Various kinds of carbinols were heated in an aqueous solution of potassium persulfate and corresponding carbonyl compounds were obtained (Table I). Of these, the starting carbinols for o- and p-tolualdehydes, imidazole-4-aldehyde, and α-naphthaldehyde are easy to prepare and yield of this reaction is so good that this method is of practical value for the syntheses of these aldehydes. Further, this reaction was applied to amines and formation of the corresponding carbonyl compounds was observed.
Reaction of 2-methyl-4-amino-5-chloromethylpyrimidine hydrochloride (I) and thiourea affords an isothiuronium salt (II) which, when heated in an aqueous acid solution, forms 4H-7-methylpyrimido[4, 5-d]-m-thiazin-2(1H)-one (III). The free base, obtained by the application of sodium hydrogen carbonate to (II), when heated in a neutral aqueous solution, affords 4H-2 (1H)-imino-7-methylpyrimido[4, 5-d]-m-thiazine (IV) and bis[2-methyl-4-aminopyrimidylmethyl-(5)] sulfide (V) in 5:1 ratio. Oxidation of (II) with hydrogen peroxide in sodium hydroxide alkalinity affords bis[2-methyl-4-aminopyrimidylmethyl-(5)] disulfide (VI). Reaction of (I) and thioformamide does not afford a thiazine ring compound but forms 2-methyl-4-aminopyrimidylmethanethiol hydrochloride, and its oxidation affords (IV).
As derivatives of 4-amino-5-phenylazouracil, its 3-methyl and 1, 3-dimethyl compounds were prepared. These compounds are easily hydrolyzed to 1-methyl- and 1, 3-dimethyl-5-phenylazobarbituric acids, which were derived from 5-phenylazobarbituric acid. The 4-amino-5-phenylazouracil compounds synthesized formed the 4, 5-diamino derivatives by reduction and also formed xanthine derivatives by highpressure reduction in the presence of formamide.
High frequency titrations of several dicarboxylic acids of C9-C18 were carried out in non-aqueous medium. In the present case, the dielectric constant Dc, which is the dielectric constant of a medium when the titration curve showed a horizontal line up to the 2nd equivalence point, was also obtained on every case, and in a smaller D, the titration curve, though it was not clear, was N-shaped. Dc and γ, which were calculated from Dc and the equation reported bef ore are shown in Table I. The values of γ were abnormally almost equal. From these results and observation of titration curves, it may be more reasonable to consider that abnormal increase of the portion of ion pair in the lower dielectric constant medium and larger γ have made the equation based on the Coulomb's forces between the two carboxyl groups unsuitable, rather than to consider that the two carboxyl groups are close to each other. Therefore, even in such low dielectric constant media, it may be taken that the distances between the two carboxyl groups of acids and of C14, C16, and C18 are not smaller than those of C6 or C9 and C10. From this conclusion, it could also be said that the consideration on the N-shaped curve described before had been appropriate.
Solubility of 41 kinds of water-insoluble or sparingly soluble medicinals including fat-soluble vitamins, steroidal hormones, non-steroidal estrogens, anticoagulants, and antiseptics in 20% aqueous solution of Tween 80 was examined. At the same time, their solubility in liquid petrolatum and 80% aqueous solution of polyethyleneglycol 300 was also measured. In general, substances dissolving well in Tween 80 solution showed high solubility in either liquid petrolatum or polyethyleneglycol solution, and the substances sparingly soluble in both of these were practically insoluble in Tween 80 solution.
Colorimetric determination of erythromycin in its solution containing naturally decomposed products was carried out. The addition of diluted sulfuric acid to the aqueous solution of erythromycin, standing this mixture at 25° for 30 minutes, alkalization, heating at 100° for 5 minutes, extraction with chloroform, and shaking the chloroform extract with saturated aqueous solution of boric acid and of methyl orange results in coloration of the chloroform layer to a yellow color. When this yellow chloroform solution is shaken with N sulfuric acid, the acid layer colors red, and this red solution has an absorption maximum at 508 mμ, the color being stable. When erythromycin solution is basified with alkali, heated, and submitted to this coloration, almost no coloration occurs, while the naturally decomposed products undergo coloration. These facts were utilized in this colorimetric determination and the values so obtained were in fairly good agreement with the values obtained by bioassay.
Recently, Tomita and others reported on an interesting reaction that the demethylation of 6-bromoveratric acid (I) with hydrogen bromide and acetic acid resulted in the transition of bromine in 6- to 5-position to form 5-bromoprotocatechuic acid (II) in a good yield. This reaction was further followed and some new observations were obtained. The use of 48% hydrobromic acid as the demethylation agent also causes similar reaction but the product from this reaction is mainly a debrominated protocatechuic acid (III) with a small amount of the transition product, 5-bromoprotocatechuic acid (II). On the other hand, the use of hydrochloric and acetic acids affords 6-bromoprotocatechuic acid (IV) and partially demethylated 6-bromoisovanillic acid (VI), and no transition of the bromine seems to have occurred. Application of anhydrous aluminum chloride to 6-bromoveratric acid (I) or 6-bromopiperonylic acid (V) also fails to cause bromine transition and 6-bromoprotocatechuic acid (IV) is formed in a good yield. The transition of the halogen atom does not occur also by the application of hydrogen bromide and acetic acid to 6-chloroveratric acid, 6-chloroveratraldehyde, 6-bromoveratraldehyde, 6-bromocreosol, 6-bromocreosol methyl ether, or 6-bromo-3, 4-dimethoxyacetophenone, and only the corresponing phenol compounds are obtained.
Application of demethylation agent to 2-bromoveratric acid (I) as in the previous case of 6-bromoveratric acid was carried out to examine the behavior of the bromine atom. It was found that the bromine in this case also underwent transition, as in the case of the 6-bromo derivative, to form the 5-bromo compound. The same reaction of 6-bromo-3-methoxybenzoic acid was found to cause the transition of bromine from 6- to 4-position.
Demethylation of 2-bromoanisic acid (I) or its methyl ester with hydrobromic acid in glacial acetic acid results in the formation of 3-bromophenol, indicating that the decarboxylation takes place first and no transition of the bromine atom occurs, as was seen in the case of 2- or 6-bromoveratric acid. The same reaction of 3-bromo-anisic acid (VI:R=H) affords 3-bromo-4-hydroxybenzoic acid (VII) and in the case of its methyl ester, 3, 5-dibromo-4-hydroxybenzoic acid (VIII) is formed. It was found that the substance of m. p. 151° described as 2-bromo-4-hydroxybenzoic acid by Hodgson and Jenkinson is none other than 2-bromo-4-hydroxybenzonitrile. The true 2-bromo-4-hydroxybenzoic acid (II) shows m. p. 206-208° and is obtained by the application of anhydrous aluminum chloride to 2-bromoanisic acid (I).
The formation of a red complex compound by hydroxamic acid with Fe3+ was utilized for the colorimetric determination of γ-butyrolactone. A comparatively stable coloration can be obtained in nitric acid solution, using iron alum as the ferric salt. In order to improve the reproducibility, detailed examination of reaction conditions was carried out, and the procedures and determination formula were established. According to this procedure, there is no interference of impurities, the determination can be carried out rapidly and in a simple manner, and its repeatability is less than ±1.0%, reproducibility ±1.3%. The optical density of the colored solution is affected by the active concentration and pH of hydroxylamine, pH of the colored solution, and concentration of the ferric salt, while the stability of the colored solution differs according to the pH of the colored solution and the temperature of the solution while it is allowed to stand. From these results, an aqueous solution of γ-butyrolactone and 1 N hydroxylamine were reacted in pH 11.0-12.0 at 40° for 20 minutes to form oxamic acid, cooled in ice, iron alum reagent acidified with nitric acid added to bring its concentration to 48% at pH 0.8, and the optical density of the colored solution was measured 10 minutes later with the Beckman Model B spectrophotometer, at 505 mμ.
2-Substituted 5-phenyl-s-triazolo[3, 4-b]-1, 3, 4-triazole (I) with a new skeleton was synthesized starting with 4-amino-5-mercapto-3-phenyl-1, 2, 4-triazole (VI), obtained by the application of hydrazine hydrate to methyl benzoyldithiocarbazinate (IV), reacting it with fatty and aromatic acid chlorides in pyridine to form 4-acylamino-5-mercapto-3-phenyl-1, 2, 4-triazole (VII), and dehydrative cyclization with phosphoryl chloride. Treatment of (VI) by boiling with 80% formic acid afforded 4-formlamidc-5-mercapto-3-phenyl-1, 2, 4-triazole (VII:R=H) and extension of the heating time failed to afford the cyclized compound (I:R=H) but the dehydrative cyclization was effected with phosphoryl chloride. Reaction of acetic anhydride to (VI) directly formed the cyclized compound (I:R=CH3). Ultraviolet absorption spectrum of the 4-acylamino compound (VII) exhibited the maximum absorption at 220 and 260mμ, and that of the cyclized product (I) at around 275mμ.
The crystals of m. p. 110°, isolated from orange oil by Komatsu and Tanaka in 1930 and named auraptin by Nomura in 1950, who assumed it to be a new furocoumarin derivative, was confirmed to be identical with isoimperatorin obtained from the root of Imperatoria ostruthium L., an Umbelliferae plant growing in Europe.
A condensation agent was prepared by heating a mixture of polyphosphoric acid (30g. of P2O5 in 20cc. of 85% H3PO4) and phosphoryl chloride in an amount 1/3 to 1/4 of the acid for 1.5-2 hours on a water bath. Heating of formyl-, acetyl-, benzoyl-, or phenylacetyl-dl-phenylalanine ethyl ester with 20-30 volumes of the condensation agent affords isoquinoline and 1-methyl-, 1-phenyl-, and 1-benzylisoquinolines in a respective yield of 3, 40, 25, and 50%. p-Methoxyphenylacetyl-, 3, 4-dimethoxyphenyl-acetyl-, p-nitrophenylacetyl-, and α-picolinyl-dl-phenylalanine ethyl ester, and benzoyl-and phenylacetyl-dl-3, 4-dimethoxyphenylalanine ethyl ester do not undergo cyclization under these conditions. Since this reaction involves evolution of carbon monoxide, the reaction mechanism is assumed to be the liberation of formic acid between α and β of α-amino acid, or between 3, 4-dihydro-3-ethoxycarbonyl groups after cyclization, forming the isoquinoline ring, and not the cyclization followed by decarboxylation and dehydrogenation or the disproportionation of the 3, 4-dihydro base. The use of the same condensation agent in the Bischler-Napieralsky reaction gave 1-benzyl-3, 4-dihydroisoquinoline in 20% yield.
Nicotinic acid and pantothenic acid-like factor in royal jelly were examined by paper chromatography and microbiological assay. Nicotinic acid-like factor in royal jelly was found to be composed of 70 γ/g. of nicotinamide-like factor and 18 γ/g, of free nicotinic acid by the differential assay using Lactobacillus arabinosus and Lact. fructosus 353, which cannot utilize nicotinic acid for growth but requires nicotinamide. This nicotinamide-like factor was further observed to be composed of nicotinamide and some other nicotinamide-like factor that gives about the same activity as nicotinamide to these two kinds of microörganisms. Examination of the pantothenic acid-like factor in royal jelly by the foregoing method using Lact. arabinosus showed that this factor gives a spot on a paper chromatogram with the same Rf value as that of standard pantothenic acid. The rate of recovery calculated from the amount spotted was about 90%. The presence of a conjugated pantothenic acid and phosphatase activity in royal jelly were not indicated respectively by digestion with diastase and examination with T. D. P.
Four kinds of dialkylaminoethyl ether and thioether derivatives of β-tetralylphen-ylmethane were prepared for use in pharmacological test. None of these compounds offered better activities as compared to diphenhydramin hydrochloride in the point of toxicity, analgesia, etc., but their local anesthetic activity was quite marked, showing stronger action than that of cocaine. However, local irritation was also observed at the same time.
5-Phenyl-5-(β-tetralyl) hydantoin (III), -3-methylhydantoin (IV), -thiohydantoin (V), and -3-methylthiohydantoin (VI) were prepared and their anticonvulsant action (electric shock and Pentetrazol) was examined with the corresponding 5-diphenyl derivatives as the control. These compounds were inferior to 5, 5-diphenylhydantoin and did not show any convulsant action except (V), which only suppressed electric shock in doses above that of LD50.
Bromination of thiaminethiazolone (I) afforded a monobromo derivative, assumed to be 3-(2-methyl-4-aminol-5-pyrimidinylmethyl)-3a-methyl-6a-bromotetrahydrofuro-[2, 3-d]thiazolin-2-one (IV). Both thiaminethiazolone acetate (V) and its 5-methyl homolog (VI) form a compound not containing bromine but one oxygen more than the original compounds by the action of bromine and the compound is assumed to be a 4, 5-epoxy compound (VI and VII).
An effective oxidizing agent is required for the complete burning of refractory substances such as pyridine, pyrimidine, thiazole, and pteridine compounds. Generative force of oxygen of several metal oxides heated in the sample heater was examined and cobaltic oxide was found to be the most suitable in the point of oxygen generating velocity and temperature. It was thereby concluded that cobaltic oxide should preferably be used in place of the conventional cupric oxide powder for the complete burning, of refractory substances.
The conventional Dumas' nitrogen determing apparatus contains a flow choking device (microstopcock or a needle valve) between the combustion tube and azotometer, but such a position often causes backflow of the sample vapor toward the mouth of the combustion tube. A new apparatus was therefore designed with a new flowchoking device provided with a glass capillary tube inserted just in front of the combustion tube, in addition to a new sampling method using cobaltic oxide and an improved modifications on the flow meter or Gysel's backflash sweeping system.
As the air flow completely burns the sample in carbon and hydrogen determination, the oxygen generated from cobaltic oxide might also burn any refractory substance taken individually into a platinum boat, because cobaltic oxide generates oxygen at 900° and its concentration may reach 1/5 to 1/6, closely approaching the value of 1/4 for oxygen in the air. Therefore, a new method has been devised in which two boats are used, one for the sample and the other for cobaltic oxide. A few of the advantages derived from this method are the easy sampling, simultaneous determination of residual ash, and the use of a much lower temperature than that in a process using conventional cupric oxide powder.
When a buffered acetic acid solution of diiodo-β-resorcylic acid is added to an acetic acid solution of some organic bases, an amorphous precipitate separates almost immediately. The precipitate is generally colored alike with the base, soluble in hot water, strong acid, strong alkali, ethanol, methanol and acetone. When cooled, the precipitation forms again from the hot water solution. Among 51 bases examined, those showing clearly detectable precipitation were the nine compounds which have quinoline and quinuclidine, isoquinoline, hydrocarbazole, hydroindolizine, or acridine ring in their configuration, Compounds which did not precipitate or precipitated only slightly were those which have none of these rings, except the quinoline ring.
When an ethanolic solution of diiodo-β-resorcylic acid is added to an aqueous or a dilute ethanolic solution of some organic bases, an amorphous precipitate separates almost immediately, at the ethanol concentration of less than 20% in the reaction mixture. Fourty-six substances were examined. The properties of the precipitate and the kind of substances which showed this reaction were almost the same as those of the reaction in acetic acid solution.
α-Dialkylaminoacyl and β-diethylaminoethyl derivatives of α-aminophenylaceto-nitrile and α-N-aralkylaminoacetyl and β-dimethylamino derivatives of isopropyl α-[N-(β-diethylaminoethyl)]aminophenylacetate hydrochloride (Avacan) were examined for analgesic activity. There was no anticipated decrease of toxicity or appearance of analgesic activity in the nitrile and its acyl derivatives, and their spasmolytic activity was inferior to that of Avacan. Local anesthetic action was not especially strong. However, β-dimethylamino derivative of Avacan (M-Avacan) showed large rise of the pain threshold compared to Avacan in both animal and human tests.
Pharmacological activity of eight kinds of camphor derivatives, dialkylaminoacylaminocamphor hydrochloride (I-VI), diethylaminoethylaminocamphor hydrochloride (VII), and diethylaminoethyl bornyl ether hydrochloride (VIII), were examined. Toxicity tested with mice was comparatively weak in (I) to (VII) and comparatively strong in (VIII). All the compounds tested possessed sedative and analgesic actions and prolong the hypnotic activity of sodium methylhexabital. Hypothermic effect is marked in (VIII), about equal to that of aminopyrine. The compounds showed spasmolytic activity against contraction of excised intestines of a rabbit or guinea pigs with acetylcholine, barium chloride, or histamine. The movement of excised rabbit auricle was suppressed only in higher concentrations of these compounds. They failed to give any marked effect on the respiration or blood pressure of an anesthetized dog and corneal anesthesia in a rabbit was observed only with (VIII), though inferior than that of procaine hydrochloride. From these results, a few of these compounds were found to possess moderate central nerve depressant action and it was thought that further studies in this direction would be of value.
4-Methylaminoantipyrine (II) and 4-ethylaminoantipyrine (III), obtained from 4-formylaminoantipyrine and diethyl sulfate, were reacted with α-bromopropionic acid, and the 4-α-bromopropionylalkylaminoantipyrines (VI and VII) thereby obtained were reacted with dialkylamines, or (II) or (III) was condensed with dialkylamines, and the corresponding 4-α-dialkylaminopropionylalkylaminoantipyrines (VIII-X) were obtained. By treating 4-aminoantipyrine (I) or (II) with chloroacetamide or by treating (I) with paraformaldehyde and potassium cyanaide in dilute hydrochloric acid, (4-antipyrine)amino- (IV) and (4-antipyrine)methylaminoacetamide (V) were obtained. Reaction of (IV) and α-bromobutyryl bromide afforded N-α-bromobutyryl-(4-antipyrine)aminoacetamide (XI), which was derived to N-α-dimethylaminobutyryl-(4-antipyrine)aminoacetamide (XII). The condensation of (I) with α-haloacylanilide derivatives (XIII-XVIII), obtained from aniline derivatives and α-haloacyl halides, gave α-(4-antipyrine)aminoacelamide derivatives (XIX-XXIV). Decomposition of sulpyrine (a) with conc. hydrochloric acid yields (II) and aminopyrine (b), and that with dil. hydrochloric acid yields (II) and a substance (c) of mp. 175°. Hydrolysis of (c) with hydrochloric acid affords (II) and formaldehyde, and its reaction with sodium hydrogen sulfite gives (a) and (II), with formic acid, (b) and 4-formylaminoantipyrine, and with benzenesulfonyl chloride, (N-methyl-N-4-antipyrinyl)benzenesulfonamide. (c) corresponds to molecular weight of 375 and was assumed to be bis (4-methylaminoantipyrinyl) methane from its ultraviolet absop-tion spectrum. Aminopyrine (b) was also obtained by the reaction of (I) and formaldehyde or formaldehyde and sodium hydrogen sulfite in hydrochloric acid.
An equation was derived for estimating the parameters, α and β, of a logistic sigmoid curve and maximum response, H, by the maximum likelihood method as follow: enx=cβy/H-y where x is the log concentration and H the maximum contraction height.
The contraction of excised small intestines with acetylcholine was converted into a logit and the regression line was calculated by the method already described. A graphic method, not requiring any complicated calculations, was forwarded with examples.
Thiophenyl esters of dicarboxylic acids, and heterocyclic carboxylic acids, such as that of furan, pyrone, pyridine and pyrazine (Table I) were prepared and submitted to antifungal screening. The antifungal spectra are shown in Table II. It was thereby noted that their thiophenyl esters of furan- and pyridine-carboxylic acids possessed marked antifungal activity. Effect of the addition of cysteine on fungal growth was examined (Table III) and no antagonism was found with thiophenyl acetate but a marked antagonism was observed in the case of thiophenyl benzoate. Antifungal mechanism was considered from these results.
Under the assumption that the antifungal mechanism of thiophenol esters was due to the acylation of SH- or NH2-group essential for fungal growth, its experimental confirmation in vitro was attempted by a model experiment using aromatic amines, such as aniline, sulfanilamide, and p-anisidine, as the acyl acceptor. The yield of the anilides thereby formed was taken as the reaction rate of the thiol esters in comparing the reactivity of such esters (Table I and II). The reactivity of aniline with antifungal CH3COSC6H5 and non-antifungal CH3COSC2H5 was compared by following the amount of thiols formed with 0.1 N iodine titration (Fig. 1) and the results indicated that the thioesters capable of acylating aromatic amines generally tended to have powerful antifungal activity. An introduction of a methyl group in the para position of the thiophenol ring lessens the rate of transacylation with attendant decrease in antifungal activity. The results shown in Fig. 1 is in agreement with the observation that esters of aliphatic thiols do not possess antifungal activity but those of aromatic thiols do.
The completely methylated compound, 6-acetyl-5, 7, 4′-trimethoxyflavone, (III) is demethylated when boiled for 1 hour with hydrochloric and acetic acid to form (VIβ), while boiling for 3 hours affords its isomer (VIα). (VIβ) changes to its isomer (VIα) when boiled with the same acids. (VIα) is insoluble in 10% potassium hydroxide even when heated, is not methylated by the usual method, and is not demethylated with aluminum chloride. On the other hand, (VIβ) dissolves in hot 10% potassium hydroxide, is methylated to (III), and demethylated with aluminum chloride to form (VIII). It may, therefore, be concluded that (VIα) and (VIβ) are isomers formed by the difference in the configuration of COCH3 in the 6-position. When (III) is allowed to stand with an excess of aluminum chloride for 5 hours at room temperature, a colorless (VII) is formed. (VII) dissolved in cold 10% potassium carbonate, is methylated to (III), and demethylated with aluminum chloride to form (VIII). Heating of (III) with an excess of aluminum chloride affords (VIII), whose mild methylation results in the formation of (VIβ) and drastic methylation, (III).
Reaction of 1 mole each of ethyl DL-dihydro-α-lipoate and acetic anhydride in pyridine at below 15° was found to result in a partial formation of ethyl DL-S6, S8-diacetyldihydro-α-lipoate, with the majority of ethyl DL-S8-acetyldihydro-α-lipoate. Ethyl DL-S6-acetyldihydro-α-lipoate was not obtained.
A prosapogenin-like substance was obtained in 0.4% yield from the dried bud of Sophora japonica L. By its hydrolysis, betulin and a new sapogenin, sophoradiol, C30H50O2, were obtained as the genin and glucose and glucuronic acid as the sugar portion.
A new analgesic, N, N-dimethyl-3-phenylsalicylamide was prepared in a good yield by the reaction of phenyl 3-phenylsalicylate and dimethylamine. This reaction can be utilized as a good process for amidation in general and 20 kinds of 3-phenylsalicylamide derivatives listed in Table I and II were prepared by this reaction.