Relating to the structure of reserpine, new aroyl derivatives of 2-methyl-and 2-ethyl-decahydro-7-isoquinolinols were synthesized as the quaternary ammonium salts. Hypotensive activity of these compounds are shown in Table I and II. 2-Methyldecahydro-7-isoquinolinol derivative was separated into the corresponding two stereoisomers (X-A and -B), while the 2-ethyldecahydro-7-isoquinolinol derivative yielded four stereoisomers (IV-B1, -B2, -C, -D). It was clarified that two stereoisomers of 2-methyldecahydro-7-isoquinolinol possess cis configuration at the ring juncture, the four stereoisomers obtained from 2-ethyldecahydro-7-isoquinolinol derivatives, one pair (IV-B1, -C) possesses cis configuration and the other (IV-B2, -D), trans configuration.
Following data have been obtained on hypocholesteremic and toxic effects of some derivatives of arylcarboxylic acid in rats. Compounds with X=Cl or CH3, Y=O and R=CH3 in the general formula, X-[chemical formula]-Y-C(R)·(CH3)COOC2H5 were effective, and the most potent effect was obtained when X=Cl. 2) It was found that some compounds with n=2 in the formula (Cl-[chemical formula]-O-C(CH3)2-COO)nR, were less toxic in acute and growth-inhibiting toxicity and more effective in hypocholesteremic activity. Among these compounds, 1, 3-propanediol bis(2-p-chlorophenoxyisobutyrate)(CLY-503) was better than clofibrate in respect to hypocholesteremic effect and toxicity. 3) General pharmacological activities, thought to be an adverse action, of CLY-503 were fewer than those of clofibrate, and hardly any appreciable effect was noted in ordinary dose levels, in its action on respiratory and circulatory functions.
The follwing data have been obtained on antiatherosclerotic activity of 1, 3-propanediol bis(2-p-chlorophenoxyisobutyrate)(CLY-503) compared with ethyl 2-p-chlorophenoxyisobutyrate (clofibrate). Hypolipidemic activity of CLY-503 was more durable in rats, and more potent in rats and cholesterol -fed mice than clofibrate in continued administration. Cholesterol and triglyceride levels decreased and phospholipid levels were unchanged or increased a little in liver of rats treated with CLY-503 or clofibrate. While lipid levels were not decreased, antiatherosclerotic activity was pronounced in cholesterol-fed rabbits treated with either of these agents. Furthermore, depression of capillary vascular permeability in mice and activation of fibrinolytic activity in rats. were recognized in both agents. However, stabilization of erythrocyte membrane of rats and inhibition of platelet aggregation of rabbits, considered as antiatherosclerotic factors other than lipids concerned, were especially noted in CLY-503.
On standing at room temperature, the ethanol solution of ascorbic acid (AAH2), 5, 6-isopropylidene ascorbic acid (Ip-AAH2) or dehydroascorbic acid (DHA) and a variety of amines (Table I) in the ratio 1 : 2 moles was discoloured to brown under autoxidative decomposition. It is evident that 1)O2 was required for the browning discoloration of AAH2-amine system, but not required for the browning of DHA-amine system ; 2) the browning intensities of the assayed amines were in the following order : primary amines>secondary amines>tertiary amines ; and it was proportional to their pKa value. As a decomposed product dioxalamide II was obtained from the system of 1) AAH2 and the amines showed in Table I and 4, 2) Ip-AAH2 and the arylamines in Table II, 3) DHA and the arylamines in Table III and IV. Oxalamide II and another two deposits, arylamine salt of 2-dehydroxy-2-arylamino ascorbic acid (I) and 2, 3-didehydroxy-2, 3-diarylamino ascorbic acid (III), were separated from the browning solution of AAH2-arylamine system. Five more decomposed were obtained from the mother solution : N, N'-mesoxalamide hydrate (IV), N-aryloxamic acid (V), azobenzene derivatives (VI), glyceric acid (VII) and L-threonic acid (VIII). 82.5% of the specific radioactivity was measured in II obtained from AAH2-14C1 and p-toluidine. From this result it was deduced that II was formed by fragmentation of the C2-C3 bond and IV and VII formed by fragmentation of the C3-C4 bond of AAH2. AAH2 was decomposed to II, IV etc. through AAH·freeradically under autoxidation.
Structure of isoniazide hydrazone of 1, 3-diketone derivatives (1, 3-Diketone-INAH) was examined by the use of mass, nuclear magnetic resonance, ultraviolet and infrared spectra. Mass spectra : Parent peak was observed abundanlty in trifluoroacetylacetone (TAA-INAH) but weakly in thenoyltrifluoroacetone (TTA-INAH), and not in benzoyltrifluoroacetone (BFA-INAH) and acetylacetone (AA-INAH). However, M-18 ion was present strongly in BFA-, TTA-, furoyltrifluoroacetone (FTA)-and AA-INAH but weakly in TAA-INAH. These observations suggest that most of isoniazide hydrazone of 1, 3-diketones may be in enol form. Nuclear magnetic resonance : FTA-and TTA-INAH have enol structure in CDCl3. Chemical shift of NH proton is 11.84 ppm and OH proton 4.16 ppm in TTA-INAH. The signal for the OH and CH2 proton in FTA-INAH appeared at 4.11 and 3.48 ppm, respectively. These two hydrazones indicated, however, to hold keto structure in DMSO-D6 solvent (Fig.5-2, Fig.6). Other six compounds are present having mainly keto form in CDCl3. It is demonstrated that plot of the chemical shift of methylene proton against one of imino proton has linear relationship with each other among compounds of six hydrazones substituted alternately with CH3, CF3, and C6H5 in 1, 3-position of diketone group (Fig.2). Ultraviolet : AA-INAH has only one peak at 307 mμin CHCl3 but showed two peaks at 220 and 280 mμ in methanol. FTA-INAH has, however, two peaks in CHCl3, indicating the presence of enol structure. From these ultraviolet and nuclear magnetic resonance spectra, variation of keto-enol sturcture of eight isoniazide hydrazones in various solvents can be elucidated unequivocally. Infrared : Assignments of infrared bands of isoniazide hydrazones of 1, 3-diketone were postulated and their structure was discussed.
Some metal complexes of isoniazide hydrazones of 1, 3-diketone, such as acetylacetone (AA)-INAH-Ni, AA-INAH-Cu, AA-INAH-Cd, thenoyltrifluoroacetone (TTA)-INAH-Cu, TTA-INAH-Ni, TTA-INAH-Zn, trifluoroacetylacetone (TAA)-INAH-Ni, furoyltrifluoro-acetone (FTA)-INAH-Cu and benzoylacetone (BA)-INAH-Cu (Group I) were prepared. These complexes are very stable and hardly soluble in water or alcohol. Some complexes of different type, such as BA-benzoylhydrazide (BH)-Ni-NH3 and TTA-BH-Cu-NH3 (group II) were also prepared. Elementary analyses indicated that the ratio of metal to ligand is 1 : 1 in group I and that of metal to ligand and ammonia is 1 : 1 : 1 in group II. Nuclear magnetic resonance : In the complexes of group I, the coordination to N of pyridine in isoniazide moiety was suggested. On the other hand, in the complexes of group II the coordination of ammonia was observed. Infrared : Shifts of amide (I, II, III, III', and V) band and pyridine vibrations of chelates from their ligands indicated the existence of chelates of isoniazide hydrazones of 1, 3-diketones, coordinated to N of pyridine in the ligand molecule. Therefore, it is strongly suggested that complexes of isoniazide hydrazones of 1, 3-diketones have a structure of I in Chart 2 and ammine complexes of benzoylhydrazide hydrazones of 1, 3-diketone a structure of Chart 1.
Kinetic examinations were made on the stability of valethamate bromide (2-diethyl-aminoethyl 3-methyl-2-phenylvalerate methobromide)(I) and its tertiary amine, 2-diethylaminoethyl 3-methyl-2-phenylvalerate hydrochloride (II), in aqueous solution and the following conclusions were drawn. I and II undergo hydrolysis in aqueous solution to form an amine (amines-) corresponding to 3-methyl-2-phenylvaleric acid and its reaction rate follows a pseudo-first order reaction. This hydrolysis is catalyzed by hydrogen or hydroxyl ton and shows a pH-rate profile as given in Fig.4. Within the experimental range, however, there was no effect of ionic strength or of buffer solution. Stability of the quaternary ammonium salt (I) and tertiary amine (II) did not differ greatly by comparing their kH but kOH of II was approximately 100 times greater than that of I. Activation energy and frequency factor of II were smaller than those of I. These facts suggest that in protonated amine type, II has an intramolecular catalytic action proposed by Hansen and others.10
Kinetic parameters with respect to the stability of the aminoethyl esters of phenyl acetic acid were measured and the following facts were revealed. 1) Stability of these esters is affected by the substituent in 2-position of phenylacetic acid. The greater the size of this substituent, the smaller became the reaction constants, kH and kOH, and greater the ΔEa and ΔS. Also k<H2O> became broader as will be seen from the pH -rate profile in Fig.2 and 3. 2) Esters of tertiary amine type have greater rate of hydrolysis than those of quaternary ammonium salt type, the rate in alkaline side being about 100 times greater in the tertiary amine-type esters. 3) There is a linear relationship between λ (polar substituent constant) of R in C6H5-CHRCOOCH2CH2N(C2H5) and kH or kOH, as shown in Fig.7 and 8, the Taft formula can be applied to it. 4) There is a linear relationship between the pKa and hydrolysis rate of C6H5CHRCOOH, as shown in Fig.9. 5) In the above 3 and 4, compounds with R as sec-butyl or diphenyl deviate from linearity and steric effect of the substituent has retarded the hydrolysis rate of these compounds.
In order to follow the correlation between stability and chemical structure of aminoalkyl esters, examinations were made on the effect of steric hindrance near the ester linkage on hydrolysis. Four kinds of phenylacetic acid derivatives having a quaternary carbon in 2-position were synthesized and their stability was examined. Alkaline hydrolysis of 2-diethylaminoethyl 2-ethyl-3-methyl-2-phenylvalerate methobromide (II) and 2-diethyl-aminoethyl 3-methyl-2-phenyl-2-propylvalerate methobromide (IV) is a second-order reaction when molar ratio of ester to alkali is 1 : 1, while that in KCl-NaOH buffer solution of pH 12.5 is a pseudofirst order reaction. This mechanism is the same as in the case of other phenylacetic acid esters with less steric hindrance. Alkaline hydrolysis of II and IV was quite slow, kOH at 60° being 0.13 in II and 0.08 l/mole/hr in IV, and about 104 times more stable than Valethamate Bromide. The activation entropy was -19.9 in II and -20.8 cal/mole/deg in IV, these values being very small. Acid hydrolysis of all these four compounds was extremely small, almost no hydrolysis being found at around 1, 200 hours at pH 0.7. These data indicate that the presence of a steric hindrance in the position close to the ester linkage is very effective in stabilization of aminoalkyl esters.
2-Bromo-5, 5-dimethyl-3-methoxy-2-cyclohexenone (V) was reduced in ether to allyl alcohols (VI and VII) with an excess of lithium aluminum hydride, and to VI, VII, and α, β-unsaturated ketone (IX) with a theoretical amount of the hydride. In benzene, V was reduced to VII and IX with an excess hydride. A mechanism is proposed for the random behavior of vinylogous esters (I-V) to lithium aluminum hydride.
When 2-(2-quinolyl) cyclohexanone oxine (Ia) was treated with tosylchloride under basic conditions of the Beckmann rearrangement, a new cyclization reaction took place to produce a new compound, 7, 8, 9, 10-tetrahydro-11a-azabenzo[a]carbazole (IIa) in almost quantitative yields. On the other hand, the normal Beckmann rearrangement proceeded when Ia was heated with conc. sulfuric acid to give the lactam compound, 2-oxo-7-(2-quinolyl) cyclohexamethyleneimine (IV) in an extremely high yield. The corresponding oximes of lepidine (Ib) and pyridine (XIV) gave also similar results. The structures of the products were confirmed by chemical methods and by the ultraviolet, infrared and nuclear magnetic resonance spectral examinations. The mechanisms of the above reactions are then discussed.
2-(2-Quinolyl) cyclohexanone (I) reacted with an excess of peracetic acid under mild conditions to be transformed to 6-oxo-6-(2-quinolyl) caproic acid (II) in an almost quantitative yield. Oxidation with perbenzoic acid gave also similar results (Table I). The mechanism of this reaction may be reasonably explained by the intermediate formation of a new heterocyclic compound (XIII) quite similar to the azacarbazole isolated from the Beckmann rearrangement of an oxime of I under basic conditions.2) The reactions of 2-(2-pyridyl) cyclohexanone (VI) with organic peracids gave essentially the same results. The structural elucidation of the products was effected by chemical methods and examinations of their infrared and nuclear magnetic resonance spectra.
Contractile activity of bradykinin fragments, from dipeptide to octapeptide, was examined with guinea pig ileum (Magnus method) and the activity was compared with that of bradykinin. Some of the peptides having arginine on the C-terminal side had a comparatively strong activity, the strongest being XXVII whose activity was 4.3% (molar ratio)of that of bradykinin. Of the peptides without arginine, XXVIII showed the strongest activity. It was found that phenylalanine in 5-and 8-positions of bradykinin was important in the activity of the fragments. Smaller fragments of peptide fractions in XXVIII were also found to have an activity. Based on these observations, it was assumed that the active fragment of bradykinin lies in H-Phe-Ser-Pro-Phe-Arg-OH (XXVII). None of the bradykinin fragments antagonised the activity of bradykinin, and XXI and XXXI potentiated the bradykinin activity. Of these fragments, XXXVII, XXXVIII, and XXXIX did not have any ileum contractile activity or anti-bradykinin activity. The fragment XL, formed by substitution of serine with β-alanine had an activity 0.018% of bradykinin, the activity having decreased to about 1/200 of that of the corresponding peptide (XXVII).
In order to carry out the conversion of protoberberine-type alkaloids to benzo[c]phenanthridine-type alkaloids by a synthetic means, thermal decomposition of the hydrochloride of tetrahydroberberine methine base (I) was carried out and hitherto unknown bases were obtained; base A of rap 168° and base B of mp 156°. By decomposition reaction, these two bases were identified as stereoisomers of 1, 2-(3, 4-methylenedioxyphenyl)-3-methyl-6, 7-(2, 3-dimethoxyphenyl)indolizidine (III). From the results of infrared and nuclear magnetic resonance (NMR) spectra, steric structures III A and III B were respectively assigned to bases A and B.
Characteristics of the acid and alkaline phosphomonoesterase in crude toxic fraction of Aspergillus fumigatus were investigated and the following results were obtained. 1) Both phosphatase in the crude toxin have not direct participation in activities of lethality, hemolysis and dermonecrosis. Identies between lethality and hemolysis were not observed by inhibition of toxic activities with Hg2+ and HCHO. 2) The optimum pH and temperature of the acid phosphatase activity are at pH 4.5 to 4.7 and 50° to 55°. The enzymes are stable between pH 2.8 and 6.7, and below 45°. It was found that the enzymes have abilities to hydrolyze p-nitrophenyl phosphate, pyrophosphate, phenyl phosphate and glucose 6-phosphate, but not to glucose 1-phosphate. MoO42- and WO42- are effective as inhibitors, whereas Fe2+ acted as activator. 3) The optimum pH and temperature of the alkaline phosphatase activity are between pH 10.0 to 10.3 and 50° to 55°, respectively. The enzymes are found to be able to hydrolyze phenyl phosphate, p-nitrophenyl phosphate, glucose 6-phosphate, but pyrophosphate was weakly hydrolyzed. The enzymes were inhibited by I2, PO42- and divalent metal ions such as Cu2+ and Pb2+, however Na+ and K+ activated them. 4) The acid and alkaline phosphatase of Aspergillus fumigatus showed immunologically different phosphatase activities, respectively.
Sesquiterpene lactones of Artemisia Feddei, Ar. montana, Ar. princip (Japan), and Ar. douglasiana (U.S.A.) were examined by thin-layer chromatograms. Mature plant is different in chemical constitution from young plant. Two new sesquiterpene lactones were isolated from the air-dried finely ground materials of young plant of Ar. douglasiana by extraction with chloroform.
Tertiary bases in the domestic Corydalis platycarpa MAKINO, and seven kinds of alkaloid, d-corybulbine, cheilanthifoline, l-capaurine, sanguinarine, and protopine were obtained. Four other kinds of alkaloid were detected but the quantity was too minute for further examination. Manske3) had found 10 kinds of alkaloid from this plant of origin, and only d-corybulbine and protopine were present in both plants.
Studies were made, in ethylene dichloride, on inhibition by methylsubstituted benzene derivatives of the photodecomposition of riboflavine tetrabutyrate and also on the interaction between substituted benzenes and the riboflavine derivative. The photodecomposition of riboflavine tetrabutyrate was inhibited by the presence of benzene derivatives having three or more substituted methyl groups; the inhibitory effects decreased in the order of hexamethylbenzene>pentamethylbenzene>1, 2, 4, 5-tetramethylbenzene>1, 2, 4-trimethylbenzene. Examinations were made on the fluorescence quenching of riboflavine tetrabutyrate by the substituted benzenes and on the new absorption bands which appeared in the vicinity of 485-490 mμ of difference spectra of the interaction systems : it was found that complexes of 1 : 1 molar ratio were formed. Analysis of solvent effects on the interaction indicated that, at the excited state, dynamic quenching mechanism was also participating. From the correspondence of the inhibition and the interaction data, it was concluded that charge-transfer force is responsible for the inhibition of photodecomposition of riboflavine tetrabutyrate by the substituted benzenes.
The six principal alkaloids of opium can be separated into three groups by sequential extractions with solvents as follows : the first group (noscapine, papaverine and thebaine) comes in chloroform, the second group (codeine and thebaine) in benzene, while the third group (morphine and narceine) remains in the aqueous phase. These separations are easy and almost quantitative, except that thebaine comes in the two extracts, but further separations to one component in one solution, are complicated and hardly expected to be quantitative. Moreover, the wavelengths at the maximum ultraviolet (UV) absorption of these alkaloids lie closely with one another and these facts make the spectrophotometric determination of the individual component difficult. These facts, expecially the proximities of the wavelengths at the maximum UV absorption of components concerned, however, are assumed to be suitable or essential to the application of Y-reference method, which has been reported by Alien and coworker as a spectrophotometric determination of one component in a two-component mixture. In the present report, three kinds of artificially prepared standard solutions of alkaloids, corresponding to the above mentioned three groups, were analysed by Alien's method, being somewhat modified. As a solution for spectrophotometric measurement, about a 10mg/100ml to 20mg/100ml in 0.1N hydrochloric acid solution for each alkaloid -group was used ; the results showed that the coefficient of variation of the analytical data and the mean value of the recoveries, obtained by 10 determinations with respect to each alkaloid, were; codeine : 1.49, 102.4% ; thebaine : 2.27, 98.3% ; morphine : 1.61, 99.3% ; narceine : 1.36, 99.0% ; noscapine : 0.81, 99.0% ; papaverine : 2.34, 100.3%; thebaine (from three-component solution) : 1.29, 100.8%.
In relation to the structure of reserpine, 4-(N, N-diethylamino)-butanol and 6-(N, N-diethylamino)-hexanol esters of benzoic acid having methoxy or ethoxycarbonyloxy groups were perpared as acid -addition salts, or quaternary ammonium salts. Hypotensive activity of these 13 new compounds were tested (Table I).
Among the neutral constituents of Pachysandra terminalis SIEB. et ZUCC., reported in the preceding paper, compound-XI was identified as taraxerol (I) and compound-III was found to be a mixture of compound-IIIA and compound-IIIB.
The methanolic extract of the leaves of Sambucus Sieboldiana BLUME. was examined and sucrose (I), methyl chlorogenate (III), kaempferol (IV), and quercetin (V) were isolated together with a flavonoid compound (VI). The structure of compound (VI), which was hydrolyzed to each mole of D-galactose, D-glucose, and kaempferol, was proved to be kaempferol-3-O-bioside by complete methylation followed by hydrolysis to 4', 5, 7-tri (O-methyl) kaempferol. By comparison of the Rf of PPC and thin -layer chromatography (TLC), and of ultraviolet (UV) and infrared (IR) spectrum, compound (VI) was identified with panasenoside (kaempferol 3-O-glucogalactoside), isolated from the herb of Panax ginseng C.A. MEYER by Komatsu, et al.
Methyl linolenate, phytol, palmitic acid, fucosterol, saringosterol, friedelin, loliolide (digiprolactone), and mannitol were isolated from the methanolic extract of Undaria pinnatifida (HARVEY) SURINGER (Laminariaceae).