The anti-inflammatory effect of bimetopyrol [2-methyl-4, 5-bis (p-methoxyphenyl) pyrrole], a newly synthesized pyrrole compound, was examined. Bimetopyrol is effective against carrageenin-induced rat paw edema ; the potency is 9.6 (6.2-15.8) and 5.4 (4.3-7.1) times more potent than phenylbutazone when given orally in tragacanth suspension and in olive oil solution, respectively. The spectrum of anti-inflammatory and other pharmacological activities of this compound is generally in common with those of other nonsteroidal anti-rheumatic drugs. Thus, bimetopyrol suppresses ultraviolet-induced erythema in guinea pigs and acetic acid-induced writhing in mice, and increases pain threshold in the yeast-injected rat paw. Also, it prevents the yeast-induced fever in rats. Bimetopyrol is not effective against permeability changes induced by serotonin, bradykinin, and dextran, again in agreement with the data obtained by indomethacin or phenylbutazone. As further comparative studies between bimetopyrol and other anti-inflammatory drugs, histological examination on cotton pellet granuloma and emigration rate of leucocytes were investigated both in vivo and in vitro and characteristic aspects of bimetopyrol were discussed. The acute LD 50 of this compound was calculated as 2, 300 mg/kg by oral administration in male rats.
The effect of bimetopyrol [2-methyl-4, 5-bis (p-methoxyphenyl) pyrrole], a novel anti-inflammatory drug, on adjuvant arthritis was compared with that of phenylbutazone, flufenamic acid, and indomethacin. 1) In the exploratory prophylactic experiment on adjuvant arthritis, all four drugs suppressed swelling in adjuvant-injected and non-injected feet in different degrees, where Bimetopyrol was several times more potent than phenylbutazone. Morbid anatomical evaluation of the animals, such as in body and organ weights and albumin-globulin ratio in serum, was also practically in agreement with that observed in foot swelling. 2) In order to obtain a more precise potency ratio between bimetopyrol and phenylbutazone, a single self-contained experiment was carried out, specified by the use of wellestablished arthritic animals, the injection of adjuvant into the tail rather than the foot and the use of a single preparation for each drug throughout the experiment. By 6-point bioassay, therapeutic potency of bimetopyrol was revealed to be 5.2 to 6.9 times more potent than phenylbutazone. 3) Possible clinical application of bimetopyrol being taken into account, medication of this drug was carried out with arthritic rats after a prolonged pretreatment with dexamethasone. The rebound of foot swelling occurring after withdrawal of corticosteroid was suppressed completely by replacement with bimetopyrol. Furthermore, thymic atrophy caused by corticosteroid was favorably recovered after this type of substitution of drugs.
Pharmacological properties of troponoid compounds were examined with tropolone (I), 5-hydroxytropolone (II), 2-C-methoxytropone (III), 2-aminotropone (IV), 5-aminotropolone (V), 4-aminotropolone (VI), 2, 5-diaminotropone (VII), 3-isopropyl-5, 7-dimorpholinomethyltropolone (VIII), 5-hydroxy-3, 7-dimorpholinomethyltropolone (IX), and 3, 5, 7-trimorpholinomethyltropolone (X). 1) I, V, and VII showed a pressor action, while VII and VIII showed a depressor action in urethaenaenesthetized rats and cats. VIII slightly supressed the pressor action induced by norepinephrine and tyramine. The mechanism of the pressor action induced by I is not clear, but it is suggested that a part of the mechanism is related to α-action. 2) V markedly potentiated the positive chronotropic action induced by isoproterenol in the heat of spinal cats. This potentiation may be due to the inhibition of cathecol-O-methyltransferase. 3) I, V, VI, and VII supressed the cardiac contractile response in isolated guinea-pig heart. 4) VII (1 mg) caused a slight vasoconstriction in the isolated perfused rabbit ear. 5) I, V, VI, and VII potentiated and IV inhibited the contraction of guinea-pig vas deferens induced by norepinephrine. 6) VII (10-5g/ml) completely inhibited the contraction of vas deferens evoked by electrical stimulation of the preganglionic fiber in the guinea-pig hypogastric nerve-vas deferens. 7) V, VII, and VIII relaxed the isolated mouse illeum, while I, IV, V, VI, VII, and VIII (10-4g/ml) inhibited the contraction of mouse illeum induced by acetylcholine. 8) All the test compounds did not show any muscle relaing action in phrenic nervediaphragm preparation of rats. 9) Acute toxicity in mice was also tested.
Reaction of thiamine analogs (Ib-d) with dialkyl benzoylphosphonates (IIa-b) in the presence of triethylamine afforded ring-expanded products, 1, 4-thiazine derivatives (IIIb-d), which were converted to monocyclic compounds (IVb-d) by hydrolysis. In the reaction of Ic-d with IIa-b, it was necessary to add IIa-b before triethylamine. It was found that the difference between the reaction behavior of Ia-b and that of Ic-d toward IIa-b is attributable to the substituents at the C-4 and C-5 positions which affect the reactivity at the C-2 position in the thiazolium ring.
Studies were made on interactions of β-cyclodextrin with six kinds of barbituric acid derivatives and thiopental. It was found by solubility analysis that complexes were formed between β-cyclodextrin and all the pharmaceuticals tested. Barbituric acid derivatives having a cyclic substituent at 5-position showed a higher degree of interaction with β-cyclodextrin than those having acyclic substituent. Thiopental, 2-thiobarbituric acid derivative formed a more stable complex with β-cyclodextrin than pentobarbital, which is a barbituric acid derivative and has the same substituent at 5-position as thiopental. Stability of aqueous preparations of sodium salts of these barbituric acid derivatives was examined and it was found that dissolved salts separated out gradually as free acids by absorption of atmospheric carbon dioxide and that chemical decomposition due to ring fission of the barbituric acid derivatives was practically negligible. Deposition of free barbituric acid derivatives from these solutions was retarded to some extent in the presence of β-cyclodextrin.
^<220>Rn from 228Ra in thorium series was deposited electrically on a negative platinum plate. 208T1 was isolated from the above by a small-type electrophoresis and its half life was determined. The period of standing after isolation of 220Rn was discussed from the theory of the production and decay of 208T1. 207T1, which is isolated from the incipitate of 219Rn from 227Ac and whose γ-ray radiation (0.2%) is hardly identified was isolated and ascertained by the same procedure from the experimental result of 208T1. Electrolyte of 0.1M citric acid and cellulose acetate are used as a support at 1000 V/11 cm for the electrophoresis. The operating time from the parent nuclide to the isolation and determination should be in all within 4 min (electrophoresis, 2 min and other treatment, 2 min). The above result makes it clear that the small-type electrophoresis can be used for the isolation of short half-life nuclides such as 208T1 (3.1 min) and 207T1 (4.79 min).
A quantitative method was devised for measuring the interparticle cohesive force in a loosely packed powder bed. A particulate solid was packed in a vessel without applying an external compressive force. A small disk with thin layer of an adhesive agent on its lower surface was placed on the surface of the packed bed applying a slight pressure so that the surface particles of the bed would stick to the disk. The disk was then pulled out and the minimal force, Ft, required to remove the particles sticking to the disk from the surrounding particles was measured by a torsion balance. The apparent cohesiveness, αc, is defined by the equation αc=F/W, where F is (Ft-W) and W is the weight of the particles sticking to the disk. The effect of disk area, load, and nature of adhesive agent on the values of F were measured and the optimal conditions were determined as 0.24 cm2 of disk area, 400 mg/cm2 of load, and the petrolatum as the adhesive agent. It is suggested that the force, F, obtained by this method is the total value of four type forces, that is, adhesive force, fA, leaning force, fL, entanglemental force, fE, and defacing force, fD.
Nine kinds of 6-phenylimidazo [2, 1-b] thiazoles (III) were prepared in a good yield by treatment of 2-aminothiazoles (I) with phenacyl bromide in BuOH for 2 hr at 110-115°. 6-Methylimidazo [2, 1-b] thiazoles (IV) were prepared in a good yield by treatment of 2-imino-3-(2-propynyl)-4-thiazoline hydrobromides (II') with an equivalent amount of alkali in EtOH. Thiocyanation of III and IV was carried out by the bromine and urea method, and the corresponding 5-thiocyanato derivatives (V, X) were obtained in a good yield. Thiocyanation of 6-phenyl-2, 3-dihydro-imidazo [2, 1-b] thiazoles (XII) proceeded similarly, giving the 5-thiocyanatoderivatives (XIII) in a good yield. Some of the related bromo compounds were also prepared by bromination and by ring closure of bromothiazoles.
In continuation of the previous work on the effect of polydispersibility on the sedimentation volume of globular particles of contact-coagulability and attraction-coagulability, the effect of polydispersibility on the sedimentation volume on non-attracting particles was examined. There is no attraction between such particles but they do undergo coagulation at a certain probability when the particles come into contact. It was thereby found that when the particle size is not too different, the particles form a sediment layer same as in the case of monodispersible particles so that there is no great change in their sedimentation volume. When the mixture contains particles of different size, small particles enter into spaces left by large particles so that the sedimentation volume as a whole becomes smaller. This tendency was found to become greater as the difference in the size of particles became greater and adhesion probability became smaller, and when the number of smaller particles became greater.
Hen egg white lysozyme was acetylated with acetic anhydride, the acetylated lysozyme was fractionated by CM-cellulose column chromatography, and four main peaks termed FI, FII, FIII, and FIV were obtained. The properties of FI, FII, and FIII were the same as described in the previous paper, while FIV possessed about 6 unmodified amino groups per molecule and retained 33% of the relative activity of M. lysodeikticus as compared with native lysozyme. Physicochemical properties, i.e., optical rotatory dispersion, pH titration of tyrosine, and differential spectrum of the enzyme by glycol chitin were investigated. Helical contents decreased about 5%, and buried tyrosine was easily titrated by spectrophotometry, and the difference in spectrum at 293 nm of the enzyme-substrate complex had a lower value in FII and FIII, but FIV exhibited 122% relative activity of the lysozyme. Quantitative precipitin reaction and immunodiffusion revealed that the antigenic determinants decreased by chemical modification. From the previous results, it might be concluded that FIV has lost the antigenic determinant though it retained the nature of a native lysozyme.
Condensation reaction of Δ1, 10-hexahydroquinolizine (I) with phenylhydrazine, semicarbazide, hydroxylamine, and hydrazine hydrate afforded 10-(phenylhydrazino) quinolizidine (II), 10-semicarbazidoquinolizidine (V), di (10-quinolizidinyl) hydroxylamine (IX) and 1, 2-di (10-quinolizidinyl) hydrazine (XI), respectively, accompanied with 10, 10'-azodi-(quinolizidine) (XII). Methiodide of V agreeded with that VI of 1-methyl-6-semicarbazonodecahydroazecine derived from known 1-methyl-6-decahydroazecinone (VIII).
Various derivatives of N-aminopyridine were synthesized and these derivatives were found to undergo reaction with various nucleophilic reagents under variety of conditions. Progress of this reaction seemed to depend on the activity of the reagents as a nucleophilic species, substituent effect of the substrate, and reaction conditions. As for the substituent effect, electron-withdrawing nature of the substituent on the amino group determines the activity of the substrate while that of the substituent on ring carbon determines the orientation of the reaction, the greater the electron-withdrawing nature of ring carbon, the greater the orientation towards the 2-position. The reaction results in addition and/or substitution reaction and the reaction can be explained witho utinconsistency by assuming the progress of this reaction in two steps of addition and liberation even when only a substitution product is obtained. Depending on whether the addition step is reversible or irreversible, each step will be controlled either by thermokinetics or by chemical kinetics, and orientation towards the 4- or 2-position will be determined by which of these forces would be stronger. Discussions are made on this mechanism.
Reduction of aristolochic acid (I) with sodium borohydride in diglyme was examined. I was reduced to 9, 10-dihydroaristolochic acid (II) at room temperature in a 80-85% yield, with the formation of a small amount of 3, 4-methylenedioxy-8-methoxyphenanthrene-1-carboxylic acid (VII) as a by-product. On heating at 90-100°, I was reduced to VII exclusively in a 75-80% yield. On the other hand, hydroboration of I at room temperature gave 1-methyl-3, 4-methylenedioxy-8-methoxyphenanthrene (IX) and 3, 4-methylenedioxy-8-methoxy-10-nitrophenanthrene (IV).
Acetamide derivatives of benzomorphans and 1, 3-dimethyl-1, 2, 3, 4, 5, 6-hexahydro-1, 5-methano-3-benzazocine were synthesized in order to examine the pharmacological effect of the acetamide group. The stereochemical pathways in the catalytic reduction of the oximes (II-A, II-B, II-C) with hydrogen and the Adams catalyst under several conditions were discussed.
(+)-Rugulosin from Penicillium variabile, viridicatin and viridicatol from P. cyclopium, and citreoviridin from P. citreo-viride were isolated in a high yield and identified as the main toxic metabolites in their culture on rice of these fungi which were found in some japanese foods like rice, Miso, and soybean sauce. Ergosterol and its peroxide were also isolated from P. variabile as by-products.
In order to develop a new molecular species of compounds with antibiological activities by the application of radiation-chemical reactions, a model experiment was carried out to see whether chloramphenicol would be formed by irradiation of 50Co γ-ray to some mixtures of nitrobenzene, p-nitrophenol, or p-bromonitrobenzene, and 2-dichloroacetamido-propane-1, 3-diol. The results showed that after irradiation of 100-200×104 R, antibacterial activities against E. coli and St. aureus of only the aqueous mixture of nitrobenzene and 2-dichloro-acetamidopropane-1, 3-diol were about 4-8 times greater than those of each irradiated component or of the mixture of each irradiated component. No formation of chloramphenicol itself was, however confirmed in the irradiation products by means of paper chromatography, bioautography, radiopaper chromatography, or Sephadex G-10 gel filtration.
Circular dichroism (CD) and optical rotatory dispersion (ORD) of peracetates of 1, 2-dideoxy-1-nitro alcohols, in which C-3 is the nearest asymmetric carbon to the nitro chromophore, were measured. Their CD curves showed a maximum at about 270 mμ. A second absorption band near 310 mμ was suggested by a tailing of the CD curves toward longer wavelengths. Compounds that have an acetoxyl group on the left side of C-3 in the conventional Fischer projection formula exhibited negative CD maxima, while a compound which has an acetoxyl group on the right side of C-3 showed a positive CD maximum.