The acetone-dried powder (PA), obtained from supernatant left after separation of the pH 5.4-precipitating fraction (crude Parotin) from the aqueous extract of bovine parotid gland, was extracted with glacial acetic acid, and the extract had a hypocalcemic activity in rabbits, but its activity fluctuated. On the other hand, the glacial acetic acid extract of the acetone-dried powder (PAI) obtained by incubation of a suspension of the sample PA in saline, had nearly constant activity. From the purification of PAI by DEAE-cellulose chromatography and gel chromatography on Sephadex G-100, a hypocalcemic protein (P-MSY) was obtained in a yield of 37 mg from 10 kg of the fresh gland. The sample P-MSY was homogeneous in disc electrophoresis and electrofocusing, and it was effective in a dose of 0.01 mg/kg at 1% level of significance against control rabbits given saline, and it has almost the same activity as purified Parotin, which was effective in a dose of 0.01 mg/kg as reported previously. P-MSY had a molecular weight of 66000 by SDS-polyacrylamide gel electrophoresis, isoelectric point of pH 5.60, and sugar content of 2.53%. These properties and the results of amino acid analysis suggest that P-MSY is a hypocalcemic protein differing from purified Parotin. Further, P-MSY was also proved to be different from β-Parotin or calcitonin in its character.

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^<13>C chemical shifts of 2-substituted naphthalenes and their 6-methoxy derivatives were determined by the aids of the additivity of the substituent effect and the selective H-D exchange reaction. The reliability of the additivity of the shielding parameters of monosubstituted benzenes for the above naphthalene series were acknowledged, and the linear relations between the chemical shifts and shielding parameters or substituent constants were confirmed.

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Selfcondensation of diethyl acetonedicarboxylate (DADC) gave two types of products and the six kinds of the products were formed by using various catalysts. In order to elucidate the reaction mechanism of DADC for giving these products, the roles of catalysts were investigated. The formation mechanism of the orsellinic acid derivatives (1, 2, 3, and 4) was proposed, and the magnesium-DADC chelated complex (B) was recommended for the intermediate of these products. Furthermore, the mechanisms giving the coumarin derivatives (5 and 6) were discussed.

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The effect of calcitonin (CT) on the bile calcium excretion in thyroparathyroidectomized rats has been investigated. A single intraperitoneal injection of calcium (4.0 mg/100 g) markedly increased the bile calcium excretion of sham-operated rats, suggesting that an increase in serum calcium elevates the excretion of calcium into the bile. In thyroparathyroidectomized rats, however, the injection of calcium did not significantly elevate the excretion of calcium into the bile. The bile calcium excretion of thyroparathyroidectomized rats injected with calcium was predominantly potentiated by the administration of CT. CT alone slightly increased the bile calcium excretion in thyroparathyroidectomized rats. In thyroparathyroidectomized rats injected with calcium, there was an increase in bile calcium excretion as early as 30 min after CT administration and the hormone markedly increased the bile calcium excretion even at the lowest dose (40 MRC mu/100 g). These results suggest that CT stimulates the excretion of calcium into the bile through the liver when calcium increases in the serum.

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Fluorometric determination of salicylamide was studied. Salicylamide fluoresced strongly when excited in a mixed solution of 0.1% boric acid, 0.005 N sulfuric acid, and 5% acetic anhydride in glacial acetic acid. This fluorophore was a salicylamide-boron-acetic acid (1 : 1 : 2) complex. The fluorescene emission maximum occurred at 388 nm, and excitation maximum at 328 nm. The linear range in the calibration curve was 5-1000 ng/ml in the final solution, coefficient of variation for salicylamide (0.28μg/ml) in the measurement ten times was 0.6%. This method was about five times more sensitive than the fluorometric method reported by Barr and Riegelman. The proposed method was successfully applied to the determination of salicylamide in urine samples, in which minimum concentration was ca. 30 ppb.

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The effect of irradiation with ultraviolet ray for methanol solution of 2-carboxystyrenes and 3, 4-dihydroisocoumarins were examined. Irradiation of 2-carboxystyrene and its β-(4'-methoxyphenyl), β-methyl, β, β-dimethyl, and β-cyclohexylidenemethyl derivatives gave the corresponding cyclized compounds. Some of these reactions were reversible since styrene derivatives were obtained from 3, 4-dihydroisocoumarins in the same manner. In the case of ring closed reactions of β-alkyl substituted 2-carboxystyrenes, such as β-methyl, β, β-dimethyl, and β-cyclohexylidenemethyl derivatives, the rearranged products were obtained. These products agreed with each of an authentic sample which was synthesized by another, method.

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Stereochemistry of four isomeric telomers (n=3) (3), arising from the free-radical telomerization of vinylene carbonate with carbon tetrachloride, was unequivocally established as all trans addition forms (3a, b, c and d), based on their conversions to the enolphosphates (4) and the heptitols (8). Synthetic potential of the telomers (3) for aldoheptoses and -octoses has been shown by transforming for example the isomer b into"racemic"D-glycero-L-gulo-and D-glycero-D-ido-heptoses and D-threo-D-ido-octose in reasonable yields.

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Using the readily obtainable 11-nitrophenol 5 prepared by selective nitration of the 12-hydroxy ester 4, syntheses of taxodione (1), royleanone (2) and their analogues (7 and 8) having the methoxy-carbonyl group in place of the 4α-methyl group were accomplished.

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Several K-region arene oxides of carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons were synthesized, and their reactivities with various nucleophiles and their acid-catalyzed reactions were discussed. Relationship between these chemical reactivities and mutagenicity was also discussed.

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Investigation of pyrolytic reactions of N-allylanilinium salts led to the finding of a new type of amino-Claisen rearrangement, aromatic ammonium N-Claisen rearrangement. This reaction enables the introduction of functional group into the ortho position of aniline derivatives. Products are potential precursors for indoline and indole preparations.

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Two new flavone, cirsitakaoside (IV), C₂₃H₂₄O₁₁, mp 246-247°, and cirsitakaogenin (VI), C₁₇H₁₄O₆, mp 259-260°, have been isolated from the fresh leaves of Cirsium japonicum D.C. var. takaoense KITAMURA (Compositae) together with pectolinarin (I). The structures of cirsitakaoside (IV) and cirsitakaogenin (VI) have been determined as 5, 7-dihydroxy-8, 4'-dimethoxyflavone-7-O-β-D-glucoside and 5, 7-dihydroxy-8, 4'-dimethoxyflavone, by chemical degradation and spectral means, respectively.

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The structure of an aminoglycoside antibiotic P-2563 (P) has been confirmed to be 3-O-(4-deoxyl-4-propionamido-α-D-glucopyranosyl)-1, 4-diamino-1, 4-dideoxyhexytol by the X-ray analysis of its monohydrobromide dihydrate crystals. The pyranose ring is expectedly in a chair form and its substituents are equatorial except that at C (1') which is axial. In the aminopolyol moiety, the arrangements around all of the C-C bonds are in staggered form. The carbon-carbon linkages from C (2) to C (6) are in s-trans zig-zag chain, and the five carbon atoms are almost coplanar. While the C (1) carbon atom is displaced from the plane resulting in the formation of an intramolecular hydrogen bond between the amino groups attached to C (1) and C (4).

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DL-Valyl-lencyl anhydride (III) was converted to mono- and di-chloro-isopropyl-isobutylpyrazines by treatment with phosphoryl chloride. These mono-chloropyrazines (VII and VIII) were oxidized and the products were converted to 2-isobutyl-5-isopropylpyrazine 1- and 4-oxides (XIV and XV) via hydrazino compounds. On the other hand, starting from 2-chloro-3-isobutyl-6-isopropylpyrazine (VII), two fungal metabolites, deoxymutaaspergillic acid (I) and 2-hydroxy-3-isobutyl-6-isopropylpyrazine 1-oxide (II), were prepared.

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3, 4-Dihydroxyphenylpyruvic acid (DHPP) was mainly metabolized to L-3, 4-dihydroxyphenylalanine (L-DOPA) through transamination, while 3-methoxy-4-hydroxy-phenylpyruvic acid (MHPP) was mainly metabolized to 3-methoxy-4-hydroxyphenyllactic acid (MHPL) through reduction. In order to explain the metabolic difference between these two aromatic α-keto acids related with DOPA, the metabolism of ¹⁴C-labeled DHPP and MHPP was compared in vitro. There was no significant difference between the two α-keto acids in the initial rate of transamination to the corresponding amino acids using rat liver mitochondrial fraction. The K_m values to mitochondrial transaminase were calculated to be 8 mM and 6 mM for DHPP and MHPP, respectively. NADH-dependent activity for reducing DHPP and MHPP to the corresponding aromatic α-hydroxy acids was the highest in the heart followed by the kidney, muscle and liver and was not inhibited with oxamate (5 mM), the inhibitor of lactate dehydrogenase, indicating that aromatic α-keto acid reductase (AKAR) predominantly participates in this reaction. The initial rate of DHPP reduction with purified rat liver AKAR preparation was, however, only about 1/10 of that of MHPP reduction. The K_m value of DHPP (3.6 mM) was about two-fold larger than that of MHPP (1.5 mM), demonstrating a lower affinity of DHPP to AKAR than that of MHPP.

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Pharmacokinetic behaviors of sulfamethoxazole (SMX) and its main metabolite, N⁴-acetyl-sulfamethoxazole (N⁴-AcSMX) in rabbits were studied under normal and diabetic condition following intravenous administration of SMX. The pharmacokinetic parameters were calculated employing a two compartment model. Under diabetic condition, the elimination rate constant of SMX from plasma showed a marked decrease. Renal excretion rate constants of SMX and N⁴-AcSMX also decreased under diabetic condition. Distribution of SMX to the tissue compartment increased in diabetic condition but that in the central compartment remained at the same value of normal condition. Changes in parameters under diabetic condition showed a recovering trend by insulin treatment. Plasma Protein binding of SMX and N⁴-AcSMX were enhanced under diabetic condition. The increase in protein binding was subjected to an increase in the concentration of albumin under diabetic condition. Insulin treatment caused a slight recover of the binding to the values of nornal condition. Thus, it was concluded that the decrease in renal excretion rate constant of SMX and the increase in plasma protein binding of SMX and N⁴-AcSMX are attributable to a decrease in elimination rate of SMX from plasma. It was also suggested that the decrease in renal excretion of SMX and N⁴-AcSMX might be caused by changes of the physiological factors such as blood glucose and acetone bodies.

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A transient species with an absorption at around 500 nm was formed on addition of Mn (II), Cu (II), Co (II), Zn (II), and Ni (II) ions to a methanol solution of the aldimine of of pyridoxal N-methochloride and ethyl alaninate. It is concluded that the species is the metal chelate of a quinoid intermediate in the metal ion mediated isomerization of the aldimine and the ketimine. The formation of the quinoid metal chelate was completed within a few seconds after the chelation of the aldimine and its rate was not greatly dependent on the metal ions. The rate of the disappearance of the quinoid metal chelate was affected by the properties and the concentrations of the metal ions and, in the case of Cu (II), by the presence of the other chelating ligand. The life time of the 1 : 1 Cuquinoid chelate was several seconds, whereas that of the 1 : 2 chelate and of the ternary complex formed from Cu (II), the quinoid, and a bidentate or tridentate ligand were longer than several hours. The phenomenon was explained on the assumption that the latter complexes are distorted octahedral and the weak coordination between Cu (II) and the carbonyl oxygen retards the protonation of the quinoid.

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Treatment of the lactim ethers (10a-d, 11a-c), prepared from N-unsubstituted 5-, 6-, and 7-membered lactams (6a-d), with phenacyl bromide or 3, 4-dimethoxyphenacyl bromide in N, N-dimethylformamide at 60°for 1-6 hr furnished the corresponding N-substituted lactams (21a-d, 22a-c) in good yields. Conversion of the lactam ketones (21a-d, 22a-c) into the N-(2-arylethyl) lactams (25a-d, 26a-c) through the lactam alcohols (23a-d, 24a-c) was effected in excellent overall yields by NaBH₄ reduction followed by catalytic hydrogenolysis. In contrast, the alkylations of O-methylvalerolactim (10b) or O-ethylvalerolactim (11b) with less reactive alkyl halides (relative to phenacyl bromide) such as MeI, EtI, PhCH₂Br, PhCH₂CH₂Br, and 3, 4-(MeO)₂C₆H₃CH₂CH₂Br were found to give mixtures of the normally N-alkylated 2-piperidones and N-methyl-or N-ethyl-2-piperidone presumed to have formed by the O→N methyl or ethyl migration during the reactions. Alkylations of the δ-valerolactam anion with 2-arylethyl bromide or its equivalents could afford the corresponding N-substituted 2-piperidones, but in unacceptable yields.

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The decomposition of crystalline glutathione (GSH) by water vapour was studied kinetically. The decomposition time course of GSH polymorphs (α and β forms) showed the pattern like autocatalytic reaction in a solid state. The logarithmic plots of the decomposed ratio vs. the reaction time were almost linear for the β form, but broken to two lines for the α form. Decomposition of the α form was more rapid than the β form under the same condition of temperature and humidity. The effect of oxygen in air on the rate was almost negligible. The reaction rate in the early stage of the decomposition was concluded to be larger than the rate calculated from the reaction model in which GSH decomposed in the saturated solution on the crystal surface. The rates were apparently proportional to about 3 to 5 powers of humidity. γ-Glutamyl bond was broken and some parts of products underwent intramolecular condensation in the decomposition. A small amount of oxidized GSH was formed but the decreased ratio of reductivity of the sample was considerable and increased with increasing decomposition ratio of GSH. Apparent activation energy for decomposition of both forms was 32 to 33 kcal/mol.

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When methyliodide and water were added to sodium phenylpropiolthioanilide suspended in ether, C-methylation and C-N bond rupture occurred at the thioamido group. S-[1-Phenyl-2-(thioacetyl) vinyl] isothiuronium p-toluenesulfonate was obtained by adding thiourea and p-toluenesulfonic acid to the ether phase. This salt did not give a free ligand, dithiobenzoylacetone, but produced a zinc chelate, bis (dithiobenzoylacetonato)-Zn (II) by adding aqueous Zn²⁺ to the aqueous alkaline solution of the salt.

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The basic fractions of methanol and water extracts of a crude drug, "Pinelliae Tuber, " showed a relaxant action and antihistamine like action upon an isolated rectum of Japanese quails. And l-ephedrine hydrochloride was isolated in the yield of 0.002% as the active principle.

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Factors affecting dissolution of digoxin from the tablets were investigated on the basis of the measurement on physical characteristics and the amount of digoxin released from 10 lots of tablets prepared by different procedures and formulations. While the hardness, friability and basket disintegration time (by U. S. P. dissolution apparatus) were influenced by the content of magnesium stearate, the disintegration time (by J. P. disintegration test method) was neither affected by the content of magnesium stearate nor the preparative procedure. Concerning the dissolution test by the U.S.P. dissolution apparatus, it was found that the dissolution rate had a tendency to increase with an increase in the rotation speed of basket. The dissolution of the tablets prepared by the powder dilution method was influenced significantly by the difference in mean particle size of digoxin powders, while the release of digoxin from the tablets produced by solvent deposition method showed a fast dissolution profile compared with the case by powder dilution method without depending on the difference in batch. Therefore, it was found that one of the predominant factors affecting the release of digoxin from digoxin tablets was either the formulation or the preparative procedure. Additionally, it was proposed that the dissolution test should be necessary for a quality test of digoxin tablets because the present J. P. disintegration test alone could not guarantee the quality of the tablets.

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Mode of calcium contraction of isolated smooth muscle cells from vas deferens of guinea pig was investigated. The cells were prepared by treatment of the vas deferens with collagenase followed by mechanical agitation. The isolated cells were contracted by administration of calcium ions under the depolarized condition. Degree of the contraction in each cell was not dependent on concentration of calcium but it seemed to be all-or-none like response while contraction of the whole tissue was graded response. The each cell had different sensitivity to calcium ions and total number of contracted cells increased with increase in concentration of calcium in the incubation medium. Rate of the contraction in each cell was dependent on temperature. The contraction was inhibited by ruthenium red but not by 2, 4-dinitrophenol. The cells were also contracted by strontium and barium ions.

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A new phenylpropanoid glycoside, martynoside (1), was isolated from the leaves and stems of Martynia louisiana MILL. (syn. Proboscidea Jussieui STEUD.) (Martyniaceae) together with acteoside (2), roseoside (3), cornoside (4), ajugol (5) and mioporoside (6). The structure of martynoside was elucidated to be 1 by chemical and spectral evidence. The isolation of catalpol (7) and cornoside (4) from the fresh unripe fruits was also described.

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A method of conversion of an adenine moiety to 6-thioguanine (and guanine) and 2, 6-diaminopurine moiety in the nucleoside and nucleotide levels were presented. The action of cyanogen bromide with adenosine N¹-oxide afforded an 1, 2, 4-oxadiazolo (3, 2-f)-purine riboside (2a), which was in a pH dependent equilibrium with N⁶-cyanoadenosine N¹-oxide (3a). Methylation followed by alkaline treatment of 3a resulted in a rearrangement leading to give 2-amino-N⁶-methoxyadenosine (5a). Catalytic hydrogenation of 5a gave 2, 6-diaminopurine riboside (6a). Sulfhydrolysis of 5a gave 6-thioguanosine (7a). By a similar reaction sequence 2'-deoxyadenosine was converted to 2'-deoxy-6-thioguanosine (7b) and 2, 6-diaminopurine 2'-deoxyriboside, respectively. Starting from the N¹-oxides of adenosine 5'-phosphate (AMP), 2'-deoxyadenosine 5'-phosphate (dAMP) and 9-β-D-arabinofuranosyladenine 5'-phosphate (araAMP), the corresponding 6-thioguanine nucleotides were likewise prepared.

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Three new polyoxypregnane derivatives were isolated from the rhizomes of Cynanchum caudatum, and their structures were established as 20-O-cinnamoylsarcostin (VI), 12-O-cinnamoylikemagenol (X) and 20-O-cinnamoylikemagenol (XI) on the basis of chemical and spectral evidences. In the elucidation of their structures, an acyl migration of C-12β ester group to C-20α was found and used for structural studies.

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For the synthesis of human β-endorphin, the C-terminal protected octadecapeptide ester, Z (OMe)-Leu-Val-Thr-Leu-Phe-Lys (Z)-Asn-Ala-Ile-Ile-Lys (Z)-Asn-Ala-Tyr-Lys (Z)-Lys (Z)-Gly-Glu (OBzl)-OBzl, was synthesized by successive azide condensation of six peptide fragments ; (position 14-15), (16-19), (20-21), (22-23), (24-26) and (27-31).

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In a conventional manner, the untriacontapeptide corresponding to the entire amino acid sequence of human β-endorphin was synthesized using amino acid derivatives, Lys (Z) Glu (OBzl), bearing protecting groups removable by methanesulfonic acid. Potency ratios of the synthetic peptide to morphin (taken as 1) was 6.5, when assayed the analgesic effect on tail pinch method in mice.

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The title trisaccharide was synthesized from 1, 6-anhydro-β-lactose. Condensation of 2, 2', 3, 3'-tetra-O-acetyl-1, 6-anhydro-β-lactose and 2, 3, 4, 6-tetra-O-acetyl-α-D-galactopyranosyl bromide by a modified Koenigs-Knorr reaction followed by acetylation gave acetylated 1, 6-anhydro-β-trisaccharide (3) in 62% yield. The β-configuration for the new galactosidic linkage was obtained from the value of the molecular rotation of 3. Deacetylation of 3 afforded 1, 6-anhydro-β-trisaccharide (4). The structure was determined by a gas chromatographic (GC) analysis and a gas chromatography-mass spectrometry of acid hydrolysate of permethylated 4. Acetolysis of 3 under mild condition proceeded cleavage of the 1, 6-anhydro-β-ring and afforded acetylated trisaccharide contaminated with acetylated galactose and lactose. From the acetolysis mixture, the title trisaccharide was isolated via acetylated β-trisaccharide followed by deacetylation. The structure was determined by GC analysis of the partial methylated alditol acetates obtained from the hydrolysate of permethylated, borohydride reduced trisaccharide.

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The anodic oxidations of ephedrine and several realted compounds have been studied in aqueous buffer solutions at a glassy-carbon electrode. The oxidation potentials of these alkanol amines are less positive than those of simple alkyl amines without β-hydroxy group. On controlled potential electrolysis, these compounds consume about two electrons per molecule, and substantially give 1-hydroxy-1-phenyl-2-propanone and the counterpart alkylamines. The relative amount of dealkylation from the amino-nitrogen is quite different from that predicted on the basis of the number of α-protons.

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In the presence of a nickel phosphine complex, the coupling reaction of Grignard reagents with chloropyrimidines such as 2-chloro-4, 6-dimethyl-(III), 4-chloro-2, 6-dimethyl-(V), 4, 6-dichloro-2-methyl-(VIII), 2, 4-dichloro-6-methyl-(X), and 2, 4, 6-trichloro-pyrimidine (XIII) was studied to give the corresponding alkyl (or arkyl) substituted pyrimidines in yields ranging from 40 to 88%. Although in the cases of VIII, X, and XIII, the selectivity on the reaction due to the position of the chloride atom was not observed, this coupling was concluded to remove the defects of the Pinner reaction for the synthesis of polyalkyl (or polyaryl) pyrimidines.

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The (S)-(+)-acid (3) obtained from (S)-(+)-alanine is protected the amino group with the benzyloxycarbonyl group and is combined with tryptamine to give the (S)-amide-urethane (5). Hydrogenolysis of 5 affords the (S)-(-)-amide (6) which is identified as the alkaloid (1) obtained from Thermoactinomyces strain TM-64.

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By the reaction of 11-chloro-11-phenyl-(II) and 11-phenyl-6, 11-dihydrodibenzo-[b, e] thiepin (III) with NCS 6, 11-dichloro-(I) and 6-chloro-11-phenyl-6, 11-dihydrodibenzo-[b, e] thiepin (XV) were prepared, respectively. The compound (I) reacted with water or aqueous ammonia to afford a new heterocyclic compound, 6, 11-epoxy-(V) or 6, 11-epimino-11-phenyl-6, 11-dihydrodibenzo [b, e] thiepin (VIII), respectively. On heating in proper solvent, I or XV underwent a novel cyclization to form a bridged compound (IX, XIII or XIV). The radical mechanism for the new cyclization was proposed.

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The synthesis of mimosamycin has been achieved in 6 steps starting from 7-hydroxy-6-methylisoquinoline (7). Copper-catalyzed autoxidation of 7, which was prepared in 80% over-all yield in 5 steps from 3-methoxy-4-methylbenzaldehyde, gave 6-methyl-3, 5-dimorpholino-7, 8-dioxo-7, 8-dihydroisoquinoline (8a). Upon treatment with sulfuric acid-methanol followed by diazomethane, the o-quinone (8a) was converted to 7-methoxy-6-methyl-3-morpholino-5, 8-dioxo-5, 8-dihydroisoquinoline (10a). Reductive acetylation of 10a with zinc-acetic acid and acetic anhydride gave 5, 8-diacetoxy-7-methoxy-6-methyl-3-morpholinoisoquinoline, which was quaternized at the isoquinoline nitrogen with methyl iodide. Treatment of the methiodide (12a) with silver oxide gave rise to in one-step 7-methoxy-2, 6-dimethyl-3, 5, 8-trioxo-2, 3, 5, 8-tetrahydroisoquinoline, which was identified with a specimen of natural mimosamycin isolated from the culture filtrate of Streptomyces lavendulae No. 314.

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Two synthetic routes leading to C-2, C-4 and C-6 deuterium-labeled dehydroepiandrosterone have been developed. d₄-Dehydroepiandrosterone was prepared from testosterone by way of the 2, 2, 4, 6-d₄-Δ^{3, 5}-dien-3-ol acetate. Alternatively, synthesis of d₅-dehydroepiandrosterone was carried out employing 3β-hydroxy-5α-androstane-6, 17-dione silyl ether as a key intermediate. Deuterium labeling was attained by reduction of the 6-oxo group with lithium aluminum deuteride and perdeuteration of active methylene groups adjacent to the 3-oxo group. In addition, d₅-dehydroepiandrosterone was transformed into the epimeric 16-hydroxy-17-ketones and 17β-hydroxy-16-ketone.

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1-Methoxycarbonyl-1, 2-dihydropyridine (1a) was reacted with singlet oxygen to afford an unstable endo-peroxide (5), which was reactive enough and produced 6 and 7 by the reaction with thiols. The product (6 or 7) afforded 8 and 9 by the further addition of thiols. Either of 6 or 7 was rearranged to 11 in hot acetic acid or toluene. As shown by the transformation of 9 into 10, the sulfur group adjacent to the nitrogen atom could be converted to the oxygen function, and using this procedure, 5-amino-5-deoxyribose derivative (19) and 5-amino-5-deoxylyxose derivative (20) were synthesized from 17 and 18, which were obtained by the osmium tetroxide oxidation of 6 and 7.

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The reagent of 2 M anhydrous p-toluenesulfonic acid in dioxane containing 2% anisole cleaves selectively tert-butyloxycarbonyl group in Boc-Trp-OH without any detectable decomposition of tryptophan residue. Another reagents such as dilute p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid in acetic acid and methanesulfonic acid or ethanesulfonic acid in dioxane, which are containing 2% anisole and 2% 1, 2-ethanedithiol or triphenylphosphine as reducing reagent, have also similar properties to those of p-toluenesulfonic acid in dioxane containing 2% anisole. The utility of the reagents was proved as applied to the syntheses of three kinds of tryptophan containing peptide derivatives by the classical solution method.

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The photolysis of 1H-1, 2-diazepine 4, 7-epidioxides (1) with a low pressure mercury lamp resulted in the formation of 5-ethoxy-1, 3, 4-oxadiazoles (3), azoxy compounds (4), and diene compounds (5). A reasonable mechanism for the formation of the products may involve initial isomerization to the 1, 2, 3-oxadiazoles (8), followed by decomposition and isomerization. However, the azepine 2, 5-epidioxide (2) gave only the diene compound (6) in a low yield and did not give any other characterized products.

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A new method for the preparation of 16β-hydroxy-17-keto steroids has been developed. 16β-Hydroxylated dehydroepiandrosterone, epiandrosterone, androsterone and estrone were prepared from the corresponding 3, 16-diacetate through the 17-ethylenehemithioketal. 16β-Hydroxydehydroepiandrosterone 3-hemisuccinate for the use of immunoassay as a hapten was prepared from the 3β, 16β-dihydroxy-17-ketone ethylenehemithioketal by the sequential reactions : tert-butyldimethylsilylation of the hydroxyl functions, selective desilylation followed by hemisuccinylation at C-3, and removal of protecting groups at C-16 and C-17. The synthesis of the related 16, 17-ketol derivatives has also been described.

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Bicyclo [4. 3. 1] decan-8-one (3) was synthesized from 8-benzoylbicyclo [4. 3. 1] decan-10-one (4) by making use of regio-selective deketalization of a bisketal (8). Bicyclo-[3. 3. 1] nonan-3-one (1) and bicyclo [3. 2. 1] octan-3-one (2) were also prepared from the corresponding 3-benzoylbicyclo [3. n. 1] alkanone, but via a modified route.

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The synthesis of 4, 5-unsubstituted alkyl 3-hydroxypyrrole-2-carboxylates was described. An equimolar mixture of glycine esters (6) and diethyl ethoxymethylenemalonate (7) gave the condensation products (8) with liberation of ethanol. 3-Hydroxypyrrole-2, 4-dicarboxylates (9) were obtained by the Dieckmann condensation of 8 using alkoxide as condensing agent. Selective partial hydrolysis of pyrrole-diesters (9) using a large excess of alkali hydroxide afforded the 4-carboxylic acids (10), which readily gave alkyl 3-hydroxypyrrole-2-carboxylates (5) on decarboxylation in boiling β-picoline or pyridineacetic acid in good yields.

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New chloromethylketone derivatives and other D-alanine-containing compounds related to the peptide moiety of the bacterial peptidoglycan were synthesized in order to search inhibitors of the peptidoglycan transpeptidase.

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Nine strains of Escherichia coli were tested for the metabolic activities on methionine, ε-N-benzoyl-lysine and their phenylacetyl derivatives, and it was observed that Escherichia coli IFO-3470 and IFO-3550 asymmetrically metabolized N-phenylacetyl-DL-methionine and α-N-phenylacetyl-ε-N-benzoyl-DL-lysine to yield L-methionine, ε-N-benzoyl-L-lysine and each corresponding D-form of phenylacetyl derivatives, respectively. The facts indicate the possibility of the resolution of other amino acids involving their analogs by the metabolism of Escherichia coli on phenylacetyl derivatives.

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As a preliminary study of pharmacokinetic behaviors of drugs in the living body under alloxan diabetes, endogenous physiological parameters such as levels of glucose and acetone bodies in blood and total protein, albumin and insulin levels in serum were determined employing rabbits under normal and alloxan diabetic conditions. Levels of glucose, acetone bodies, total protein and albumin were increased under alloxan diabetic conditions. The increases were reduced to the normal levels by insulin treatment. From changes of levels of blood glucose, levels of insulin, total protein and albumin in serum and body weight after ceasing insulin treatment, the stages of hyperglycemia as well as hyperproteinemia and hyperalbuminemia were considered to be suitable for the study of pharmacokinetic behaviors of drugs in alloxan diabetic rabbits.

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Spectrofluorometric assay for the quantitative determination of ecarazine hydrochloride (I) and its metabolite, 3-methyl-s-triazolo (3, 4-a) phthalazine (III) were described. I and III were extracted from plasma at weakly alkaline pH with chloroform and fluorescence of III was directly measured (Ex 250, Em 410 nm). The chloroform layer containing I was treated with alkali at elevated temperature to give s-triazolo (3, 4-a) phthalazine-2H-3-one (II). The fluorescence of II was measured at an emission wavelength 470 and excitation of 266 nm. There was a linear relationship between concentration of I and fluorometric response up to 10μg/ml in plasma. This assay was sensitive enough to be useful for the determination of I and III and had a sensitivity limit of 0.2 and 0.07μg/ml, respectively. Other antihypertensive agents and some metabolites had no detectable effect on the present assay. The method was applied to the determination of plasma levels in rats and dogs after oral or intravenous administration (3 or 10 mg/kg) of I.

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Reduction of the N, N'-disubstituted carbodiimides with sodium borohydride in isopropanol performs a convenient synthetic method of the corresponding formamidines. tert-Butanol, pyridine, and tetrahydrofuran proved also available as solvents for the procedure, while methanol or ethanol was unsuitable for the lower yield of the formamidine, probably due to the further reduction to proceed.

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Thermal and photochemical behaviors of N-[(N-nitrosobenzylamino) methyl] benzamide in acidic media at room temperature have been demonstrated in characteristic fashions of its acid-catalyzed decompositions, i.e., in situ formation of phenyldiazomethane, thermal denitrosation, photolytic denitrosation, and photorearrangement of nitroso group. These reactions are controlled by the acid and the solvent used.

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It has been found that the reaction of the trans-(2a or 3a) or the cis-isomer (2b or 3b) of 5-ethyl-2-oxo-4-piperidineacetic acid (2) or its ethyl ester (3) with 10% EtOH-HCl at reflux for 20-27 hr gave an equilibrated 70 : 30 mixture of the trans-(3a) and the cis-isomer (3b) of the ester (3) in a good yield. Such a cis-trans isomerization did not occur at all when the trans-(2a) or the cis-lactam acid (2b) was similarly esterified but at 15°for 16 hr, whereas at 32°it did occur to a slight extent. In contrast to the N-unsubstituted lactam acids (2a, b), trans-(5a) and cis-1-benzyl-5-ethyl-2-oxo-4-piperidineacetic acid (5b) could be converted into the corresponding ethyl esters (7a, b) by similar esterifications even at 32°with complete retention of their original stereochemistry. The cis-trans isomerization of the methyl esters (6a, b) of 2a, b in 10% MeOH-HCl seemed somewhat easier than that of the ethyl esters (3a, b) in 10% EtOH-HCl. On the other hand, the N-benzylated methyl esters (8a, b) did not isomerize in 10% MeOH-HCl even after 5 hours'reflux.

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A simple method for labeling methyl group with deuterium at 3-position of pyrazolone ring was established. Trideuterium labeled aminopyrine obtained by the present method did not indicate the isotope effect. It is available for a tracer as well as an internal standard on gas chromatography-mass spectrometry.

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The hydrolysis of 3α, 20α-disulpho-oxy-5α-pregnane (5α-pregnane-3α, 20α-diol disulfate, VII) in boiling 3 N hydrochloric acid gave Δ¹³-steroid as a main product, which was completely identical with the synthetic one (Va) prepared by the dehydration of 5α-pregnane-3α, 17α-diol (IVa). Other minor products obtained and identified were the E-isomer of 17-ethylidene compound (IIb) and intact aglycone (VI).

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From leaves of Stevia ovata LAG. (Compositae), there were isolated five kinds of kaurane-type ester-glucosides, paniculosides-I, -II, -III, -IV, and -V, all of which had already been isolated from leaves of S. paniculata LAG.

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