyl chloride gave 3-phenyl- or p-tolyl-sulfonylpyridine (IIIb or IIIt) and 4-phenyl- or p-tolyl-sulfonylpyridine (IVb or IVt), with 2-pyridinecarbonitrile (I1') at the same time. Application of methanesulfonyl chloride and potassium cyanide to 2- (I1), 3- (I2), and 4-pyridinecarbonitrile 1-oxide (I3), and 4-chloropyridine 1-oxide (I4) resulted in the formation of 2-methylsulfonyl substituted compounds in all cases. In the case of I2, 4-methylsulfonyl derivative was also formed in a minute amount.
Effect of chlormezanone on the drug disposition of aspirin was studied in mice given orally aspirin [carboxyl-14C] with or without chlormezanone. The concomitant administration of chlormezanone decreased the stomach content of aspirin-14C, and significantly increased the peak blood level. The distribution of radioactivity in the tissues including the liver and kidneys also increased by the combined use of chlormezanone. In addition, significant difference in urinary excretion of radioactivity was found between aspirin alone and aspirin plus chlormezanone groups. These results indicated that chlormezanone facilitated the gastrointestinal absorption of aspirin and increased the distribution of the drug in the body. Influence of chlormezanone on the metabolism of aspirin was examined by comparing quantitatively the concentration of metabolites in the plasma, tissues, and urine between the two groups. In both groups, aspirin was metabolized in vivo to salicylic acid, salicylic acid glucuronide, o-hydroxyhippuric acid, and gentisic acid. These metabolites in the plasma, liver, and kidneys showed higher concentrations due to increase of total radioactivity in aspirin plus chlormezanone group than in aspirin alone group. However, it was considered that chlormezanone had no effect qualitatively on the in vivo metabolism of aspirin, since no difference in the composition of metabolites was found between the two groups.
Metabolism of chenodeoxycholic acid, a therapeutic agent for gallstone dissolution, was examined in rats, hamsters, and rabbits. In the rat liver, chenodeoxycholic acid was found to be converted into taurochenodeoxycholate, a part of which was converted into tauromuricholate. In the rat colon, these conjugated bile acids were hydrolyzed into the corresponding free bile acids and a considerable part of the free chenodeoxycholic acid and muricholic acid were further metabolized to lithocholic acid and hyodeoxycholic acid, respectively, by the action of microorganisms. Main metabolites excreted in the rat feces were identified as muricholic acid, hyodeoxycholic acid, and lithocholic acid. Direct microbial conversion of muricholic acid into hyodeoxycholic acid was established by in vitro experiment in which muricholic acid was incubated with rat feces suspension. Lithocholic acid and its metabolite, 3α, 6β-dihydroxy-5β-cholanoic acid, were not found in the small intestine. It seems likely that lithocholic acid is poorly absorbed after its formation in the colon. In the hamster liver, chenodeoxycholic acid was converted into tauro- and glycochenodeoxycholates. In the hamster intestinal tract, these conjugated bile acids were deconjugated to form chenodeoxycholic acid, which was further metabolized to lithocholic acid. It was found by the double labeled tracer technique using chenodeoxycholic acid [7β-3H, 24-14C] that a considerable amount of lithocholic acid was reabsorbed from the hamster colon. The absorbed lithocholic acid was completely rehydroxylated to chenodeoxycholic acid. Thus, lithocholic acid was not circulated in the enterohepatic circulation. In the rabbit colon, chenodeoxycholic acid was metabolized to lithocholic acid, a part of which was reabsorbed and reached the liver. In contrast to the hamster, the absorbed lithocholic acid was not hydroxylated in the rabbit liver, and entered into the enterohepatic circulation.
The presence of complexes of monomer sodium lauryl sulfate (SLS) and alkylparaben (methyl-, ethyl-, and butyl-parabens) can be observed by gel filtration on Bio-Gel P-4. Stability constants for the complex formation from monomer SLS and respective alkyl parabens in aqueous SLS solutions below critical micelle concentration (s) (cmc) were estimated from the elution curves of SLS and alkylparabens obtained by the tail analysis on Bio-Gel P-4. It was found that stability constants increased as the carbon number of alkyl group for alkylparabens increased. It was observed that stability constants for the complex formation in SLS micellar solutions solubilizing alkylparabens were nearly equal to those in the SLS solution below cmc. However, the partition ratio of respective alkylparabens between the aqueous and SLS micellar phases, found by considering a complex formation in the solubilized system, was approximately equal to the apparent partition ratio obtained without considering the complex formation, because concentration of the complexes was negligibly low compared with those of free alkylparabens in the aqueous phase.
Subnanogram amount of two odorous materials, 2-methylisoborneol and geosmin, was determined in source water of water supply by gas chromatography-mass spectrometry (GC-MS). The analytical method involved adsorption on Amberlite XAD-2 polystyrene macroreticular resin, desorption from XAD-2 with ether, and selected ion monitoring at m/e 95 and 112 for 2-methylisoborneol and geosmin, respectively, by means of GC-MS. Replicated analysis of spiked water with 0.01 to 1.0 ppb level of both compounds revealed that the recovery was more than 90% and the detection limit was as low as 0.01 ppb.
Hydrolysis of trichloroethyl phosphate, a model compound of phosphate esters, was examined in vitro using mucosal fluid of intestine and mucosal homogenate of the gastro-intestinal tract of rats. Hydrolytic activity in mucosal fluid varied depending on pH and prewashing. Hydrolytic activity in the mucosa decreased in the order of duodenum, jejunum, and ileum. Some hydrolysis took place by mucosal homogenate of stomach at pH 7.4 whereas little hydrolysis was observed at pH 1.2. Therefore, the ester is expected to be hydrolyzed in the mucosal fluid in intestine before absorption or be hydrolyzed in the mucosa after it is taken up intact.
Three urinary metabolites in rabbits administered with 5-(4-oxo-Δ2-cyclohexenyl)-5-allylbarbituric acid (oxo-Δ2-CAB) were isolated by column chromatography on Amberlite XAD-2 resin and on silica gel. Two of these were identified by direct comparison with authentic samples as 5-(4-hydroxy-Δ2-cyclohexenyl)-5-allylbarbituric acid (OH-Δ2-CAB) and unchanged oxo-Δ2-CAB. The remaining metabolite was presumed as 5-(4-hydroxycyclohexyl)-5-allylbarbituric acid (OH-CHAB) by spectral and elementary analysis data.
Application of alkane- or arene-sulfonyl chloride and potassium cyanide to phenanthridine 5-oxide (I) in acetone-water results in the introduction of a sulfonyl group into 6-position, with liberation of oxygen from the N-oxide group, forming 6-alkylsulfonyl- or 6-arylsulfonyl-phenanthridine (IIx), with 6 (5H)-phenanthridinone (IV). The same reaction of acridine 10-oxide (V) unexpectedly resulted in the failure to form a product with introduction of a sulfonyl group and 9 (10H)-acridinone (VII) is obtained as the main product with both reagents, with the formation of 2-chloroacridine (VI) and acridine (V') at the same time.