By the reaction of 2-amino-, 2-amino-4-methyl-, and 2-amino-4-phenyl-thiazoles, and 2-amino-6-methylbenzothiazole with phenyl, o-, m-, and p-tolyl, m- and p-chlorophenyl, and benzoyl isothiocyanate, 1-(phenyl-, o-, m-, and p-tolyl-, m- and p-chlorophenyl-, and benzoyl)-3-(2-thiazolyl-, 4-methyl-2-thiazolyl-, 4-phenyl-2-thiazolyl-, and 6-methyl-2-benzothiazolyl) thioureas were prepared. 2-Thioureido-4-methyl- and 2-thioureido-4-phenyl-thiazoles were prepared from the 1-benzoyl compound and 1, 3-bis (4-methyl-2-thiazolyl) thiourea from 2-amino-4-methylthiazole and carbon disulfide, and their reaction of metal ions was examined. These thiazolyl-thiourea derivatives react in hydrochloric acid solution with palladium (II), platinum (IV), and gold (III), in neutral to weak acidity with copper (II), silver (I), and mercury (II), and in ammonia alkalinity with nickel (II), cobalt (II), bismuth (III), cadmium (II), and lead (II). The limit of detection is 0.2γ/cc. for Cu2+, and Ni2+, 0.5γ/cc. for Pd2+ and Ag+, 1.0γ/cc. for Hg2+ and Cd2+, 2.0γ/cc. for Pb2+ and Au3+, 5.0γ/cc. for Bi3+, and 10.0γ/cc. for Pt4+. Sensitivity of these reagents is higher than that of phenylthiourea derivatives. Separatory determination of these ions is possible by adjusting the reaction of the solution in using thiazole-thiourea derivatives as the reagent. By adjusting the test solution to hydrochloric acidity, palladium alone can be detected. Addition of potassium cyanide to the test solution and adjusting the solution to alkalinity, platinum alone can be detected, while treatment of the test solution containing cyanide with hydrochloric acid and adjusting the solution to acidity with acetic acid allows detection of copper alone. Of these reagents tested, the 4-methyl-2-thiazolylthiourea derivative is especially adapted as a reagent for detection of palladium, platinum, and copper.
1-p-Chlorophenyl-3-(4-methyl-2-thiazolyl) thiourea reacts sensitively with palladium in hydrochloric acid solution to form an orange-colored solution and can be utilized as the colorimetric reagent for palladium. The procedure for this determination is as follows: One cc. of palladium test solution (containing 0-50γ/cc. of Pd) is accurately measured into a 5cc. measuring flask, 0.5cc. of 10% hydrochloric acid solution, 0.5cc. of distilled water, 2cc. of 0.2% acetone solution of the reagent, and 1cc. of acetone are added to bring the whole volume to 5cc. The solution is allowed to stand for 10 minutes and the absorbance of the solution is measured at 460mμ. By this procedure, palladium in the concentration of 0-50γ/cc. can be determined colorimetrically. Presence of platinum is a source of error for determination of palladium but the presence of less than 20% of platinum against palladium enables determination of palladium within 1% accuracy. In the absence of platinum, palladium can be determined with high sensitivity by using absorbance at 430mμ.
Past procedures for analysis of arsenic in organic compounds depended on wet oxidation method and none used the combustion method. Thinking that the combustion held less factors for error than the wet oxidation method, analysis of arsenic was carried out by the combustion method. The sample was weighed in a quartz boat and burned in oxygen stream in the combustion tube provided with a side tube (Fig. 1). Arsenic compounds are converted into arsenic trioxide and remains as white crystals along the inner wall of the quartz funnel This boat is weighed and the value of arsenic is calculated from the difference in weight of the funnel. This analytical procedure is quite simple, requires only a short time, and can be adopted for routine analysis. Examinations are now being made on this procedure for analysis in the presence of halogen or sulfur.
Treatment of aromatic N-oxides with acetic anhydride, benzoyl chloride, or tosyl chloride results in formation of an acyl adduct in which, differing from that of the parent compound, the N-O linkage has become weakened and the compound is easily reduced to the tertiary amines with sulfur dioxide or sulfite solution. Even in such a simple reaction, however, the nature of the acyl group has a great effect. For example, the benzoyl adduct is easily reduced by sulfite solution but not by sulfur dioxide gas. The tosyl adduct of pyridine 1-oxide undergoes reduction but that of quinoline 1-oxide is not reduced and undergoes rearrangement to carbostyril.
Treatment of qulnoline 1-oxide with benzoyl chloride and alkali at room temperature afforded, besides the rearrangement product, carbostyril, an intermediate (I), of m. p. 126-128°, C16H13O3N. (I) was extremely labile and easily decomposed into carbostyril and benzoic acid that it was not possible to make any conclusive proof of its structure, either chemically or physically. However, result of chemical reactions suggested that it might be 1-benzoyloxy-2 -hydroxy-1, 2-dihydroquinoline. Formation of (I) suggests that a steric factor is also important, besides polarization effect, in rearrangement reaction of N-oxides under such a mild condition.
In order to examine the presence of a common antigen among snake venoms of allied species, antigen-antibody reaction in agar gel was carried out on 10 kinds of Formosan and Japanese snake venom. Bowen's method produced 7 sedimentation zones from the venom of Mamushi, 5 from that of Trimeresurus, 4 from that of Tr. flavoviridis, 3 from that of Tr. gramineus, 2 from those of Tr. mucrosquamatus and Tr. okinavensis, and 1 from that of Agkistrodon acutus. There were common antigens corresponding to each sedimentation zone but no such zone was observed in the venom of Cobra family. From the result of Ouchterlony method, the antigen common to Habu and Mamushi venom was found to be a protein similar also serologically, and one kind of serologically identical antigen was found to be present in the venom of Trimeresurus, Tr. flavoviridis, Tr. okinavensis, Tr. gramineus, and Agkistrodon acutus. Effect of Mamushi antiserum on various enzyme activities in snake venom was examined and it was found that, while cholinesterase, proteinase, and L-amino acid oxidase were not affected, 5′-nucleotidase, phosphomonoesterase, and lecithinase-A were completely inhibited, and phosphodiesterase was inhibited 80%, both in Mamushi and Cobra venom. Cobra venom and Mamushi antiserum do not produce a sedimentation zone but, since the kind of enzyme affected and the degree of inhibition by antiserum are the same in both venoms, it seems possible to assume that this inhibition is also due to antienzyme in the case of cobra venom.
The venom of cobra (Naja naja atra) and Habu (Trimeresurus) contains phosphodiesterase which severs the 5′-position of cyclic 3′, 5′-adenylic acid to form 3′-adenylic acid, besides the enzyme which severs the 3′-position to form 5′-adenylic acid. The three kinds of phosphodiesterase fractionated and purified from the venom of Mamu-shi (Agkistrodon halys) hydrolyze any of the cyclic nucleotides, such as cyclic 2′, 3′-adenylic acid or cyclic 3′, 5′-adenylic acid but the velocity of hydrolysis is faster in cyclic 3′, 5′-adenylicacid. Activity of diesterase-I is the strongest and this preparation contains the enzyme that severs the 5′-position though weak in activity, besides that severs 3′-position of cyclic 3′, 5′-adenylic acid. The diesterases-II and -III do not produce 3′-adenylic acid from cyclic 3′, 5′-adenylic acid so that they are considered to act only on the 3′ linkage. Non-specific phosphomonoesterase of snake venom also hydrolyzes 3′(2′)-adenylic acid.
Polarographs and relationship between that and biochemical properties were examined of 2, 4, 6-triamino-5-(R-phenyl) azopyrimidines (A) and 2, 6-diamino-4-hydroxy-5-(R-phenyl) azopyrimidines (B) (in which R is H, Cl, SO3H, COON, or PO3H2). These compounds show reduction wave due to the reaction of -N=N-+2H++2e⇔-NH-NH- and -NH-NH-+2H++2e→-NH2+NH2-, its diffusion current constant being ca. 5 (μA⋅mM-1⋅mg.-2/3⋅sec.1/2). The pyrimidine bases and proton adducts of (A) and (B), and 4-phenoxide type anion of (B) indicate different E1/2. The apparent pK calculated from wave height-pH curve is 4.9-7.2 in (A) and 12 in (B), which are greater than the true pK of 4.38-5.38 in (A) and 9.55 in (B). From these values, proton recombination velocity constant was calculated as log k 3.4-9.7 for (A) and 13 for (B). p-Carboxyphenyl and p-sulfophenyl homologs of (A) indicate prewave due to adsorption and the area occupied by the adsorbed molecule on electrode surface was calculated as 112 Å2 from their wave height. The E1/2 of p-substituted compounds of (A) at pH 1 followed Hammett's rule and is represented as E1/2=-0.4+0.14σ. The E1/2 of the antagonist of reduction of folic acid, (A) (R: 4-Cl, 2-Cl, 2, 4-di-Cl) and (B) (R: H) at pH 7.3 is in a more positive potential and those of others (A, R: 4-SO3H, 4-COON, 4-PO3H2, 3-PO3H2) are in the negative potential.
As a model enzyme system of aromatic hydroxylation, there are the reactions by Fenton's reagent, hydrogen peroxide irradiated with ultraviolet ray, and ascorbic acid-Fe2+. Using these reactions, experiments were carried out on umbelliferone, herniarin, dimethylesculetin, coumarin, and o-coumaric acid, and the reaction products were compared with that of in vivo tests reported previously. The hydroxylation products obtained from the foregoing reactions were similar to those of in vivo reaction. The reaction with ascorbic acid and Fe2+ differed from that of other two reactions and the present series of experiments supported the theory that hydroxyl group can be introduced easily into electronegative position. At the same time, demethylation was also found to take place and demethylation by the foregoing reactions is the first of such example. o-Coumaric acid was formed from coumarin and this was proved for the first time in vivo by the present authors, later supported by Booth and others. Since coumarin was formed from o-coumaric acid, cis-trans isomerization was found to occur both in vivo and in vitro.
Treatment of riboflavin monophosphite, with N-bromosuccinimide, N-bromoacetamide, or bromine in aqueous acid solution oxidized it to the corresponding phosphate. Neither degradation of riboflavin moiety nor acid-catalyzed hydrolysis was observed. Addition of pyridine or sodium acetate to the reaction mixture retarded the reaction markedly. Using this reaction, isobutyl, sec-butyl, cyclohexyl, benzyl, and 2-benzyloxycarbonylaminoethyl phosphate were obtained as crystalline barium salt from the corresponding phosphites.
According to past studies, it is known that, among the compounds of azo dye system, 4-hydroxynaphthalene-1-sulfonic acid derivatives have antiviral activity comparable to the corresponding naphthlonic acid derivatives. Assuming that N-Dodecanoyl-4-hydroxynaphthalene-1-sulfonamide, a type of compounds in which the acetamido group indo N-Dodecanoyl-4-acetamidonaphthalene-1-sulfonamide (PANS-610), an excellent antiviral substance, had been substituted with a hydroxyl, and its hydroxyl derivatives might have a fair degree of antiviral activity, these compounds were prepared and their antiviral activity tested. Contrary to expectations, however, none of these compounds possessed antiviral activity to any extent and this fact suggests that substitution of acetamido group in PANS-610 with hydroxyl is not a good policy.
In order to elucidate the relationship between chemical structure and antiviral activity of N-dodecanoyl-4-acetamidonaphthalene-1-sulfonamide (PANS-610), N-alkanoyl 4-acetamido-5, 6, 7, 8-tetrahydronaphthalene-1-sulfonamide, in which the naphthalene ring in PANS-610 had been substituted with tetralin ring, and its position isomers were prepared and their antiviral activity tested. None of these compounds prepared showed any antiviral activity in vivo and it was presumed that the tetralin ring is not effective for appearance of antiviral activity in PANS-610.
Branched-chain fatty acids are expected to have better properties than straight-chain fatty acids from surface chemistry and it was considered that the antiviral activity might be increased by improvement of surface activity through introduction of a branched acyl group into the dodecanoyl group in N-dodecanoyl4-acetamidonap hthalene-1-sulfonamide (PANS-610). Therefore, required branched-chain fatty acids were prepared and their chlorides were condensed with 4-acetamidonaphthalene-1-sulfonamide to obtain N-alkanoyl-4-acetamidonaphthalene-1-sulfonamide with a branched-chain acyl in N1-position. Examination of antiviral activities of these compounds showed that some of them possessed in vivo activity comparable to that of PANS-610. However, synthetic procedures for these compounds are much more complicated than that for PANS-610 and it seems that introduction of a branched-chain acyl group is not practicable.
According to the assumption that an antiviral drug against neurotropic viral diseases should possess neurotropy, especially cerebrotropy, hydrophobic alkyl group and hydrophilic amino group was introduced into thiobarbituric acid to form 5-alkyl-4-amino-2-thiouracil and its effect on the Nakayama strain of Japanese B encephalitis virus was examined. As a result, it was found that 5-(2-isobutyl-4-methylpentyl)-4-amino-2-thiouracil and 5-(2-ethyldecyl)-4-amino-2-thiouracil exerted remarkable effect in vivo but not any activity against the virus in vivo.
6-Alkylated 3-mercapto-5-hydroxy- and 3, 5-dihydroxy-as-triazines were prepared and their antiviral activity against the influenza virus, strain PR-8, was tested by chorioallantoic mambrane culture method. In the 3-mercapto-5-hydroxy-as-triazine series, the propyl and tridecyl derivatives inhibited viral multiplication, and only the nonyl derivative alone was active in the 3, 5-dihydroxy-as-triazine series.
A new method for synthesis of 2-methyl-4-anisoyl-10-hydroxydecahydroisoquinoline (IVα) and its isomer (IVβ) had already been described and examinations were also made on the plane structure and steric structures of these compounds. In continuation, attempts were made in the present series of work to prepare 2-methyl-4-benzoyl-10-hydroxydecahydroisoquinoline (XXVIα) and its isomer (XXVIβ), in which the side chain at 4-position had been substituted with a benzoyl group. The present reaction was found to proceed smoothly when the methoxyl in para-position had been eliminated and formation of two kinds of stereoisomers, as in the case of 4-anisoyl derivative, was observed. Examinations were also made on the physical and chemical properties of these isomers, and the mode of their isomerization, and observations similar to the isomers of α- and β-types of the 4-anisoyl compound were gained. It was thereby assumed that these isomers (XXVIα) and (XXVIβ) are the stereoisomers with different steric configuration of the side chain at 4-position, as in the case of the 4-anisoyl compound.
In continuation of the preceding work, dehydration of angular hydroxyl and Grignard reaction of the carbonyl in the side chain at 4-position in 2-methyl-4-benzoyl-10-hydroxydecahydroisoquinoline (XXVIα) and its isomer (XXVIβ) were examined. As a result, it was found, as in the case of previously reported 4-anisoyl compound, that the α-type was highly reactive and β-type was less reactive, and this was considered to be due to the difference in their steric configuration. Dehydration of the products (XXXα and XXXβ) of the Grignard reaction differed from that in the case of the 4-anisoyl compound, resulting in the formation of (XXXI) by dehydration of angular hydroxyl from α-type and formation of (XXXII) by dehydration of hydroxyl in the side chain at 4-position and its isomer (XXXII′) from the β-type.
Detailed reports have been given on the syntheses of 4-anisoyl and 4-benzoyl derivatives on 2-methyl-10-hydroxydecahydroisoquinoline and it was clarified that this reaction was a combination of the so-called Mannich reaction and the subsequent aldol condensation-type of cyclization. Applicability of this reaction was then examined in the case of N-methylethylamines possessing p-propoxybenzoyl, cyano, and ethoxycarbonyl as the negative atom group in the β-position. Isolation of the Mannich reaction product (intermediate) in the first step was found to depend on the kind of negative atomic group present but this reaction progressed smoothly in any of the cases to form 2-methyl-10-hydroxydecahydroisoquinoline compounds. Consequently, this reaction is available as a method for synthesis of 4-substituted 10-hydroxydecahydroisoquinoline compounds.
Following the confirmation of the formation of 4-substituted 2-methyl-10-hydroxy-decahydroisoquinoline by the reaction of N-methylethylamines with negative group in the β-position to activate the neighboring methylene, cyclohexanone, and formaldehyde solution, examinations were made on the same reaction with N-ethylbenzyl-amines possessing negative atom group in the β-position. It was thereby confirmed that the isoquinoline derivatives are obtained as in the case of N-methyl compounds. It was found that the compounds prepared by this process can also be prepared by the method of Mannich and Hieronimus, and this has provided a strong evidence for the reaction mechanism and appropriateness of the plane structure described in Part V of this series.
Examinations were made on Kruse-Mellon method for colorimetric determination of ammonia by its oxidation with Chloramine-T and coloration with a mixed reagent of pyridine, 3-methyl-1-phenyl-2-pyrazolin-5-one (pyrazolone), and 4, 4′-bis (3-methyl-1-phenyl-2-pyrazolin-5-one (bispyrazolone). The pigment formed by this reaction was proved to be rubazonic acid. From its formation mechanism, this process was modified so as to extract oxidation product of ammonia with carbon tetrachloride, reacting this product with bis-pyrazolone to form rubazonic acid, and to reduce the pigment formed at the same time as a by-product with pyrazolone. The sensitivity to ammonia was increased two-fold from the original process and adverse effect of metal ions, like copper and iron, was removed.
3-Mercaptopropanol (R′-SH) and 3-acetyl-3-mercaptopropanol (R″-SH) indicate anodic wave due to electrode reaction of RSH+Hg→RSHg+H+e(pH<pK′) and RS-+Hg→RSHg+e(pH>pK′). The pK′ calculated from the E1/2-pH curve is 9.5 for R′-SH and 7.5 for R″-SH, which agree with the value obtained by titration method. Total wave-height is proportional concentration and to the square root of mercury pressure, and the diffusion current constant is 1.8 for R′-SH and 1.7 for R″-SH. Bis (3-hydroxypropyl) disulfide (R′-S-S-R′), bis (1-acetyl-3-hydroxypropyl) disulfide (R″SSR″), and dipropyl disulfide (Pr-S-S-Pr) all show two-electron reduction wave to thiol. Its E1/2 is independent of pH and shifts to negative potential with increase of concentration. These thiols and disulfides show adsorption wave. From the area occupied by the adsorbed molecule (25 Å2 for R′-S-Hg and 31 Å2 for R″-S-Hg) calculated from the limit value of this wave height, it is assumed that R′-SHg forms a single molecular layer with the S-Hg bond axis perpendicular to the mercury surface. These substances indicate A. C. polarograms corresponding to the adsorption and regular waves. The wave height and concentration in these cases are in the relation of adsorption isotherm.
Normal- (I) and iso-dihydrothiamine (II) indicate cathodic wave (E1/2 -1.27 to -1.55V, kD 13.6 μA⋅mM-1⋅mg.-2/3⋅sec. 1/2), considered to be due to reduction of the pyrimidine portion in acid reaction but pseudo-dihydrothiamine (III) does not indicate such a wave. (I), (II), and (III) indicate anodic wave (E -0.3V, kD -1.4) with dropping mercury electrode, probably by the formation of a mercury complex. With the rotating platinum electrode, (I) indicates an anodic wave (E1/2 +0.6V), assumed as due to its oxidation to thiamine. (I) and (II) change in aqueous solution, irrespective of the presence or absence of oxygen, into 3-acetyl-3-mercapto-1-propanol, tris (2-methyl-4-amino-5-pyrimidylmethyl) hexahydro-s-triazine (VII), and (III). (I), (II), and (III) all react with equivalent amount of p-chloromercuribenzoate to forms a reaction product of 3-mercapto-1-propanol and p-chloromercuribenzoate. (VII) indicates a reduction wave of the pyrimidine ring.
Determination of penicillin V can be effected by the dye method using a basic color, Methyl Green. In this procedure, a sample is bound with Methyl Green in Sørensen buffer of pH 3.0, the combined substance is extracted with benzene, and submitted to colorimetry. This procedure (i) enables separatory determination of penicillin V and its decomposition product or precursor, phenoxyacetic acid, (ii) the procedure is simple and measurement can be made rapidly, and (iii) accuracy is good and the value obtained agrees with the potency obtained by biological tests. Due to its sensitivity, this process is not applicable for measurement of penicillin concentration in a body fluid but can be used for purity tests of drug preparations. There is also a possibility of its use for the test of culture filtrate.
Domesticine (IV), the main phenolic base of Nandina domestica THUNB. (Japanese name “Nanten”), was submitted to cleavage reaction of its methylenedioxy group by metallic sodium in liquid ammonia, as in the case of O-methyldomesticine (I) reported in the preceding paper. As a result, only one kind of decomposed phenolic base (V) (hydrochloride: m. p. 277°(decomp.), C18H19O3HCl) was obtained. This substance (V) no longer contains methylenedioxy group but has one methoxyl group. Its O-methylated compound (VIa), m. p. 122-124°, [α]D25+150.6°(MeOH), C20H23O3N, was found to have three methoxyls and its infrared spectrum failed to show the presence of a phenolic hydroxyl. Its ultraviolet spectrum (Fig. 1) clearly indicated that it is an aporphine-type base and the presence of one methoxyl at 10-position was assumed. On the other hand, synthetic procedure for dl-1, 2, 10-trimethoxyapophine (VIb) appearing in the literature was followed by the route shown in Chart 1 and the objective racemic compound (VIb), m. p. 140-141°, was obtained. Comparison of the synthesized product (VIb) and the foregoing cleaved O-methylated base (VIa) showed that the two are entirely identical, possessing the same planar structure. From the foregoing experimental results and the fact that methylenedioxy group undergoes one-sided cleavage to produce a new hydroxyl group, the methylenedioxy group in domesticine (IV) must have similarly undergone one-sided cleavage to produce a new phenolic hydroxyl and to form 1, 10-dihydroxy-2-methoxyaporphine (V).
Each of the antibiotics contained in a mixed preparation of oleandomycin containing ascorbic acid and tetracycline was successfully separated and determined by colorimetry. In this case, a sample solution (containing 100-1000γ/cc. as tetracycline) is passed through a column of Permutit in order to adsorb tetracycline alone, the column is washed thoroughly with distilled water, and further washed with 10cc. of 7% sodium carbonate solution to elute the adsorbed tetracycline. A mixture of 2cc. of this eluted solution, 3cc. of 3% sodium carbonate solution and 0.5cc. of 0.3% potassium ferricyanite is heated at 40° for 25 hours and absorbance of this solution at 530mμ is measured. In the case of oleandomycin, 2cc. of the sample solution (containing 50-450γ/cc. as oleandomycin), added with 1cc, of 5% sodium carbonate and 1cc. of 5% sodium chloride solution, and 3cc. of ethylene dichloride, shaken thoroughly, and centrifuged. Two cc. of the organic solvent layer so separated is shaken with a mixture of 2cc. of distilled water and 0.5cc. of 0.5 N hydrochloric acid to extract oleandomycin into the aqueous layer. Two cc. of this solution is submitted to colorimetric determination for oleandomycin with diazobenzenesulfonic acid and ascorbic acid, as reported previously. The value obtained by the present process with a mixed sample solution after being allowed to stand over a long period agreed well with the values obtained by biological method.
Harder's gland is a kind of endocrine glands present in the eye cavity and is present in majority of mammals, except the human kind, birds, and reptiles. However, the action of this gland as a secretion gland has not been clarified as yet. In order to clarify deficiency symptoms of this gland, Harder's gland was taken out from mature rabbit and its growth was observed. Further, its serum sodium, potassium, calcium, phosphoric acid, phosphatase activity, and amount of blood sugar were measured, comparing the results with those of normal rabbits. There were no changes in the values of serum sodium and potassium, phosphoric acid, and blood sugar, but the amount of serum calcium showed decrease rate of 7.67% and this was especially true of serum phosphatase activity, there being a marked decrease of ca. 61% in alkaline phosphatase activity. This may be taken as one of the characteristic deficiency symptoms. Consequently, it may be presumed that Harder's gland is secreting a substance which affects the amount of serum calcium and phosphatase activity.
Following previous reports on the pharmacological action of the fats of pearl barley, pharmacological action was tested of coixol (6-methoxybenzoxazol-2-one), one of the components present in its root. 1) Toxicity is small and no untoward effect was observed on oral administration of 500mg./kg. for 30 days. 2) General pharmacological tests revealed that it effected inhibition of movement of isolated toad heart and rabbit intestine, transitory fall of blood pressure, excitation of respiration, and fall of blood sugar level. 3) It obstructed oxygen uptake of diaphragm, anaerobic glycolysis of diaphragm, and actomyosine-ATP reaction. 4) Its central action was analgesic and sedative, and it gave functional change in rabbit EEG. It also gave transitory inhibition of multisynaptic reflex. 5) It effected fall of body temperature and antagonize TTG fever, but did not antagonize DNP fever.
Among the imidazoisoquinoline derivatives prepared to date, 9, 10-dimethoxy-3-(2-furyl)-5, 6-dihydroimidayo [5, 1-a] isoquinoline was found to have some activity of contracting uterus. Therefore, the same derivatives with furfuryl and furylethyl group in place of furyl in 3-position werepre pared and their pharmacological activity was examined. The compound with furylethyl group was found to have a strong uterus contracting action. This compound was prepared by application of 2-furyla-cetic acid or 3-(2-furyl) propionic acid azide to glycine ethyl ester to form the amide, derived to the azide through the hydrazide, condensed with homoveratrylamine, and submitted to isoquinoline cyclization by the usual procedure.
In order to clarify the botanical origin and morphological properties of the Chinese drug “San cha-tsu” (_??__??__??_) imported into Japan, external and internal structure, difference, and characteristics of false fruit were examined in Crataegus cuneata SIEB. ET ZUCC. (Figs. 1-15), C. pinnatifida BUNGE (C. oxyacantha L. var. pinnatifida (BUNGE) REGEL) (Figs. 16-23), and C. oxyacantha L. (Figs. 29-39). These were compared with some kinds of Crataegus drugs with different Chinese names. It was thereby found that the crude drugs in the Japanese market are of two kinds, those of C. cuneate and C. pinnatifida. There were no false fruits which could be taken as those of C. oxyacantha.
Primary cleavage of thalicberine (I) itself with metallic sodium in liquid ammonia was carried out and the cleaved phenolic product thereby obtained was submitted to counter-current fractional extraction with a buffer solution of pH 5.6 to separate the unreacted material. The cleaved phenolic base (III) was methylated and the infrared absorption spectrum (in chloroform) of the O-methyl compound (+, +) (IV) so obtained was compared with that of the O-methyl ether of dauricine (V), i.e. O-methyldauricine (IV) (-, -), and the two spectra were found to be entirely identical. Consequently, (III) and (IV) were found to be optical antipodes.
Glucuronic acid and glucuronolactone are in equilibrium in aqueous solution and their ratio is dependent on temperature. Their transition velocity differs markedly with temperature and is also increased by mineral acid which, however, does not affect componental ratio at equilibrium. Results are presented on the measurement of componental ratio at equilibrium, transition velocity, periodical change, and action of mineral acids.
Catalytic reduction of 16-anhydrogitoxigenin and its acetate over palladium-carbon results in preferential reduction of the double bond between 16- and 17-positions and α, β-unsaturated lactone ring remains unhydrogenated. In these cases, the yield of 17α-digitoxigenin is far greater than that of digitoxigenin. 17α-Digitoxigenin was found to be without cardiotonic action.
Catalytic reduction at ordinary temperature and pressure over Raney nickel was carried out on N-oxide compounds with sulfur-containing substituent, 4-phenylthiopyridine 1-oxide (I), phenyl 4-pyridyl sulfone 1-oxide (II), 4-ethylthiopyridine 1-oxide (III), and sodium salt (IV) of 4-mercaptoquinoline 1-oxide. (I) and (II) underwent rapid reduction, as in the case of previously reported N-oxides, and respectively afforded 4-phenylthiopyridine (V) and phenyl 4-pyridyl sulfone (VI). In the case of (III), absorption of hydrogen stopped after about one-half the calculated amount of hydrogen had been absorbed and a part of the starting material was recovered together with 4-ethylpyridine (VII). This fact suggests that the sulfone group might work as a catalyst poison but thioether in aryl thioethers has not proved to be of great hazard. In the case of alkyl thioethers, the thioether group does act as a catalyst poison but the action of Raney nickel on the N-oxide group is so great that the reduction proceeds with considerable speed before the catalyst loses its activity. In the case of (IV), absorption of hydrogen also stops after about one-half the theoretical amount had been absorbed, and quinoline (VIII) and 4, 4′-diquinolyl sulfide 1, 1′-dioxide (IX) are obtained. This shows that the reduction of N-oxide group is followed by desulfurization by Raney nickel, by which the catalytic activity of Raney nickel is lost, and the unreacted material (IV) changes into (IX) during aftertreatment. 4-Mercaptoquinoline 1-oxide (X) itself does not undergo reduction of the N-oxide group and the starting compound is recovered almost completely.
Having some doubts about the position (N or N′) at which the acyl group is introduced in acylation of N-antipyrinyl-2-methylalanine amide (VIII), reported in the preceding paper, introduction of acyl group was examined in the most simple of the compounds with similar structure N-antipyrinylglycine amide (I). Comparison of infrared spectra of N-acetyl-N-antipyrinylglycine amide (II) and (VIII) proved that acylation of these compounds resulted in introduction of acyl group into N. Haloacylation of (I) Was also proved to give N-substituted compound.