Three β-substituted pyridine N-oxides (I, II and III) were subjected to 1, 3-dipolar cycloaddition with phenyl isocyanates having an ortho, meta or para substituent group. 3-Methyl- (I) and 3, 5-dimethyl-pyridine N-oxide (II) afforded the 2, 3-dihydropyridine derivatives, and the 3, 5-dibromo compound (III) afforded a 2, 3-dihydro-2-oxo-oxazolo-[4, 5-b] pyridine (IX) by the elimination of hydrogen bromide from the 2, 3-dihydropyridine thus formed. The presence of an o-substituent group or nitro group in the phenyl isocyanate resulted in a reduced cycloaddition yield. The structures of the 2, 3-dihydropyridine adducts were determined by X-ray crystallographic analysis.

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Intensely fluorescent products were formed from cephalexin and cephradine in acidic solution containing hydrogen peroxide by hydrolysis at high temperature. A fluorescent product was formed from cephatrizine in solutions containing mercuric chloride by warming at 60° for 50 min after cleavage of the β-lactam ring with 1N NaOH. Each of the fluorescent products was readily extracted with ethyl acetate or an acetone-chloroform mixture from neutral solutions, and could be partitioned into alkaline solution. The urinary excretion of these antibiotics in human volunteers after oral administration was investigated using these new methods.

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New dilactones (2a-j, 3a, and 3b) having a 3, 7-dioxabicyclo [3.3.0] octane-2, 8-dione system (1f) have been prepared starting from diethyl 2-formyl succinate (5). Treatment of a 2-ethoxycarbonyl-3-hydroxymethyl-4-butanolide derivative (9) with acidic ethanol gave 3, 7-dioxabicyclo [3.3.0] octane-2, 8-dione (2a). Alkylation of 2a with various alkyl halides gave C₁-substituted-3, 7-dioxabicyclo [3.3.0] octane-2, 8-diones (2b-g) in moderate yields. The same compounds (2b-g) were also prepared from 9 after alkylation followed by acid treatment. 1-(6-Methoxycarbonyl-2-hexynyl)-3, 7-dioxabicyclo [3.3.0] octane-2, 8-dione (2h) and the 1-(6-cyano-2-hexynyl) analog (2i) were also prepared from 9. Partial hydrogenation of the acetylenic derivatives (2h and 2i) gave the corresponding cis-olefinic compounds (3a and 3b), which are potential synthetic intermediates for 10-oxa-11-deoxyprostaglandin E₂ (4).

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When phenylalanine was treated with the hydrogen peroxide-cupric ions system in acetate buffer (pH 6.0), o-tyrosine, m-tyrosine and p-tyrosine were identified as hydroxylated products. Cupric ions markedly accelerated the decomposition of phenylalanine as compared with other transition metal ions. Radical scavengers, e.g., potassium iodide, dimethyl sulfoxide, formic acid and ethyl alcohol, largely prevented the decomposition of phenylalanine. Superoxide formed from hypoxanthine-xanthine oxidase was found to decompose phenylalanine to some extent. These results suggest that a transient free radical intermediate, formed from hydrogen peroxide, is primarily responsible for the decomposition.

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The 1, 3-dipolar cycloaddition of 4-benzyloxy-6-methylpyrimidine 1-oxide (Ia) with dimethyl acetylenedicarboxylate (DMAD) gave dimethyl α-oxo-α'-(4-benzyloxy-6-methyl-2-pyrimidinyl) succinate (IIa), which was readily hydrolyzed to methyl 4-benzyloxy-6-methyl-2-pyrimidineacetate (IIIa). A similar reaction of 4-methoxy-(Ib) and 4-ethoxy-6-methylpyrimidine 1-oxide (Ic) gave corresponding methyl 2-pyrimidineacetates (IIIb, c). On the other hand, 6-methyl-4-piperidinopyrimidine 1-oxide (Id) reacted with DMAD to give a betaine derivative, 1-(6-methyl-4-piperidino-1-pyrimidinio)-1, 2-bis (methoxycarbonyl) ethenyl-2-oxide (IV).

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The rates of transacylation were studied between crown ethers (1, 2, 3) having sulfhydryl groups at the end of side arms of different lengths and α-, β-, γ-, and ε-amino acid p-nitrophenyl ester salts (4, 6, 7, 8). It was shown that regioselectivity of the reaction can be successfully correlated with the distance of the catalytic site from the polyether ring. It was also shown that introduction of ether oxygen in the side arm can be used to keep the side arm sticking up from the polyether ring in the complex.

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In addition to stephanthraniline A and stephanthraniline C, whose structures have been reported previously, five new pregnane derivatives, stephanthraniline B (12β-O, N-methyl-anthraniloyl-20-O-acetyldihydrosarcostin), SG-A (12β-O-(2-methylbutyryl)-20-O-acetylsarcostin), SG-B (20-O-(2-methylbutyryl) sarcostin), SG-C (20-O-tigloylsarcostin), and dihydrogagaminin (12β-O-cinnamoyl-20-O-nicotinoyl-dihydrosarcostin) were isolated from the aerial parts of Stephanotis japonica MAKINO (Asclepiadaceae) and their structures were determined. Penupogenin, kidjoranin, and gagaminin were also isolated and identified.

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The kinetic parameters, K_m and log V_max, of the cleavage of dinucleoside phosphates, GpU, GpC and ApU, by RNase Rh from a Rhizopus sp. were measured at various pH's. Analysis of the pH profiles of K_m and V_max of these dinucleoside phosphates according to Dixon's theory suggested that two functional groups having pK_a values of 7.0-7.3 and 3.25-3.5 are present in the active site of RNase Rh. The former value may correspond to a histidine residue. The pH dependence of the rates of inactivation of RNase Rh by photoxidation and carbethoxylation also indicated that a functional group having pK_a about 7.0 was involved in the active site. Amino acid analysis of photooxidized RNase Rh showed that only a histidine residue had been destroyed. In the carbethoxylation of RNase Rh, the formation of carbethoxyhistidine caused a corresponding loss of activity of RNase Rh without modification of tyrosyl residues. It was concluded that a histidine residue having pK_a about 7.0 is involved in the active site of RNase Rh.

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The oxidation of 4'-, 3'-, and 2'-substituted 2-nitrobenzenesulfenanilides (4'-Br (3e), 4'-CO₂Et (3f), 4'-COMe (3g), 4'-OEt (3h), 4'-NO₂ (3i), 4'-SO₂NH₂ (3j), 3'-Me (4b), 2'-OMe (5a), 2'-Me (5b)) with lead dioxide was carried out in acetonitrile containing 1% CF₃COOH and 1% (CF₃CO)₂O. The oxidation of 3e, 3f, 3g, 3h, 3i, and 4b gave the corresponding 2, 7-disubstituted phenazines (2e-i and 2b), whereas that of 3j, 5a, and 5b did not. N-(2-Nitrophenylthio) acetamide (6) was obtained on the oxidation of 3e-j, 4b, 5a, and 5b. 2, 2'-Dinitrodiphenyl disulfide (7) was obtained from 3f, 3g, 3h, 3j, and 5a. The oxidation of 5b gave a small amount of N-(2-nitrophenylthio)-2'-methyl-p-benzoquinoneimine (8b), whereas that of 5a gave a mixture of N-(2-nitrophenylthio)-2'-methoxy-, p- and o-benzoquinoneimines (8a and 8a').

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A simple and rapid fluorodensitometric method for the simultaneous determination of 1, 4-dimorpholino-7-phenylpyrido [3, 4-d] pyridazine (DS-511) and its metabolites in plasma was established. DS-511 and the metabolites were extracted from plasma with ethyl acetate. The organic layer was subjected to thin-layer chromatography with ethyl acetate-benzene (3 : 2). The air-dried chromatogram was moistened with 1-butanol, then the fluorescent spots were quantitatively determined with a spectro-densitometer in a fluorescence mode. A linear calibration plot for DS-511 was obtained in the concentration range of 0.02-0.50 μg per 1 ml of plasma. The accuracies as the coefficients of variation were 8 and 3% at concentrations of 0.05 and 0.25 μg of DS-511 per 1 ml of plasma, respectively. This method can be used to analyze plasma levels of DS-511 after its administration to rats and dogs, and should also be applicable to human plasma.

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We have found a new insertion reaction of diazoalkanes, especially phenyldiazomethane, with dialkylaminomethyl esters of dialkyldithiocarbamic acid and of ethylxanthic acid. The scope and limitations of this reaction are described.

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An enzyme fraction which catalyzes the reduction of cis-2-alkenoyl-Coenzyme A (-CoA) to the corresponding saturated acyl-CoA derivatives has been separated from Escherichia coli extracts. The enzyme catalyzes the reduction of cis-2-octenoyl-CoA with an apparent Michaelis-Menten constant of 2.0×10^-5M in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), but not in the presence of reduced nicotinamide adenine dinucleotide (NADH). The reductase is inactive on cis-3- or trans-2-isomers. The reductase is stable at 45°, but its activity is lost on heating at 55° for 10 min. Some other properties of this enzyme are also described.

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Regioselective sulfenylations of dianions derived from 1, 3-dicarbonyl compounds were investigated with readily available sulfenylating agents such as diphenyl disulfide, phenyl benzenethiosulfonate, and phenylsulfenyl chloride, employing sodium hydride and butyl lithium or lithium diisopropylamide as bases. Sulfenylations of the dianions prepared from the β-ketoesters Ia, Ib and VI, the β-ketoamide Ic, and the 1, 3-diketones X and XIII with diphenyl disulfide afforded IIIa, IIIb, VIII, IIIc, XII, and XV, respectively, in fairly good yields.

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A method for the enzyme immunoassay of insulin is described. Insulin was conjugated with horseradish peroxidase by the periodate oxidation method. Separation of the bound and free fractions was accomplished by a double-antibody solid phase method using Sepharose 4B-anti-rabbit IgG goat IgG. The amount of bound enzyme-labelled insulin was determined by measuring the fluorescence developed after incubation with tyramine and hydrogen peroxide. Tyramine was a better fluorogenic substrate for the determination of peroxidase activity homovanilic acid. Insulin levels in serum could be measured over the range of 2.5 to 160 μU/ml, which is similar to that of insulin radioimmunoassay. Insulin values in 34 serum samples were determined using this method and RIA. A good correlation (γ=0.89) was obtained. The coefficient of variation was 0.6-2.6%. The method is roughly equivalent to RIA with respect to sensitivity. EIA largely overcomes the problems of RIA because there is no radiation hazard or disposal difficulties. Moreover, the laboratory equipment required is relatively inexpensive and readily available, while the label enzyme, HRP, is reasonably price and has a long shelf life. The enzyme immunoassay of insulin described in this paper should make it possible to perform routine assays even in laboratories with limited facilities.

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The asymmetric bromolactonization of (S)-N-(α, β-unsaturated) acylproline ((S)-17a) prepared from the α, β-unsaturated acid (10a) was found to occur stereoselectively to give the bromolactone (18a) in which one diastereomer (18Aa) was predominant. Debromination of 18a followed by acidic hydrolysis, afforded the (R)-α-hydroxy acid ((R)-12a) in 92% optical purity. Reaction of (R)-12a with methylithium gave the (R)-α-hydroxy ketone ((R)-9a), a model compound of the optically active anthracyclinone AB ring system, in good yield. When the reaction scheme established by the model study was applied to 10b, c, which possess the AB and ABCD ring systems of anthracyclinones (2), (R)-α-hydroxy acid methyl esters ((R)-21b, c) could be prepared in 97% and 87% optical yields, respectively. Alkaline hydrolysis of optically pure (R)-21b, c independently prepared from the pure debrominated lactones (19Ab, c) gave (R)-12b, c. Although the reaction of tetracyclic (R)-12c with methyllithium did not proceed in the expected manner, bicyclic (R)-12b was successfully converted to optically pure (R)-9b, which has previously been utilized as a starting material for the synthesis of optically active natural and unnatural 2.

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The solid-state decomposition of sulpyrine was investigated at 80° under oxygen gas. The initial rate of decomposition depended on the water content. When the amount of water present was insufficient to dissolve all the sulpyrine, the rate was of zero-order and increased in proportion to the amount of water. On the other hand, in the presence of a larger amount of water, sulpyrine decomposed in an apparent first order reaction, but the rate was dependent on the amount of water. It is proposed as a mechanism that sulpyrine is hydrolyzed to 4-methylaminoantipyrine (MAA), and then MAA is further oxidized in the aqueous layer. The first order rate constant of decomposition of MAA estimated in saturated solution of sulpyrine in the presence of solid phase was in good agreement with that estimated in sulpyrine solution of lower concentration. As reaction products, aminopyrine (Am), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-formylmethylaminoantipyrine (FMAA) were identified. It is proposed that Am and AA may be formed from MAA by methyl rearrangement, while FAA and FMAA may be formed from MAA and Am, respectively, by oxidation of the methyl to a formyl group via intermediates.

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5-Oxo-1, 2, 3, 5-tetrahydro-5H-imidazo [1, 2-b] isoquinoline (IIa) and related compounds were synthesized from homophthalic acid and an aliphatic 1, 2- or 1, 3-diamine. In addition, homophthalic acids or o-carboxyphenylmalonic acid diesters were allowed to react with an aliphatic 1, 2- or 1, 3-aminoalcohol or aminothiol with heating in the presence of p-toluenesulfonic acid, yielding a series of oxazolo- or oxazino-isoquinolones (VI) or thiazolo- or thiazino-isoquinolones (IV). Oxidation of IV gave the corresponding sulfoxides (VII) and sulfones (VIII). Treatment of o-cyanomethylbenzenesulfonyl chloride with an N-alkyl 1, 2- or 1, 3-diamine gave N-alkyl-imidazo- or pyrimido-benzothiazine-5, 5-dioxide (XI). The compounds thus prepared were evaluated for their anti-inflammatory effect in rats, using the carrageenin paw edema method, and some of the condensed heterocyclic isoquinolone derivatives were found to exhibit strong anti-inflammatory activity. These compounds were also examined for analgesic activity in terms of the inhibition of acetic acid induced writhing. Compound VIIIk showed stronger anti-inflammatory activity than phenylbutazone, as well as analgesic activity comparable to that of aminopyrine, and had very low toxicity.

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The lipid extract of the soft coral, Sarcophyton glaucum, was found to contain significant amounts of cembrane-type diterpenes. The structures of four major components, sarcophytol-A, sarcophytol-A acetate, sarcophytol-B, and sarcophytonin-A were characterized on the basis of spectral data and degradative studies by ozonolysis. Sarcophine and 16-deoxosarcophine, which were reported to be abundant in S. glaucum collected in the Red Sea, were not found yet.

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Four triterpenoid saponins, which were tentatively named prosapogenins CP₂, CP₆, CP₇ and CP₈, were isolated from the alkaline hydrolysate of crude saponin obtained from Clematis chinensis OSBECK. On the basis of chemical and physicochemical evidence, they were characterized as follows : CP₂ (I), oleanolic acid 3-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside ; CP₆ (III), hederagenin 3-O-β-D-ribopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside ; CP₇ (VII), oleanolic acid 3-O-β-D-glucopyranosyl-(1→4)-β-D-ribopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside ; CP₈ (IX), hederagenin 3-O-β-D-glucopyranosyl-(1→4)-β-D-ribopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranoside.

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Two cembranolide diterpenes were isolated from the Japanese soft coral Lobophytum pauciflorum (Ehrenberg). The structures of these diterpenes were identified as I and II, involving a 13-membered carbocyclic ring system unique in the soft coral literature.

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The reaction of 4-isoxazolin-3-ones with phosgene or trichloromethyl chloroformate gave various 3-chloroisoxazolium chlorides in good yields, and these were converted to 4-isoxazolin-3-thiones on treatment with sodium hydrosulfide. Pyrolysis of 3-chloro-2-methylisoxazolium chlorides afforded 3-chloroisoxazoles. In the presence of tri-n-butylamine, 3-chloro-2-methyl-5-phenylisoxazolium chloride condensed carboxylic acids with alcohols or amines to give the corresponding esters or amides in high yields, together with 2-methyl-5-phenyl-4-isoxazolin-3-one.

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Reduction of aldehydes and ketones with pyridine-borane in trifluoroacetic acid was examined. Symmetric ethers were obtained by the reduction of aldehydes ; the combination of an aldehyde and alcohol resulted in the formation of an unsymmetric ether under the same reduction conditions. Aryl ketones and aryl alcohols were reduced directly to the corresponding arenes, while dialkyl ketones were reduced to the alcohols. Alkyl alcohols were not reduced and were recovered intact.

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In contrast to other nucleophilic reagents, dimethyloxosulfonium methylide and nitromethane attack 1-oxoquinolizidine (1) in a stereoselective manner to yield only the axially substituted products, quinolizidine-1-spirooxirane (2) and 1 (e)-hydroxy-1 (a)-nitromethylquinolizidine (4a). This high stereoselectivity can be explained in terms of an interaction between the lone pair on the ring nitrogen atom and the cationic center of the reagents.

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The reaction of 3-chloro-2-methylisoxazolium chlorides with phenols or thiophenols in the presence of triethylamine or sodium methoxide gave 2-methyl-3-phenoxy- or 2-methyl-3-phenylthioisoxazolium chlorides, which were converted to 3-phenoxy- or 3-phenylthioisoxazoles in moderate yields by heating in an appropriate solvent. On pyrolysis of the 3-alkylthioisoxazolium salts prepared from 4-isoxazolin-3-thiones and alkyl halides, the yields of 3-alkylthioisoxazoles depended on the nature of the 2-substituent of the onium salts. 2-Benzyl-3-alkylthioisoxazolium salts gave the best yields. Mixtures of a 2-benzyl-4-isoxazolin-3-thione and a large excess of alkyl halide gave 3-alkylthioisoxazoles in good yields on heating.

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In order to clarify the involvement of the kallikrein-kinin system in anaphylactic shock, Shimeji kininase, which is able to block kinin action in the body due to rapid kinin destruction, was tested on anaphylactic shock in rats. The anaphylactic shock in rats at 15 days after sensitization with egg albumin was hardly suppressed by Shimeji kininase alone or mepyramine alone, but the rats were markedly protected when this enzyme was used together with mepyramine. The rats at 30 days after sensitization were completely protected against shock by mepyramine alone and were also protected to some extent by Shimeji kininase alone. Thus, at the early phase after sensitization, both kinins and histamine appear to play important roles in anaphylaxis in rats, but in the late phase after sensitization, histamine is considered to play a more important role than kinins. In the rats at 15 days after sensitization, the high molecular weight kininogen level in plasma did not alter on challenge with antigen, and plasma prekallikrein activation was not detected. On the other hand, a slight but significant decrease of low molecular weight kininogen level and an increase of kinin level on challenge with antigen were observed.

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Various reactions of 3-methyl- (Im) and 3-phenyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine (Ip) were examined. Im was prepared by cyclization of 5-amino-4-methylaminopyrimidine (II) with nitrous acid, and Ip was prepared by the catalytic reduction of 7-chloro-3-phenyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine (IIIp) using palladium on magnesium oxide carrier as a catalyst. In warm alkaline solution Im underwent ring fission to give 5-amino-1-methyl-1H-1, 2, 3-triazole-4-carboxaldehyde (IVm). In dilute sulfuric acid both Im and Ip underwent ring fission to yield IVm and 5-amino-1-phenyl-1H-1, 2, 3-triazole-4-carboxaldehyde (IVp), respectively, in good yields. However, the reaction of Im with the methoxide ion resulted in the formation of 7, 7'-bis [3-methyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine] (Vm) and 3-methyl-7-(5-amino-1-methyl-1H-1, 2, 3-triazol-4-yl)-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine (VIm), although the yields were poor. Both Im and Ip dimerized in the presence of the cyanide ion to give Vm and 7, 7'-bis [3-phenyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine] (Vp), respectively, in good yields. N, N-Dimethylaniline (IX) reacted with Im in dulute sulfuric acid to give 5-amino-4-[bis [4-N, N-dimethylaminophenyl] methyl]-1-methyl-1H-1, 2, 3-triazole (VIIIm) in poor yield. VIIIm was also obtained by condensation of IX and IVm in dilute sulfuric acid.

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The Michael reaction of diethyl malonate with chiral α, β-unsaturated aldimines (4), prepared from crotonaldehyde and optically active α-amino acid tert-butyl esters (3), was found to give the corresponding β-substituted aldehydes (5) in reasonably high optical yields after hydrolysis. A proposed stereochemical mechanism of the reaction is presented.

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Sesamol (II), a monophenolic antioxidant present in sesame oil, was found to interact readily with nitrite. In dilute aqueous solutions with II in excess, it rapidly and completely removed nitrite to produce an equivalent amount of 3, 4-methylenedioxy-6-nitrosophenol (III) ; the rate was fastest at pH 2.0, followed by pH 3.0 and 4.0 in that order. In dilute solutions with nitrite in excess, the amount of III formed, which corresponded well to that of nitrite lost, was less than that of II initially present, and some side reactions may have occurred. Compound II either prevented the N-nitrosation of dimethylamine, as did pyrocatechol and L-ascorbic acid, or accelerated the reaction, depending upon the conditions. Compound III showed a catalytic effect on the N-nitrosation.

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Treatment of 4-hydroxymethyl-1-phenylazetidin-2-ones (2a) and (2b) with methanesulfonic acid afforded 4-anilino-2-oxo-tetrahydrofurans (3a) and (3b), respectively. In a similar way, 3-(2-hydroxybenzyl)-1-phenylazetidin-2-one (8), 1-(4-methoxyphenyl)-4-(2-piperidino) azetidin-2-one (13), 3-(2-aminobenzyl)-1-phenylazetidin-2-one (16) and 1-(4-methoxyphenyl)-3-(2-piperidinomethyl) azetidin-2-one (19) were subjected to cleavage of the amide bond to give the corresponding lactone and lactams (9), (14), (17) and (20), respectively. The amide bond of β-lactams was also found to be cleaved by alkyl lithium in the presence of N, N, N', N'-tetramethylethylenediamine to give β-aminoketones.

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A stereoselective synthesis of 1-methyl (e)-4-phenyl (e)-trans-quinolizidin-2-one (16a) and 7-methyl (e)-4-phenyl (e)-trans-quinolizidin-2-one (23a) was accomplished during model studies for a stereoselective synthesis of quinolizidine-type Nuphar alkaloids. Condensation of ethylpyridine (11) with acetonitrile followed by ketalization gave the ketal (13), which was hydrogenated to afford two diastereoisomers (14a and 14b) in a 1 : 1 ratio. Deketalization of 14a or 14b afforded a diastereoisomeric mixture (1 : 1 ratio) of the aminoketone (15), which was condensed with benzaldehyde to give two quinolizidin-2-ones (16a and 16b) in 63 and 17% yields, respectively. The latter isomerized smoothly into the former on treatment with aqueous alkali in methanol. Similarly, the ketal (20) derived from 2, 5-lutidine (18) was hydrogenated to give the trans- and cis-piperidines (21a and 21b) in a 2 : 1 ratio. Treatment of both of them with hydrochloric acid effected deketalization and isomerization to yield a mixture of the trans- and cis-aminoketone (22a and 22b) in a 6 : 1 ratio, whereas deketalization with aqueous acetic acid or p-toluenesulfonic acid gave the mixture in a 1 : 3 ratio. Condensation of the mixture of 22a and 22b (6 : 1 ratio) with benzaldehyde gave two quinolizidin-2-ones (23a and 23b) in 65 and 10% yields, respectively. These were also obtained in 31 and 27% yields, respectively, from the mixture of 22a and 22b (1 : 3 ratio).

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Affinoside B, a novel cardiac glycoside with a diosphenol system in ring C of the aglycone and with a doubly linked 3-O-methyl-4, 6-dideoxy-2-hexosulose sugar moiety, was isolated from Anodendron affine DRUCE and the structure was determined by direct single crystal X-ray analysis.

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The effects of bile salts on the dissolution behavior of indomethacin and phenylbutazone were investigated. Bile salts such as sodium desoxycholate and sodium cholate considerably enhanced the dissolution of both drugs in pH 7.3 buffer at 37°. The results indicated that the enhancement of the dissolution of indomethacin in the presence of bile salts was mainly due to micellar solubilization. On the other hand, the enhanced dissolution of phenylbutazone may be due to the wetting effect, increasing the effective surface area of the powder.

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Mercurated pyridine-3-carboxylic anhydride (III), obtained by the reaction of pyridine-2, 3-dicarboxylic acid with mercuric oxide, showed a carbonyl absorption in the IR spectrum at extremely low wave number, indicating that the oxygen-mercury bond is ionic in nature, and thus that compound (III) takes an ionic structure (III'). The carbon bonded with mercury is reactive with nucleophilic reagents (SH^-, CN^-, I^-), as would be expected.

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The photosensitized oxygenation of 1H-1, 2-benzodiazepines (6) in methanol gave fragment products (7-14). Phenyl ketones (7) are assumed to originate from the 5-hydroperoxide (5), and cinnamic acids (8 and 9), 3-methoxy-3H-1, 2-benzodiazepines (10), and indazoles (11-14) from the 3-hydroperoxide (16). Similar photooxygenation of 1-methyl-1H-1, 2-benzodiazepines (23) gave 3-oxo-1, 2-benzodiazepines (25), which may be formed via the zwitterionic 3-peroxide (24).

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The tolerance development in Straub tail reaction [STR] on successive treatments with morphine was studied. Morphine at 20 mg/kg, four times a day, produced tolerance in STR more rapidly than 10 mg/kg, four times a day. Significant tolerance in STR developed when morphine was injected daily into the cerebral ventricle in mice. STR in tolerant mice was markedly reduced by treatment with L-5-hydroxytryptophan compared to that in non-tolerant mice. The cortical 5-hydroxytryptamine [5-HT] content in tolerant mice was significantly decreased compared to that in non-tolerant mice. These results suggest that cortical 5-HT may play an important role in tolerance development in STR.

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O-Acetylserine (2), a substrate for cysteine synthase and β-substituted alanine synthase (s) in plants, was identified after transformation to N-acetylserine in the greenishwhite epicarp and the reddish mesocarp of the intact fruits of water-melon (Citrullus vulgaris) in concentrations of 1.05×10^-6% and 0.98×10^-7%, respectively. No endogenous N-acetylserine was detected by the same procedure.

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In a previous paper, we described the formation of the 8, 5-diazaphenothiazino [8, 7-h]-phenothiazine derivative (2) by acetylation of 2, 3-dihydro-3-imino-4-methyl-4H-1, 4-benzothiazine (1a). This paper deals with the acetylation of the desmethyl derivative (1b). When a suspension of 1b in acetic anhydride was heated under reflux for 2 hr, the bis [1, 4] benzothiazino [3, 2-b ; 2', 3'-e] pyridine derivative (5a) was obtained instead of the expected analog of 2. The structure of 5a was assigned on the basis of infrared, nuclear magnetic resonance and mass spectral data, and microanalysis. Treatment of 5a with Raney Ni afforded the desulfurized compound 6, which was identical with an authentic sample prepared by acetylation of 2, 6-dianilino-4-picoline (7). Deacetylation of 5a was attempted, and the monoacetyl compound 5b and the deacetyl compound 5c were obtained.

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A biologically active substance with contracting activity towards isolated guinea-pig ileum has been isolated from the gorgonian Euplexaura erecta collected in Japanese coastal waters, and it was identified as prostaglandin F_2α. This is the first report of the isolation of prostaglandins from gorgonians obtained outside the Caribbean area.

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Treatment of rats with saponin (fraction 5) from the roots of Panax ginseng C.A. MEYER caused a decrease in the activity of hepatic serine dehydratase (EC 4.2.1.13). Maximum decrease in the enzyme activity was observed 2 hr after the administration of the ginseng saponin, and it was found that this response depended on the amount of fraction 5 administered to rats. In contrast, when the animals were starved, ginseng treatment resulted in an increased level of the enzyme.

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A formal synthesis of the four stereoisomers (type 2) of dl-2, 3-cis-emetine has been effected through the synthesis of the lactam acid 10 from methyl dl-cis-5-ethyl-2-oxo-4-piperidineacetate (4). The steps involved are conversion of 4 into the lactim ether 5 or 6, N-alkylation of 5 or 6 with 3, 4-dimethoxyphenacyl bromide, NaBH₄ reduction of the resulting lactam ketone 7 followed by catalytic hydrogenolysis to give the lactam ester 9, and alkaline hydrolysis of 9.

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The use of konjac gls as a vehicle for sustained drug release in the form of a rectal suppository was examinied in rats. Dibucaine dispersed in the konjac gels was released in the rectum at a rate predictable from in vitro release studies. No observable destruction of rectal mucosa was noted on microscopic observation, even after two 24 hr contacts (3-week interval) with drug-free gels.

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The ternary complex of tetranactin, NH⁺₄ and SCN^- was studied from an ab initio quantum chemical point of view. When NH⁺₄ is inserted into tetranactin, the interaction energy is -109.0 kcal/mol. When SCN^- interacts with the tetranactin-NH⁺₄ complex, the interaction energy is -49.4 kcal/mol. This value isalmost entirely due to the electrostatic interaction between SCN^- and NH⁺₄. Therefore the interaction energy on ternary complex formation will be over -158.4 kcal/mol. The ternary complex of tetranactin, NH⁺₄ and an uncoupler such as picric acid or SF6847 should be similar.

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Treatment of aryl-bis (6-amino-1, 3-dimethyluracil-5-yl) methanes, which were prepared by the condensation of 6-amino-1, 3-dimethyluracil with aryl aldehydes, with diethyl azodicarboxylate in the presence of sulfolane led to the formation of the corresponding 1, 3-dimethylpyrimido [4, 5-b] quinoline-2, 4 (1H, 3H) diones (1, 3-dimethyl-5-deazaalloxazines).

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Guanylate cyclase activity was examined in inflammatory granuloma tissue induced by subcutaneous injection of carrageenin solution in the rat. Enzymological properties of guanylate cyclase in this tissue, such as pH optimum, metal ion requirement, etc., were examined, with special reference to the intracellular distribution of the enzyme. Differences were found between guanylate cyclase in the soluble fraction and that in the particulate fraction in the response to Mn²⁺ and Triton X-100 in this tissue.

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An indirect method is described for the micro-determination of primary and secondary amines in the presence of tertiary amine by means of a catalytic indicator reaction. The copper bis (dithiocarbamate) complex formed from primary or secondary amine and carbon disulfide in the presence of copper was removed by extraction into chloroform. The remaining copper in aqueous solution was determined by measuring the rate of oxidation of pyrocatechol violet by hydrogen peroxide. A simplified complementary tristimulus colorimetry (SCTS method) was used for determination of the reaction rates, since it has the advantage of permitting accurate determination of the rate constants in the presence of color impurities. Quantitative recoveries were obtained of microamounts of primary and secondary amines with good accuracy (from -2.9% to +2.9% error). The method presented is sensitive and does not require a separate calibration curve for each primary and secondary amine.

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Condensation of adenine (1a) with 1-O-acetyl-2, 3, 5-tri-O-benzoyl-β-D-ribofuranose (2a) in acetonitrile in the presence of stannic chloride at room temperature gave blocked nucleoside. After removal of the benzoyl group, adenosine (4a) was obtained in 78% overall yield. When 1, 2, 3, 5-tetra-O-acetyl-β-D-ribofuranose (2b) was used instead of 2a in the same reaction, 2', 3', 5'-tri-O-acetyladenosine (3b) was obtained in 77% yield. In both cases, the α-isomer or 1-, 3- or 7-riboside could not be detected in the reaction. In an application of this reaction, 6-chloropurine (1b) and purin-6-yl benzyl disulfide (1c) were coupled with 2a or 2b followed by reaction with thiourea or β-mercaptoethanol to give 2', 3', 5'-tri-O-acyl-6-thioinosine (3c). Coupling of 6-methylthiopurine (1d) with 3a after deblocking of the acyl group yielded 9-β-D-ribofuranosyl-6-methylthiopurine in 75% yield. In addition, 2, 6-dichloropurine (1e) coupled with 2b under the same conditions to give 9-β-D-ribofuranosyl-2, 6-dichlororopurine tri-O-acetate in 81% yield.

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The effect of antacids on the dissolution behavior of tetracycline hydrochloride and methacycline hydrochloride from commercial capsules was studied. The dissolution of the tetracyclines was found to be markedly retarded by antacids such as aluminium silicate and magnesium trisilicate. An attempt was made to elucidate the mechanism of this effect. The results suggest that the effects of antacids on the dissolution may be due to the adsorption of the drugs on antacid particles as well as to the increased pH of the medium. A study was also carried out to determine the influence of stomachics using Cinnamomi Cortex as a test material. In dissolution experiments on commercial capsules, a significant dissolution inhibition by the stomachic was found.

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The thermolysis of the 3-substituted 3H-1, 2-benzodiazepines (1) afforded 1 : 1 mixtures of trans- (2) and cis- (3) 3-vinylindazoles, whereas their photolysis gave only the transisomers (2). The 3-substituted 5-methyl-3H-1, 2-benzodiazepines (4) gave similar results. These findings suggest that the thermolysis occurs in a stepwise manner via the diradical intermediate (9), whereas the photolysis proceeds in a concerted manner.

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A mutagen, 2-amino-6-methyldipyrido [1, 2-a : 3', 2'-d] imidazole (Glu-P-1), was reacted with DNA in the presence of rat liver microsomes. The major modified base was identified as 2-(C⁸-guanyl) amino-6-methyldipyrido [1, 2-a : 3', 2'-d] imidazole (1).

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Hosukinidine, (20R, 22R, 25S)-veratra-5, 12-dien-3β-ol, and epirubijervine, (22R, 25S)-solanid-5-ene-3β, 12β-diol, were isolated from illuminated Veratrum plant.

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