Recent studies on the elucidation of the structures and stereochemistry of the Alangium alkaloids ankorine, alangicine, alangimarckine, desmethylpsychotrine, demethyltubulosine, and 10-demethylprotoemetinol by stereospecific synthesis have been reviewed. In these studies, the target molecules have been synthesized by the"lactim ether method"invented for the racemic series and by the"cincholoipon-incorporating method"for the chiral series. The syntheses of emetine, 9-demethylcephaeline, 10-demethylcephaeline, and 9-demethylprotoemetinol by the latter method and the results of some preliminary studies have been also summarized.
When anthrone (I) and its derivatives were oxidized with pyridine N-oxide (PNO) using FeSO4 as a catalyst, [9, 9'-bianthracene]-10, 10'(9H, 9'H)-dione (III) and its related dimer were produced. This reaction gave a dimer in good yield (87.4-91.5%) in acetic acid solvent. In this reaction 1, 8-dihydroxyanthrone (VI) gave a pseudoequatorial-pseudoequatorial type dimer VIIb. On the other hand, in n-amyl alcohol solvent I was further oxidized to form [Δ<9, 9'-(10H, 10'H)>-bianthrone]-10, 10'-dione (V) and 1-hydroxy-2-methoxyanthrone (Xb) gave helianthrone (XI). Using 0.007 mol catalyst for one molar anthrone derivatives, their dimers were obtained in the best yield. A large quantity of catalyst did not give a good results.
Chemical constituents of the bark of X. ailanthoides SIEB. et ZUCC. [F. ailanthoides (SIEB. et ZUCC.) ENGL.], Rutaceae, were examined. Xanthyletin (1) was isolated as a major component along with three coumarins [luvangetin (13), auraptene (32), and umbelliferone (14)], three alkaloids [des-N-methylchelerythrine (21), acetonylchelerythrine (30), and oxynitidine (39)], three amide derivatives [N-isobutyl-(2E, 4E)-2, 4-tetradecadienamide (33), 4-methoxy-1-methyl-2-quinolone (22), and arnottianamide (40)], five lignans [(-)-asarinin (41), (-)-syringaresinol (42), (-)-epipinoresinol (43), (-)-pinoresinol (44), and (-)-secoisolariciresinol (45)], and two other components [β-sitosterol (11) and β-amyrin (20)]. Other than the above seventeen known components, one new alkaloid designated as ailanthoidine (37) and one new lignan, pluviatilol 3, 3-dimethylallyl ether (23), were isolated.
Acetyl shengmanol xyloside (5) and 24-O-acetylhydroshengmanol xyloside (6) were isolated from the rhizome of Cimicifuga dahurica. Shengmanol xyloside (1) was detected in the rhizome by high performance liquid chromatography (HPLC). It was found that the total content of these glycosides was 0.56% in the rhizome from the result of quantitative determination with HPLC. The above glycosides contents were determined to be 0.29% and 0.43% in the fresh rhizomes of C. acerina and C. acerina var. peltata by the same method. Cimigenol xyloside (4), 25-O-acetylcimigenol xyloside (2), and 25-O-methylcimigenol xyloside (3) seem not to be present in the fresh rhizomes of these Cimicifuga plants.
A series of hydroxyalkyl, acyloxyalkyl, alkoxy (alkylthio) alkyl, acyl, carboxy or 1H-tetrazol-5-yl substituted 5H- benzopyrano [2, 3-b] pyridine derivatives were synthesized by various methods, and the relationship between their structures and inhibitory activities of passive cutaneous anaphylaxis was studied. 9-Chloro-5-oxo-7-(1H-tetrazol-5-yl)-5H- benzopyrano [2, 3-b] pyridine (XIVa-3) administered orally was found to be most potent among the compounds tested.
Effects of three kinds of anti-"Oketsu"drugs, tohkaku-johki-toh, keishi-bukuryo-gan and tohki-shakuyaku-san, and twelve kinds of component crude drugs on blood coagulation-fibrinolysis system and platelet aggregation were investigated, and the following results were obtained. Tohkaku-johkitoh and keishi-bukuryo-gan showed remarkable inhibitory effects on fibrinolysis, coagulation and platelet aggregation. Tohki-shakuyaku-san showed distinct acceleration on fibrinolysis and strong inhibition on coagulation and platelet aggregation. It was, therefore, suggested that the anti-"oketsu"drugs had a clear possibility to affect the blood coagulation-fibrinolysis system. In twelve crude drugs, Rhei Rhizoma (dai-oh) had the strongest inhibitory effects on fibrinolysis and coagulation. However, it has become apparent that these effects were ascribed to the protein contents. Five crude drugs except Paeoniae Radix (shakuyaku) in tohki-shakuyaku-san formula were proved to accelerate fibrinolysis in vitro.
By use of the same kind of rabbits, the difference in the effects of anticholinergic drugs on the secretion of gastric juice under normal conditions from that under alloxan diabetes conditions was investigated. The pepsin activity was determined according to the method for the determination of pepsin activity established in the Committee on the examination of a method of measurement of gastric juice belonging to Japan Gastroenterological Society, the acidity by Topher-Michaelis method and the blood suger level by Glucose B-Test. The basic values such as the amount of secreted gastric juice, pepsin activity, the amount of secreted pepsin, the acidity of free hydrochloric acid, the amount of secreted free hydrochloric acid, total acidity and the amount of secreted acid under disease conditions were lower than those under normal conditions and the main causes of decreases in the amounts of secreted pepsin and acid seemed to be due to a decrease in that of secreted gastric juice. The comparison of the degrees of decrease of various kinds of amounts secreted by use of anticholinergic drugs and of each value estimated at the time with the maximum mean rate of decrease by the administration of anticholinergic drugs under both conditions afforded no significant difference. However, the amounts of various kinds of secretion reached a minimum under disease conditions earlier than those under normal conditions. Under both conditions, the time necessary for the reaction with tertiary amines was shorter than that with quaternary ammonium salts.
By use of rabbits with alloxan diabetes the effect of anticholinergic drugs on the secretion of gastric juice after the administration of oral antidiabetics as a treatment of alloxan diabetes was examined from the standpoint of mutual interaction among drugs. The pepsin activity was determined according to the method for the determination of pepsin activity established in the Committee on the examination of a method of measurement of gastric juice belonging to Japan Gastroenterological Society, the acidity by Topher-Michaelis method and the blood sugar level by Glucose B-Test. The promoting action of the secretion of gastric juice by oral antidiabetics was inhibited by use of anticholinergic drugs. The amounts of secreted pepsin and acid showing the same tendency as that of secreted gastric juice were mainly influenced by that of secreted gastric juice. The effect was smaller in the case of the administration of anticholinergic drug 2-3h after oral antidiabetics than that in the case of the simultaneous administration of these drugs. Biguanide drugs showed higher rate of decrease from the maximum value of the amounts of secreted pepsin and acid than sulfonamide or sulfonylurea drugs. Moreover, in the case of the administration of anticholinergic drugs at a suitable interval after oral antidiabetics, the period for both secreted amounts to attain a minimun became longer after a combined treatment. The rate of decrease with quaternary ammonium salts was slightly higher than that with tertiary amines.
The hygroscopic behavior of five polymorphic forms (forms I, II, III, a monohydrate and an amorphous form) of tulobuterol hydrochloride was compared under various relative humidities (R.H.) at 30°C. Form I uptook moisture above 91% R.H. while forms II and III uptook it above 75% R.H. They immediately transformed into the monohydrates after uptaking moisture. The transformation kinetics was represented by the model of Avrami-Erofeev and it was found that form I was highly dependent on the relative humidity than forms II and III. No difference in the hygroscopic rate constants was found among them. The monohydrate was stable under pretty high humidity, i.e. 75-91% R.H., but was dehydrated under less than 59% R.H. The dehydration kinetics at 0% R.H. was described by the first-order rate process, the activation energy of which was 20.0 kcal/mol. The amorphous form revealed the characteristic behavior of hygroscopicity. This form uptook moisture rapidly above 59% R.H. at the initial stage, then transformed into form II at 59% R.H. Above 75% R.H., the amorphous form transformed into monohydrate via form II. In conclusion, form I was the most stable over the wide range of humidity.
The distribution of 14C-timiperone, a butyrophenone antipsychotic, was studied in rat and monkey by means of autoradiography. Tissue levels of radioactivity in the rat at 2h after a single oral administration of 0.5mg of the drug per kg were high in the order of the gastrointestinal contents, liver, urinary bladder, salivary gland, thyroid, pituitary, adrenal, harderian gland, kidney, lung, heart, testis, skeletal muscle and brain. In the rat brain, higher concentrations of radioactivity were detected in the striatum, nucleus accumbens and frontal cortex in which cerebral dopamine receptors were localized, as compared with other brain regions. The tissue levels of radioactivity persisted up to 10h after dosing. Repeated oral administration did not affect the distribution pattern of radioactivity. In the monkey which received a single oral dose of 1mg per kg, tissue levels of radioactivity at 2h after the administration were high in the order of the gastrointestinal contents, gall-bladder, liver, kidney, thyroid, pituitary, salivary gland, lung, heart, eye, blood, bone marrow, skeletal muscle and brain. In the monkey brain, radioactivity was localized in the brain regions including the caudate nucleus, putamen and cortex. The monkey uveal tract had a similar concentration of radioactivity to the blood. Thus, it was confirmed that 14C-timiperone could be transferred to the cerebral dopaminergic systems associated closely with the exhibition of antipsychotic activity of major tranquilizer.
In order to obtain the reaction kinetics and the rate constant for a certain reaction by a single kinetic pursuit, several possible integrated rate equations were included in the program for the determination of the reaction kinetics. The rate constant for each rate equation was calculated by the least-squares method from the values of kt and t. Then, the value of conversion (x, M) at the appropriate time was calculated using the thus obtained rate constant (k). The sum of the squares of deviation between the observed and calculated points at the same time was divided by the square of initial concentration to normalize : Sq=Σ (Δx)2/a2. The rate equation to give the minimun value was chosen as the one for this reaction. Several examples were given with some discussions.
From the fresh whole plants of Ixeris debilis, paraffins (A) ; fatty acid esters of β-amyrin, germanicol, taraxasterol and lupeol (B) ; acetates of α-amyrin, β-amyrin, taraxasterol, φ-taraxasterol and lupeol (C) ; hexacosanol and higher fatty acids (C20-C32) (D) ; and palmitic, ursolic and oleanolic acids (E) were isolated and identified. Also in the fresh whole plants of I. dentata, paraffins (A) ; fatty acid esters of α-amyrin, β-amyrin, germanicol and lupeol (B) ; acetates of bauerenol, α-amyrin, β-amyrin, germanicol and lupeol, and olean-12-en-3-one, olean-18-en-3-one and lup-20 (29)-en-3-one (C) ; α-amyrin, β-amyrin and taraxasterol (D) ; and higher fatty acids (C14-C24) (E) were proved to be found. B and C were supposed to be principal components of the milky juice of both plants by comparison with thin layer chromatography patterns.
The constituents of the fruits of Ligustrum obtusifolium SIEB. et ZUCC. were examined. 4-(2-Acetoxyethyl)-1, 2-dihydroxybenzene (a new component), p-hydroxyphenethyl alcohol (tyrosol), p-hydroxyphenethyl β-D-glucoside, 3, 4-dihydroxyphenethyl alcohol, 3, 4-dihydroxyphenethyl β-D-glucoside, α-amyrin, β-amyrin, ursolic acid acetate, oleanoic acid acetate, ursolic acid, oleanoic acid, 2α-hydroxyursolic acid, maslinic acid, β-sitosterol and β-sitosteryl β-D-glucoside were identified from the methanolic extract.
Forty-eight compounds of phenothiazines, benzo [α] phenothiazines, phenoxazines, benzophenoxazines and pyrido [3, 2-α] phenoxazines were prepared and their antitumor activity was examined using a solid type of Ehrlich carcinoma. The compounds which exhibited over 50% Ratio [(sample tumor weight/control tumor weight)×100] in forty-eight compounds were ten, that is, 2-chloro-5-oxo-5H-phenothiazine (4), ethopromazine hydrochloride (7), chlorpromazine hydrochloride (8), perazine dimaleate (11), fluphenazine dimaleate (12), trimeprazine tartrate (13), trimeprazine dimaleate (14), trimeprazine hydrochloride (15), 9-methyl-12H-benzo [α] phenothiazine (16) and 4-hydroxy-9-oxo-9H-benzo [α] phenoxazine (39). No other compounds were found to be high effective.