p-Chloro (trifluoromethyl) phenyl or p-tolylsulfonylurea derivatives were prepared by the reaction of 2-arylsulfonylimino-1, 3-oxathiolanes (III) with various amines. The oxathiolanes (III) were prepared by treatment of 2-hydroxyethyl N-arylsulfonyldithiocarbamate (II), which were obtained from sodium arylsulfonyliminodithiocarbonate and ethylene chlorohydrin, with ethyl chloroformate. The compounds (II) were also converted to N-arylsulfonylimino-1, 3-dithiolanes (IV) by treating with sulfuric acid. The preparation of N-p-chlorophenylsulfonylimino-1, 3-dioxolane (VII) was also described. Further 1-p-chlorophenylsulfonyl-2-thio-3-n-propylurea (IX) was obtained by treatment of IV (X=Cl) with n-propylamine.

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The exchange reactions between TPD and polyfunctional thiols such as glutathione, 2-aminoethylmercaptan, 2-hydroxyethylmercaptan and 2-carboxyethylmercaptan were examined under an anaerobic condition. The following conclusions were drawn from the results presented. From an analysis of the pH-rate profile of the reactions between TPD and thiols containing the amino group in a molecule, the reaction was revealed as the combination of the following three reactions through the pH range of 3 to 12, HB₁SSPr + NH₃⁺RS^-→HB₁S^- + NH₃⁺RSSPr B₁SSPr + NH₃⁺RS^-→B₁S^- + NH₃⁺RSSPr B₁SSPr + NH₂RS^-→B₁S^- + NH₂RSSPr where HB₁SSPr is the protonated form of TPD, NH₃⁺RS^- is the protonated amino-thiol anion, HB₁S^- is the protonated thiamine and NH₃⁺RSSPr is the protonated amino-alkyl propyl disulfide. On the other hand, in the reaction between TPD and thiol, 2-hydroxyethylmercaptan, the following two reaction equations were presented through the experimental pH range of 3.5 to 12.0. HB₁SSPr + RS^-→HB₁S + RSSPr B₁SSPr + RS^-→B₁S + RSSPr The second order rate constants of individual reactions were determined. The activation energies of these reactions obtained were about 10 kcal mole^-1, and the values of activation entropies were 5 to 24 cal mole^-1 deg^-1. These second order rate constants were correlated with the pK_a values of the thiol group with Bronsted equation, log k=αpK_a + C, with a resultant very large α value. From this relationship, it may be concluded that these thiols are an extremely good nucleophile to the disulfide bond and especially to protonated TPD.

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As the results of further investigation on nucleophilic substitution reactions of 14-hydroxy-codeine 6-tosylate (VIII) and its isomers which are performed to examine the effects of 14β-hydroxyl group on these reactions comparing with the known results in 14β-hydrogen-morphine alkaloids, a new epoxide in morphines, 8β, 14β-epoxy-codide (III), which formed probably by internal SN-reaction with neighbouring group participation of the 14β-hydroxyl group to the 8-position in intermediates in the reactions, and a vicinal-cis-diol, 14-hydroxy-dihydropseudocodeine (XIV), were isolated.

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Synthesis and the results of pharmacological tests of 14-hydroxy-dihydro-allopseudocodeine 8-ethers (VIII) were described. The potent local anaesthetic activity of the 8α-ethers and the contrary relationship between analgetic activity and local anaesthetic activity with the change of alkyl chain on ether group were observed in guinea pigs.

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Studies on the inhibition of tryptophan pyrrolase by eleven phenols, six tryptophan analogs and seven hydrazine derivatives were carried out. Serotonin, 5-hydroxytryptophan, epinephrine, norepinephrine and dopamine were found to inhibit the enzyme significantly. On the other hand, phenylhydrazine was the most potent inhibitor among the compounds tested. However, hydrazine hydrochloride, the parent compound of phenylhydrazine, was not inhibitory.

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For the purpose of testing the biological activity, spiro [4-hydroxycyclohexane-1, 4'-2', 3'-dihydro-6'-methoxy-2'-methyl-1'H-isoquinoline] (III) was synthesized by a sequence of reactions including the Schmidt reaction on the indanone (XIV). The compound (III) was found to have a considerably lower anti-cholinesterase activity than galanthamine (I).

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Partition coefficients and biological activities of substituted benzene derivatives have been analysed with respect to the substituent constants σ_i and σ_π, and suggested that they are essentially dependent on the molecular electronic conditions.

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The reaction of seven kinds of conjugated bicycloalkenones (I, III, V, VII, IX, XV and XX) with hydrazoic acid were studied. From compounds (I, III, V and VII), enone type lactams were obtained and from compounds (IX, XV and XX), α, β-unstaturated α-aminoketones were obtained. The three types of reaction products (a) lactams, b) α, β-unsaturated α-aminoketones and c) β-diketones) were observed from present and previous results. The correlation between the structure of α, β-unsaturated ketone and the reaction product was discussed.

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In order to explain the rate difference of Zimmermann reaction with the 16-oxosteroids in terms of the conformational concepts, two pairs of the epimeric 17-bromo-16-ketones in estratriene and androst-5-ene series have been synthesized (Chart 1 and 2). The conformation of ring D with a ketone at C-16 was examined on the basis of their spectral data litsed in Table I. Contrary to the expectations, however, no definite evidence for the long-range effect on the conformation of ring D due to the structure alteration in distant part of the molecule has been obtained.

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Photochemical reaction of dimethylsufoxonium 3-ethoxycarbonyl-2-phenylallylide (I) gave diethyl p-terphenyl-2', 5'-dicarboxylate (II) in low yield. Irradiation of dimethylsulfoxonium 1, 2-dicarbomethoxy-5-carbethoxy-4-phenyl-1, 4-pentadien-3-ylide (VI) with an ultraviolet lamp afforded three products, 3-carbethoxy-1, 2-dicarbomethoxy-4-methylnaphthalene (VII) (37.5% yield), dimethyl 3-oxo-1, 3-dihydronaphtho [1, 2-c] furan-4, 5-dicarboxylate (VIII) (0.39% yield) and dimethyl 3-oxo-1, 3, 4, 5-tetrahydronaphtho [1, 2-c]-furan-4, 5-dicarboxylate (IX) (0.35% yield).

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Several benzothiazole 3-oxides were synthesized by N-oxidation of parent bases with organic peracids. Among the oxidizing reagents, monopermaleic acid gave the best result. On oxidation of 6-substituted benzothiazoles, substituents in the 6-position affect yields of the N-oxides ; electrondonating groups caused increase in the yields and electronattractive groups did decrease. Benzothiazoles bearing a functional group in the 2-position could not be oxidized to the N-oxides only to be hydrolyzed or recovered on the treatment with monopermaleic acid. In order to decide that the oxidized benzothiazoles are N-oxides and not S-oxides, dipole moments were measured.

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The antagonistic phenomena between crystalline tetrodotoxin and guanidine in the sympathetic nerve-smooth muscle preparations were investigated and the following results were obtained. In the hypogastric nerve-vas deferens preparation of the guinea-pig, the contractions of the vas deferens induced by the electrical stimulation of the pre- and post-ganglionic fiber of the hypogastric nerve were suppressed after the administrations of crystalline tetrodotoxin 5×10^-8M and procaine 10^-4M, and the suppression by tetrodotoxin was antagonized by guanidine 10^-3M or methylguanidine 10^-3M, and that by procaine was only temporally antagonized. These antagonistic phenomena were observed also on the guinea-pig trachea preparation and the nictitating membrane of cat. In the hypogastric nerve-vas deferens preparation of the guinea-pig, moreover, the contraction which could not be observed in the absence of Na⁺ in the external solution was recovered by applying guanidine into the solution. From these results, it is concluded that tetrodotoxin and guanidine or methylguanidine would be antagonistic at the presynaptic site of sympathetic nerve ending.

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Four epimeric 16-deuterio-5α, 14β-androstan-17-ols were prepared from 3β-hydroxy-5α, 14β-androstan-17-one by the reaction sequence illustrated in Chart 1. The conformation of ring D in 14β-steroids is discussed based upon the correlation of dihedral angles with the observed coupling constants of H16, 17 (see Table I).

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Optically active α-tosylamino-β-propiolactone (III) was synthesized from N-tosyl-L-asparagine via L-2-tosylamino-3-aminopropionic acid. The β-propiolactone (III) reacted with amino acid esters or peptide esters in organic solvents to form L-seryl peptide esters in good yields. Racemization did not actually occur during the peptide coupling reaction.

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The relationships between stability in culture media and in vitro anti-bacterial activity against Bacillus Calmette-Guerin (BCG) were investigated with furyl methyl ketone isonicotinoylhydrazone (FKI), glucose isonicotinoylhydrazone (G-INAH), and sodium pyruvate isonicotinoylhydrazone (P-INAH). FKI was found to be essentially equal to isoniazid in its activity under the equimolar basis. Thus its stability which was dominantly affected by several amino acids resulted to have no influence on the evaluation of the activity. On the other hand, a significant relationship was found among G-INAH and P-INAH, which can not inhibit growth of BCG until they release sufficiently large amount of isoniazid by hydrolysis. P-INAH was found to be hydrolyzed with such an extraordinary rapidity as 6 and 23 times greater than G-INAH in Kirchner and Long medium, respectively. This instability inversely related to the enhancement of its activity which consequently resulted in the same one as isoniazid. While G-INAH was observed to be hydrolyzed in Kirchner medium about 4 times as rapidly as in Long medium and it showed to have greater activity in the former than in the latter. The release rate of isoniazid might be inversely proportional to the stability and directly to the activity of these drugs. Another in vitro experiment with drug exposure times suggested that the bactericidal effect of drugs was probably displayed in the relatively early stage of test incubation period.

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In our previous papers, it was shown that phenacetylurea administered to rabbits is metabolized to 3-methoxy-4-hydroxyphenacetylurea, but in mice it is not converted to this unique metabolite. The present study revealed that the above metabolite is also excreted as one of the major metabolites in the urine of guinea pigs and a human after doses of phenacetylurea, as well as rabbits, whereas rats apparently do not follow to this pathway. Although in these species of animals and in a human the metabolic patterns of phenacetylurea were somewhat different each other, the drug was metabolized by two main pathways, hydroxylation of aromatic ring and hydrolysis of ureide group in all species examined. The identification and determination of the metabolites in animal species were facilitated by use of ¹⁴C-labeled phenacetylurea.

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16-Epiestriol 16- and 17-monoglucuronides (XI, V) were prepared from 3-benzyloxy-17β-hydroxyestra-1, 3, 5 (10)-trien-16-one (I) employing Koenigs-Knorr reaction as shown in Chart 1. These synthetic glucuronides readily underwent hydrolysis with beef-liver β-glucuronidase preparation to furnish 16-epiestriol and free glucuronic acid.

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The absorption of ion pair complexes was studied in rats by means of in situ rectal perfusion technique. Two combinations, sodium lauryl sulfate-basic drugs and saccharin sodium-basic drugs were examined in detail. The disappearance from the perfusate of both components were determined in order to elucidate the mechanism of ion pair absorption. Basic drugs except some quaternaries tested were absorbed much faster in the presence of lauryl sulfate and saccharinate anions but the converse could not be applied for the anionic components. Blood level analyses of basic drugs also demonstrated such absorption enhancement effect. Enhancement of the absorption of cationic drugs could better be related to the binding behavior of those drugs to the rectal mucosal preparations than their apparent chloroform or benzene/water partition coefficients.

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Fragmentation of methyl substituted oxindoles (I-V) and 2-indolinethiones (VI-X) induced by electron impact were investigated. Main fragments of the oxindoles are M-Me, M-CO, and M-HCO. M-1, M-S and M-SH are main fragments in the indolinethiones and M-CS is observed as a minor fragment. Fragmentation of 1, 1'-dimethyl-3, 3'-bioxindole and its thione derivative are also discussed.

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Fermentation of kessane, a constituent of valerian roots, with Cunninghamella blakesleeana has afforded seven oxygenated derivatives which have been concluded to be kessan-7-ol (II), 8-epi-kessanol (III), 2-epi-α-kessyl alcohol (IV), kessan-3ξ-ol (V), kessan-4β-ol (VI), kessan-9ξ-ol (VII), and kessane-3ξ, 7-diol (VIII) on the basis of the chemical and physico-chemical properities.

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Treatment of 6-azido-6-deoxy-1, 2-O-isopropylidene-5-O-tosyl-α-D-glucofuranose (6b) or its 3-O-acetyl derivative (6a) with LiAlH₄ in tetrahydrofuran gave a 5, 6-epimine (7a) which was characterized as its acetate (8). In comparison with the case of the 3-O-benzyl derivative (2) reported earlier, it was suggested that the free 3-hydroxyl group participates in the substitution of the 5-O-tosyloxy group by the formed 6-amine, decreasing the yield of 5, 6-epimine. It was found that treatment of these 6-azido-5-O-tosylates with sodium borohydride and tris (α, α'-dipyridyl) cobalt (II) bromide resulted in formation of the corresponding 6-amino-5-tosylates (10b and 13). Reactions of the latter with bases were also discussed.

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Synthesis of every kinds of peptide fragments of bradykinin and results of the biological activities of the synthetic bradykinin fragments on contracting effect of a guinea pig ileum, inframmatory activity on rat's hind paw and vasodilation on rat are described. So far as concerning with the contracting effect, the active site of bradykinin seems to be the phenylalanylserylprolylphenylalanine moiety. The inflammatory activity is fairy high as compared with that of bradykinin.

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(S)-3-Benzyloxycarbonyl-5-oxo-4-oxazolidineacetic acid (IIa) and (S)-3-benzyloxycarbonyl-5-oxo-4-oxazolidinepropionic acid (IIb) were utilized for the selective protection of side-chain carboxyl group of corresponding α-aminodicarboxylic acids and the synthesis of β-aspartyl and γ-glutamyl peptides as an α-carboxyl protected intermediates. It was found that 5-oxazolidinone ring, the α-carboxyl protecting group, was easily removed under not only the condition of alkaline hydrolysis but also catalytic hydrogenolysis. Thus a facile synthesis of β-aspartyl and γ-glutamyl peptides was achieved by the coupling of IIa and IIb with benzyl ester of amino acids and peptides followed by hydrogenolytic removal of all the protecting groups.

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The chemical shifts of angular methyl protons of 5α, 13α-androstane derivatives were measured in deuteriochloroform and the effects of various substituents in ring D on shift values were estimated. The pyridine-induced solvent shifts in 18-proton signal were recognized with the 16- and 17-hydroxylic compounds. Correlation of the coupling constant (JH_{15, 16}) and conformation of ring D has also been discussed.

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Potentiation of cyclophosphamide activity by non antitumor agents which might affect the liver microsomal enzymes, was examined with Sarcoma 180. That activity of low dose, only 24% inhibition in tumor growth, was enhanced to 94% by imipramine. But any potentiation was not shown by phenobarbital, pentobarbital, isoniazid, meprobamate or glutethimide. The cyclophosphamide activating enzymes in liver were enhanced by phenobarbital but not imipramine treatment, besides both concentrations of the activated and intact cyclophosphamide in blood were not elevated and not maintained by the latter. Nigrosine stainability of the tumor cell was stimulated by less than 1 mg/ml of imipramine in vitro, that was a different phenomenon from the surface activity of Tween 80. One of the possible couses for enhancement in antitumor activity of cyclophosphamide by imipramine was considered to be the stimulation of membrane permeability.

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The results of photolysis of bufadienolides, which have an α-pyrone ring on a C₁₇ position of the steroidal moiety, particularly those of 14β-hydroxy compounds such as bufalin (I), bufotalin (X), gamabufotalin (XVI) and their acetates (II, XI and XVII), are described. Photolysis of I or II in ethanol gave the photoproduct (III), or (IV). The spectral data suggested III and IV had a partial structure either A or B (Chart 1). Then the structure of III and IV were finally proved to be identical with the authentic samples which were prepared from I. Photolysis of I or II in methanol gave V or VI. By hydrolysis III and V were easily converted into the corresponding carboxylic acid (VII), from which methyl ester (V) was prepared by the treatment with diazomethane (Chart 2). Photolysis of X or XI, having 16-β-acetoxyl groups besides 14β-hydroxyl group, in methanol, afforded XII or XIII, respectively (Chart 3). When XVI or XVII, 11α-hydroxy and 11α-acetoxy compounds, were irradiated in methanol, XVIII or XIX were obtained, respectively (Chart 4). These results indicate that photolysis of the other 14β-hydroxy compounds in bufadienolides might be considered to afford the photoproducts having the same moiety as above. A plausible mechanism for the formation of III, V, XII, XVIII, and etc. via the photopyrone (c), the formyl ketene (d) and enol from (f) is depicted in Chart 5.

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Although in the photolysis of 14β-hydroxy compounds, as described in the previous paper, ring formation reaction between C₂₁ and 14β-hydroxy group is observed, in the case of resibufogenin (I) and 14α-artebufogenin (IV), which are 14β, 15β-epoxy- and 15-oxocompounds, the photolysis products (A and B, in Fig. 1) were unstable and could not be isolated. However, it should be noted that by treatment with acid the photolysis products were converted into the stable 21-OCH₃ structure, i.e. methyl 3-hydroxy-21-methoxy-15-oxo-5β, 14α-chola-20 (21), 22-dienoate (II) and methyl 14β, 15β-epoxy-3β-hydroxy-21-methoxy-5β-chola-20 (21), 22-dienoate (IV). The fact that the epoxy ring was intact during photolytic conditions was indicated by thin-layer chromatography (Fig. 1) in the irradiation of I by the appearance of spot A which had different Rf value compared with that of spot B, a photolysis product of IV. Furthermore, the progress of the photo-reaction was followed by UV spectra measurement (Fig. 4) and a plausible mechanism for the formation of II and IV is depicted in Chart 2.

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Resibufogenin (IX), which is 14β, 15β-epoxy compound in bufadienolides, occurs in nature, but the corresponding 14α, 15α-epoxy compound is unknown. In order to examine the ring-opening reaction of 14, 15-epoxy function with hydroiodic acid, 14α, 15α-epoxy-3β-hydroxy-5β-bufa-20, 22-dienolide (VI) and its 3-acetate (VII) were synthesized (Chart 1). Reaction of 14β, 15β-epoxy compound (IX) or 14α, 15α-epoxy compound (VI) with hydroiodic acid gave Δ¹⁴-anhydrobufalin (II), which was a normal reduced product, 14α-artebufogenin (XI), and 14β-artebufogenin (XIII), respectively. A similar reaction of two acetates (X or VII) gave the corresponding acetates, IV, XII and XIV, respectively (Chart 2). The formation of 14α- and 14β-artebufogenin indicates that the acid-catalyzed ring-opening reaction occurred at a time. Based on these results, reaction of 5, 6-epoxy function was reexamined. As was excepted, reaction of 5β, 6β-epoxy compound (XV) or 5α, 6α-epoxy compound (XVI) afforded 3β-acetoxy-5, 6β-dihydroxy-5α-cholestane (XIX), besides cholesteryl acetate (XVII) and cholesterol (XVIII).

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5 (4)-Formamido-4 (5)-imidazolethiocarboxamide and 1-β-D-ribofuranosyl-5-amino-4-imidazolethiocarboxamide were active against various tumors. Their metabolites in urine of mice were determiend with thin-layer chromatography. 5 (4)-Amino-4 (5)-imidazolethiocarboxamide, which was inactive against Nakahara-Fukuoka sarcoma, was excreted intact and 6-mercaptopurine was not found in urine after the intraperitoneal injection. On the other hand, the large quantity of 6-mercaptopurine was found in urine after the administration of 5 (4)-Formamido-4 (5)-imidazolethiocarboxamide. 1-β-D-Ribofuranosyl-5-amino-4-imidazolethiocarboxamide was mainly excreted intact, and a small quantity of 5 (4)-amino-4 (5)-imidazolethiocarboxamide and a trace amount of 6-mercaptopurine were found in urine.

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