Anti-carrageenin edema activity of compounds related to anthranilic acid was tested in rats by subcutaneous administration. Inhibitory effect of these compounds against heatinduced denaturation of bovine serum albumin and heat-induced hemolysis of dog red blood cells was also tested in vitro. Flufenamic acid and phenylbutazone, among the control drugs used here, demonstrated good correlation between their in vivo and in vitro potencies. Almost all of N-phenylanthranilic acid derivatives showed relatively high activity in both in vitro tests, regardless of their in vivo effectiveness. In both in vitro tests, good agreement was found in the potencies of these derivatives against protein denaturation and hemolysis, except that the compound with either CF3 plus COOH, COOH, or SO3H substituent had no effect on hemolysis. Acridine-4-carboxylic acid derivatives generally showing high toxicity in rats had no inhibitory effect on carrageenin edema even at a toxic dose, but significantly high inhibition in vitro was found in these derivatives. Acridine-4, 9-dicarboxylic acid derivatives were mostly inactive both in vivo and in vitro. Only the dichloro-substituted compounds slightly inhibited the development of edema in the hind paw of rats following their subcutaneous injection, and showed a marked inhibition in vitro against both protein denaturation and hemolysis. The dichloro-substituted derivative of 9-oxo-acridan-4-carboxylic acid was the most effective in the carrageenin edema test among the compounds related to anthranilic acid tested, except flufenamic acid. This derivative also greatly inhibited both protein denaturation and hemolysis in vitro. The trifluoromethyl substituted derivative was the second in its potency against carrageenin edema. Monochloro or monomethyl substitution resulted in a slight increase of the antiedema activity of 9-oxo-acridan-4-carboxylic acid, but not so much as the dichloro compound in enhancement of the in vitro activities.
Polarographic behavior of the methyloximes of testosterone, pregnenolone, estrone, isoandrosterone, and related ketosteroids was examined. Of these compounds, testosterone methyloxime showed two reduction waves, where the half-wave potentials were linearly dependent on pH. With respect to the reduction process of this compound, a mechanism involving two two-electron reductions has been proposed from the result of controlled potential electrolysis and of pH effect on the rate-determining step (Chart 1). The nonconjugated ketosteroid methyloximes also exhibited a reduction wave in acid solution. The half-wave potential and current constant measured at pH 1.00 are collected in Table IV. In addition, the nature of the polarographic wave characteristic to these compounds has been described.
A total of 75 kinds of compounds, comprising 27 kinds of phenylthiourea derivatives, 25 kinds of p-ethoxyphenylthiourea derivatives, and 23 kinds of 3-bromo-4-ethoxyphenylthiourea derivatives, were synthesized and screened for antibacterial activity using sensitive strain of human-type tubercle bacilli H37Rv with Tween-albumin medium, by the in vitro multiple dilution method. Inhibition of bacillary growth by the control agents was found in 0.0313 μg/ml of INH, 0.08-0.156 μg/ml of TBI, 0.313 μg/ml of PAS, and 1.56-3.13 μg/ml of DAT, but none of the synthesized compounds showed better activity, growth inhibition being seen with 3.13 μg/ml of 1-phenyl-3-(4-dimethylaminophenyl)-2-thiourea and with 6.25 μg/ml of 1-phenyl-3-(2-ethylhexyl)-, 1-(4-ethoxyphenyl)-3-(4-bromophenyl)-, 1-(4-ethoxyphenyl)-3-(4-acetylphenyl)-, 1-(4-ethoxyphenyl)-3-(4-butoxycarbonylphenyl)-, and 1-(4-ethoxyphenyl)-3-(2-diphenyl)-2-thioureas.
The reaction of 2-alkyl-3-oxoperhydro-2H-1, 4-thiazine-5-carboxylic acids (IVa-d) with sulfuryl chloride gave 2-alkyliden-3-oxoperhydro-2H-1, 4-thiazine-5-carboxylic acids (VIa-d). Similarly, 2-alkyl-3-oxoperhydro-2H-1, 4-thiazines (XVa-c) afforded 2-alkylidene derivatives (XVIIa-c). The reaction of 2, 2-dimethyl-3-oxoperhydro-2H-1, 4-thiazine-5-carboxylic acid (XIa) with sulfuryl chloride, on the other hand, gave 2, 2-dimethyl-3-oxo-3, 4-dihydro-2H-1, 4-thiazine-5-carboxylic acid (XIIIa) and 2, 2-dimethyl-3-oxo-3, 4-dihydro-2H-1, 4-thiazine (XIV), and the latter was also obtained by the reaction of 2, 2-dimethyl-3-oxoperhydro-2H-1, 4-thiazine (XVIII) with sulfuryl chloride. When 2-isopropyliden-3-oxoperhydro-2H-1, 4-thiazine-5-carboxylic acid (VIb) was allowed to react with bromine, 1-(α-bromo) isopropyl-2-oxa-5-aza-7-thiabicyclo [2. 2. 2]-octa-3, 6-dione (VIIIa) was obtained, presumably by the elimination of hydrogen bromide from the dibromide (VIIa) formed as an intermediate. VIIIb was also obtained by the reaction of VIb with sulfuryl chloride.
Pharmacological action of the saponin obtained from the crude drug, Mu-bie-zi (seed of Momordica cochinchinensis), was examined. 1) LD50 of this saponin in mice was 32.35 mg/kg by intravenous injection and 37.34 mg/kg by intraperitoneal injection. 2) Intravenous injection of 6.6 mg/kg of this saponin produced transitory stimulation of respiration and fall of blood pressure in rats. 3) This saponin increased peripheral blood flow in a dog. 4) This saponin inhibited cardiac movement in excised frog heart and inhibited intestinal motility in excised duodenum of a rabbit. 5) With the excised ileum of a guinea pig, 2×10-4g/ml of this saponin fortified the acetylcholine reaction and inhibited the papaverine effect but higher concentration (over 4×10-4g/ml) of this saponin produced irreversible contraction of the ileum. 6) Oral or subcutaneous administration of this saponin in a rat inhibited the carageenin edema on foot pad. 7) Physiological saline solution of 2×10-4g/ml of this saponin completely hemolyzed rabbit erythrocytes.
2-Picoline (I), 4-picoline (V), quinaldine (VI), 4-methylquinoline (VII), 2-methylbenzothiazole (VIII), and 2-methylbenzimidazole (XXX) as the compounds containing active methyl group were reacted with o-phenylenediamine (II), o-aminothiophenol (XIII), or o-aminophenol (XXVIII) as the ortho-substituted bifunctional compounds, in the presence of surfur, and corresponding 2-substituted benzazoles were obtained. Reaction conditions to obtain a good yield in the case of I and II were examined from the molar ratio of the reactants, reaction temperature, and time, and the optimal conditions were found to be the molar ratio of 1 : 1 -1.2 : 3 for I, II, and sulfur, reaction temperature of 160-170° (bath temperature), and reaction time of 10 hours.
Effect of 1, 1'-decamethylenediguanidine dihydrochloride, phenylhydrazine hydrochloride, 5-nitrosotropolone, 2-(2-aminoethyl)-1'-(p-chlorophenyl) isothiuronium bromide hydrobromide (AEPCIT), vitamin K3, 2-methyl-3, 6-dibromo-1, 4-benzoquinone, ubiquinone-0 (UQ-0), UQ-7, and UQ-9 on the incorporation of mevalonate [2-14C] into cholesterol was examined in the rat liver homogenate. Of the test compounds, 1, 1'-decamethylenediguanidine dihydrochloride, vitamin K3 and 2-methyl-3, 6-dibromo-1, 4-benzoquinone showed a potent inhibitory action, but phenylhydrazine hydrochloride and UQ-0 showed only a slight inhibition. Further, examination was made on the effect of 1, 1'-decamethylenediguanidine dihydrochloride, vitamin K3, and 2-methyl-3, 6-dibromo-1, 4-benzoquinone on the incorporation of mevalonate [2-14C] into total nonsaponifiable lipid and, using a thin-layer chromatogram scanner, changes in the distribution of radioactivity of the intermediates in total nonsaponifiable lipid due to them were examined. In the case of 1, 1'-decamethylenediguanidine dihydrochloride and vitamin K3, only the peak of squalene remained, the peaks of cholesterol and lanosterol disappearing. At the same time they partially inhibited the incorporation of mevalonate [2-14C] into total nonsaponifiable lipid. On the other hand, in the case of 2-methyl-3, 6-dibromo-1, 4-benzoquinone, the peaks of radioactivity were not found, and also the incorporation of mevalonate [2-14C] into total nonsaponifiable lipid was inhibited completely. On the basis of these experiments, the inhibition sites of test compounds on cholesterol biosynthesis were discussed.
A new triterpene glycoside, ovalifolioside (I), C35H58O7, was isolated from the leaves of Lyonia ovalifolia var. elliptica. Acidic hydrolysis of I gave an aglycone, ovalifoliogenin (II), C30H50O3 and L-arabinose. From the NMR and mass spectral data, II was assumed to be a pentacyclic triterpene derivative, possessing three hydroxyl groups in A and B rings, and no hydroxyl group in D and E rings. II formed an acetonide (IV) with acetone and p-toluenesulfonic acid. IV was oxidised with chromic acid to a ketone (V), which was reduced by the Wolff-Kishner method to an isopropylidene compound (VI), C33H54O2. VI was identified with the acetonide of 3β, 23-dihydroxyolean-12-ene, which was derived from hederagenin via an unambiguous route.
Three kinds of saponin, named senegin-II, -III, and -IV, were isolated from Senegae radix (root of Polygala senega LINNE var. latifolia TORRY et GRAY, Polygalaceae). Senegin-II, C70H104O32·4H2O, colorless needles, mp 247-248°, is a glucoside of presenegenin bonded with rhamnose, fucose, xylose, galactose, glucose, and 3, 4-dimethoxycinnamic acid. Senegin-III, C69H102O31·4H2O, crystalline powder, mp 247-248°(decomp.), is a glucoside of presenegenin bonded with rhamnose, fucose, galactose, glucose and 4-methoxycinnamic acid. Senegin-IV, C75H112O35·4H2O, crystalline powder, mp 250°(decomp.), is a glucoside of presenegenin bonded with 2 moles of rhamnose, fucose, xylose, galactose, glucose, and 4-methoxycinnamic acid. In addition to these substances, the presence of 1, 5-anhydro-D-sorbitol and phenolic glycosides was detected.
In the reaction of 3-indoleacetonitrile derivatives and carbon disulfide, indole derivatives without a substituent in 2-position afford ketenethioacetal derivatives (II) while those with carbonyl or carboxyl in 2-position form condensed thiopyrone ring, thiopyrano-[3, 4-b] indole derivatives (III). Substitution of the methylthio group in these II and III compounds with amines was carried out. In the reaction of III and hydrazine hydrate, the product was a ring-cleaved 2-(2-hydrazinocarbonyl-3-indolyl)-3-hydrazino-3-mercaptoacrylonitrile (IX) whose treatment with ketone or aldehyde afforded a cyclized product, 4-cyano-3-mercaptopyrido [3, 4-b] indole derivative. Treatment of IX with carbon disulfide and dimethyl sulfate resulted in the formation of a compound with a thiadiazole ring, 5-cyano-3-methylthio-1-oxo-1, 3, 4-thiadiazolo [2, 3-b] harman (XV).
A aromatic halogeno or nitro compounds (Va-1) which are reactive to nucleophilic reagents reacted with N-aminopyridinium halide (I) in sodium ethoxide solution and afforded pyridine N-arylimine derivatives (Via-i) as stable crystalline product. This is a new synthetic method for the preparation of pyridine N-arylimines. Ultraviolet (UV) and nuclear magnetic resonance (NMR) spectral data of these compounds suggest that the π-electron density of the pyridine and the aryl group is increased by distribution of the negative charge at the imine nitrogen.
The previous assumption that the aromatic ring systems of pyridine N-arylimine (II), a kind of stable pyridinium N-ylide, have a greater π-electron density than that of the corresponding parent compounds was tested by the nitration of pyridine N-(nitrophenyl)-imines (IIa-e). In this reaction, the benzene ring was first nitrated easily to the trinitro compound (IIc) and a nitro group was further introduced into 4-position of the pyridine ring, which was reactive to nucleophilic reagents and underwent substitution to afford alkoxy and chloro compounds (III, IV, V). This reactivity of the pyridine ring is similar to that of pyridine N-oxide derivatives. The imine nitrogen of pyridine N-arylimines was oxidized with hydrogen peroxide accompanying the N-N bond cleavage to convert to the nitro group together with other minor products.
Starting with 4-chloro-1-methyl-5-nitroimidazole (V), 4-substituted (alkoxy, aryloxy, alkylthio, alkylamino, arylamino)-1-methyl-5-nitroimidazole (VI), 5-substituted (alkyl or aryl)-3-(1-methyl-5-nitroimidazole-5-yl)-1, 2, 4-oxadiazole (XII), and 5-substituted (alkyl or aryl)-2-(1-methyl-4-nitroimidazole-5-yl)-1, 3, 4-oxadiazole (XVI) were synthesized (Table I-V). Antimicrobial activity of their derivatives in vitro was examined and the results are listed in Table VI.
2-Methyl-4(or 5)-substitutedstyryl-5(or 4) nitroimidazole (X), 1, 2-dimethyl-4-substitutedstyryl-5 (or 4)-nitroimidazole (XI), and 1, 2-dimethyl-4-nitro-5-substitutedstyryl imidazole (XII) were prepared respectively by the reaction of 2, 4(or 5)-dimethyl-5(or 4)-nitroimidazole (IV), 1, 2, 4-trimethyl-5-nitroimidazole (V), and 1, 2, 5-trimethyl-4-nitroimidazole (VI) with benzaldehyde derivatives (X) in the presence of piperidine (Table I, II and III). 1, 2-Dimethyl-4-nitro-5-[(β-hydroxy-β-phenyl) ethyl] imidazole (XIII), 1-benzyl-2-methyl-4-nitro-5-[(β-hydroxy-β-phenyl) ethyl] imidazole (XIV), and 1-β-hydroxyethyl-2-methyl-4-nitro-5-[(β-hydroxy-β-phenyl) ethyl]i midazole (XV) were prepared respectively by the reaction of VI, 1-benzyl-2, 5-dimethyl-4-nitroimidazole (VII), and 1-β-hydroxyethyl-2, 4-dimethyl-5-nitroimidazole (VIII) with X in the presence of sodium ethoxide (Table IV, V and VI). 1-Methyl-2, 4-bis [β-(2-furyl) vinyl]-5-nitroimidazole was obtained by the reaction of V with furfural (XVI) and 1, 2-dimethyl-4-nitro-5-[2'-furyl-3'-(1", 2"-dimethyl-4"-nitro-5"-imidazolyl) propyl] imidazole (XVIII) was obtained by the reaction of VI with XVI. Antimicrobial activity of their derivatives in vitro was examined and the results are listed in Table VII.
Examinations were made on the effect of swelling characteristics of a gel on the different property between lower and higher G-number gets. Measurement was made on the volume of the gel matrix (Vg) of Sephadex G-10 to G-200 and Bio-Gel P-2 to P-100 to find the isotherm from adsorption of some dyes from aqueous solution. The Vg value of Sephadex G-10 was about 16 times greater than that of G-200. G-series of Sephadex and P-series of Bio-Gel were divided into two groups from the markedly different Vg values between lower and higher G- or P-number gels. Adsorption isotherm of food dyes was divided into three classes according to the shape of the initial slope of the curve; (1) S-2 curve for food red 3 on Sephadex G-10, (2) L-2 curve for food violet 1 on Sephadex G-10, and (3) constant partition curve for food blue 1 on Sephadex G-10, and for food violet 1, food red 3, and food blue 1 on Sephadex G-200.
A method is described for the purification of enterogastrone, an inhibitor of the secretion of gastric juice, from the extracts of the upper part of porcine small intestine. The starting material used was Tannate purified enterogastrone concentrate (Greengard and Grossman), which was subjected to column chromatography on Sephadex G-100 and eluted with 0.2M acetic acid. Turther purification of the active material from gel filtration was made by column chromatography on CM-cellulose. The purified enterogastrone so obtained showed inhibitory activity 200 times that of the fraction obtained by the first purification step.
In order to clarify the solubilizing action of acid amides, quantum chemical approach using LCAO-MO method was made and the following results were obtained. 1) On the basis of molecular orbital considerations, it was found that acid amides act as electron acceptors. 2) Solubilizates which have electron-donating tendency towards acid amide formed more stable complexes than solubilizates which have electron-accepting tendency. 3) Formation constants of complexes had a linear relationship with parameters of energy level of the lowest vacant molecular orbitals (λιυ) of aromatic acid amides, and π-electron densities of the oxygen atom in acid amide groups. 4) The extent of planarity of the solubilizate molecules was correlated to formation constants of complexes.
For the synthesis of glaupalol, a new type of furanocoumarin isolated from the rhizomes of Glaucidium palmatum SIED. et ZUCC., attempts were made without success to prepare the intermediate, 1-(3, 6-dihydroxy-2-methyl) phenyl-3, 3-dimethyl-4-penten-1-one (2) which is obtained on alkaline fusion of glaupalol and can be reconverted into glaupalol by its carboxylation with dimethyl carbonate and sodium hydride. On the other hand, the Claisen rearrangement of synthesized 4-(3, 3-dimethylallyloxy)-6-methoxy-5-methylcoumarin (45) in N-methylpiperidine leads to the formation of O-methylglaupalol (4) which is readily converted into glaupalol (1) with boron tribromide in methylene chloride. The key intermediate (45) was synthesized from 6-hydroxy-2-methylbenzoic acid (29). Potassium persulfate oxidation of the acid (29) gives the toluhydroquinone carboxylic acid (30) which is partially methylated with methyl iodide and potassium carbonate to furnish 6-hydroxy-3-methoxy-2-methylbenzoic acid (33). Treatment of the O-acetate (38) of this acid with thionyl chloride followed by diethyl malonate in the presence of lithium hydride, and subsequent hydrolysis with acetic acid yields 4-hydroxycoumarin (3) which is converted into the dimethylallyl ether (45) using its silver salt and 1-bromo-3-methyl-2- butene. Synthetic glaupalol was identical in all respects with natural glaupalol.
Reaction of quinoline 1-oxide (I) with potassium cyanide in the presence of tosyl chloride was examined. Reaction in a mixture of chloroform and water gave not quinaldonitrile (II) but carbostyril, whereas II was formed in a good yield when tosyl chloride in ethanol was added at -10° to a mixture of I in ethanol and potassium cyanide in a small amount of water, followed by stirring the reaction mixture at the same temperature for 3 hours. The latter procedure was applied to some aromatic N-oxides of pyridine series and was found to be generally applicable (Table I).
The permeability of potassium chloride through the gelatin membrane undissolved by heating is discussed by considering both the velocity of permeation at the membrane surface and permeability inside the membrane. The correlation between the reciprocal of the apparent membrane permeability coeffiicient, defined by the concentration difference, P', and thickness of membrane, L, was found to be linear. The permeability coefficient in the membrane, P*, the velocity of permeation at the interface, k, and the corresponding membrane thickness, L*, expressing resistance at the interface to diffusion, can be calculated from this linear correlation. The difference in the permeation condition affects k but not P*. When k>>2P*/L, the rate-determining process is in the membrane and when k>>2P*/L, the rate determening process is at the interface. Using our apparatus, the mechanism of the membrane permeability for the gelatin membrane is a coupled mechanism. In a thin membrane, the permeation at the membrane interface works as the rate-determining process and the permeation in the membrane takes the place with increasing L. With increasing the gelatin content, KCl permeability in the membrane is reduced and the apparent membrane constant designating its porosity is also reduced. Even if the gelatin content varied, k and L* keep constant.
Autoxidation of diphenylmethane was examined at 35° in dimethyl sulfoxide-t-BuOH (4 : 1) solvent in the presence of KOH (initial concentration, CK0). The reaction proceeds cosecutively, according to the following scheme. [numerical formula] The order and rate-constant of each reaction were determined as follows : -dCD/dt=kD1CDCK0 (eq.3), dCP/dt=kH1CHCK00.5(eq.15) It was found that the reaction of diphenylmethane to benzohydrol was inhibited by benzohydrol, and that the rate-constant, kD1, depended on CH as kD1=kD2/(1+ACH2)) (eq. 4). The constant, kD2, decreased during the reaction and kD2 was regarded as a function of reaction time, t, and represented it as AD2=1/(p+qt0.5) (eq. 9). The constant, kH2, depended on water content, CW0, as kH1=kH2/(1+αCW02) (eq. 16). Several constants were determined from these experiments, and the rate equations were found as follows : [numerical formula]
In order to examine their oral progestational activity, some 17α-acyloxy-3, 5-pregnadien-20-one derivatives (IIIa, IIIb, IIIc, IIId, IIIe, VI, VII, VIII, and IX) were synthesized. III, VI, and VII were obtained by dehydration of 4-en-3-ol derivatives, which were obtained by selective reduction of 17α-acyloxyprogesterone derivatives with sodium borohydride, in the presence of phosphomolybdic acid in acetone solution at room temperature or boiling temperature. VIII and IX were obtained by the reaction of 17α-acyloxyprogesterone derivatives with acetyl chloride at room temperature. The effect of substituents in 3, 5-diene derivatives on the oral progestational activity was discussed.