Polarographic determination was carried out on 2, 4, 5-trichlorophenyl 3-iodo-2-propynyl ether (TCPI) in pharmaceutical preparation, and simultaneous determination of TCPI and 2, 4, 5-trichlorophenyl 2-propynyl ether (TCPH) in their mixture. Under the present experimental conditions, TCPI is polarographically active but TCPH is not. For the determination of TCPI in pharmaceutical preparation, the sample is dissolved in or diluted with ethanol, the second wave in the polarogram is measured, and calculation made by the standard addition method. Simultaneous determination of TCPI and TCPH is made by measuring the second wave in the polarogram to obtain the amount (A) of TCPI, deiodination-reduction is carried out with sodium borohydride, copper salt is formed by the use of the Ilosvay reagent, which is decomposed with ethanolhydrochloric acid mixture, and polarogram of the decomposed solution is measured. The sum (B) of TCPI and TCPH is calculated from this measurement, and the amount (C) of TCPH is calculated from (B)-(A)=(C).
2-Phenylphthalimidine derivatives having substituents in the phenyl ring of 2-position and in 5- and 6-positions were synthesized from ring-substituted anilines and 4-hydroxy-phthalaldehyde, 5-bromo-4-hydroxyphthalaldehyde, 4-cyanophthalaldehyde, 3, 4-diformylbenzoic acid, or 1, 2, 4, 5-tetraformylbenzene. Maxima of fluorescence wavelength of these 5, 6-disubstituted-2-phenyl group and electron-accepting groups into the 5- and 6-positions of the phthalimidine ring, while a blue shift appear when an electron-accepting group is introduced into the phenyl ring and electron-donating groups into the phthalimidine ring. Relative fluorescence intensity of these derivatives was compared.
Fluorescence reaction in acid medium was found between 4-hydroxyphthalaldehyde, 5-bromo-4-hydroxyphthalaldehyde, 4-cyanophthalaldehyde, 3, 4-diformylbenzoic acid, or 1, 2, 4, 5-tetraformylbenzene and p-anisidine, aniline, or sulfanilamide. The fluorescence reaction of these phthalaldehyde derivatives is due to the formation of 5, 6-substituted 2-phenylphthalimidine derivatives and it seemed possible to utilize this reaction for fluorescence analysis of aromatic primary amines. A highly sensitive fluorometric determination of sulfanilamides using various phthalaldehyde derivatives was established.
When aqueous acid solution of Homochlorcyclizine dihydrochloride (HCC·2HCl) is heated, it turns turbid and further gives rise to an oily deposit. This deposit proved to consist of p-chlorobenzhydrol, p-chlorobenzhydryl chloride, and p-chlorobenzophenone. In the water phase, besides intact HCC·2HCl, N-methylhomopiperazine was found as a water-soluble moiety of decomposition products. The degradation shows first-order type process. In the aqueous solution of HCC·2HCl there is a following equilibrium : [chemical formula] where HCC+ and HCC2+ represent uni- and bivalent HCC ions, respectively. The apparent rate constant k of the degradation of HCC·2HCl varies with the mole fraction F of HCC2+ according to k=k'F, where k' is therate constant of the decomposition of HCC2+. This indicates that of the two ionic species of HCC, only HCC2+ is susceptible to the decomposition, which starts with the cleavage of the bond between p-chlorobenzhydryl group and nitrogen atom. Finally, the activation energy and the frequency factor of the decomposition of HCC2+ were calculated and the equation, expressing k as a function of pH and absolute temperature T, was presented : [numerical formula] where pK is negative common logarithm of the equilibrium constant K for the equilibrium (1) at T°K and R is gas constant.
Polarographic studies were made on 4, 4'-diacetoxydiphenyl-2-pyridylmethane (DADP), used as a constipation remedy. There is one AC polarographic wave but DC wave is not marked. The wave height in AC polarogram shows linear increase in proportional to the concentration, and decreases with increasing pH, dioxan, and lithium chloride. The electrode reaction of DADP was assumed to be a catalytic hydrogen wave by the pyridinium ion formed below pH 10. Determination of DADP in a tablet can be made by extracting the tablets with dioxan or ether and measuring the AC polarographic wave height by the standard addition method. This method is not interfered by 100-fold amount of lactose, starch, or magnesium oxide, 50-fold amount of dioctyl sodium sulfosuccinate, or two-fold amount of 4, 4'-dihydroxydiphenyl-2-pyridylmethane.
Potential effect of chemical radio-protectors, S-2-aminoethylisothiuronium bromide hydrobromide (AET) and 2-mercaptoethylamine (MEA), was tested by survival of ddY miceirrad iated with a lethal dose of X-rays, and characteristics of these compounds were comparatively examined. Both AET and MEA show comparatively acute toxicity and intraperitoneal injection of their lethal dose to mice results in their death within 24 hr. Comparison of the toxicity of AET and MEA, with consideration on their molecular weight, shows that the toxicity of AET is about twice stronger. Optimal period of the administration of AET and MEA for effective appearance of their protective power is 5-30 minutes before irradiation, and both were ineffective if given after irradiation. Toxicity and protective action of AET do not change if it is converted to mercaptoethylguanidine (MEG) by adjusting its moleous solution to pH 7.0 with sodium hydroxide. Protective effect of AET per aquecule is 2-4 times stronger than that of MEA. It was found that the protection of AET and MEA is not only effective against lethal action of X-ray irradiation but also markedly effective in protecting against weight loss.
This experiment was undertaken to determine the radioprotective activity of vitamin E and its esterified derivatives, using survival time and body weight changes in X-irradiated mice as the pharmacological indices. Male mice of ddY strain, 5 to 6 weeks old, were used in this experiment. Each group consisting of 10 mice was exposed to 700 R whole body X-irradiation, which caused 100% mortality of the mice without medication within 2 weeks after X-irradiation under the condition adopted for this experiment. The test preparations such as vitamin E, and its acetate, ferulate, caffeate, and succinate were dissolved in sesame oil or cottonseed oil, or suspended in 5% Tween 80 aqueous solution, and administered intraperitoneally 24 or 3 hr. before the irradiation or 5 min after irradiation ; 1 mmole/kg of vitamin E, acetate or ferulate, 0.5 mmole/kg of the caffeate, or 0.25 mmole/kg of the succinate. The potency of radioprotective effect of each preparation was evaluated, based on the elongation of survival time up to 30 days and increase in body weight two weeks after irradiation, comparing with the control. Tween 80, used as the detergent to emulsify the preparation, did not show any influence on survival time and body weight. Sesame oil was slightly radioprotective on survival time and body weight. Cottonseed oil caused decrease in body weight under a certain circumstance. Under the condition of this experiment, vitamin E was little effective, while the acetate was slightly effective, and the other esters were significantly effective, and it was found that radioprotective effect was increased by esterification of vitamin E. It was also found that estimates of the effect based on survival time and on body weight were agreement. Radioprotective effect of the preparations seemed to depend the solvent used and the time of administration.
Previously, it was reported that ether extract of the root of Angelica pubcscens MAXIM. (Umbelliferae) upon saponification and vacuum distillation afforded a new coumarin, angelical, which was shown to be 6-formyl-7-methoxycoumarin (VI). The ether extract of the plant material was reinvestigated by column chromatography over silica gel and afforded a new coumarin, angelol (I), C20H24O4, mp 104-105°, [α]23D-112.9°, in addition to the known coumarins, bergapten, osthol, and glabra-lactone. The structure of the coumarin (I) was elucidated as 6-(1-angeloyloxy-2, 3-dihydroxy-3-methylbutyl)-7-methoxycoumarin by the procedure shown in Chart 1 and 2. In this work, angelical could not be isolated and was found to be an artifact produced by thermal cracking of the coumarin (I) during the vacuum distillation.
Absolute configuration of the asymmetric center adjacent to the benzyl position of angelol (I) was shown to be R from the fact that ORD curve of the ketone (XII) derived from isopropylideneangelol (III) showed a negative cotton effect while that of the model compound (XXIX) having R configuration was positive, indicating that XII must have S configuration. According to the reports of Freudenberg and co-workers, in which it was stated that configuration shown in XXX either alone or in combination with other asymmetric center is levorotatory or less dextrorotatory than its diastereomer the configuration at the benzyl position of I may be R from the fact that compound XXXI formed by the treatment of XI, ethanolysis product of I, with metaperiodic acid was levorotatory. Further support can be obtained from the comparison of the ORD curve of the compound XXXIV derived from III showing negative cotton effect at 288 mμ which must be attributed to the active aromatic absorption bands with the results of the work carried out by Swan and coworkers shown in the Table I.
Reaction of 2-(methylsulfonyl) quinoxaline (I) and ketone (II) was carried out in benzene, in the presence of sodium amide. The ketones used were acetophenone (IIa), propiophenone (IIb), diethyl ketone (IIc), acetone (IId), methyl ethyl ketone (IIe), methyl propyl ketone (IIf), methyl isopropyl ketone (IIg), cyclopentanone (IIh), and cyclohexanone (IIi) (Chart 1). Only IIc did not undergo this reaction and others respectively afforded 2-(2-quinoxalinyl) acetophenone (IIIa), 2-(2-quinoxalinyl) propiophenone (IIIb), 1-(2-quinoxalinyl)-2-propanone (IIId), 1-(2-quinoxalinyl)-2-butanone (IIIe), 1-(2-quinoxalinyl)-2-pentanone (IIIf), 1-(2-quinoxalinyl)-3-methyl-2-butanone (IIIg), 2-(2-quinoxalinyl) cyclopentanone (IIIh), and 2-(2-quinoxalinyl) cyclohexanone (IIIi) (Chart 2 and Table I). It was assumed that, among these products, only IIIb would be difficult to effect enolization (Chart 4).
The conidia of Cochliobolus miyabeanus was incubated in distilled water and variation in the spore substances with germination was followed. In the first stage of germination and germ-tube forming stage, soluble carbohydrate was consumed, with increase in amino acids, RNA, and fatty acids. In the germ-tube elongation stage, insoluble carbohydrates decreased, and the sterol fraction containing ergosterol and glucose began to increase. Over 70% of soluble carbohydrate was trehalose, which underwent active metabolism since the start of incubation, and decreased to one-third the original amount within 15 minutes. From these facts, it was considered that trehalose is the most important metabolic substrate in the first stage of germination.
Pharmacological properties, mainly sympathomimetic action, were examined on 2-(2-diethylaminoethyl)-1'-phenylisothiuronium bromide hydrobromide (DEPT), one of the 2-aminoethylisothiuronium (AET) derivatives. DEPT showed a pressor action on urethane anesthetized rat, guinea pig, rabbit, cat, and dog. DEPT caused a prolonged contraction of nictitating membrane of cat, and induced contraction of isolated vas deferens of guinea pig and seminal vesicle of rat. While DEPT showed negative inotropic and chronotropic actions on isolated heart of guinea pig, this compound showed positive inotropic and negative chronotropic actions on vagotomized open chest dog. DEPT caused a prolonged vasoconstriction on isolated perfused rabbit ear. Thus the primary mechanism of pressor action of DEPT was considered to be the vasoconstriction of peripheral vessels. Both pressor and vasoconstricting actions of DEPT were blocked by dibenzyline and potentiated by pretreatment with reserpine or guanethidine. These results suggested that the sympathomimetic action of DEPT might be classified as direct action on adrenergic α-receptors. In spinal cat, supersensitization of pressor response and of the contraction of nictitating membrane to tyramine after DEPT was observed, but those to noradrenaline was statistically nonsignificant.
Two kinds of new triterpenoid saponins were isolated from Caulophyllum robustum MAXIM. (=C. thalictroides (L.) MICHX. subsp. robustum (MAXIM.) KITAM.). (A) C35H56O3·H2O, mp 228° (decomp.), [α]22D+53.21° (c=0.6, Me2SO), was assumed to be 3-O-(α-L-arabopyranosyl)-hederagenin, and (B) C41H66O13·H2O, mp 252-255° (decomp.), [α]22D+43.8° (c=0.96, Me2SO), was thought to be 3-O-(2-β-D-glucopyranosyl-α-L-arabopyranosyl)-hederagenin.
Three kinds of saponin, named chikusetsusaponin-III, -IV, and -V, were isolated in crystalline form from a Chinese crude drug, Chikusetsu-Ninjin (rhizome of Panax japonicum C.A. MEYER ; Araliaceae), chikusetsusaponin-III, C47H80O17·2H2O, formed colorless prisms, mp 196-197°, and is protopanaxadiol or 20-epiprotopanaxadiol bonded with glucose and xylose. Chikusetsusaponin-IV, C47H74O15·4H2O, formed colorless prisms, mp 235° (decomp.), and is an oleanolic acid bonded with glucose, arabinose, and glucuronic acid, forming permethylated compound, C57H94O16, of mp 141-142°. Chikusetsusaponin-V, mp 230° (decomp.), is an oleanolic acid bonded with glucose and glucuronic acid. Further elucidation of the total structure of these saponins is in progress.
Several heterocyclic amidines, 1-phenyl-(I), 1-(3-chlorophenyl)-(II), 1-(4-chlorophenyl)-(III), 1-(3, 4-dichlorophenyl)-(IV), 1-(3-methylphenyl)-(V), and 1-(4-methylphenyl)-4-guanylpiperazine sulfate (VI), 1-guanylpiperidine sulfate (VII), 1, 4-diguanylpiperazine dihydrochloride (VIII), 4-guanylmorpholine sulfate (IX), and 1-guanylpyrrolidine sulfate (X) were synthesized and examined pharmacologically. 1-Phenyl-4-guanylpiperazine derivatives showed muscle relaxing action and their activities were in the following order : d-tubocurarine>IV, succinylcholine>II, III, V, VI, >I. I, II, III, V, VI, and VII caused a temporary hypotention, while IV, IX, and X showed the pressor action in rats and cats. Pressor action of noradrenaline was not affected and that of tyramine was inhibited by I, II, III, V, and VI. Local anesthetic action, antihistamine, antiacetylcholine, and antiserotonin activities of test compounds were not so strong. Acute toxicities in mice were also tested.
Numerous aryl thiocarbamate compounds were synthesized and the relation between their chemical structure and selective antifungal activity was examined. A group of compounds having selective activity against the Trichophyton species, the representative of pathogenic Eumycetes, were discovered. These compounds possessed a fundamental structure of Ar1-N (CH3)-C (=S)-O-Ar2, in which Ar1 is a phenyl or substituted phenyl or 1-naphthyl group, and Ar2 is a substituted phenyl or 2-naphthyl group. Carbamates and dithiocarbamates had less effect than the corresponding thiocarbamates.
Some observations were made on the anti-trichophyton action of 2-naphthyl N-methyl-N-arylthiocarbamate (A). In vitro antifungal activity decreased slightly when the thiocarbamate was changed to carbamate, and a marked lowering in the in vitro effect was observed. The antifungal activity disappeared entirely when the thiocarbamate was changed to dithiocarbamate and thiolcarbamate. When the aryl group in A is a naphthyl, antifungal activity is present only when 1-naphthyl is present and other three combinations are entirely ineffective. When the aryl is a substituted phenyl, compounds having methyl, methoxyl, or halogens, those with the Hammet constant in the range of +0.23 to -0.27, have marked antitrichophyton activity in vivo, but those with nitro, formyl, carboxyl, sulfonamido hydroxyl, or dimethylamino group show marked decrease in the effect. The series of compounds having the A type will henceforth be designated as naphthiomates.
Examinations were made on the effect of oral administration of 2-naphthyl N-methyl-N-arylthiocarbamates (naphthiomates), an effective antimicotic agent for external use, against experimental trichophytosis. Finely powdered 2-naphthyl N-methyl-N-(m-tolyl)-thiocarbamate (naphthiomate-T) and 2-naphthyl N-methyl-N-(1-naphthyl) thiocarbamate (naphthiomate-N) showed an effect comparable to griseofulvin in about four-fold dose of the latter. In vivo metabolism of naphthiomate-T was examined in guinea pigs and rabbits, and it was found that the majority is excreted in the feces without decomposition, and little is absorbed through the intestinal tract. N-Methyl-m-toluidine and β-naphthol were detected from urine, feces, and blood as the metabolites.
2-Aminoalkanethiol reacted with formaldehyde in the absence of an acid to give 3, 3'-methylene-dithiazolidine. On treatment with hydrochloric acid, the product converted into thiazolidine hydrochloride liberating formaldehyde. The formation of 3, 3'-alkylene-dithiazolidine was not found in the reaction of 2-aminoalkanethiol with other carbonyl compounds. Reaction of 3, 3'-methylene-dithiazolidine with phenol, benzylmercaptan, and acetylchloride was examined.
The condensation product of DL-trans-2-aminocyclohexanethiol (Irac.) and D-glucose was fractionated into a pair of diastereomers (IIa and IIb) by recrystalization from ethanol. On treatment with cyclohexanone, IIa and IIb were derived into (+)-trans-perhydrocyclohexa [d]-thiazole-2-spiro-1'-cyclohexane (IIId) and the (-) antipode (IIIe) respectively, expelling D-glucose. IIId and IIIe were easily hydrolyzed in hydrochloric acid solution to give (-)-trans-2-aminocyclohexanethiol (Ie) and the (+) antipode (Id) respectively, with inversion of the sign. This procedure provides a new method for optical resolution of resolvable 2-aminoalkanethiol.