Cytidine diphosphate (CDP)-choline, CDP-dimethylaminoethanol, CDP-methylaminoethanol, and CDP-riboflavin can be obtained by the reaction of cytidine 5′-phosphoromorpholidate (I) with the appropriate phosphate. CDP-ethanolamine was obtained in 81% yield by the reaction of I with 2-benzyloxycarbonylaminoethyl phosphate and subsequent removal of the protective group.
In order to obtain the starting material (III) for the synthesis of the compound (IV), a kind of compounds related to azabenzomorphan, various kinds of 4-substituted quinoline derivatives were synthesized. At the same time, nitrilation of 4-bromomethylcarbostyril (IX) was examined. Attempts to prepare X by nitrilation of IX unexpectedly afforded the dimeric type XI, whose structure was proved by its chlorination and reduction. In order to obtain II by decarboxylation of the amino acid (I), IX was condensed with diethyl acetamidomalonate and XXI thereby formed was hydrolyzed and submitted to decarboxylation to form the amino acid (I). However, decarboxylation of I was not effected.
In order to synthesize 3-methyl-1, 2, 3, 4, 5, 6-hexahydro-2, 6-methanobenzo [d] [1, 3] diazocine (I), the route shown in Chart 1 was followed, starting with 4-ethoxycarbonylmethylcar-bostyril (III) and 4-(2-methylaminoethyl)-3, 4-dihydrocarbostyril (XI) was obtained via IV, VI, IX, and X. The Ladenburg reduction of XI furnished the objective cyclized compound (I). Although there are literature regarding reductive cyclization of 3-(2-aminoethyl)-oxindole derivative, it is interesting that a reductive cyclization was effected in a six-membered ring lactam like XI.
In order to examine their anticonvulsive action, (phenylacetyl) carbamates were synthesized by the reaction of phenylacetyl isocyanate or 2-phenylbutyryl isocyanate with monohydric or dihydric alcohols. Some of the (phenylacetyl) carbamates showed a strong anti-convulsive action but derivatives of dihydric alcohols had only a weak effect.
Comparative examinations were made on thermal decomposition reaction of primary, secondary, and tertiary alkyl phenylacetylcarbamates. Primary and secondary alkyl esters undergo decomposition at a comparatively high temperature (220-230°) and form corresponding alcohols, 2, 2′-diphenyldiacetamides, phenylacetonitriles, and alkyl phenylacetates besides carbon dioxide. Further examination by gas chromatographic analysis showed the formation of alkyl phenylacetimidates, alkyl carbamates, and dialkyl iminodiformates, in addition to the foregoing. Tertiary alkyl phenylacetylcarbamates undergo decomposition at a comparatively low temperature (110-170°) and form carbon dioxide, phenylacetamides, and corresponding unsaturated hydrocarbons.
In order to examine their anti-convulsive action, a series of N-acyl-2-phenylacetamides and N-chloroacetyl-, N-(3-chloropropionyl)-, and N-(3-aminopropionyl)-2-phenylacetamides were synthesized. All of the compounds synthesized had only a weak pharmacological activity.
Decomposition reaction of the side chain in shionone (I) was carried out by the process shown in Chart 1, and several of its derivatives (III to XVI) were obtained. From its NMR spectrum, the diphenylvinyl derivative (VI) derived from 3β-acetoxytrinorshionanoic acid (III) was found to possess a methylene group adjacent to the diphenylvinyl group. This methylene group was found to bond to the quaternary carbon from the NMR spectrum of bromo compound (VII), obtained by the bromination of VI with N-bromosuccinimide, The NMR spectra of 3β-acetoxytetranorshionanoic acid (VIII), obtained by ozone oxidation of VI, the methyl ester (IX) of VII, and VI suggested that this methylene group is located in a position which receives steric hindrance. From these experimental evidences, it was assumed that the side chain of shionone has a partial structure of -CH2-CH2-CH=C(CH3)2 and that this side-chain is bonded to the six-membered ring in an axial conformation. Chemical evidences were also obtained for the facile submission of VII to methanolysis and allylic rearrangement, and the presence of bromine in the allylic system in VII.
The streaming potential of sulfisoxazole, sulfadimethoxine, and N1-acetylsulfisoxazole was measured with the aid of Hazel-type cell in sucrose, and sodium chloride solution, and sodium chloride in 10% sucrose solution. The electrokinetic potential (ζ-potential) of these sulfamines surfaces was calculated from the streaming potential data with Helmholtz-Smoluchowski equation. ζ=H/P⋅4πηκ/D It was thereby recognized that these sulfamines charge negatively in above solutions, and the potential (-ζ) increased in the order of sulfisoxazole>sulfadimethoxine>N1-acetylsulfisoxazole. This is considered to be due to dissociation of the proton of N1 in sulfisoxazole and sulfadimethoxine, whose pKa is 5.00 and 5.94, respectively. On the other hand, N1-acetylsulfisoxazole has no proton to cause dissociation, and its negative charge is considered to be due to the potential difference according to the Coehn rule.
Examinations were made on the effect of bezoar, a crude drug used as a home remedy for hypertension, and calcium cholate, one of its components, on hypertension adult rats. The bezoar was found to have the activity of lowering high blood pressure, cardiotonic, antifebrile, and cholegenic actions, and also a very weak acute toxicity. On the other hand, calcium cholate had only a weak cardiotonic and cholegenic actions, besides antifebrile properties, and a weaker acute toxicity than bezoar.
The unsaturated fatty acids with 18 carbon atoms, most abundantly found fatty acids in nature, were irradiated in a large dose of over 108r. with electron rays and γ-rays from cobalt-60, and the results were analyzed by infrared spectrophotometer and gas chromatography. Increase in the absorption band at 965cm-1 in their infrared spectra indicated the occurrence of cis-trans isomerization and this change was especially marked in methyl linolenate. A mixture of methyl oleate, methyl linoleate, and methyl linolenate, used as internal standard for methyl myristate, was irradiated with over 108r. dose in oxygen-free state and the result was examined by gas chromatography. The decomposition rate constant of these unsaturated fatty acids by radioactive rays was calculated as the primary reaction from the result of gas chromatographic analysis and it was found that they underwent decomposition in proportion to the square of the number of double bonds in the molecule. No difference was found in these results between electron rays and γ-rays from cobalt-60.
Absorption of terephthalic acid through the digestive tract and its excretion in urine of rats were examined. Terephthalic acid suspension was administered orally in dose of a 200mg./kg. body weight. About 55% of administered terephthalic acid was excreted in urine and about 30% in feces within 24 hours after the administration. To eliminate a possible influence of absorption of terephthalic acid through the digestive tract, (200mg./kg. body weight was given by injection (i.p.) and most of terephthalic acid was recovered quantitatively in urine. This result indicates that the amount of terephthalic acid excreted in urine was influenced by its absorption through the digestive tract. When rats were fed with a diet added with 0.5% terephthalic acid (about 330mg./kg. body weight per day), 78-85% of added terephthalic acid was excreted in urine. A part of orally administered terephthalic acid was absorbed through the digestive tract and the rest excreted in feces. Almost all of injected terephthalic acid was excreted in urine within 24 hours after administration.
General pharmacological action of decanhydroxamic acid, such as its effect on body temperature, peripheral nervous system (local surface anesthesia, intestines, vesicles, uterus, skeletal muscle, iris), blood (effect on the number of erythrocytes, leucocytes, hemoglobin, hemolytic action, blood coagulation inhibitor), and analgesic action, were examined. The acid was found to have atropine-like, papaverine-like, anti-acetylcholine, and antihistamine actions, and a slight effect on blood (number of erythrocytes, leucocytes, and hemoglobin), but no marked effect was found on other factors.
Pharmacological action of decanohydroxamic acid, such as its action on the circulating system and respiration, local action, and acute toxicity, was examined. The action of this acid on the circulating system is mainly vasodilation and depression of the total carotid pressure, and no marked changes were produced in heart movement and cardiogram. A very slight irritation was observed as its local action, especially in an emulsified ointment on the skin, but not when the acid was used as a lipophilic ointment. Acute toxicity of the acid was very weak, the 2.5% Tween suspension giving the values of over 1430mg./kg. in mice by subcutaneous and intraperitoneal injection, over 7200mg./kg. in mice by oral administration; 1% CM-cellulose suspension giving the values of 6500mg./kg. in mice and over 2000mg./kg. in rats, both by oral administration.
In order to examine their anti-convulsive action, a series of 1-(2-phenylbutyryl)-3-substituted-ureas were synthesized by the reaction of 2-phenylbutyryl isocyanate with amines possessing hydrophilic or lipophilic group. None of the synthesized compounds, however, exhibited any notable pharmacological activity.
2-Sulfanilylamino-1, 3, 4-thiadiazoles (VII) possessing a heterocycle in the 5-position were synthesized by the condensation of N-acetylsulfanilyl chloride with 2-amino-1, 3, 4-thiadiazole with a heterocyclic substituent in the 5-position. The latter was obtained by heating the corresponding aldehyde thiosemicarbazone with ferric chloride solution. The treatment of the aldehyde 3-thio-4-(N-acetylsulfanilyl) semicarbazone with ferric chloride also afforded VII. Various kinds of 2-dialkylaminoacylamino-1, 3, 4-thiadiazoles were obtained by the application of haloacyl halide to 2-amino-1, 3, 4-thiadiazole, followed by amination. The addition of amines to 2-crotonamido-1, 3, 4-thiadiazole gave the dialkylaminobutyrylamino derivative.
Anti-polio virus activity of 112 benzimidazole derivatives was examined by employing a simple screening method which indicates inhibition of the plaque formation by polio virus type I (Mahoney strain). Rate of inhibition was calculated by the following equation. [rate of inhibitions]=[No. of plaque in sample]/[No. of plaque in control]×[mean diameter (mm.) of sample plaque]2/[mean diameter (mm.) of control plaque]2 These results are shown in Table IV. Among the compounds tested 2-(p-aminophenyl) benzimidazole (No. 10359) showed an anti-polio virus activity comparable to that of 2-(o-hydroxybenzyl) benzimidazole. Other six 2-phenylbenzimidazole derivatives showed a moderate activity.
Stability of sodium o-iodohippurate [131I] in various formulae and storage conditions was studied. Protecting effect against self-radiation damage was found in benzyl alcohol, citric acid, and sodium o-iodohippurate itself, while addition of sodium chloride gave no effect on the stability of this compound. This radioactive compound seemed to be more stable in lower pH and more iodines were released by autoclaving. There was no significant effect of storage temperature but there was a marked effect of direct sunlight. Several preliminary experiments were made to determine the reliability of paper chromatographic method for detecting radiochemical purity of this compound. Prevention of loss of radioactivity before measurement, exchange reaction during development, and comparison of the accuracies of scanning method, counting method, with well-type scintillation counter, and electrophoretic method were described.
When fowl or mammals were fed with a diet containing terephthalic acid and tetracycline-type antibiotics, the level of the latter in blood was more elevated and more potentiated than those fed with the acid free diet. Terephthalic acid however, has not been approved for use since a practical assay procedure for it has not been established. Semimicrodetermination of terephthalic acid in biological materials was examined and this method was found to be suitable for its assay in urine. The procedure is as follows: One to 5ml. of urine is taken into a test tube and mixed with an equal amount of 20% perchloric acid. The mixture is shaken well and stood for 15 minutes. The supernatant is centrifuged (3, 500r.p.m) for 5 minutes, the precipitate is added to 10ml. of 10% perchloric acid, shaken well, stood for 10 minutes and centrifuged (3, 500r.p.m. 5min.). The precipitate is extracted with 10ml. of ethanol for 10 minutes and finally centrifuged (3, 500r.p.m.). The re-extraction is necessary. The absorbance of the ethanolic extract is measured at 240mμ and its value is converted to the content of terephthalic acid by the following equation. terephthalic acid content (mg./ml. of sample)=E240/ml. of sample (treated)-E240/ml. of sample (control)/110