Many difficulties occur as for instance consideration on packing and compression conditions on compression designs and no report has been established thus subject. We propose a dimensionless number [numerical formula], where, m is the packed weitht, D is the diameter of a flat type compression punch, S is the tablet thickness and ρ is the density of the packed substance. It is possible to express several compression equations by Nb, because the relation between Nb and porosity is [numerical formula]. In the middle pressure region used in usual pharmaceutical tableting process Balshin-type-plot (log P=f(Nb)) is suitable for compression designs, in the low pressure region Kawakita-type-plot ([numerical formula]) is better, and in the high pressure region, Athy-Konopicky-type-plot (P=log n) is more convenient.
As a result of the colouring detection of glucuronic acid by the hydroxamic acid method, the reaction and the equilibrium between glucuronic acid (GH) and its lacton (GL) were re-examined. The reaction scheme, [chemical formula], described in a previous paper was confirmed. By the determination of the influence of pH and buffer concentration on the rate constants, following equation were also obtained. [chemical formula]
Binding of pentobarbital (sodium 5-ethyl-(1-methylbutyl)-barbiturate) with plasma of male and female rats, dogs, and monkeys was studied in vitro using the method of equilibrium dialysis in 1/15 M phosphate buffer (pH7.4). Rat plasma had the most extensive binding capacity, followed by dog and monkey plasma, and the plasma of female had more extensive capability than male in rat and dog, but it was reversed in monkey. The use of ether as an anaesthetic at the time of blood collection lowered the extent of binding.
Metabolism of Norphenylephrine (NP) in animals as studied as a part of the biological studies of the compound.3H-labeled NP was injected intraperitoneally to the rat, and the acidic, basic and neutral metabolic products were separated after hydrolyzing the collected urine by the usual way. After this treatment, the identification of the metabolites in the blood and the urine of rabbit, rat and guinea pig was carried out by using gas-liquid chromatography, paperchromatography and thin-layer chromatography. NP, the N-monomethyl derivative of NP(P) and its oxidation product, m-hydroxymandelic acid (m-HMA), were isolated from rabbits' urine. NP, P and its oxidation product, m-hydroxyphenyl ethyleneglycol (m-HPG) and m-HMA were found in rats' urine. In guinea pigs' urine, NP, m-HPG and m-HMA were detected by comparison with the authentic sample.Metabolites in blood were the same as described in the case of urine except that no P was detected in rats' and rabbits' blood.
Bromelain in a concentration of 0.1 mg/ml, likewise chymotrypsin, trypsin, and papain, potentiated the response of isolated guinea-pig ileum to bradykinin, but not to acetylcholine and histamine. In higher concentration of the enzymes, however, the contraction induced by bradykinin, acetylcholine and histamine was depressed. The intensity of this potentiation or depression effect was correlated with the caseinolytic activities of the proteolytic enzymes. This phenomenon was not found in the case of compounds with a large molecule such as DNA, casein, and egg albumin. Heat denaturation of the proteolytic enzymes eliminated their potentiation or depression effect. Even if the proteolytic activity of bromelain or papain was completely inhibited by p-chloromercuribenzoate, this potentiation or depression effect was still present. These inactivated enzymes were not reactivated by incubation with guinea-pig ileum. From these results, possible mechanism of this effect was discussed.
Polarography of thiachromone 1, 1-dioxide (I) derivatives was carried out and the relation between structures and half-wave reduction potentials (E1/2) was examined. Compound I exhibits two polarographic waves at -0.431 and -1.096 V vs. S.C.E. (pH 6.45). It is concluded through controlled potential electrolysis that the 1st wave is the two-electron reduction wave of △2 between SO2 and C=O groups, and the 2nd wave is that of C=O. The 1st wave is a diffusion current and decreases in wave height at pH above 6 due to decomposition. The height of the 2nd wave increases with increase of pH up to 7, i.e. that is kinetic current, while the reduction wave of thiachromanone 1, 1-dioxide (VI) is a diffusion current. It may be presumed that on polarographic reduction of I, VI is not produced directly from I but via any intermediate which depends on pH. Conjugation effect of SO2 group and substituent effect on E1/2 of △2 and C=O of thiachromone 1, 1-dioxide derivatives are also discussed.
Syntheses were carried out on 4, 5, 6, 7-tetrahydrobenzothiazole-2-thiol, 5, 6-dihydro-4H-cyclopentathiazole-2-thiol, and their derivatives substituting the thiol group in 2-position and introducing alkyl and aryl group into the 3-position. NMR spectra of these compounds are described.
Using the synthesized Na-X zeolite as the starting substance, ion exchange was carried out with NH4+, Li+, K+, Mg2+, Ca2+, Sr2+, Ba2+, Co2+, Ni2+, and Cu2+ by the Batch method. Copper exchanger was not formed and Antlerite (3CuO·SO3·2H2O), a basic copper sulfate, formed instead. Differential thermal analysis of ion-exchanged zeolite was carried out and it was found that the transition temperature became higher in the order of Co, Mg, Ba, Na, NH4, Ca, and Sr. Dehydration peak of the water of crystallization was found at 190-230°. Nitrogen gas adsorption indicated the change in internal surface area of zeolite obtained by ion exchange, and a correlation was found between the water content and ionic radius. External surface area of ion exchanged zeolite is thought to remain almost unchanged by ion exchange but that of zeolite with poor ion exchange rate is large and such samples was presumed to undergo partial decomposition of the crystal structure during ion exchange. Quantity of adsorption on the external surface of zeolite with good exchange rate was 8-15 ml/g.
Quantitative studies were made on the anaerobic degradation of eight thiamine O-esters (B1-O-CO-R ; R=CH3, C3H7, C6H5, C6H4-p-NO2, OC2H5, OC4H9, OCH2CH2C6H5, and N(CH3)2) in aqueous solution at 100° in a pH range of 1 to 5. Each of these esters was degraded by a pseudo-first-order reaction and all of their minimum rate constants were found within a range of pH 2 to 3. These esters were found also to give thiamine and 2-methyl-4-amino-5-hydroxymethyl-pyrimidine (IX), together with the corresponding thiazole moiety, as their degradation products. The relative amount of thiamine formed from the respective esters varied with the pH of the solution as well as with the ester moiety. On the basis of an assumption that IX was produced not only from thiamine but also from each of the thiamine O-esters directly, the rate constants of the hydrolysis of the esters to thiamine, and of IX formation directly from these esters were calculated by using an analog computer. Hydrolysis of the esters to thiamine had a dominant dependence on pH and all of their minimum rates were found at about pH 3. IX was produced more directly from each of these esters than from thiamine. All of the rates of direct formation of IX from each of the esters were less affected by the variation of the ester moiety, while the rates of hydrolysis of the respective esters to thiamine were more affected.
The reaction of 2-thiophenecarboxaldehyde (IV) and 2-furylacetic acid gave cis-2-furyl-3-thienylacrylic acid (IIa) and trans-2-furyl-3-thienylacrylic acid (IIb). IIa produced cis-(Va) and trans-2-furyl-3-thienylacrylamide (Vb), but IIb only formed Vb. In a similar manner, the reaction of 5-nitro-2-thiophenecarboxaldehyde (VI) and 2-furylacetic acid gave two kinds, α-type (IIIa) and β-type (IIIb), of 2-furyl-3-(5-nitro-2-thienyl) acrylic acid (III). IIIa also produced cis-(VIIa) and trans-2-furyl-3-(5-nitro-2-thienyl)acrylamide (VIIb), but IIIb only gave VIIb. Stereoisomeric determination of these compounds was made from the results of ultraviolet and infrared spectra, and from the measurement of their dipole moments.
3-(5-Nitro-2-thienyl)-2-aryl(or heteroaryl) acrylic acids (VI) were derived, through the corresponding acid chlorides, to 3-(5-nitro-2-thienyl)-2-aryl(or heteroaryl)acrylic acid hydrazides (VII) by the usual method. In order to obtain 2-substituted 5-[1-aryl(or heteroaryl)-2-(5-nitro-2-thienyl)vinyl]-1, 3, 4-oxadi-azole, VII was reacted with ethyl orthoformate and gave 5-[1-aryl(or heteroaryl)-2-(5-nitro-2-thienyl)vinyl]-1, 3, 4-oxadiazole (V : R2=H). The reaction of VII and acyl chloride gave 1-acyl-2-[3-(5-nitro-2-thienyl)-2-aryl(or heteroaryl)acrylic acid]hydrazide (XI) whose reaction with phosphoryl chloride under reflux afforded the anticipated 2-alkyl(aryl or heteroaryl)-5-[1-aryl(or heteroaryl)-2-(5-nitro-2-thienyl)vinyl]-1, 3, 4-oxadiazole (V). Heating of VII with bromine cyanide, in sodium hydrogencarbonate solution gave 2-amino-5-[1-aryl(or heteroaryl)-2-(5-nitro-2-thienyl)vinyl]-1, 3, 4-oxadiazole (V : R2=NH2).
An alkaline proteinase of Aspergillus melleus has been purified approximately 11.2-fold from a culture extract by treatment with lead subacetate, fractionation with ammonium sulfate, treatment with acrinol, fractionation with acetone, and gel-filtration on Sephadex G75. The purified proteinase obtained as pillar-shaped crystals was monodisperse in both the ultracentrifugation and the moving-boundary electrophoresis. The optimum pH and temperature for the activity were 9 and 52°, respectively. At 20°, the enzyme was highly stable at the range of pH 4.5 to 9.5. At pH 7, the activity was lost at 65° within ten minutes. None of the metallic salts tested increased the activity, but Hg2+ and Ag+ were found to be inhibitory. Sulfhydryl reagent, reducing and oxidizing reagents tested had no effect on the activity, but potato trypsin inhibitor, di-isopropyl-fluorophosphate and soy-bean trypsin inhibitor caused a marked inhibition.
A semi-alkaline proteinase of Aspergillus melleus has been purified approximately 15.7-fold from a culture extract by pH treatment, lead subacetate treatment, decolorization with Amberlite IRA93, fractionation with ethanol and ammonium sulfate, dialysis, treatment with acrinol and acid clay, precipitation with acetone, and gel-filtration on Sephadex G75. The purified proteinase obtained as needle crystals or pillar-shaped crystals was monodisperse in both the ultracentrifugation pattern and the moving-boundary electrophoresis. The optimum pH and temperature for the activity were 8 and 50°, respectively. At 20°, the enzyme was highly stable at the range of pH 5 to 9. Metallic salts except HgCl2, AgNO3 and FeCl3, sulfhydryl reagent, reducing and oxidizing reagents tested had no effect on the activity, but potato trypsin inhibitor, soy-bean trypsin inhibitor, di-isopropyl-fluorophosphate and N-bromosuccinimide caused a marked inhibition.
Some physicochemcial properties and amino acid compositions of the Aspergillus melleus proteinases were investigated. 1) Semi-alkaline proteinase from Aspergillus melleus : The molecular weight was 30300 using the Svedverg's formula, based upon the values of the sedimentation coefficient (S020, w=2.98S), the diffusion coefficient (D020, w=8.75×10-7 cm2/sec), and the partial specific volume (V=0.728). The enzyme contains 16.35% of nitrogen and is composed of 314 residues of amino acid ; Asp. 36, Glu. 18, Ser. 37, Thr. 25, Gly. 45, Ala. 46, Val. 33, Leu. 21, Ileu. 15, Pro. 9, Phe. 7, Tyr. 11, Trp. 2, Arg. 2, Lys. 5, His. 2, (amide-NH3)16. 2) Alkaline proteinase from Aspergillus melleus : The molecular weight was 27900 using the Svedverg's formula, based upon the value of the sedimentation coefficient (S020, w=2.85S), the diffusion coefficient (D020, w=9.05×10-7 cm2/sec), and the partial specific volume (V=0.726). The enzyme contains 16.10% of nitrogen and is composed of 282 residues of amino acid ; Asp. 33, Glu. 16, Ser. 33, Tyr. 17, Gly. 45, Ala. 39, Val. 22, Leu. 16, Ileu. 10, Pro. 6, Phe. 5, Tyr. 15, Trp. 3, Arg. 5, Lys. 12, His. 5, (amide-NH3)16.
The membrane permeation in vivo of pharmaceuticals is considered to be affected by the proteins present, and this is thought primarily to be due to the bonding of pharmaceuticals with proteins by the Langmuir-type equation. In order to clarify this mechanism, intrinsic permeability constant, Pf, was theoretically derived assuming that the pharmaceuticals bound to proteins do not take part in membrane permeability and that those not bound alone would be taking part. Pf agrees with the apparent permeability constant, P, when the protein concentration is zero. As a model for pharmaceuticals, methyl orange was selected and its permeability through a cellophane membrane in the presence of bovine serum albumin was examined at pH 7.0, with reference to the appropriateness of the theoretical formula. It was thereby found that, while P changed greatly in the presence of bovine serum albumin, Pf remained constant either in the presence or absence of the albumin and agreed with the permeability constant, P°, of methyl orange alone. This fact satisfies the theoretical formula and suggests that only the pharmaceuticals not bond to proteins alone take part in the membrane permeability of pharmaceuticals in the presence of proteins.
The 55 derivatives of arylhaloacetamide, which were synthesized, were tested for their fungicidal and bactericidal properties against Trichophyton asteroides and other fungal or bacterial pathogens in vitro. Outstanding among them was N-(α-naphthyl)iodoacetamide (NIA), which was found to combine a strong fungicidal action with less skin irritation and toxity to mammals compared to pentachlorophenol (PCP) as a control substance. The results of therapeutic test in guinea pigs revealed that a hydrophilic ointment containing 1-2% NIA had about 50% cure rate on experimental candidiasis and dermatomycosis, and that containing PCP or salicylic acid besides NIA, about 60%.
Two unkown aminofluoropyridines, 2-amino-5-fluoropyridine and 2-amino-3-fluoropyridine, were prepared and 16 kinds of new fluorine-containing sulfonamides were synthesized to test their in vitro antibacterial activity.
The reaction of o-, m- and p-acetotoluidide with 2-propanol was studied in concentrated sulfuric acid. By the isopropylation of p-acetotoluidide two substances were produced : 4-methyl-3, 5-(I) and 4-methyl-2, 5-diisopropylacetanilide (II). From o- and m-isomers arose 2-methyl-3, 5-(XI) and 5-methyl-2, 4-diisopropylacetanilide (VI) respectively. The structures of the products were determined by bromination of corresponding aniline derivatives which were obtained by acid hydrolysis of isopropylation products. IR and NMR spectra of the products were also measured to get further evidences on the structures. The isopropylation reaction of acetotoluidides in concentrated sulfuric acid proceeded under the orientation of alkyl rather than acetamide substituents.
In connection with the question of a relationship between chemical structure and selective toxicity of halogenoacetamide compounds, antimicrobial activity was examined in a group of compounds having a general formula of Ar-N(-R)-C(=O)-CH2X, where Ar was limited to 2, 4, 5-substituted phenyl or naphthyl group. The compounds showed stronger activity when X was fluorine, chlorine, bromine, and iodine in that order, and also showed antimicrobial activity of a wide spectrum. Compounds having electronegative substituents in the 2-, 4-, and 5-positions showed a good activity, and 2, 4, 5-trichlorophenylmonoiodoacetamide and 2, 4, 5-trichlorophenylmonobromoacetamide were especially good, showing a broad spectrum and excellent therapeutic effect against experimental trichophytosis in animals. All the compounds, except those with fluorine, showed a low acute toxicity. The characteristic pharmacological action included hypothermia and a slight sedative action. Fluorine-substituted compounds of this series are known to be an aconitase inhibitor of the TCA cycle, have a strong toxicity in mammals, and show central stimulation and inhibition of respiratory and circulatory organs.
Application of 3, 4, 6-trichloropyridazine to N-substituted 2-aminobenzenethiol, obtained by alkaline decomposition of 3-substituted 2(3H)-benzothiazolinone, afforded 4-(N-substituted o-aminophenylthio)-3, 6-dichloropyridazine whose treatment with a weak acid effected its Smiles rearrangement, followed by condensation-cyclization to 5-substituted 3-chloro-5H-benzo[b]pyridazino[4, 3-e][1, 4]thiazine, a derivative of 3, 4-diazaphenothiazine. This was derived further to 5-substituted 3-methoxy derivative by the application of sodium methoxide. This process offers a general method for the synthesis of 3, 4-diazaphenothiazines with a substituent in the nitrogen at 5-position. The compounds similarly obtained, 5-(2-dimethylaminoethyl)-3-methoxy-(XIV) and 3-chloro-5-(2-pyrolidinoethyl)-5H-benzo[b]pyridazino[4, 3-e] [1, 4]thiazine (XV), showed antihistamine action approximately equal to that of Antazoline.
Influence of particle size on angle of repose (a), and on internal frictional coefficient (μ1) and cohesive force (C1) obtained by shear strength method was discussed for white alundum. Presence of critical particle size was confirmed at 45-50 μ, and a, C1, and μ1 increase markedly with the decrease of particle size in the region smaller than this size. Cohesive force (C1) is proportinal to μ1 and linearly related to C/Mg calculated from the data of angles of repose. It is concluded that cohesive force is negligibly small in the region above the critical size, but in the region below this size it affects the physical properties of powders, such as angle of repose.