Of the amino compounds used as starting materials, 4-amino-4'-fluorodiphenyl ether (II) and 4-amino-4'-dimethoxydiphenyl ether (IV), other than 4-amino-, 4-amino-4'-chloro-, and 4-amino-4'-bromo-diphenyl ethers, and 4-amino- and 4-amino-4'-chloro-diphenyl sulfides, were obtained by the respective reduction of 4-nitro-4'-fluorodiphenyl ether (I) and 4-nitro-4'-methoxydiphenyl ether (II) with stannous chloride and hydrochaotic acid after formation of I and II, respectively by the reaction of the potassium salt of p-fluorophenol and p-methoxyphenol with p-chloronitrobenzene by the Ullmann method. For the syntheses of A and B type compounds (by A- and B-type reactions), the starting amino compound was reacted with the corresponding halogenoacetyl chloride in xylene or acetic acid to obtain the halogenated diphenyl ethers (V to XXXII). The yield was higher when acetic acid was used as a solvent. Antimicrobial activity of the compounds V to XXXII was examined in vitro, and XV and XXVIII were found to have a strong antifungal activity.
Four compounds were isolated from the wood of Xanthoxylum inerme KOIDZ. (Fagara boninensis KOIDZ.), (Japanese name "Akow-zansho"). One is an alkaloid, 4-methoxy-1-methyl-2-quinolone (III), mp 99-103°, which was isolated for the first time from a natural source. Two others were known coumarins, 6, 7, 8-trimethoxycoumarin (I), mp 107-108°, and aesculetin dimethyl ether (II), mp 147-147.5°. The fourth was a phenolic lignan, dl-syringaresinol (VIII), mp 179-185.5°. On the other hand, seven components were isolated from the bark of the same plant. Four of them were benzo[c]phenanthridine alkaloids, nitidine (XI)(chloride, mp 275-276° : dihydro base (XII), mp 223.5-224°), avicine (XIV)(dihydro base (XIII), mp 223-224°). chelerythrine ψ-cyanide (X), mp 240-245°(decomp.), and oxynitidine (XV), mp 283-285°, assumed to be an artefact alkaloid. One was a water-soluble quaternary tetrahydrobenzylisoquinoline alkaloid, L-(+)-armepavine metho salt (XVIII) (iodide, mp 204-206°), which was isolated from natural source for the first time. The others were an unknown base, X. bon. unknown base I, mp 252-254.5°(decomp.), and aesculetin dimethyl ether (II).
A lysine-colistin, an analog of the natural antibiotic colistin, was synthesized by the cyclization of linear decapeptide obtained from acyl-tetrapeptide, formyl-tetrapeptide, and dipeptide by a stepwise reaction. Lysine-colistin is a new peptide containing six moles of lysine instead of six moles of α, γ-diaminobutyric acid in colistin. Lysine-colistin and linear acyl-decapeptide had the same antibiotic activity as colistin against many gram-negative bacterias.
Pharmacological studies were carried out on central effect of Chinese cinnamon which is one of the most important crude drugs in Chinese medicine. Chinese medicirie uses this crude drug as a sedative, antipyretic, and analgesic. Representative prescriptions which contain cinnamon are Keishikanzo-To ( ?? ?? ?? ?? ?? ), Keishikakei-To ( ?? ?? ?? ?? ?? ), and Ryokeijutsukan-To ( ?? ?? ?? ?? ?? ). Cinnamaldehyde and essential oil-free aqueous extract of Chinese cinnamon were examined using mice, and the following results were obtained. Cinnamaldehyde showed sedative activities (decrease of spontaneous motor activity, antagonistic effect to methamphetamine-induced hyperactivity, motor incoordination in rotar-rod test, and prolongation of hexobarbital-induced anesthesia) and hypothermic activity, as well as antipyretic one in typhoid-paratyphoid vaccine-febrile mice. After its administration, electrocorticogram in rabbits with chronically implanted electrodes indicated its shift to a low voltage and high frequency in the spontaneous discharge and a little prolongation of arousal response by acoustic stimulation. On the other hand, the aqueous extract did not show any remarkable activities, but this fact does not necessarily imply that the extract does not contain any pbarmacologically active substances. No synergistic effect of the two materials was obtained in two tests of ana1gesic effect in writhing symptom and inhibitory effect on methamphetamine-induced hyperactivity. Thus, cinnamaldehyde was found to play some part in the therapeutic effect of cinnamon.
For the purpose of testing their biological activity, 4-dimethylaminoalkyl-4-(m-methoxyphenyl) cycloalkanol derivatives (VIII to XI) were synthesized from 1-(m-methoxyphenyl)-4-acetoxycyclohexane dimethylamide derivatives (XVIII to XX and XXIX), which were obtained from 1-(m-methoxyphenyl)-4-acetoxycyclohexanecarboxylic acid derivatives (XII to XIV) and 1-(m-methoxyphenyl)-4-hydroxycycloheptanecarboxylic acid (XXV), in tetrahydrofuran with lithium aluminium hydride. 1-Dimethylaminomethyl-1-(m-methoxyphenyl)-4-acetoxy- or benzoyloxy-cycloalkanes (XXIII, XXIV, and XXXII) were prepared by acetylation or benzoylation of VIII and XI. Some of the compounds were found to have a considerably lower anticholinesterase activity than galanthamine (I), as shown in Table I.
Photochemical reaction of 3-tosyl-1, 2-dihydro-3H-pyrazino[3, 2, 1-kl]phenoxazine (Ia) was examined under various conditions and the formation mechanism of the products, 6-tosyl-1, 2-dihydro-3H-pyrazino[3, 2, 1-kl]phenoxazine (IIa) and 1, 2-dihydro-3H-pyrazino-[3, 2, 1-kl]phenoxazine (IIIa), was clarified.
Constituents of Hernandia ovigera L. (Hernandiaceae) collected in the Bonin Islands were examined. A neutral component, desoxypicropodophillin (9) and known alkaloids, hernovine (1), thalicarpine (6), hernangerine (3), and N-methylhernangerine (4) were detected in the rootbark. From the trunk-bark, a new alkaloid, hernandonine, was isolated and characterized in addition to the known alkaloids, hernovine (1), thalicarpine (6), hernangerine (3), N-methylhernangerine (4) and xanthoplanine (8). Hernandonine, orange-yellow needles, mp>280°, C18H9O5N. The structure (11) was suggested for this alkaloid from its spectral data, and confirmed by its synthesis from N-methylhernovine (2) according to the method previously reported by Tomita, et al.
1. Less polar glycosides such as oleandrin were observed when the fresh leaves of Nerium odorum were dried in an oven at the temperature above 80°, or by incubation of the homogenate of the fresh leaves. More polar glycosides were found in the fresh and air-dried leaves. 2. Oleandrin (0.13%), adynerin (0.035%), odorosid A (0.03%), 16-deacetylanhydrooleandrin (trace), and oleandrigenin (trace) were isolated, together with unknown cardenolides, Subst. III (0.03%) and V (trace), from the oven-dried leaves.
3-Nitroquinoline (I) was reacted with aqueous sodium hypobromite in methanolic KOH at definite temperature (37-40° for condition A, 0-5° for condition B, and -40--35° for condition C). The products obtained under these conditions were 3-bromo-4-methoxyquinoline (IIa), 3, 6, 8-tribromo-4-methoxyquinoline (IIb), 3-bromo-2, 4-dimethoxyquinoline (IIIa), 3, 6-dibromo-2, 4-dimethoxyquinoline (IIIb), 3, 6, 8-tribromo-2, 4-dimethoxyquinoline (IIIc), 2, 4-dimethoxy-3-nitroquinoline (IVa), 6-bromo-2, 4-dimethoxy-3-nitroquinoline (IVb), 2, 4, 6-tribromoaniline (Va), and 2, 4, 6-tribromo-3-methoxyaniline (Vb). Similarly, the reaction of 2-alkoxy-3-nitroquinoline (VII, 2-CH3O, VIII, 2-C2H5O) gave 2-alkoxy-3-bromo-4-methoxyquinoline (IIIa ; IX) and 2-alkoxy-4-methoxy-3-nitroquinoline (IVa ; X). The same reaction of 2-alkoxy-4-methoxy-3-nitroquinoline (IVa, 2-CH3O, X, 2-C2H5O) gave 2-alkoxy-3-bromo-3, 4-dihydro-4, 4-dimethoxy-3-nitroquinoline (XI ; XII). This reaction was discussed as an addition-elimination mechanism involving CH3O- addition at the 4-position of I, followed by bromination at the 3-position and elimination of HNO2 o HBr.
An addition-elimination reaction, which was reported in the reaction of 3-nitroquinoline with aqueous sodium hypobromite in methanolic KOH, also occurred in the case of other nitroquinolines, i.e., 6-, 5-, 8-, and 4-nitroquinolines. 6-Nitroquinoline (I) gave 6-bromo-5-methoxyquinoline (IIa), 6, 8-dibromo-5-methoxyquinoline (IIb), 6-bromo-5, 7-dimethoxyquinoline (IIIa), 5, 7-dimethoxy-6-nitroquinoline (IIIb), 8-bromo-5, 7-dimethoxy-6-nitroquinoline (IIIc), and 8-bromo-6-oxo-5, 5, 7-trimethoxy-5, 6-dihydroquinoline (IV) on being reacted in the same way as in the reaction of 3-nitroquinoline. Other nitroquinolines and their products from the same reaction were ; 5-nitroquinoline (XI); 5-bromo-6-methoxyquinoline (XIIa), 6-methoxy-5-nitroquinoline (XIIb), 8-methoxy-5-nitroquinoline (XIIIa), 5, 7-dibromo-6, 8-dimethoxyquinoline (XIVa), and 6, 8-dimethoxy-5-nitroquinoline (XIVb). 8-Nitroquinoline (XVIII); 8-bromo-7-methoxyquinoline (XIX), 5-methoxy-8-nitroqninoline (XX), and 6-bromo-5, 7-dimethoxy-8-nitroquinoline (XXI). 4-Nitroquinoline (XXII); 4-bromo-3-methoxyquinoline (XXIIIa), 3-methoxy-4-nitroquinoline (XXIIIb), 2, 3-dimethoxy-4-nitroquinoline (XXIV) and 4-methoxyquinoline (XXV). The reaction of 2-nitroquinoline (XXX) gave only 2-methoxyquinoline (XXXI).
Circular dichroism (CD) and optical rotatory dispersion of 1-deoxy-2-O-methyl-1-nitro-D-mannitol and four acetyl derivatives of 1-deoxy-1-nitro alcohols were measured. Their CD curves showed maxima (or shoulders) at about 310 mμ and 280 mμ. It was found that the rules relating the configuration at C-2 of 1-deoxy-1-nitro-alcohols to the signs of their CD maxima also applied to these compounds, i.e., compounds that have an acetoxyl group on the left side of C-2 in the conventional Fischer projection formula showed negative maxima, whereas those having the acetoxyl group on the right side of C-2 showed positive maxima. However, 2, 3, 4, 5, 6, 7-hexa-O-acetyl-1-deoxy-1-nitro-D-glycero-L-glucoheptitol, which has a C-2 acetoxyl group on the left side, showed a negative CD maximum at 314 mμ and a positive CD maximum at 284 mμ.
Citromycin (I) is converted into inactive citromycinic acid (II) by treatment with 3N hydrochloric acid and toxicity of II was less than one-half of that of I. Deformiminocitromycin (III) obtained by treatment with methanolic ammonia and deformiminocitromycin N-acetate (V) obtained by treatment with N-acetoxysuccinimide no longer had the original antibacterial activity. These facts indicate that antibacterial activity of citromycin requires the partial structure of (i) formation of a lactam ring in the streptolidine moiety and (ii) protection of the terminal amino group in glycine by a basic group like formimino, and that deformimination and N-acetylation results in the loss of its antibacterial activity.
When sulpyrine and aminopyrine are administered to the horse, unchanged aminopyrine and its metabolites, 4-methylaminoantipyrine and 4-aminoantipyrine, are detected in the urine by means of thin-layer chromatography (TLC) and gas liquid chromatography. Further identification of aminopyrine and these metabolites was carried out by the gas chromatography-mass spectrometry (GC-MS) method. The procedures for separation and identification are as follows : The excretions were adjusted to pH 9 with ammonium hydroxide and extracted with chloroform. The extract was separated by TLC. The spots were located by ultraviolet ray and scraped off from the plate. After elution, the base was determined by GC-MS. GC-MS provides a simple, sensitive, and convenient system for the separation and identification of complex mixtures, such as metabolites of various drugs in biological materials. This method fully meets the need for the rapid determination of doping agents.
When antipyrine is administered to the horse, unchanged antipyrine, 4-hydroxyantipyrine, and 3-hydroxymethyl-2-methyl-1-phenyl-3-pyrazolin-5-one are excreted in the urine. In the present study, a method was established to detect and identify these substances by thin-layer chromatography, gas chromatography, and gas chromatography-mass spectrometry.
Fifty derivatives of long-chain alkylamines containing a variety of hetero atom in their chain were synthesized and their toxic effect on the larvae of Ancylostoma caninum and Ascaris lumbricoides var. suum was examined in vitro. Several of these derivatives were found to have a high toxic effect on the test parasites but N-(2-dodecyloxyethyl)-pyrrolidine had the strongest toxicity for both parasites.
Treatment of N-(2, 2-diethoxyethyl)-N-methyl-1, 3-bis(3, 4-dimethoxyphenyl)propylamine (X) with 6N hydrochloric acid at 20-25° resulted in the formation of an eight-membered ring to give homoisopavine (XI) in a good yield.
Isocorydine (V) was newly isolated as an alkaloid of the fruit of Nandina domestica THUNB. Demethylation of O-methyldomesticine (I), the major alkaloid of this plant, was carried out and it was found that dl-domesticine is obtained when 36% hydrobromic acid is used and d-domesticine (II) when pyridine hydrochloride and sodium thioethoxide are used for this reaction.
The neutral volatile oil of the flower stalk of Petasites japonicus was separated into 17 parts by gas chromatography and the substances corresponding to peaks 7, 11, 12, and 16 were respectively proved to be thymolmethylether, β-elemene, β-caryophyllene, and fukinone.