The Effects of 2-amino-2-thiazoline hydrobromide (2-AT) on several skeletal muscle preparations were examined, and the following results were obtained. 2-Amino-2-thiazoline hydrobromide (2-AT) blocked neuromuscular transmission in the sciatic-sartorius of the frog and in the phrenic-diaphragm of the rat followed by an initial facilitation of the twitch ; this block was not antagonized by cholinesterase inhibitors such as neostigmine. In chicks, intravenous injection of 2-AT produced a spastic paralysis resemble that of depolarizing agents and in gastrocnemius preparations of hen, close arterial administration of 2-AT gave a contracture. Close arterial administration of 2-AT on tibialis anterior preparation of the cat produced a block of the neuromuscular transmission elicited by electrical stimulation of the sciatic nerve ; this block was not antagonized by neostigmine as in the case of diaphragm. The neuromuscular block produced by d-tubocurarine was recovered by 2-AT and vice versa. Furthermore no fall in tension occurs during the tetanic stimulation. From the results mentioned above it might be concluded that 2-AT was a depolarizing neuromuscular b1ocking agent and that its potency was one hundredth that of decamethonium bromide in the phrenic-diaphragm preparation of the rat.
The mechanism of the coloration reaction of 1, 2- and 1, 4-naphthoquinone derivatives with acid hydrazides in alkali hydroxide solution was examined. The substitution occurs in the 4-position in 1, 2-naphthoquinone-4-sulfonate, 3-chloro-1, 2-naphthoquinone, 4-chloro-1, 2-naphthoquinone and 1, 2-naphthoquinone. In the 1, 4-napthoquinone derivatives, coloration occurs by either substitution or addition in 2-chloro-1, 4-naphthoquinone, 2-methoxy-1, 4-naphthoquinone, 1, 4-naphthoquinone-2-sulfonate, 2-methyl-1, 4-naphthoquinone, 2-methyl-3-ch1oro-1, 4-naphthoquinone, 2-methyl-3-methoxy-1, 4-naphthoquinone, 2-chloro-3-methoxy-1, 4-naphthoquinone, 2-chloro-3-acetoxy-1, 4-naphthoquinone and 2-chloro-3-acetanilino-1, 4-naphthoquinone. Unsubstituted acid hydrazides react with 1, 4-naphthoquinones to show a more bathochromic coloration than the a-substituted acid hydrazides and it was assumed that this ia due to the possible enolization of the acid amide bonding of the reaction product.
From the correlations infered from the corrected ring 1H chemical shifts of 3-substituted pyridines and the substituent constants σπ, π-electron charge density distributions have been estimated, and compared with those given by SCFMO calcu1ations. The former show some discordances with the latter, but agree well with the chemical evidence.
Chemical shifts of the corrected ring 1H of 6-substituted quinoline derivatives have been examined with respect to the substituent constants σπ, and from which π-electron charge density distributions have been estimated. These molecular parameters are in good agreement with the chemical evidences, but afford several discordances with the results given by SCFMO calculation.
A method is described for the fractional determination of 1-methyl-3-[di(2-thienyl)-methylene] piperidine (I) and its N-demethylated derivative (II). The fractional determination was made possible by coloration of II on1y with a Ninhydrin-acetic acid reagent and by coloration of both I and II with a Ninhydrin-su1furic acid reagent after the method of Kase, et al. with minor modifications. By this method one can determine as little as 5 μg of I and 2.5 μg of II per ml of benzene extracts from biological materials. The color reaction with the Ninhydrin-acetic acid reagent may be used also for the determination of several kinds of N-unsubstituted piperidine, morpholine, and pyrrolidine derivatives.
5-Nitro-2-fury1 isocyanate and (5-nitro-2-fury1) vinyl isocyanate were each reacted with hydrazoic acid to obtain their corresponding (5-nitro-2-furyl) carbamoyl azide and (5-nitro-2-furyl) vinylcarbamoyl azide. These two latter compounds were reacted with strongly basic aliphatic amines (benzylamine, butylamine, isopropylamine, piperidine) of below pKb 4.6, and seven kinds of corresponding new urea compound were obtained.
Tritiation of d-biotin by the Wilzbach method and stability of the labeled compound obtained were examined. 3H-d-Biotin labeled by gas exposure method contained a considerable amount of decomposed products in some cases. The production of 3H-d-dethiobiotin, formed by cleavage of the chemical bond of C-S-C in d-biotin by a11owing to stand the tritiated material was confirmed by reverse isotope dilution analysis. The radioactive peak of 3H-d-biotin appeared at first as a larger one then decreased when this labeled compound was reexposed to tritium gas repeatedly. 3H-d-Dethiobiotin was also found to be formed as a by-product through the labeling procedure of d-biotin. Storage of 3H-d-biotin in MeOH-panthenol (10 : 1) solution was found to be the most protective condition from β-radiolysis induced by self-absorption.
The mode of interaction of aminopyrine with 2- and 3-aminobenzoic acids in aqueous media was studied through quenching of fluorescence of aminobenzoic acids by aminopyrine and related compounds, and formation of charge-transfer complexes was presumed from the fo11owing results. (1) Analysis of the data by the Stern-Volmer equation revealed that complexes of 1 : 1 molar ratio were formed between aminopyrine and aminobenzoic acids. (2) The F0/F-pH curves indicated the participation of non-ionized species of aminopyrine in the complex formation. (3) Relative fluorescence intensities of aminopyrine-aminobenzoic acid system increased with increasing ionic strength. (4) Quenching constants decreased with decreasing polarity of solvents expressed by Z-values. (5) There was a parallel relationship between energy levels of the highest occupied molecular orbitals of pyrazolone derivatives (antipyrine and its 4-substituted derivatives) and quenching constants. (6) In correspondence with the magnitude of energy level values of the lowest empty molecular orbitals of aminobenzoic acids, the quenching constants of mixed systems of pyrazolone derivatives and 3-aminobenzoic acid were larger than those of mixed systems of the respective pyrazolone derivatives and 2-aminobenzoic acid.
Adenosine and inosine were found to be solubilized markedly in 1 : 1 mixed aqueous solution of boric acid and sodium hydroxide. Guanosine, when added in high concentration, was gelatinized in the same solution. 2', 3'-O-Isopropylideneadenosine was not solubilized. In the case of adenosine and inosine, formation of soluble complexes of 2 : 1 : 1 (nucleoside-H3BO3-NaOH) molar ratio was ascertained through solubility measurements. The results of electric conductance measurements indicated formation of 2 : 1 complexes of nucleoside (adenosine or inosine) and boric acid. The pH-titration curves revealed that chelate compounds in which boric acid is bound to the sugar moieties of nucleosides were formed. Overall formation constants of chelation in acid and alkaline solutions were determined. Ionization constant of adenosine-boric acid chelate was also determined, which was in good accord with that of D-ribose-boric acid chelate. Two crystalline chelates were separated from acid and alkaline mixed solutions of adenosine and boric acid. The infrared spectrum of acid crystalline chelate was quite similar to that of 2', 3'-O-isopropylideneadenosine. Other analytical data such as elemental analysis, ultraviolet absorption, and solubility data were also consistent with those obtained in solution.
New compounds, thieno [2, 3-b] indoles (VII) were synthesized by the reaction of 3-phenacyloxindoles (I) and phosphorus pentasulfide. It was clarified that the thieno-indoles (VII) so obtained underwent the Diels-Alder reaction ; i.e. underwent the retro-Diels-Alder reaction when reacted with dimethyl acetylenedicarboxylate. The product (IX) obtained by the Diels-Alder reaction with maleic anilide further underwent amination to form the compound (X) and then IX, and alkaline hydrolysis of X gave the compound (XI).
The chemical shifts of the ring 1H of 6-quinoxalines have been corrected from nitrogen anisotropy, nitrogen electric field and ring current effects. The corrected shifts have also been correlated with the substituent constants σπ, and those corresponding to the π-electron charge density-ρ-distirubutions were estimated, and converted to ρ values.
Qualitative and quantitative studies were made on the reduction of 4-nitroquinoline 1-oxide by ascorbic acid. It was confirmed that 4-hydroxyaminoquinoline 1-oxide and 4-aminoquinoline 1-oxide were formed as the main and minor reduction products, respective1y, of the nitro compound. Methods for the determination of these reduction products were established, which included paper chromatographic separation and fluorometric measurements of N-oxide compounds. By using these methods examinations were made on the effect of pH, temperature, and ascorbic acid concentration on the yields of both reaction products. In a typical experiment carried out at pH 8.0 and 37°, 87% of the nitro compound was converted into the hydroxyamino compound. It was revealed that the formation of the hydroxyamino compound in alkaline solution was inhibited by the presence of thiol compounds, such as glutathione, L-cysteine, and thiamine. From the experimental results it was presumed that the amino compound was formed through self-oxidation-reduction of the hydroxyamino compound. Possible significance of the above observations in chemical carcinogenesis has also been discussed.
The ring-carbon in the 2-position of 2-(methylsulfonyl) quinoline (I) is active to nucleophilic reagents and the methylsulfonyl group is substituted (Chart 2). Application of the Grignard compound as the nucleophilic reagent resulted in the formation of 2-phenyl- or 2-alkyl-quinoline (VIII), but 2-quinolyl 2-quinolylmethyl sulfone (IX) was sometimes formed (Chart 3). Application of phenyllithium as the lithium compounds resulted in the formation of 2-phenylquinoline (VIIIa), as in the base of phenylmagnesium bromide, and IX. Reaction of I with pehnylacetonitrile in benzene, in the presence of sodium amide, afforded α-phenyl-2-quinolineacetonitrile (X) as would be expected from the result of reactions of (methylsulfonyl) benzodiazines. In the case of the reaction with ethyl malonate, products in which this ester had taken part were not obtained and only that with sodium amide, 2, 2'-iminodiquinoline (VII), was obtained. Reaction of I with ethyl cyanoacetate or with acetonitrile invariably gave bis (2-quinolyl) acetonitrile (XI), and a reaction with acetophenone gave the anticipated 2-(2-quinolyl) acetophenone (XII) (Chart 4 and 5). Finally, the reaction of I with ethyl cyanoacetate in dimethyl sulfoxide, in the presence of potassium cyanide, afforded quinaldonitrile (VI) and ethyl α-cyano-β-imino-2-quinolinepropionate (XIII), the latter assumed to have been formed by the addition of ethyl cyanoacetate to the -C=N group in VI (Chart 7).
Polarographic determination of 4-iodothymol was studied. Potassium chloride and tetraethylammonium bromide were used as supporting electrolytes. In the case of potassium chloride a wave owing to nonfaradaic current was obtained at about -1.2 V (vs.Hg pool), and the limiting current of this wave was not proportional to the 4-iodothymol concentration. On the other hand, in a tetraethylammonium bromide solution, a well-defined wave which was attributed to the reduction of 4-iodothymol was obtained at around -1.6 V (vs. Hg pool). The limiting current of this wave was proportional to the 4-iodothymol concentration and to the square root of Hg column height. The temperature coefficient for wave-height was 1.7% deg-1. These facts show that 4-iodothymol is reduced under the control of diffusion. 4-Iodothymol can be polarographically determined in the concentration range of 0.05 to 0.5 mg/m1. 4-Iodothymol in drugs was extracted with petroleum ether and determined with good accuracy by this method.
A procedure was proposed for the gas-liquid chromatographic determination of 4-iodothymol (I) which is the main component in an anthelminthic preparation, and thymol (II) which was possible to co-exist as impurity. The compounds were extracted from the sample with chloroform and determined with a gas-liquid chromatograph equipped with hydrogen flame ionization detector using n-heptadecane as an internal standard. Conditions for the determination were as follow ; stainless steel column ψ0.3cm×75cm, liquid phase 5% APG-L+1% PEG 6000, supportor Celite 545, carrier gas 30ml/min, programmed temperature 100-190°, 6°/min. Results of the determination of an anthelminthic preparation were shown. The method was also applied for the determination of I in Ascaris lumbricoides of swine treated with a solution (1 : 5000) of I for 5 hours at 37°. The mean recovery of I in the body of ascaride was 92.2% and the incorporated amount of I was about half of the quantity originally applied.
Some eighty N-alkyl-α-methyl propionanilide derivatives were synthesized for evaluation as local anesthetic, from which 2-methyl-2-propylamino propiono-o-toluidide hydrochloride was selected as the one most valuable for clinical use. A convenient synthesis of the latter was also described.
L-α-Tosylamido-β-propiolactone (V) was obtained by diazotization of L-2-tosylamido-3-aminopropionic acid (III), which was derived from L-asparagine (I), in aqueous organic acid solution at low temperature. N-Tosyl-L-serine (IV) and L-2-tosylamido-3-chloropropionic acid (VI) were selectively prepared from III in the other proper diazotization conditions. V was quantitatively hydrolyzed with water to yield IV, which afforded L-serine (VII) by the usual detosylation. Treatment of V with amines afforded the corresponding three type products, which were amino acid types (A), amide types (B) and betaine types (C).
Aminoethyl 4, 4-diphenyl-3-butenoates (IV) and 4, 4-diphenyl-3-butenamides (V) were prepared from 4, 4-diphenyl-3-butenoic acid (II). 4, 4-Diphenyl-4-hydroxybutyramides (VII) were prepared from γ, γ-diphenyl-γ-butyrolactone and VII was found to be derived to V by dehydration while saponification of V afforded II. VII was also obtained by the reaction of γ-phenyl-Δβ, γ-butenolide and piperidine to form 3-benzoylpropionyl piperidide (IX) and the Grignard reaction of IX with phenylmagnesium bromide. The hydrochloride of IVa, b, c showed a strong action of slackening the smooth muscles in vitro but its action in vivo was not satisfactory.
2-Nitroquinoline (I) is formed, together with carbostyril (III) when 2-iodoquinoline (II) is reacted with sodium nitrite in dimethylformamide or in dimethyl sulfoxide (Chart 1). Cataltic reduction of I over Raney nickel catalyst, at ordinary temperature and pressure, gives 2-aminoquinoline (IV) while reduction with glucose or arsenious acid, in the presence of sodium hydroxide, affords 2, 2'-azodiquinoline (V) as the product (Chart 2). The nitro group in I easily undergoes substitution with various nucleophilic reagents (Chart 3) but does not react with phenylmagnesium bromide or phenyllithium at ordinary temperature. I also does not react with ethyl cyanoacetate when heated in benzene, in the presence of sodium amide, but when heated in dimethyl sulfoxide, in the presence of potassium cyanide, they react to form ethyl α-cyano-2-quinolineacetate (XI), though in a low yield. XI is also formed from II by a similar sequence of reaction (Chart 4).
2-Chlorothioxanthen-9-one (IVa) was prepared from 2-aminothioxanthen-9-one (IIIa). IVa was also obtained from o-mercaptobenzoic acid, chlorobenzene and concentrated sulfuric acid. 2-Chlorothioxanthen-9-ol (Va) was prepared by the reduction of IVa with sodium amalgam and ethano1. Va was condensed with malonic acid to 2-chlorothioxan-thene-9-malonic acid (VIa), and the acid was decarboxylated to 2-chlorothioxanthene-9-acetic acid (VIIa). Similarly 3-chlorothioxanthene-9-acetic acid (VIIb) was obtained from 3-aminothioxanthen-9-one (IIIb). 4-Aminothioxanthen-9-one (IIIc) was prepared by the reduction of 4-nitrothioxanthen-9-one (IIc) with stannous chloride and hydrochloric acid, which result is contrary to that presented in the literature. 4-Chloro-thioxanthene-9-acetic acid (VIIc) was obtained from IIIc. 2-Diethylaminoethyl ester hydrochlorides (VIIIa-c) of VIIa-c were obtained. Oxidation of VIIa-c with hydrogen peroxide gave 2-, 3- and 4-chlorothioxanthene-9-acetic acid 10, 10-dioxide (IXa-c) from which were derived their 2-diethylaminoethyl ester hydrochlorides (Xa-c). The anti-acetylcholine, anti-barium chloride and anti-histamine activities of VIIIa-c and Xa-c were examined and it was found that the introduction of chlorine on the 2- or 3-position of thioxanthene rings of the 2-diethylaminoethyl ester hydrochlorides of thioxanthene-9-acetic acid and its 10, 10-dioxide resulted in the weakening of the antiacetylcholine activity.
In the survey of the root constituents of cultivated Japanese valerian, kesso root, a number of sesquiterpenoids have been isolated or detected. This valerian is characterized by containing sesquiterpenoids of the kessane skeleton (in particular, α-kessyl alcohol) in large quantities, but no kessyl glycol.
The flavonoid constituents of Panax ginseng C.A.MEYER were studied. A new natural flavonoid, named panasenoside (III), C27H30O16·H2O, mp 225-228° (decomp.), was isolated from this plant, together with kaempferol (I) and trifolin (II) (kaempferol-3-O-galactoside). The hydrolysis of III with diluted acid produced one mo1e each of kaempferol, glucose and galactose. The position of the sugar binding was proved to be on 3, since complete methylation of III with diazomethane and subsequent hydrolysis afforded 4', 5, 7-tri-O-methylkaempferol. III was also partially hydrolysed with a glycosidase of Aspergillus oryzae var. microsporus TRR-18 ("Vernase"), and trifolin was obtained. The panasenoside formula is therefore kaempferol-3-O-glucogalactoside.
Many reports have hitherto appeared on the roots of Ophiopogon japonicus KER-GAWLER var. genuinus MAXIM. (Liliaceae) but none on its fruits. From the stanppoint of the development of unused natural materials, components in the fruit of this plant were examined. Butanol extract of the fruits afforded a flavonol glycoside of mp 227-228° in 0.04% yield, and this glycoside was found to be composed of kaempferol with 1 mole each of glucose and galactose bonded at 3-position. Since this a new glycoside, it was named ophioside. The order of the bonding of sugars is now under examination.
As the components of C.grayanum MAXIM., a glycoside chrysosplenoside A (A) was previously isolated, a glycoside E (E) was also isolated recently. The seasonal relative abundance of A and E varied, A was the main compouent from March to May, while the abundance of E inereased in the later seasons. E, C25H28O13·H2O, mp 242-243°, was assumed to be 5, 2'-dihydroxy-3, 7, 4', 5'-tetramethoxyflavone 2'-monoglucoside. E was named chrysosplenoside E, and chrysosplenol E was the name given to the aglycone.
Condensation products of monomethylpyridazine 1-oxides and various substituted benzaldehydes were prepared and their anti-cancer activity was examined using Ehrlich carcinoma cells. 4-(p-Nitrostyryl) pyridazine 1-oxide (IVa), 5-(m-nitrostyryl) pyridazine 1-oxide (Vb), 5-(p-methoxystyryl) pyridazine 1-oxide (Vc), 5-(3', 4'-dimethoxystyryl) pyridazine 1-oxide (Vd), 6-(m-nitrostyryl) pyridazine 1-oxide (VIb) and 6-(p-methoxy-styryl) pyridazine 1-oxide (VIc) were found to have some anti-cancer effect against solid tumor, but none of the synthesized compounds showed a better effect than 6-mer-captopurine.
The optimum condition for the fotmation of bis (N-cyanomethyl-N-hydroxyamino) methane has been investigated. The reaction at -20 to -10°in weakly acidic media and at the molar ratio of formaldehyde-hydroxylamine-hydrogen cyanide of 3 : 2 : 2 gave the best yie1d. Products possessing an alkyl side-chain were similarly obtained from the reaction of two moles of 2-hydroxyamino-2-alkylacetonitrile with one mole of formaldehyde. The reaction route was discussed to deduce the route α as being more likely on the basis of the results obtained and from other observations.