Various methods for the preparation of optically active compounds which have recently been developed by the author, are reviewed. Those exploited novel methods include 1) synthesis of optically active compounds by the novel use of meso compounds ; 2) asymmetric halolactonization reaction ; 3) asymmetric epoxidation in the presence of optically active molybdenum catalysts ; 4) asymmetric reduction of ketones with lithium aluminum hydride partially decomposed by optically active compounds. Efficient syntheses of optically active synthetic intermediates for biologically active compounds such as prostaglandins, steroids, anthracyclines, etc., could be achieved by employing the developed methods.
7-Carboxy-9-ethyl-2, 3, 6, 9-tetrahydro-1-methyl-6-oxo-1H-imidazo[1, 2-a]pyrido[2, 3-d]pyrimidin-4-ium chloride (5), consisting of a new heterocyclic ring system, was produced when 8-ethyl-5, 8-dihydro-2-[N-(2-hydroxyethyl)-N-methylamino]-5-oxopyrido[2, 3-d]pyrimidine-6-carboxylic acid (3) was treated with SOCl2. The structure of 5 was assigned on the basis of chemical and spectral evidence. The hydroxide (6) derived from 5 was unstable and was readily converted into a pseudo base (7). Oxidation of 7 with KMnO4 in alkaline medium gave 5-oxo compound (8). Reduction of 6 or 7 with NaBH4 afforded 5-unsubstituted 1H, 5H-imidazo[1, 2-a]pyrido[2, 3-d]pyrimidine derivative (9). The 5-positions of 6 and 7 reacted with methoxide, ethoxide, and carbanions of acetone and nitromethane to give the corresponding 5-methoxy (11), -ethoxy (12), -(2-oxopropyl) (13), and -nitromethyl derivatives (14), respectively. Antibacterial agents, piromidic acid (1) and pipemidic acid (2), as well as 3 were hydrogenated with Pd-C as a catalyst across the 3, 4 C=N bond, giving the 3, 4-dihydro derivatives 15, 16, and 10, respectively. Structure-activity relationships of these compounds were discussed briefly.
Diels-Alder reaction of furfurylamine derivatives (4a-g) with maleic anhydride is examined. Cycloaddition occurred highly stereoselective manner to give the lactam carboxylic acid (13a-g) in good to excellect yield. Evidences from chemical conversions and spectral examination revealed that the cycloaddition proceeded exclusively in exo manner in contrast to the ordinary Diels-Alder reaction.
Ethyl cellulose microcapsules containing aqueous gelatin solution were prepared by the microencapsulation by a multiple (WI/O/WII) emulsion method. Some physical and dynamical factors that affect the formation of emulsion were examined and discussed in the first emulsification. Furthermore, the size, distribution and yield percentage of microcapsules were calculated. The mean length diameter of emulsion (WI/O) was clearly influenced by the viscosity ratio of the internal phase (μi) to the external phase (μe), and then it showed the minimum value at a characteristic viscosity ratio, μi/μe' near to 1.0. In the first emulsification stage, high yield of microcapsules were obtained in the following conditions : 1) Sufficient amounts of sodium sulfate to inhibit coacervation were added in an aqueous solution of gelatin. 2) The mixed solution was mechanically emulsified with a chemistirrer at the high revolution number as possible.
Some physical and dynamical factors affecting the second emulsification were investigated in ethyl cellulose microcapsules containing aspirin prepared by a multiple (WI/O/WII) emulsion method. Furthermore, the dissolution rates of aspirin from microcapsules were measured. The following results were obtained ; In the second emulsification at preparation, the mean length diameter of microcapsules decreased initially and was leveled off later with an increase in the gelatin concentration in outer aqueous phase. The yield of microcapsules decreased as the revolution number of agitation became higher. The change in the serum concentration of aspirin after administration of aspirin microcapsules was apparently different from the plain powder, showing delayed release properties at the early time periods and a flatter response decay at the later time periods.
A method for the simultaneous determination of phenytoin and it's primary metabolite in humans, 5-(p-hydroxyphenyl)-5-phenylhydantoin, in human serum, was developed by column extraction-high-performance liquid chromatography. Simple and rapid extraction from the serum was carried out by using Extrelut[○!R] pre-packed column and chloroform. The chromatographic procedure utilized a reversed-phase column with 0.01% ammonium acetate in 50% methanol and monitored at 250 nm. The anticonvulsants were eluted at a flow rate of 1.0 ml/min, and their quantities were estimated from their peak height ratios to that of phenacetin added as an internal standard. The method was applied to patient serum samples and compared with a commercially available enzyme immnunoassay kit.
From the roots of Scutellaria baicalensis GEORGI, three new flavonoids, III, IV and V were isolated along with dihydrooroxylin A (I) and chrysin (II). The chemical structures of III, IV and V were established as 2', 5, 8-trihydroxy-7-methoxyflavone, 2', 5, 8-trihydroxy-6, 7-dimethoxyflavone and 4', 5, 7-trihydroxy-6-methoxyflavanone, respectively, by chemical and physical analyses.
Ten derivatives of isothiourea including 8 new compounds were synthesized and screened for the anti-tumor activity. Twenty nine derivatives of azine, 27 thiourea derivatives, 6 thiazole derivatives, 20 triazoline derivatives and 7 guanidine derivatives were also synthesized and screened for the anti-tumor activity. The anti-tumor activity was assayed by the use of ascitic or solid type of Ehrlich carcinoma. Among them, N-phenyl-S-benzylthioisothiourea·HCl, S-furfurylthioisothiourea·HCl, N-phenyl-S-furfurylthioisothiourea·HCl, 4, 4'-diacetylaminobenzalazine and 2, 3-dihydro-4-methyl-2-(2'-pyridylmethylenehydrazono)thiazole·2HCl were effective against the solid type of Ehrlich carcinoma.
The general acetylation of aromatic amides with substituted phenyl acetates, derived from the formation of N-acetyl-o-ethoxybenzamide in a molten mixture of aspirin and ethenzamide, was studied. Amides, i.e. benzamide or ethenzamide, were allowed to react with various substituted phenyl acetates (substituent ; 2, 4-(NO2)2, o-NO2, m-NO2, p-NO2, o-Cl, p-Cl, o-COOH, o-COOMe, p-COOH, H, o-Me, or p-Me) either in the molten state or in xylene, in order to examine the substituent effect on transacetylation. It was found that benzamide and ethenzamide were acetylated with substituted phenyl acetates and that the electron attracting group of phenyl acetate accelerated the acetylation of amide.
The absorption, excretion and metabolism of tulobuterol were studied in various aged rats after oral administration of 14C-tulobuterol. The blood levels of 14C after oral dosing in various aged rats, decreased gradually according to a biphasic process, that is, the first peak appeared at 30-40 min and the second one at 1-2 hr. The excretion of 14C after oral dosing was generally rapid and the radioactivities in the urine and feces for 7 days after oral dosage in various aged rats were 59-66% and 33-36% of the dose, respectively. The biliary excretion of 14C until 24 hr was estimated to be 59-66% of the dose in all aged rats studied, but the rate of excretion in 21-day-old rats was slower than those of 49- and 150-day-old rats. Furthermore, the excretion amount of the ring hydroxylated metabolites, such as 4-hydroxy form (II) and 4-hydroxy-5-methoxy form (IV) into the bile of the 21-day-old-rats was different from those of the 49- and 150-day-old rats. The relation between the activity of metabolizing enzymes in the liver and the age of rats was also studied. The metabolic activity of tulobuterol in the rat liver gradually increased until the 28th day, and thereafter decreased with an increase in the age.
The interaction of guanethidine (Guan) and phenoxybenzamine (PBA) has been studied for the responses to hypogastric nerve stimulation (HS) and transmural stimulation (TS) of guinea pig vas deferens. Response to TS (40 pulses at 20 Hz) was fully inhibited and the peak of response to HS at 20 Hz was inhibited by about 60% by the addition of Guan (3×10-5M). After treatment with PBA (1×10-8-1×10-7M), the peak of response to HS was significantly inhibited and sometimes completely by the addition of Guan. But when the concentration of PBA was increased to 1×10-6M or 1×10-5M, the reduction of the peak of response to HS by Guan became less concentration-dependent. Inhibitory effect of Guan on response to TS was also prevented by pretreatment with PBA (1×10-6-1×10-5M). On the other hand, after treatment with PBA (1×10-7M or 1×10-6M) methamphetamine (1×10-5M) fully restored the response to TS but scarcely restored the peak of response to HS in the presence of Guan. After the addition of methamphetamine, inhibitory effect of Guan on the peak response to HS was prevented soon and completely by washout of Guan. PBA seems to cause inhibition of Guan uptake at nerve endings. But after treatment with PBA the conduction of impulse to nerve endings seems to be partially blocked by the addition of Guan and methamphetamine does not seem to antagonized the conduction blocking activity induced by Guan.
In order to develope a non-steroidal anti-inflammatory drug, N-(3-dialkylamino-2-hydroxypropyl)-4-phenylpiperidine·2HCl was synthesized. Five compounds were examined for anti-inflammatory effects on swelling of rat hind paw induced by dextran and on mice scald oedema, diuresis effects, depression effects of normal body temperature. In general, the order of anti-inflammatory effects of these compounds was IIIe>IIId>IIIb>IIIc>IIIa. The inhibition percentage of scald oedema of compound No. IIId, e were higher than that of cortisone acetate and aspirin. These compounds had scarcely diuresis action. The order of depression effects on normal body temperature was IIIc>aminopyrine>IIIe≒IIId>IIIb>IIIa.
The reaction of dimethylsulfonium acetylcarbamoylmethylide (1) with isoquinoline 2-oxide (2) in the presence of acetyl chloride gave 2-[1(2H)-isoquinolylidenemethyl]-6-methyl-5-methylthio-1, 3-oxazin-4-one (3). When 3 was treated with mineral acid, 3-hydroxy-2-(1-isoquinolyl)-3-methyl-4-methylthioglutarimide (10) was obtained as a ring transformation product. 10 was dehydrolized with acid catalyst to 6-hydroxy-3-[1(2H)-isoquinolylidene]-4-methyl-5-methylthiopyridin-2(3H)-one (11). The treatment of 3 with diethylamine (or ethanolic potassium hydroxide) gave 2-diethylamino (or hydroxy)-4-oxopyrimido[4, 3-a]isoquinoline (17 or 18). On the reaction of 3 with acetic anhydride, 2-[1 (2H)-isoquinolylidene]-3-oxobutanenitrile (16) was obtained as a ring opening product.