Works on the synthesis of pyrimidine derivatives and thier structure-activity relationships for the development of analgetic-antipyretic, antiinflammatory, sedative and diuretic drugs are described. This article is constructed as follows : 1) 1, 3-disubstituted 5-dialkylaminouracils and aminopyrine 2) 1, 5-disubstituted or 1, 3, 5-trisubstituted barbituric acids and phenylbutazone 3) 5, 6-dialkyluracils and barbital 4) 2, 4-dioxo-1, 2, 3, 4-tetrahydropyrrolo [2, 3-d]-or [3, 2-d] pyrimidines and caffeine. As a result, bucolome (5-butyl-1-cyclohexylbarbituric acid) is developed as a antiinflammatory drug.
2, 6-Dimethyl-1-ethoxycarbonylmethylpyridinium bromide (Ia) reacted with ketene-thioacetal derivatives (II) in the presence of potassium carbonate to afford 3-ethoxycarbonylindolizine derivatives (IV) and 3-vinylindolizine derivatives (V). While, 2-aminopyridinium salts (VII) reacted with II in the presence of potassium carbonate only to give 3-vinylimidazo [1, 2-α] pyridine derivatives (VIII). Ia was treated with sodium hydride, carbon disulfide and then dimethyl sulfate to afford methyl 2-hydroxy-5-methylindolizine-3-dithiocarboxylate (XIII). Also, imidazo [1, 2-α] pyridine-3-dithiocarboxylate derivatives (XVIII, XIX) were obtained from VII. Some reactivities of XIII, XVIII and XIX with amines or active methylene compound were described.
2-Amino-3-methoxycarbonylmethylthiazolium bromide (IV) reacted with ketenethioacetal derivatives (IIa-d) in the presence of sodium hydride or triethylamine to afford stable intermediate, 2-imino-2, 3-dihydrothiazole derivatives (Va-e). Va, b, d were treated with sodium methylate to give imidazo [2, 1-b] thiazole derivatives (IXa-c) by intramolecular nucleophilic substitution reactions.
The rates of the nitrosation of phenyl cyclohexanecarboxylate (abbreviated as PCC) with nitrosyl hydrogensulfate (NHS) in 0-7% oleum to form ε-caprolactam have been investigated by measuring the volume of evolved carbon dioxide. The rate equation of the reaction is written as follows : Rate=(κ1e+κ2esCso3+κ2enCNHS)CPCC A probable mechanism which involves the rate-determining steps of formation of pentamethylene ketene (PMK) by deprotonation from cyclohexanecarbonyl cation formed by elimination of phenolate anion and sulfur trioxide from an adduct of PCC and SO3 (κ1, main path, 90.4%), and by the elimination of SO3, phenol and proton from the adduct (κ2es, 5.3%) followed by a rapid attack of NHS on the double bond of PMK, and a rate-determining formation of cyclohexanone oxime hydrogensulfate from the adduct of NHS and PCC (κ2en, 4.3%) was discussed and postulated.
A new sensitive fluorometric HPLC method for the determination of a mucolytic agent N-acetyl-L-cysteine (NAC) and its metabolite L-cysteine (CySH) in biological fluids was developed. By the addition of a fluorescent agent, N-(9-acridinyl) maleimide (NAM), to NAC and CySH, stable fluorescence of NAM derivatives were developed at room temperature in a buffer solution, and the derivatives were separated and determined by HPLC. To standard or test solutions containing NAC and CySH were added 0.5 M Na2CO3-H3BO3-KCl buffer solution (pH 8.8), 5N NaOH and acetone solution of NAM (0.5-2×10-6 mol/ml), and the mixture was allowed to stand for 2 h at room temperature. An aliquot of this solution (5-20 μl) was injected into the HPLC equipped with fluorometric detector. The separation of the derivatives were carried out on an aminoalkyl chemically bonded silica by using acetonitrile/0.05 M CH3COONa as mobile phase system for the analysis of NAC and on an octadecyl chemically bonded silica by using acetonitrile/0.05 M CH3COONH4 for the analysis of CySH. The fluorescence intensities of the derivatives were determined at 360 nm (excitation) and 435 nm (emmision). This method is simple, specific and sensitive compared with the gas chromatographic procedure for the determination of NAC and CySH in the plasma and tissues of rats after single oral administration of NAC.
Phase diagrams of the polyethoxyoleylether-water binary system and the polyethoxy-oleylether-water-cetostearyl alcohol ternary system were made. With the binary system, a liquid crystalline (LC) phase having a face-centered cubic structure and, in the both sides, two LC phases having hexagonal structures were found. With the ternary system, three LC phases were found in addition to those corresponding to the LC phases in the binary system. The LC phase which appeared in the low alcohol concentration area was lamellar and that which appeared in the middle alcohol concentration area (D2 phase) was also lamellar but the structure of lypophilic layer was thought to be the same as that of α-alcohol. The molar ratio of cetostearyl alcohol to polyethoxy-oleylether in the D2 phase was 3 : 1, suggesting the molecular arrangement proposed by Shah. This phase was much similar to the LC phase which was found in an O/W emulsion including cetostearyl alcohol. The LC phase which appeared in alcohol rich area was seen to be closely packed with spherules. Under polarized light, they shined in Maltese Cross. This phase gave only one X-ray diffraction peak.
Complexes of several barbiturates and polyethylene glycol (PEG) are prepared by the coprecipitation method and the evaporation of equilibrated mixture from pyridine. Powder X-ray diffraction patterns and DSC curves indicate that phenobarbital, cyclobarbital, barbital, and pentobarbital form the complexes with PEG. It is also found that the grinding of barbiturates with PEG forms the complexes in a similar manner. From IR shifts of barbiturates in CCl4 solution containing different amounts of tetraethylene glycol dimethyl ether, it is found that barbiturates are present in the molecular level in the solid complexes and that hydrogen bonding is formed between the N-H group of barbiturates and the oxygen atom of PEG. To investigate the effect of polymer chain length on the complex formation, the solubility phase diagram method and the viscosity measurement by Ostwald's viscometer are performed. It is assumed that one drug molecule interacts with two repeating units of -(CH2-CH2-O)-in PEG and for PEG at least four repeating units of -(CH2-CH2-O)- are needed to form the complexes.
Sizes of sequentially extruded multilamellar liposomes were measured by a method of quasi elastic laser light scattering (QELS method). Sequential extrusion was started with 1.0 μm filter, then 0.8, 0.6, 0.4, 0.2, and finally with 0.08 μm filters. Polydispersity and skewness of size distribution were analyzed by a cumulative expansion method. Mean diameter, polydispersity, and skewness decreased due to the sequential extrusion through polycarbonate membrane filters. Effects of the addition of cholesterol into lecithin on these physico-chemical parameters were also studied. Liposome size was decreased by the extrusion until with 0.4 μm filter. But further sequential extrusion did not induce a large decrease in the size, suggesting that the most liposomes pass through the pore by changing their shape.
General pharmacological studies were made on gomisin A and schizandrin which are the constituents of "Hoku-gomisi", the fruit of Schizandra chinensis BAILL. (Schizandraceae) used as an antitussive and a tonic. In the experiments by using mice, gomisin A prolonged intensively hexobarbital-induced sleeping time at doses smaller that 1/40 of LD50, inhibited spontaneous and methamphetamine-induced motor activity, and showed a hypothermic effect and at higher doses an analgesic effect by pressure pain method, while schizandrin showed the same effects except for the sleep-prolongating effect and inhibited writhing symptom by AcOH. At higher doses, both compounds showed a muscle relaxant effect. From these results, it was conceivable that the action of both compounds was a sedating or tranquilising effect. The efficacy of gomisin A was durable and intense, and that of schizandrin was transient. But on the analgesic effect gomisin A was inferior to schizandrin. Moreover, gomisin A showed an antitussive effect in guinea pigs. In the experiments by using rats, gomisin A showed inhibitory effects on gastric contraction (i.v.) and stress-induced gastric ulceration (p.o.), whereas schizandrin showed the same actions, choleretic action, and an inhibitory effect on gastric secretion. In the inhibition of gastric ulceration, the action of schizandrin was superior to gomisin A, and it was suggested that the action of gomisin A depended on the inhibition of gastric contraction to depress stressor factor, and that the action of schizandrin was mainly due to the inhibition of gastric juice secretion and gastric contraction.
1-Phenyl, 1-methoxy, 1-phenoxy, 1-benzylphthalazine 3-oxides (Ia-d) reacted with dimethyl acetylenedicarboxylate (II) to afford four kinds of adducts : methyl 6-substituted pyrrolo [1, 2-α] phthalazine-1, 2, 3-tricarboxylate (IVa-d), dihydro derivative of IV (Va, c, d, VIa, d), 4-substituted 2-phthalazinium 3-methoxy-1-methoxycarbonyl-2, 3-dioxopropylide (VIIb, c, d). In the reaction of Ia with II, two products (VIII, IX), which showed the same molecular formula C20H16O5, were also obtained. It is considered that these products are formed by the liberation of nitrogen from the 1, 3-dipolar cycloadducts. The structures of VIII and IX have not been determined. Ia-d reacted with methyl propiolate (III) to afford methyl 6-substituted pyrrolo-[1, 2-α] phthalazine-1, 3-dicarboxylates (Xa-d). In the reaction of Ia with III, structure-unknown product (X, C18H14O3) was also obtained.
Acylaminoguaiazulenes, mainly dicarboxylic acid monoguaiazulenamides, were synthesized and their antiulcer activity was investigated by Shay ulceration method in the rat. Dicarboxylic acid monoguaiazulenamides, particularly aliphatic dicarboxylic acid monoguaiazulenamides, showed a high antiulcer activity. Compounds (1g, h) were more effective than guaiazulene in both administrations (s.c. and i.d.). Structure-activity relationship of these compounds was briefly discussed.
The electron impact mass spectra of six novel diterpenes (lactone type), isolated from the fraction exhibiting anti-complement activity of Cinnamomi Cortex, have been investigated. A characteristic fragmentation pattern, which is useful to decide the chemical structures of related diterpenes, was provided.
A method for the quantitative determination of salicylic acid and benzoic acid by gas chromatography with flame thermionic detector was developed. The carboxylic acids were converted into the corresponding amides with isopropylamine by mixed carbonic anhydride method. The reaction was performed quantitatively in chloroform in the presence of triethylamine and ethyl chlorocarbonate, and less than 30 min was required for a quantitative derivatization. This method permitted the determination of the drugs at serum levels down to 20-30 ng/ml.
A new method was established for the determination of acid chloride by high performance liquid chromatography. Acid chlorides were transformed to their esters by methanol and determined by reversed-phase column. This method is not only simple but also accurate, and able to determine decomposed substances of acid chlorides simultaneously.
A method for the fluorescent labeling of carboxylic acids with 4-hydroxymethyl-7-methoxycoumarin (I) in the presence of diethyl azodicarboxylate and triphenylphosphine is described. The reaction of aliphatic and aromatic acids with I at room temperature for fifteen minutes in tetrahydrofuran gave the corresponding esters in a good yield. Thin-layer chromatographic separation and fluorescent measurement of the esters allow the determination of carboxylic acids.
From the methanol extract of the whole herb of Swertia tetrapetala PALL. (Gentianaceae), were isolated 1, 8-dihydroxy-3, 5-dimethoxyxanthone, 1-hydroxy-2, 3, 5-trimethoxyxanthone, 1-hydroxy-2, 3, 4, 7-tetramethoxyxanthone, luteolin, luteolin-7-o-glucoside and a bitter principle, swertiamarin. 1-Hydroxy-2, 3, 5-trimethoxyxanthone was found at first time in this plant among the Genus Swertia. Isolated xanthones suggest that this plant might be related with the Genus Frasera.