3-Camphoryl isocyanate (IV) was obtained almost quantitatively from 3-aminocamphor (I) and carbonyl chloride, and the reaction of IV and various alkylamines afforded the corresponding 1-alkyl-3-(3-camphoryl) ureas (V to XII). Reaction of 3-methylaminocamphor (XIII) and alkylcarbamoyl chlorides gave 1-alkyl-3-methyl-3-(3-camphoryl) ureas (XV to XIX). Similarly, 1-alkyl-3-(3-camphoryl)-thioureas (XXII to XXIX) were prepared from 3-camphoryl isothiocyanate (XXI) and amines, and 1-methyl (or ethyl)-3-methyl-3-(camphoryl) thioureas (XXX and XXXI) from XIII and methyl or ethyl isothiocyanate. These synthesized compounds were submitted to pharmacological tests. The products from the reaction of I and carbon disulfide, and of XIII and carbon disulfide were respectively assumed as 7a-hydroxy-3aβ, 7aβ-bornano [3, 2-d] thiazolidine-2-thione (XX) and its N-methyl compound (XXXVIII) from their infrared and nuclear magnetic resonance spectra, analytical values, and structure of their derivatives.
3-Aminocamphor (I), 3-methylaminocamphor (II), and camphoryl derivatives (III to VI, X to XXIV) of amino acids, their ethyl esters, and amides were synthesized and submitted to pharmacological tests. Good analgesic and antipyretic action was found in N, N-dimethyl-2-(3-camphorylamino)acetamide (XV) and N, N-dimethyl-2-(3-camphoryl-methylamino)acetamide (XX). Secondary amines among these compounds were acetylated and comparative examination was carried out on the compounds formed. Amino acid amides having bornanol ring in place of camphor ring (XXX to XXXIII, XXXVI to XXXIX) were synthesized and their pharmacological actions were compared. Such compounds were found to be inferior to 2-(3-camphorylamino)aceto- and propionamides (XIV to XXIV) in pharmacological activity.
Effect of serum, serum albumin, and cortisol in suppressing the action of cardiotonic glycosides was examined with isolated embryonic chick heart. 1) Action of digitoxin, digoxin, and g-strophanthin on isolated embryonic heart was markedly suppressed by the addition of serum but this suppressive effect was weaker in serum from adrenalectomized rat than normal serum. Addition of cortisol to the serum of adrenalectomized rat made the suppressive effect approximately equal to that of normal serum. 2) Toxicity of these cardiotonic glycosides in the Locke solution containing cortisol was clearly weaker than that in the Locke solution. This toxicity in the Locke solution containing cortisol and albumin was almost the same as that in normal serum. These evidences indicate antagonism of cortisol against the action of cardiotonic glycosides in isolated embryonic chick heart.
Experiments were designed to examine whether or not the lethal dose of digitoxin for cats is dependent on its amount bound to the heart muscle. 1) The lethal dose was larger when digitoxin was injected directly into mesenteric vein than into jugular or femoral vein. 2) A marked decrease in lethal dose was observed after bilateral ligation of renal arteries. 3) It was found that there exists a correlation between the lethal dose and the amount of digitoxin taken up by the heart muscle. 4) An established theory, supported by many pharmacologists, that cardiac arrest caused by digitoxin may result from an accumulation of the drug in the heart was discussed on the basis of these observations.
Attempts have been made to clarify whether in vivo metabolism of digitoxin in rats is affected by pretreatment with carbon tetrachloride or by adrenalectomy. The tissue distribution and urinary excretion following intravenous injections of digitoxin were examined in animals sacrificed at 6 and 24 hours. In the rats poisoned by carbon tetrachloride, high concentration of digoxigenin glycosides, the hydroxylation products of digitoxin, was found in blood, kidney, and adrenals. Urinary excretion of digoxigenin glycosides was markedly increased. After adrenalectomy, such increase in urinary output of the hydroxylation products could not be observed in these animals. The significance of the tissue distribution in relation to the pharmacological effect of digitoxin was discussed.
Chemical nature of cardiac hormone was examined and the presence of factors inhibiting and promoting cardiac movement was revealed. Of these factors, the one effective in inhibiting the cardiac movement was found to decrease the incorporation of 32P into cardiac muscles and this incorporation mechanism was examined in the present work. This factor decreases the incorporation of 32P into the acid-soluble phosphorus compounds and phosphoprotein fraction in rat myocardium, increases the incorporation of 32P into the phospholipid and nucleic acid fractions, and decreases such incorporation into the myocardium as a whole. This point was examined in connection with phosphoric acid metabolism and it was found that this substance increases oxygen consumption of myocardium slice, decreases P/O ratio in myocardial mitochondrium, increases the serum alkaline phosphatase activity, decreases blood citric acid and serum iron, and decreases the stored-type iron in iron phosphate. Organ weight is also decreased but arginase activity in such organs is increased. The substance had no effect on inorganic phosm phorus in the serum, serum calcium, and plasma creatinine phosphorus.
(-)-3, 4, 14-Trihydroxymorphinan derivatives were prepared from morphine alkaloids in order to examine the pharmacological effect of the hydroxyl in the 4-position and its various ethers in the morphinan-type compounds.
Reactivity of enamine formation between 6-ketone compounds (I and III) of morphine alkaloids and various secondary amines was compared. In codeinone-type α, β-unsaturated ketone (IV), addition of amine to its conjugated double bond was found to occur preceding enamine formation with the 6-carbonyl group.
Reduction of the enamine (I) of the 6-ketone compounds of morphine alkaloid with sodium borohydride and formic acid and also its catalytic reduction were examined. Catalytic reductive amination of the 6-ketone compounds (IV, V, VI) was also carried out.
The main product from catalytic reductive amination of the 6-ketone compound of morphine alkaloid, and that of catalytic reduction and reduction of its enamine (I) with sodium borohydride and formic acid were found to have the 6α-amino group through the consideration of their reaction mechanism, synthesis of isomers by a different route, and by comparison of their nuclear magnetic resonance spectra (Chart 1 and Tables I and II). In the 14-hydroxy system, nucleophilic substitution reaction with secondary amine was found to be unaccompanied by reversion, contrary to the 14-H system (Chart 2). Addition of amine to the α, β-unsaturated ketone (XIII) was proved to form 8β-amino group by synthesis (Chart 4).
It has been believed that iodine titration of sulpyrine (I) for its determination depended on the formation of an iodine addition product, sodium 1-phenyl-2, 3-dimethyl-3, 4-diiodo-5-oxo-4-pyrazolidinylmethylaminomethanesulfonate (II). However, it was found, through the fall of pH at the time of titration, analysis of the reaction product at the end-point of titration to show quantitative formation of a sulfate ion, and formation of 4-(methylamino) antipyrine (IV) and 4, 4′-[methylenebis(methylimino)] diantipyrine, that the mechanism of this titration reaction should be as shown in Chart 1 and the side-chain of sulpyrine is hydrolyzed and oxidized by iodine, and there is no formation of II.
10-Amino-10, 11-dihydrodibenzo [b, f] oxepin (III), not possessing a methoxyl group, has a considerably strong analgesic effect. The pharmacological effect of its trimethoxyl derivative (II) has better solubility than III, although its pharmacological action is weaker than that of III. In order to obtain the dimethoxyl compound (IV), methyl (2-bromo-4, 5-dimethoxyphenyl) acetate (V) and phenol were submitted to the Ullmann condensation to VIIa, which was cyclized to VIII with polyphosphoric acid, and finally submitted to the Leuckart reaction. In this case, the formamido compound (IX) was accompanied by the by-product formation of X and XI unless a large amount of formamide was used or formic acid added in the Leuckart reaction, 10-Hydroxy compounds (XVI and XVIII), and their acetyl compounds (XVII and XIX) were synthesized.
4-Alkyl-5-(5-nitro-2-furyl)-2, 4-pentadienoic acids (II) were prepared by the reaction of ketene with α-alkyl-5-nitro-2-furanacroleins (I) in the presence of an appropriate catalyst such as boron trifluoride followed by acid treatment of the intermediate β-lactone. Amides (IV) of II shown in Table I were obtained by the known method. Antibacterial and antifungal activity against five kinds of microörganisms is summarized in Table II.
Analysis was made on the composition of torula yeast, prepared from sulfite pulp waste liquor, using Torulopsis utilis, in order to elucidate the factor accelerating animal growth. Ethanol extract of torula yeast was fractionated and examination was made on several crystalline substances obtained. Besides D-galactose, ergosterol, and myristic acid, 1, 2, 3, 5, 6-penta-O-acetyl-α-D-galactofuranose was obtained in 0.11% yield. This is the first example of its presence in a natural product and it is interesting that a substance with so many acetyl groups had been found in nature.
Condensation of 1, 2, 3, 4, 5, 6-hexahydrobenzo[b][1, 5]diazocine (IV) with formaldehyde, benzaldehyde, or acetaldehyde afforded respectively 3, 4-dihydro-2H, 6H-1, 5-methanobenzo[b][1, 5]diazocine (Va), its 11-phenyl (Vb), and 11-methyl derivatives (Vc). Reaction of 2, 3, 45, -tetrahydro-1H-benzo[e][1, 4]diazecine (VII) with formaldehyde or benzaldehyde afforded 2, 3-dihydro-5H-1, 4-methanobenzo[e][1, 4]diazepine (VIIIa) and its 10-phenyl derivative (VIIIb). From their nuclear magnetic resonance spectra and Dreiding models, it was assumed that the substituent at the 11-position of Vb and Vc had configuration of A-formula, and the phenyl group at the 10-position of VIIIb had configuration of B-formula. Whereas the phenyl derivatives (Vb and VIIIb) were hydrolyzed to IV or VII and benzaldehyde by merely being dissolved in 0.1N hydrochloric acid, Va, Vc, and VIIIa were found to be not hydrolyzed by this acidity.
Structures of a series of dehydrogenation products of tuberostemonine have been advanced based on the evidence obtained from their ultraviolet, infrared, and nuclear magnetic resonance spectra. The structure (IXa or IXb) for tuberostemonine has been deduced from the structures of these dehydrogenation products and the results obtained by physicochemical studies of the alkaloid.
Dry distillation of the N-acylated compound (I) of 6-aminohexanoic acid with soda lime gives 2-alkyl(or aryl)-4, 5, 6, 7-tetrahydro-3H-azepine (II) in 50-70% yield. The picrate of II, when repeatedly recrystallized on heated with 98% ethanol on a water bath for 2-3 hours, completely undergoes ring fission with addition of 1 mole of water to the picrate of the amino-ketone type base (III) which reverts to the original base (II) when distilled. Such structural changes were followed through infrared and ultraviolet absorption spectra.
Dry distillation of cis-, trans-VII(R=C6H5-, p-CH3C6H5-, C6H5CH2-) and trans-XII (R=CH3-, C6H5-) with an equal amount of soda lime results in the formation of the corresponding cis-, trans-VIII and trans-XIII in yields given in Tables I and II. Similar treatment of XVII results in cyclization but the trans compound of XIX does not form XX. Catalytic reduction of VIII and XIII in ethanol over palladium-carbon effects their reduction but not XVIII. Ultraviolet spectra of VIII, XIII, and XVIII are given in Figs. 1 and 2.
A colorimetric method for determination of cholestan-3α-ol in the presence of cholestan-3β-ol and cholesterol was examined and the standard procedure was established. A test sample dissolved in chloroform is placed on a thin layer of Silica Gel G in a line and chromatographed with hexane-ethyl acetate (4:1) as the developing solvent. The spot corresponding to cholestan-3α-ol, which can be detected by coloration upon exposure to iodine vapor, is eluted with chloroform and submitted to Janovsky (reverse Zimmermann) reaction. After concentration of the eluate, the residue obtained is heated with 3, 5-dinitrobenzoyl chloride in pyridine. The ester formed is extracted with hexane and subjected to treatment with dimethylformamide and ethylenediamine to produce a colored solution. Intensity of this color, which exhibits absorption maximum at 528mμ, is a function of the cholestan-3α-ol concentration. Based upon the present method, cholestan-3α-ol (50-150μg.) can be determined in the presence of cholestan-3β-ol and cholesterol with satisfactory accuracy.
Dry distillation of acyl (formyl or acetyl) compounds of 2-methylbenzylamine, with addition of potassium tert-butoxide as a condensation agent, affords 1, 2-dihydroisoquinoline derivatives, though in a small amount. This product is dehydrogenated by picric acid to isoquinoline-type compound.
It has been found that a large amount of mercury is lost when the aqueous solution of mercury salt is evaporated to dryness in a sample dish for measurement of its radioactivity. Effect of the kind of mercury salts on the loss of mercury was examined. Various reagents were added to the solution of mercury nitrate, the solution was evaporated to dryness, and radioactivity (c. p. m.) of the residue was measured to find the effect of such an agent in preventing the loss of mercury. It was found that ammonium sulfide and sodium diethyldithiocarbamate are effective in such inhibition. Ammonium sulfide had the power to stop the loss completely but its use seemed inconvenient. Combined use of sodium sulfide and ammonium chloride had the same effect. Diethyldithiocarbamate was convenient for use but its power to stop the loss of mercury was slightly insufficient.