Allyl β-keto carboxylates undergo the following four different palladium-catalyzed reactions with high selectivity by selecting reaction conditions. 1. Decarboxylation-allylation to give α-allyl ketones. 2. Decarboxylation-dehydrogenation to give α, β-unsaturated ketones by the reaction in boiling acetonitrile. 3. Decarboxylation-deacetoxylation of α-acetoxylmethyl-β-keto carboxylates to give α-methylene ketones in acetonitrile at room temperature. 4. Decarboxylation-hydrogenolysis to give ketones by the reaction of ammonium formate. Palladium-catalyzed reaction of allylic esters with formic acid-triethylamine gives 1-olefins with high selectivity by using palladium-tributylphosphine as a catalyst. Allylic group can be used as a protecting group of carboxylic acids. Amines are also protected by forming allyl carbamates. They are deprotected by the palladium-catalyzed reaction of formic acid-triethylamine. The formal 3-butenylation of the lactone by Pd-catalyzed alkylation with allylic carbonate followed by hydrogenolysis with ammonium formate was used in the synthesis of optically active steroid C, D-ring and side chain. Moreover, stereoselectivities in methylations of 2, 3-dialkylcyclopentanone enolates derived by the Michael addition to 2-alkylcyclopentanones, obtained by Pd-catalyzed decarboxylation-dehydrogenation, were examined.
Construction of quinoline ring system employing an electrocyclic reaction of the corresponding azahexatriene derivatives has been developed. Moreover, the reaction of 2-isopropenylphenyl isocyanide with copper (I) chloride also afforded 4-methylquinoline.
A series of (2-pyrimidinylamino) phenylacetic acids was synthesized and tested for antiinflammatory activity and analgesic activity. These compounds were prepared by the condensation of anilines with 2-chloropyrimidines. Among them, 2-[3-fluoro-4-(2-pyrimidinylamino) phenyl] propionic acid (3i) showed potent anti-inflammatory activity. The structure-activity relationships are discussed.
A series of 1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids with a variety of substituents was prepared and evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. The introduction of alkoxy group into 8 position of quinoline nucleus provided significantly active compounds. However, the conversion to 3-quinolinecarboxylic acids with alkoxy group at 6 or 7 position and the replacement of alkoxy group with alkylthio, alkylsulfonyl and other groups resulted in substantial reduction or loss of activity. Among the analogues, 8-butoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (69) was found to possess remarkably potent activity by oral administration. Structure-activity relationships are discussed.
In the previous paper, the anti-ulcer effect of an extract of Panacis Japonici Rhizoma, saponin fractions and chikusetsusaponin III was reported. In the present experiment, further examination was made on the mode of the anti-ulcer effect of chikusetsusaponin III, in several experimentally induced ulcers, and revealed that the anti-ulcer action of chikusetsusaponin III does not ascribe to an inhibition of gastric acid secretion. It was further concluded that chikusetsusaponin III may directly activate gastric membrane-protective factors, or that the anti-ulcer action may be related to the activation of natural body protection mechanisms through gastric mucosal irritating effects of the saponin in general.
Two steroidal sulfates, tentatively named Rs-1 and 2 which were detected with pinacryptol yellow reagent, were isolated from a methanol extract of the aerial parts of Reineckia carnea KUNTH (Liliaceae). Rs-1 and 2 were characterized as kitigenin 4-O-sulfate and its proto-type, 26-O-β-D-glucopyranosyl 22-methoxy-5β-furostane-1β, 3β, 4β, 5β, 26-pentaol 4-O-sulfate, respectively. Further, three kinds of steroidal glycosides, named Rg-1, and compound I and II were separated from the MeOH extract. Rg-1 was established as pentologenin 5-O-β-D-glucopyranoside, and the others were elucidated as a mixture of convallamarogenin and isorhodeasapogenin carrying the sugar moieties of 1-O-α-L-rhamnopyranosyl-(1→2)-β-D-fucopyranosido-3-O-α-L-rhamnopyranoside and 1-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranosido-3-O-α-L-rhamnopyranoside, respectively.
In new borns, measurement of 17α-hydroxyprogesterone (17-OHP) is used in the initial diagnosis of congenital adrenal hyperplasia (CAH) due to deficiency in steroid 21-hydroxylase. Therefore, we attempted to develop a highly sensitive enzyme immunoassay (EIA) for the determination of 17-OHP in dried blood samples. The specificity of various antibodies and sensitivity of various combinations of antibody and enzyme conjugate were studied. The most sensitive combination of antibody and enzyme conjugate was a bridge heterologous system by using anti-17-OHP-4-carboxyethylthioether-BSA antiserum and 17-OHP-4-carboxymethylthioether-horseradish peroxidase conjugate. The detection limit of this system was 0.25 pg/assay and its 50% displacement value was 2.6 pg/assay for 17-OHP. The application of this method for the determination of 17-OHP levels in dried blood disc of new born babies and the observation of 17-OHP levels of CAH babies were described.
In order to clarify the effect of cytochrome b5 on Δ16-C19-steroid synthesizing activity in the testicular microsomes of neonatal pig, the effects of antibody and pyridine nucleotide on cytochrome b5 were investigated. Furthermore, the relationship between Δ16-C19-steroid synthesizing activity and cytochrome b5 was studied by use of adrenal microsomes or a reconstituted enzyme system of cytochrome P-450 (17α-hydroxylase/lyase) purified from adrenal microsomes. With anti-cytochrome b5 IgG no remarkable change was observed in the 17α-hydroxylase/lyase activity of testicular microsomes. Δ16-C19-Steroid synthesizing activity was, however, strongly inhibited. In the testicular microsomes or the reconstituted enzyme system of cytochrome P-450 (17α-hydroxylase/lyase) isolated from testicular microsomes, synergetic effects of nicotinamide adenine dinucleotide phosphate and nicotinamide adenine dinucleotide against the Δ16-C-19-steroid synthesizing activity and 17α-hydroxylase/lyase activity was observed. A strong effect was detected on the Δ16-C19-steroid synthesizing activity, while this synergetic effect against 17α-hydroxylase/lyase activity was weak. Although in adrenal microsomes little Δ16-C19-steroid synthesizing activity was detected, this activity was restored by the addition of cytochrome b5 isolated from testicular microsomes. Similarly to microsomes, Δ16-C19-steroid activity was restored by the addition of cytochrome b5 to the reconstituted enzyme system of cytochrome P-450 (17-hydroxylase/lyase) isolated from adrenal microsomes.
Dissolution behavior and effect of food on the bioavailability of a newly designed sustained-release granules of the ophylline (THP-G) were studied. In vitro dissolution rate of theophylline was measured according to the JPX dissolution test procedures in pH 1.2, 3.0, 5.0, and 6.8 solutions. The effect of food on the bioabailability after oral administration of 2.0 g of THP-G (400 mg of theophylline) was investigated in three volunteers following a cross-over design. The standard breakfast consisted of 140 g of bread, 200 ml of milk, and 20 g of butter. In vitro dissolution rates at pH 1.2 and 3.0 were 0-order, but at pH 5.0 and 6.8 were 1-order. The bioavailability in non-fasting state was about 80% that in fasting one.
The anti-allergic effects of EB-382, a non-steroidal antiinflammatory agent, were examined on the experimental animal models of allergic reactions. EB-382 showed no inhibition against the heterologous passive cutaneous anaphylaxis reaction in guinea-pigs (type I). EB-382 suppressed significantly the active Arthus reaction in rabbits at doses of 3 and 10 mg/kg, p.o. and the reversed passive Arthus reaction in guinea-pigs at a dose of 3 mg/kg, p.o. (type III), respectively. EB-382 showed no inhibition on the complement fixation reaction of sheep erythrocytes in vitro (type II) and the tuberculin-induced delayed type allergic reaction in guinea-pigs (type IV). It is suggested that EB-382 is a new type of non-steroidal antiinflammatory agent with a precedent pharmacological action, since it shows an inhibitory effect on the experimental model of type III of allergic reaction.